Trial Outcomes & Findings for Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia (NCT NCT00103285)

Last Updated: 2021-06-14

Results Overview

EFS for SR-Average with standard and Intensified Consolidation. Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

5377 participants

Primary outcome timeframe

6 years

Results posted on

2021-06-14

Participant Flow

Participant milestones

Participant milestones
Measure	Group 0 Induction Therapy All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) \< 0.1% OR MRD \>= 0.1% and \< 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD \>= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm I-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm II-combination Chemotherapy Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm I-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 3-SR-high ALL, Combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine \& vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine
Induction STARTED	5377	0	0	0	0	0	0	0
Induction COMPLETED	4028	0	0	0	0	0	0	0
Induction NOT COMPLETED	1349	0	0	0	0	0	0	0
Response Assignment STARTED	0	939	937	503	509	249	248	643
Response Assignment COMPLETED	0	807	853	441	425	201	199	523
Response Assignment NOT COMPLETED	0	132	84	62	84	48	49	120

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 0 Induction Therapy All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) \< 0.1% OR MRD \>= 0.1% and \< 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD \>= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm I-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm II-combination Chemotherapy Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm I-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 3-SR-high ALL, Combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine \& vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine
Induction Adverse Event	14	0	0	0	0	0	0	0
Induction Death	24	0	0	0	0	0	0	0
Induction Physician Decision	103	0	0	0	0	0	0	0
Induction Withdrawal by Subject	1	0	0	0	0	0	0	0
Induction Ineligible	43	0	0	0	0	0	0	0
Induction Refusal	906	0	0	0	0	0	0	0
Induction Other	258	0	0	0	0	0	0	0
Response Assignment Adverse Event	0	8	3	2	3	1	1	2
Response Assignment Death	0	5	2	2	3	1	0	8
Response Assignment Lost to Follow-up	0	9	5	5	1	2	2	5
Response Assignment Physician Decision	0	13	14	9	13	7	4	35
Response Assignment Protocol Violation	0	2	0	0	0	0	0	0
Response Assignment Withdrawal by Subject	0	4	1	1	2	2	0	2
Response Assignment Ineligible	0	8	6	2	0	3	1	5
Response Assignment Refusal	0	53	5	3	25	15	30	10
Response Assignment Other	0	30	48	38	37	17	11	53

Baseline Characteristics

Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 0 Induction Therapy n=5377 Participants All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) \< 0.1% OR MRD \>= 0.1% and \< 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD \>= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV
Age, Categorical <=18 years	5377 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	4.45 years STANDARD_DEVIATION 2.10 • n=5 Participants
Sex: Female, Male Female	2489 Participants n=5 Participants
Sex: Female, Male Male	2888 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1097 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4038 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	242 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	36 Participants n=5 Participants
Race (NIH/OMB) Asian	253 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	24 Participants n=5 Participants
Race (NIH/OMB) Black or African American	326 Participants n=5 Participants
Race (NIH/OMB) White	4046 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	692 Participants n=5 Participants
Region of Enrollment United States	5377 participants n=5 Participants

PRIMARY outcome

Timeframe: 6 years

Population: Only eligible patients are included in this population. Populations are based on enrollments for all four arms initially, and then only for Arms I and II (standard therapy) once Arms III and IV (intensified therapy) were closed to accrual.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=500 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=509 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy n=245 Participants Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy n=246 Participants Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Event-free Survival (EFS) for SR-Average ALL Patients Standard and Intensified therapy	83.82 percent probability Interval 78.86 to 88.78	88.89 percent probability Interval 84.79 to 92.99	88.34 percent probability Interval 83.99 to 92.69	90.51 percent probability Interval 86.55 to 94.47
Event-free Survival (EFS) for SR-Average ALL Patients Standard therapy	87.41 percent probability Interval 83.63 to 91.19	88.29 percent probability Interval 84.76 to 91.82	—	—

PRIMARY outcome

Timeframe: 6 years

Population: Only eligible patients are included in the analysis.

Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=928 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=929 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Event-free Survival (EFS) for SR-Low Patients	95.22 Percent probability Interval 93.6 to 96.9	93.96 Percent probability Interval 92.1 to 95.8	—	—

SECONDARY outcome

Timeframe: At 1, 6 and 12 months after diagnosis and, 3 months post-therapy

Population: This analysis is restricted to the 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites, who consented to and completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning).

To identify potentially modifiable factors associated with impaired health related quality of life (HRQOL) at different periods of therapy in the patients who are SR-average enrolled on the standard risk ALL study.Standardized scores will be computed for child function using the gender and age-adjusted scores available from normative data from a healthy population of about 10,000 children. The various domains of family functioning will be assessed using well-validated instruments and analyzed as a dichotomous variable (impaired vs. non-impaired family functioning). Multiple regression analysis will be used to test the effect of family functioning (adjusted for therapy given, age at diagnosis, gender, socioeconomic status and other factors) on child function.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=160 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Physical Impairment 1 mth after diagnosis	76.39 Percentage of participants Interval 68.6 to 83.1	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Physical Impairment 6 mths after diagnosis	42.75 Percentage of participants Interval 34.2 to 51.7	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Physical Impairment 12 mths after diagnosis	29.41 Percentage of participants Interval 21.9 to 37.8	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Physical Impairment 3 mths post therapy	27.84 Percentage of participants Interval 19.2 to 37.9	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Social Impairment 1 mth after diagnosis	43.36 Percentage of participants Interval 35.1 to 51.9	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Social Impairment 6 mths after diagnosis	23.66 Percentage of participants Interval 16.7 to 31.9	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Social Impairment 12 mths after diagnosis	23.53 Percentage of participants Interval 16.7 to 31.6	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Social Impairment 3 mths post-therapy	25.77 Percentage of participants Interval 17.4 to 35.7	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Emotional Impairment 1 mth after diagnosis	38.89 Percentage of participants Interval 30.9 to 47.4	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Emotional Impairment 6 mths after diagnosis	17.56 Percentage of participants Interval 11.5 to 25.2	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Emotional Impairment 12 mths after diagnosis	13.97 Percentage of participants Interval 8.6 to 21.0	—	—	—
Health-related Quality of Life Relative to Physical, Social and Emotional Impairment Emotional Impairment 3 mths post-therapy	8.25 Percentage of participants Interval 3.6 to 15.6	—	—	—

SECONDARY outcome

Timeframe: MRD at Day 29 of therapy

Population: 4981 eligible evaluable patients enrolled on AALL0331 had MRD data at Day 29

Event-Free survival by Day 29 MRD status (negative vs positive), Event Free Probability (time from study entry to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=4614 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=367 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Event-Free Survival Probability According to MRD Status End Induction (Day 29)	91.39 Percent Probability Interval 90.41 to 92.37	79.86 Percent Probability Interval 75.04 to 84.68	—	—

SECONDARY outcome

Timeframe: Overall Survival Probability of 6 years

Population: 4981 eligible evaluable patients enrolled on AALL0331 had MRD data at Day 29.

Overall survival by Day 29 MRD status (negative vs positive), Overall survival defined as time from study entry to death or date of last contact for patients who are alive.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=4614 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=367 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Overall Survival Probability (OS) According to Induction Day 29 MRD Status	97.07 percent probability Interval 96.5 to 97.68	90.47 percent probability Interval 86.92 to 94.02	—	—

SECONDARY outcome

Timeframe: Early Marrow Status at Day 15, MRD Status at Day 29 of therapy.

Population: Patients who had MRD day 29 data but their Bone Marrow (BM) days 8/15 data were missing are excluded. This analysis was done with patients who had both MRD and BM data. There were 5 patients excluded in both MRD Negative and MRD Positive groups due to missing days 8/15 BM.

Early Marrow Status defined as M1 versus M2/M3 marrow is correlated with MRD (Positive vs. Negative)

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=4609 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=362 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Early Marrow Status (EMS) by MRD Status End Induction (Day 29)	4378 Participants	258 Participants	—	—

SECONDARY outcome

Timeframe: At 1 month after diagnosis and 3 months post-therapy.

Population: Parents of 159 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the BASC-2 Anxiety Scale at 1 month after diagnosis, and 3 months post-therapy. Of these, 159 patients had data at 1 month after diagnosis and 96 patients had data at 3 months post therapy.

Percentage of patients with elevated Anxiety.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=159 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Optimal Time Point for Advance Health Related Quality of Life Intervention At 1 month after diagnosis	25.2 Percentage of participants Interval 18.5 to 31.9	—	—	—
Optimal Time Point for Advance Health Related Quality of Life Intervention At 3 months post-therapy	24.0 Percentage of participants Interval 16.0 to 32.0	—	—	—

SECONDARY outcome

Timeframe: 6 years

Population: CCR: Complete Continuous Remission, where time to event is defined as the time from start of consolidation therapy to first event or date of last follow up for those who did not experience an event. All patients enrolled on the SR-High were used in this analysis regardless of completion of therapy.

Event Free Probability where EFS time is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=636 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Event-free Survival (EFS) for SR-High Patients.	85.58 percent probability Interval 85.55 to 85.61	—	—	—

SECONDARY outcome

Timeframe: 6 years

Population: Patients on the two arms being compared got similar therapy. All patients included in this analysis are MRD negative. SR-Average patients who were CNS2 at diagnosis were excluded in order to have comparable patient cohorts. SR-Low patients are TEL/Trisomy positive while SR-Average patients are TEL/Trisomy negative.

Event-free probability where EFS is defined as time from randomization to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free.

Outcome measures

Outcome measures
Measure	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=926 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=422 Participants Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV
Event-Free Survival (EFS) for Low MRD (Negative) Subjects by Genetic Subset (TEL/Trisomy Positive vs Negative)	95.22 Percent probability Interval 93.58 to 96.86	88.52 Percent probability Interval 84.56 to 92.48	—	—

Adverse Events

Group 0 Induction Therapy

Serious events: 29 serious events

Other events: 790 other events

Deaths: 0 deaths

Group 1-SR-low ALL, Arm I-combination Chemotherapy

Serious events: 14 serious events

Other events: 901 other events

Deaths: 0 deaths

Group 1-SR-low ALL, Arm II-combination Chemotherapy

Serious events: 7 serious events

Other events: 909 other events

Deaths: 0 deaths

Group 2-SR-avg ALL, Arm I-combination Chemotherapy

Serious events: 4 serious events

Other events: 487 other events

Deaths: 0 deaths

Group 2-SR-avg ALL, Arm II-combination Chemotherapy

Serious events: 3 serious events

Other events: 500 other events

Deaths: 0 deaths

Group 2-SR-avg ALL, Arm III-combination Chemotherapy

Serious events: 0 serious events

Other events: 237 other events

Deaths: 0 deaths

Group 2-SR-avg ALL, Arm IV-combination Chemotherapy

Serious events: 1 serious events

Other events: 234 other events

Deaths: 0 deaths

Group 3-SR-high ALL, Combination Chemotherapy

Serious events: 12 serious events

Other events: 629 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Group 0 Induction Therapy n=1306 participants at risk All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) \< 0.1% OR MRD \>= 0.1% and \< 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD \>= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm I-combination Chemotherapy n=931 participants at risk Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm II-combination Chemotherapy n=931 participants at risk Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=501 participants at risk Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=509 participants at risk Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy n=246 participants at risk Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy n=247 participants at risk Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 3-SR-high ALL, Combination Chemotherapy n=638 participants at risk Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine \& vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Vascular disorders Hypotension	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Anemia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Hemolysis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Cardiac arrest	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Myocardial infarction	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Abdominal pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Ascites	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Cecal hemorrhage	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colitis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colonic perforation	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Diarrhea	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophageal perforation	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophagitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Mucositis oral	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Oral hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Pancreatitis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal necrosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Small intestinal perforation	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Typhlitis	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Death NOS	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Edema trunk	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders General disorders and administration site conditions - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
General disorders Multi-organ failure	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Sudden death NOS	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Cholecystitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Hepatic failure	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Hepatobiliary disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Portal hypertension	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Immune system disorders Anaphylaxis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Appendicitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Appendicitis perforated	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Encephalitis infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Encephalomyelitis infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Enterocolitis infectious	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Infections and infestations - Other, specify	0.46% 6/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.1% 7/638 • Number of events 7 Only eligible patients are included in the toxicity analysis.
Infections and infestations Lung infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Pleural infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Sepsis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Vascular access complication	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Investigations Activated partial thromboplastin time prolonged	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Alanine aminotransferase increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Alkaline phosphatase increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Investigations Aspartate aminotransferase increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Blood bilirubin increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations CPK increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Investigations Fibrinogen decreased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Investigations - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Lipase increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Neutrophil count decreased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Platelet count decreased	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Investigations Serum amylase increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Investigations White blood cell decreased	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Acidosis	0.08% 1/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Dehydration	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hyperglycemia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypoalbuminemia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypocalcemia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hyponatremia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Depressed level of consciousness	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Encephalopathy	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Intracranial hemorrhage	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Nervous system disorders - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Peripheral motor neuropathy	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Seizure	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Confusion	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Acute kidney injury	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Bladder perforation	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Apnea	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Vascular disorders Thromboembolic event	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.

Other adverse events

Other adverse events
Measure	Group 0 Induction Therapy n=1306 participants at risk All patients receive cytarabine intrathecally (IT) on day 1; vincristine IV on days 1, 8, 15, and 22; dexamethasone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). Patients with Down syndrome (DS) receive leucovorin calcium PO at 48 and 60 hours after each dose of methotrexate IT. Patients are assessed for response on day 29. Patients with M1 bone marrow AND minimal residual disease (MRD) \< 0.1% OR MRD \>= 0.1% and \< 1% proceed to therapy in part II. Patients with M2 bone marrow OR M1 bone marrow AND MRD \>= 1% proceed to extended induction therapy. Patients with M3 bone marrow are removed from the study. cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm I-combination Chemotherapy n=931 participants at risk Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 1-SR-low ALL, Arm II-combination Chemotherapy n=931 participants at risk Patients receive experimental consolidation therapy (vincristine sulfate, mercaptopurine, MTX, leucovorin calcium and pegaspargase), experimental interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine, MTX and pegaspargase), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm I-combination Chemotherapy n=501 participants at risk Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and methotrexate. Patients with Down syndrome (DS) receive leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and methotrexate. Patients with DS receive leucovorin calcium), and standard delayed intensification (DI) therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and methotrexate. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm II-combination Chemotherapy n=509 participants at risk Patients receive standard consolidation therapy (vincristine sulfate, mercaptopurine and MTX. Patients with Down syndrome (DS) receive leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm III-combination Chemotherapy n=246 participants at risk Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), standard interim maintenance therapy (vincristine sulfate, dexamethasone, mercaptopurine and MTX. Patients with DS receive leucovorin calcium), and standard DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine and MTX. Patients with DS receive dexamethasone, leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 2-SR-avg ALL, Arm IV-combination Chemotherapy n=247 participants at risk Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine and vincristine sulfate, pegaspargase, MTX. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (vincristine sulfate, MTX and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, MTX. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine: Given PO cyclophosphamide: Given IV thioguanine: Given PO vincristine sulfate: Given IV	Group 3-SR-high ALL, Combination Chemotherapy n=638 participants at risk Patients receive intensified consolidation therapy (cyclophosphamide, cytarabine, mercaptopurine \& vincristine sulfate, pegaspargase, methotrexate. Patients with DS receive oral leucovorin calcium), augmented interim maintenance therapy (2 courses - vincristine sulfate, methotrexate and pegaspargase. Patients with DS receive leucovorin calcium), and augmented DI therapy (2 courses - vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, cyclophosphamide, cytarabine, thioguanine, methotrexate. Patients with DS receive dexamethasone and leucovorin calcium), followed by maintenance therapy. Therapies are given by mouth, injection, and infusion for up to 2 or 3 years. doxorubicin hydrochloride: Given IV or IT 3-dimensional conformal radiation therapy: Some patients undergo cranial radiotherapy cytarabine: Given IV or SC dexamethasone: Given IV or PO pegaspargase: Given IM methotrexate: Given IM or IT leucovorin calcium: Given PO mercaptopurine
Infections and infestations Urinary tract infection	0.31% 4/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	3.3% 31/931 • Number of events 34 Only eligible patients are included in the toxicity analysis.	2.0% 19/931 • Number of events 24 Only eligible patients are included in the toxicity analysis.	4.4% 22/501 • Number of events 30 Only eligible patients are included in the toxicity analysis.	3.3% 17/509 • Number of events 21 Only eligible patients are included in the toxicity analysis.	3.3% 8/246 • Number of events 8 Only eligible patients are included in the toxicity analysis.	3.2% 8/247 • Number of events 11 Only eligible patients are included in the toxicity analysis.	4.1% 26/638 • Number of events 31 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Duodenal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Duodenal perforation	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Anemia	6.6% 86/1306 • Number of events 88 Only eligible patients are included in the toxicity analysis.	27.7% 258/931 • Number of events 438 Only eligible patients are included in the toxicity analysis.	24.9% 232/931 • Number of events 356 Only eligible patients are included in the toxicity analysis.	23.8% 119/501 • Number of events 183 Only eligible patients are included in the toxicity analysis.	25.0% 127/509 • Number of events 213 Only eligible patients are included in the toxicity analysis.	22.4% 55/246 • Number of events 113 Only eligible patients are included in the toxicity analysis.	36.4% 90/247 • Number of events 150 Only eligible patients are included in the toxicity analysis.	33.4% 213/638 • Number of events 466 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Blood and lymphatic system disorders - Other, specify	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 16 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.79% 4/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.4% 9/638 • Number of events 9 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Bone marrow hypocellular	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Febrile neutropenia	10.0% 130/1306 • Number of events 131 Only eligible patients are included in the toxicity analysis.	57.0% 531/931 • Number of events 1045 Only eligible patients are included in the toxicity analysis.	59.6% 555/931 • Number of events 1045 Only eligible patients are included in the toxicity analysis.	54.3% 272/501 • Number of events 513 Only eligible patients are included in the toxicity analysis.	64.8% 330/509 • Number of events 733 Only eligible patients are included in the toxicity analysis.	58.5% 144/246 • Number of events 259 Only eligible patients are included in the toxicity analysis.	60.7% 150/247 • Number of events 316 Only eligible patients are included in the toxicity analysis.	74.5% 475/638 • Number of events 1260 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Hemolysis	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Hemolytic uremic syndrome	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Blood and lymphatic system disorders Spleen disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Cardiac arrest	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Cardiac disorders - Other, specify	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Conduction disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Left ventricular systolic dysfunction	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Mobitz (type) II atrioventricular block	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Myocarditis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Pericardial effusion	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Sinus bradycardia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Sinus tachycardia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Supraventricular tachycardia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Ventricular arrhythmia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Ventricular tachycardia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Cardiac disorders Wolff-Parkinson-White syndrome	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Ear and labyrinth disorders Ear and labyrinth disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Ear and labyrinth disorders Ear pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Ear and labyrinth disorders External ear inflammation	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Ear and labyrinth disorders External ear pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Ear and labyrinth disorders Hearing impaired	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Ear and labyrinth disorders Middle ear inflammation	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 8 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.1% 7/638 • Number of events 14 Only eligible patients are included in the toxicity analysis.
Endocrine disorders Adrenal insufficiency	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Endocrine disorders Endocrine disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Blurred vision	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Extraocular muscle paresis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Eye disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Eye pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Glaucoma	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Keratitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Optic nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Photophobia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Retinal detachment	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Retinopathy	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Eye disorders Vitreous hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Abdominal distension	0.54% 7/1306 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Abdominal pain	1.8% 24/1306 • Number of events 24 Only eligible patients are included in the toxicity analysis.	3.4% 32/931 • Number of events 38 Only eligible patients are included in the toxicity analysis.	2.9% 27/931 • Number of events 32 Only eligible patients are included in the toxicity analysis.	5.4% 27/501 • Number of events 32 Only eligible patients are included in the toxicity analysis.	4.7% 24/509 • Number of events 29 Only eligible patients are included in the toxicity analysis.	2.8% 7/246 • Number of events 10 Only eligible patients are included in the toxicity analysis.	6.1% 15/247 • Number of events 19 Only eligible patients are included in the toxicity analysis.	5.6% 36/638 • Number of events 42 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Anal mucositis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Anal necrosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Anal pain	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Ascites	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Cecal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colitis	0.38% 5/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.6% 10/638 • Number of events 12 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colonic fistula	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colonic hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colonic obstruction	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colonic perforation	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Colonic ulcer	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Constipation	0.92% 12/1306 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.6% 15/931 • Number of events 17 Only eligible patients are included in the toxicity analysis.	1.3% 12/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 10 Only eligible patients are included in the toxicity analysis.	2.0% 10/509 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.2% 14/638 • Number of events 15 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Dental caries	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Diarrhea	1.8% 24/1306 • Number of events 24 Only eligible patients are included in the toxicity analysis.	8.8% 82/931 • Number of events 91 Only eligible patients are included in the toxicity analysis.	6.8% 63/931 • Number of events 67 Only eligible patients are included in the toxicity analysis.	9.4% 47/501 • Number of events 56 Only eligible patients are included in the toxicity analysis.	8.6% 44/509 • Number of events 49 Only eligible patients are included in the toxicity analysis.	6.9% 17/246 • Number of events 20 Only eligible patients are included in the toxicity analysis.	10.5% 26/247 • Number of events 28 Only eligible patients are included in the toxicity analysis.	10.7% 68/638 • Number of events 88 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Dyspepsia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Dysphagia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Enterocolitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophageal obstruction	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophageal pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophageal stenosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophageal ulcer	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Esophagitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastric fistula	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastric perforation	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastritis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.4% 9/638 • Number of events 10 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 6 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastrointestinal fistula	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gastrointestinal pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Gingival pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Ileal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Ileal perforation	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Ileal ulcer	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Ileus	0.77% 10/1306 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Intra-abdominal hemorrhage	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Lip pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Lower gastrointestinal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Malabsorption	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Mucositis oral	0.69% 9/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	6.7% 62/931 • Number of events 64 Only eligible patients are included in the toxicity analysis.	5.7% 53/931 • Number of events 61 Only eligible patients are included in the toxicity analysis.	7.2% 36/501 • Number of events 42 Only eligible patients are included in the toxicity analysis.	8.1% 41/509 • Number of events 52 Only eligible patients are included in the toxicity analysis.	7.7% 19/246 • Number of events 28 Only eligible patients are included in the toxicity analysis.	9.3% 23/247 • Number of events 28 Only eligible patients are included in the toxicity analysis.	12.7% 81/638 • Number of events 93 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Nausea	0.46% 6/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.5% 14/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	2.8% 14/501 • Number of events 16 Only eligible patients are included in the toxicity analysis.	2.2% 11/509 • Number of events 12 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	3.3% 21/638 • Number of events 25 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Oral hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Oral pain	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.2% 11/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.8% 14/501 • Number of events 17 Only eligible patients are included in the toxicity analysis.	2.0% 10/509 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.8% 18/638 • Number of events 18 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Pancreatic hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Pancreatic necrosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Pancreatitis	1.4% 18/1306 • Number of events 19 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.8% 9/509 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 7 Only eligible patients are included in the toxicity analysis.	3.1% 20/638 • Number of events 28 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Proctitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal fistula	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal mucositis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Rectal pain	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Small intestinal mucositis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Small intestinal obstruction	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Small intestinal perforation	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Stomach pain	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Toothache	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Typhlitis	0.46% 6/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.6% 8/509 • Number of events 8 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.7% 11/638 • Number of events 13 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Upper gastrointestinal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Gastrointestinal disorders Vomiting	0.84% 11/1306 • Number of events 11 Only eligible patients are included in the toxicity analysis.	5.2% 48/931 • Number of events 53 Only eligible patients are included in the toxicity analysis.	4.0% 37/931 • Number of events 42 Only eligible patients are included in the toxicity analysis.	7.2% 36/501 • Number of events 47 Only eligible patients are included in the toxicity analysis.	6.5% 33/509 • Number of events 40 Only eligible patients are included in the toxicity analysis.	7.7% 19/246 • Number of events 24 Only eligible patients are included in the toxicity analysis.	7.3% 18/247 • Number of events 19 Only eligible patients are included in the toxicity analysis.	8.2% 52/638 • Number of events 65 Only eligible patients are included in the toxicity analysis.
General disorders Chills	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Edema face	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
General disorders Edema limbs	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
General disorders Edema trunk	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
General disorders Facial pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
General disorders Fatigue	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.7% 16/931 • Number of events 16 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 11 Only eligible patients are included in the toxicity analysis.	1.6% 8/509 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.7% 11/638 • Number of events 11 Only eligible patients are included in the toxicity analysis.
General disorders Fever	0.46% 6/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	9.0% 84/931 • Number of events 104 Only eligible patients are included in the toxicity analysis.	11.6% 108/931 • Number of events 128 Only eligible patients are included in the toxicity analysis.	9.8% 49/501 • Number of events 58 Only eligible patients are included in the toxicity analysis.	10.4% 53/509 • Number of events 66 Only eligible patients are included in the toxicity analysis.	14.6% 36/246 • Number of events 45 Only eligible patients are included in the toxicity analysis.	8.1% 20/247 • Number of events 23 Only eligible patients are included in the toxicity analysis.	11.1% 71/638 • Number of events 84 Only eligible patients are included in the toxicity analysis.
General disorders Flu like symptoms	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Gait disturbance	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
General disorders General disorders and administration site conditions - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.1% 7/638 • Number of events 7 Only eligible patients are included in the toxicity analysis.
General disorders Hypothermia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Injection site reaction	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Irritability	0.15% 2/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
General disorders Localized edema	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
General disorders Multi-organ failure	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Upper respiratory infection	0.38% 5/1306 • Number of events 5 Only eligible patients are included in the toxicity analysis.	8.8% 82/931 • Number of events 107 Only eligible patients are included in the toxicity analysis.	10.1% 94/931 • Number of events 118 Only eligible patients are included in the toxicity analysis.	11.8% 59/501 • Number of events 69 Only eligible patients are included in the toxicity analysis.	12.0% 61/509 • Number of events 83 Only eligible patients are included in the toxicity analysis.	6.9% 17/246 • Number of events 24 Only eligible patients are included in the toxicity analysis.	6.1% 15/247 • Number of events 18 Only eligible patients are included in the toxicity analysis.	13.5% 86/638 • Number of events 107 Only eligible patients are included in the toxicity analysis.
Infections and infestations Urethral infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
General disorders Non-cardiac chest pain	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
General disorders Pain	0.69% 9/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.5% 14/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	1.5% 14/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 8 Only eligible patients are included in the toxicity analysis.	3.3% 8/246 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	3.0% 19/638 • Number of events 26 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Cholecystitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Gallbladder obstruction	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Gallbladder pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Hepatic failure	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Hepatic necrosis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Hepatic pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Hepatobiliary disorders - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Hepatobiliary disorders Portal hypertension	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.3% 8/638 • Number of events 8 Only eligible patients are included in the toxicity analysis.
Immune system disorders Allergic reaction	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Immune system disorders Anaphylaxis	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	8.2% 76/931 • Number of events 83 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	12.2% 62/509 • Number of events 66 Only eligible patients are included in the toxicity analysis.	12.6% 31/246 • Number of events 32 Only eligible patients are included in the toxicity analysis.	13.0% 32/247 • Number of events 35 Only eligible patients are included in the toxicity analysis.	14.4% 92/638 • Number of events 102 Only eligible patients are included in the toxicity analysis.
Immune system disorders Autoimmune disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Immune system disorders Immune system disorders - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Infections and infestations Abdominal infection	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.5% 14/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	2.0% 5/246 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.94% 6/638 • Number of events 7 Only eligible patients are included in the toxicity analysis.
Infections and infestations Anorectal infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Infections and infestations Appendicitis	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Appendicitis perforated	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Arteritis infective	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Bladder infection	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.79% 4/509 • Number of events 4 Only eligible patients are included in the toxicity analysis.	2.0% 5/246 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.9% 12/638 • Number of events 19 Only eligible patients are included in the toxicity analysis.
Infections and infestations Bone infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Bronchial infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.4% 13/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	1.4% 13/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Infections and infestations Catheter related infection	0.61% 8/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	3.1% 29/931 • Number of events 32 Only eligible patients are included in the toxicity analysis.	4.0% 37/931 • Number of events 45 Only eligible patients are included in the toxicity analysis.	5.2% 26/501 • Number of events 29 Only eligible patients are included in the toxicity analysis.	4.1% 21/509 • Number of events 27 Only eligible patients are included in the toxicity analysis.	5.7% 14/246 • Number of events 19 Only eligible patients are included in the toxicity analysis.	5.3% 13/247 • Number of events 17 Only eligible patients are included in the toxicity analysis.	5.3% 34/638 • Number of events 40 Only eligible patients are included in the toxicity analysis.
Infections and infestations Conjunctivitis infective	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Device related infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Infections and infestations Encephalitis infection	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Encephalomyelitis infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Endocarditis infective	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Enterocolitis infectious	0.92% 12/1306 • Number of events 12 Only eligible patients are included in the toxicity analysis.	3.7% 34/931 • Number of events 38 Only eligible patients are included in the toxicity analysis.	3.3% 31/931 • Number of events 39 Only eligible patients are included in the toxicity analysis.	2.8% 14/501 • Number of events 15 Only eligible patients are included in the toxicity analysis.	3.3% 17/509 • Number of events 20 Only eligible patients are included in the toxicity analysis.	2.8% 7/246 • Number of events 7 Only eligible patients are included in the toxicity analysis.	5.7% 14/247 • Number of events 17 Only eligible patients are included in the toxicity analysis.	7.7% 49/638 • Number of events 63 Only eligible patients are included in the toxicity analysis.
Infections and infestations Esophageal infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Eye infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Gum infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.1% 7/638 • Number of events 8 Only eligible patients are included in the toxicity analysis.
Infections and infestations Hepatic infection	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Hepatitis viral	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Infections and infestations - Other, specify	17.4% 227/1306 • Number of events 312 Only eligible patients are included in the toxicity analysis.	52.5% 489/931 • Number of events 962 Only eligible patients are included in the toxicity analysis.	49.7% 463/931 • Number of events 906 Only eligible patients are included in the toxicity analysis.	49.7% 249/501 • Number of events 467 Only eligible patients are included in the toxicity analysis.	58.5% 298/509 • Number of events 643 Only eligible patients are included in the toxicity analysis.	54.5% 134/246 • Number of events 298 Only eligible patients are included in the toxicity analysis.	57.5% 142/247 • Number of events 341 Only eligible patients are included in the toxicity analysis.	68.0% 434/638 • Number of events 1120 Only eligible patients are included in the toxicity analysis.
Infections and infestations Infective myositis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Joint infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Kidney infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Laryngitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Lip infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Infections and infestations Lung infection	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	7.9% 74/931 • Number of events 91 Only eligible patients are included in the toxicity analysis.	9.6% 89/931 • Number of events 103 Only eligible patients are included in the toxicity analysis.	10.6% 53/501 • Number of events 63 Only eligible patients are included in the toxicity analysis.	10.4% 53/509 • Number of events 59 Only eligible patients are included in the toxicity analysis.	11.4% 28/246 • Number of events 37 Only eligible patients are included in the toxicity analysis.	7.3% 18/247 • Number of events 19 Only eligible patients are included in the toxicity analysis.	11.4% 73/638 • Number of events 92 Only eligible patients are included in the toxicity analysis.
Infections and infestations Lymph gland infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Meningitis	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Infections and infestations Mucosal infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Infections and infestations Nail infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Otitis externa	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Otitis media	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	4.4% 41/931 • Number of events 50 Only eligible patients are included in the toxicity analysis.	5.2% 48/931 • Number of events 53 Only eligible patients are included in the toxicity analysis.	4.4% 22/501 • Number of events 27 Only eligible patients are included in the toxicity analysis.	4.9% 25/509 • Number of events 27 Only eligible patients are included in the toxicity analysis.	2.4% 6/246 • Number of events 7 Only eligible patients are included in the toxicity analysis.	5.7% 14/247 • Number of events 16 Only eligible patients are included in the toxicity analysis.	6.9% 44/638 • Number of events 52 Only eligible patients are included in the toxicity analysis.
Infections and infestations Papulopustular rash	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Paronychia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Penile infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Peripheral nerve infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Peritoneal infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Pharyngitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	1.5% 14/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.8% 9/501 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Infections and infestations Pleural infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Rash pustular	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Salivary gland infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Infections and infestations Sepsis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.7% 11/638 • Number of events 11 Only eligible patients are included in the toxicity analysis.
Infections and infestations Sinusitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	4.7% 44/931 • Number of events 51 Only eligible patients are included in the toxicity analysis.	4.1% 38/931 • Number of events 46 Only eligible patients are included in the toxicity analysis.	3.8% 19/501 • Number of events 26 Only eligible patients are included in the toxicity analysis.	5.1% 26/509 • Number of events 29 Only eligible patients are included in the toxicity analysis.	2.0% 5/246 • Number of events 8 Only eligible patients are included in the toxicity analysis.	3.2% 8/247 • Number of events 8 Only eligible patients are included in the toxicity analysis.	3.1% 20/638 • Number of events 22 Only eligible patients are included in the toxicity analysis.
Infections and infestations Skin infection	0.61% 8/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	3.4% 32/931 • Number of events 36 Only eligible patients are included in the toxicity analysis.	4.0% 37/931 • Number of events 40 Only eligible patients are included in the toxicity analysis.	4.4% 22/501 • Number of events 24 Only eligible patients are included in the toxicity analysis.	5.5% 28/509 • Number of events 33 Only eligible patients are included in the toxicity analysis.	2.8% 7/246 • Number of events 7 Only eligible patients are included in the toxicity analysis.	2.8% 7/247 • Number of events 8 Only eligible patients are included in the toxicity analysis.	5.8% 37/638 • Number of events 43 Only eligible patients are included in the toxicity analysis.
Infections and infestations Small intestine infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Infections and infestations Soft tissue infection	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Infections and infestations Splenic infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Tooth infection	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Tracheitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Vaginal infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Infections and infestations Vulval infection	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Infections and infestations Wound infection	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.5% 14/931 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.8% 9/509 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.7% 11/638 • Number of events 11 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Fall	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Fracture	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Intraoperative gastrointestinal injury	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Intraoperative ocular injury	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Intraoperative respiratory injury	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Intraoperative venous injury	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Postoperative hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Prolapse of intestinal stoma	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Vascular access complication	0.61% 8/1306 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.1% 7/638 • Number of events 7 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Venous injury	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Wound complication	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Injury, poisoning and procedural complications Wound dehiscence	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Activated partial thromboplastin time prolonged	1.3% 17/1306 • Number of events 17 Only eligible patients are included in the toxicity analysis.	2.5% 23/931 • Number of events 24 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.8% 9/501 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.6% 8/509 • Number of events 9 Only eligible patients are included in the toxicity analysis.	2.0% 5/246 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	3.6% 23/638 • Number of events 31 Only eligible patients are included in the toxicity analysis.
Investigations Alanine aminotransferase increased	13.3% 174/1306 • Number of events 177 Only eligible patients are included in the toxicity analysis.	48.7% 453/931 • Number of events 1316 Only eligible patients are included in the toxicity analysis.	47.6% 443/931 • Number of events 1235 Only eligible patients are included in the toxicity analysis.	41.3% 207/501 • Number of events 500 Only eligible patients are included in the toxicity analysis.	49.1% 250/509 • Number of events 689 Only eligible patients are included in the toxicity analysis.	50.0% 123/246 • Number of events 362 Only eligible patients are included in the toxicity analysis.	43.3% 107/247 • Number of events 372 Only eligible patients are included in the toxicity analysis.	48.6% 310/638 • Number of events 1009 Only eligible patients are included in the toxicity analysis.
Investigations Alkaline phosphatase increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	2.2% 11/501 • Number of events 12 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Investigations Aspartate aminotransferase increased	4.5% 59/1306 • Number of events 60 Only eligible patients are included in the toxicity analysis.	23.6% 220/931 • Number of events 335 Only eligible patients are included in the toxicity analysis.	20.2% 188/931 • Number of events 278 Only eligible patients are included in the toxicity analysis.	17.8% 89/501 • Number of events 133 Only eligible patients are included in the toxicity analysis.	17.9% 91/509 • Number of events 137 Only eligible patients are included in the toxicity analysis.	22.0% 54/246 • Number of events 82 Only eligible patients are included in the toxicity analysis.	23.5% 58/247 • Number of events 98 Only eligible patients are included in the toxicity analysis.	25.7% 164/638 • Number of events 288 Only eligible patients are included in the toxicity analysis.
Investigations Blood bilirubin increased	1.5% 20/1306 • Number of events 20 Only eligible patients are included in the toxicity analysis.	8.3% 77/931 • Number of events 90 Only eligible patients are included in the toxicity analysis.	5.7% 53/931 • Number of events 89 Only eligible patients are included in the toxicity analysis.	5.6% 28/501 • Number of events 42 Only eligible patients are included in the toxicity analysis.	5.9% 30/509 • Number of events 42 Only eligible patients are included in the toxicity analysis.	10.6% 26/246 • Number of events 34 Only eligible patients are included in the toxicity analysis.	6.5% 16/247 • Number of events 19 Only eligible patients are included in the toxicity analysis.	6.7% 43/638 • Number of events 52 Only eligible patients are included in the toxicity analysis.
Investigations CPK increased	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Investigations Cholesterol high	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Investigations Creatinine increased	0.54% 7/1306 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Electrocardiogram QT corrected interval prolonged	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Investigations Fibrinogen decreased	3.8% 50/1306 • Number of events 50 Only eligible patients are included in the toxicity analysis.	4.4% 41/931 • Number of events 58 Only eligible patients are included in the toxicity analysis.	4.3% 40/931 • Number of events 48 Only eligible patients are included in the toxicity analysis.	6.2% 31/501 • Number of events 35 Only eligible patients are included in the toxicity analysis.	4.7% 24/509 • Number of events 28 Only eligible patients are included in the toxicity analysis.	6.9% 17/246 • Number of events 23 Only eligible patients are included in the toxicity analysis.	4.9% 12/247 • Number of events 17 Only eligible patients are included in the toxicity analysis.	4.5% 29/638 • Number of events 36 Only eligible patients are included in the toxicity analysis.
Investigations GGT increased	2.1% 28/1306 • Number of events 29 Only eligible patients are included in the toxicity analysis.	5.3% 49/931 • Number of events 79 Only eligible patients are included in the toxicity analysis.	2.3% 21/931 • Number of events 22 Only eligible patients are included in the toxicity analysis.	2.0% 10/501 • Number of events 13 Only eligible patients are included in the toxicity analysis.	3.3% 17/509 • Number of events 26 Only eligible patients are included in the toxicity analysis.	4.1% 10/246 • Number of events 13 Only eligible patients are included in the toxicity analysis.	4.9% 12/247 • Number of events 17 Only eligible patients are included in the toxicity analysis.	4.2% 27/638 • Number of events 45 Only eligible patients are included in the toxicity analysis.
Investigations INR increased	0.38% 5/1306 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Investigations Investigations - Other, specify	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	2.4% 12/501 • Number of events 15 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.9% 12/638 • Number of events 17 Only eligible patients are included in the toxicity analysis.
Investigations Lipase increased	2.1% 28/1306 • Number of events 29 Only eligible patients are included in the toxicity analysis.	4.1% 38/931 • Number of events 43 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 9 Only eligible patients are included in the toxicity analysis.	2.0% 10/509 • Number of events 15 Only eligible patients are included in the toxicity analysis.	2.0% 5/246 • Number of events 5 Only eligible patients are included in the toxicity analysis.	5.7% 14/247 • Number of events 17 Only eligible patients are included in the toxicity analysis.	4.4% 28/638 • Number of events 42 Only eligible patients are included in the toxicity analysis.
Investigations Lymphocyte count decreased	0.61% 8/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	6.0% 56/931 • Number of events 94 Only eligible patients are included in the toxicity analysis.	7.7% 72/931 • Number of events 117 Only eligible patients are included in the toxicity analysis.	4.8% 24/501 • Number of events 39 Only eligible patients are included in the toxicity analysis.	8.4% 43/509 • Number of events 95 Only eligible patients are included in the toxicity analysis.	5.7% 14/246 • Number of events 24 Only eligible patients are included in the toxicity analysis.	9.3% 23/247 • Number of events 50 Only eligible patients are included in the toxicity analysis.	7.2% 46/638 • Number of events 118 Only eligible patients are included in the toxicity analysis.
Investigations Neutrophil count decreased	12.7% 166/1306 • Number of events 172 Only eligible patients are included in the toxicity analysis.	76.0% 708/931 • Number of events 2226 Only eligible patients are included in the toxicity analysis.	78.1% 727/931 • Number of events 2182 Only eligible patients are included in the toxicity analysis.	74.9% 375/501 • Number of events 1101 Only eligible patients are included in the toxicity analysis.	84.3% 429/509 • Number of events 1457 Only eligible patients are included in the toxicity analysis.	74.8% 184/246 • Number of events 620 Only eligible patients are included in the toxicity analysis.	81.4% 201/247 • Number of events 731 Only eligible patients are included in the toxicity analysis.	89.3% 570/638 • Number of events 2396 Only eligible patients are included in the toxicity analysis.
Investigations Platelet count decreased	8.3% 108/1306 • Number of events 111 Only eligible patients are included in the toxicity analysis.	28.1% 262/931 • Number of events 405 Only eligible patients are included in the toxicity analysis.	21.4% 199/931 • Number of events 297 Only eligible patients are included in the toxicity analysis.	21.6% 108/501 • Number of events 143 Only eligible patients are included in the toxicity analysis.	29.7% 151/509 • Number of events 236 Only eligible patients are included in the toxicity analysis.	25.2% 62/246 • Number of events 89 Only eligible patients are included in the toxicity analysis.	32.0% 79/247 • Number of events 142 Only eligible patients are included in the toxicity analysis.	42.9% 274/638 • Number of events 567 Only eligible patients are included in the toxicity analysis.
Investigations Serum amylase increased	1.3% 17/1306 • Number of events 17 Only eligible patients are included in the toxicity analysis.	1.8% 17/931 • Number of events 19 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 11 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	3.1% 20/638 • Number of events 24 Only eligible patients are included in the toxicity analysis.
Investigations Weight gain	0.69% 9/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.8% 17/931 • Number of events 18 Only eligible patients are included in the toxicity analysis.	1.7% 16/931 • Number of events 18 Only eligible patients are included in the toxicity analysis.	2.0% 10/501 • Number of events 12 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	2.0% 5/246 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	3.1% 20/638 • Number of events 22 Only eligible patients are included in the toxicity analysis.
Investigations Weight loss	0.54% 7/1306 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.2% 11/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	1.2% 6/501 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.5% 16/638 • Number of events 17 Only eligible patients are included in the toxicity analysis.
Investigations White blood cell decreased	8.1% 106/1306 • Number of events 110 Only eligible patients are included in the toxicity analysis.	32.7% 304/931 • Number of events 765 Only eligible patients are included in the toxicity analysis.	37.1% 345/931 • Number of events 903 Only eligible patients are included in the toxicity analysis.	31.9% 160/501 • Number of events 354 Only eligible patients are included in the toxicity analysis.	36.9% 188/509 • Number of events 547 Only eligible patients are included in the toxicity analysis.	36.2% 89/246 • Number of events 235 Only eligible patients are included in the toxicity analysis.	45.7% 113/247 • Number of events 337 Only eligible patients are included in the toxicity analysis.	42.0% 268/638 • Number of events 927 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Acidosis	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.94% 6/638 • Number of events 6 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Alkalosis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Anorexia	1.2% 16/1306 • Number of events 16 Only eligible patients are included in the toxicity analysis.	4.5% 42/931 • Number of events 51 Only eligible patients are included in the toxicity analysis.	3.8% 35/931 • Number of events 51 Only eligible patients are included in the toxicity analysis.	4.6% 23/501 • Number of events 41 Only eligible patients are included in the toxicity analysis.	5.9% 30/509 • Number of events 37 Only eligible patients are included in the toxicity analysis.	2.8% 7/246 • Number of events 8 Only eligible patients are included in the toxicity analysis.	8.9% 22/247 • Number of events 26 Only eligible patients are included in the toxicity analysis.	10.5% 67/638 • Number of events 91 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Dehydration	1.5% 19/1306 • Number of events 19 Only eligible patients are included in the toxicity analysis.	5.8% 54/931 • Number of events 67 Only eligible patients are included in the toxicity analysis.	5.5% 51/931 • Number of events 62 Only eligible patients are included in the toxicity analysis.	6.6% 33/501 • Number of events 38 Only eligible patients are included in the toxicity analysis.	8.8% 45/509 • Number of events 55 Only eligible patients are included in the toxicity analysis.	6.5% 16/246 • Number of events 17 Only eligible patients are included in the toxicity analysis.	8.5% 21/247 • Number of events 26 Only eligible patients are included in the toxicity analysis.	13.0% 83/638 • Number of events 105 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Glucose intolerance	0.54% 7/1306 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.4% 9/638 • Number of events 13 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypercalcemia	0.38% 5/1306 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hyperglycemia	5.9% 77/1306 • Number of events 77 Only eligible patients are included in the toxicity analysis.	5.6% 52/931 • Number of events 57 Only eligible patients are included in the toxicity analysis.	4.8% 45/931 • Number of events 50 Only eligible patients are included in the toxicity analysis.	8.8% 44/501 • Number of events 52 Only eligible patients are included in the toxicity analysis.	7.3% 37/509 • Number of events 44 Only eligible patients are included in the toxicity analysis.	8.5% 21/246 • Number of events 27 Only eligible patients are included in the toxicity analysis.	7.3% 18/247 • Number of events 21 Only eligible patients are included in the toxicity analysis.	11.1% 71/638 • Number of events 102 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hyperkalemia	1.7% 22/1306 • Number of events 22 Only eligible patients are included in the toxicity analysis.	2.0% 19/931 • Number of events 19 Only eligible patients are included in the toxicity analysis.	1.8% 17/931 • Number of events 19 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.6% 13/509 • Number of events 15 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	3.9% 25/638 • Number of events 26 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypermagnesemia	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.4% 7/501 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypernatremia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.79% 4/509 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypertriglyceridemia	0.61% 8/1306 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 6/501 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.1% 7/638 • Number of events 8 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hyperuricemia	0.46% 6/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypoalbuminemia	2.0% 26/1306 • Number of events 26 Only eligible patients are included in the toxicity analysis.	7.1% 66/931 • Number of events 75 Only eligible patients are included in the toxicity analysis.	3.7% 34/931 • Number of events 37 Only eligible patients are included in the toxicity analysis.	3.4% 17/501 • Number of events 17 Only eligible patients are included in the toxicity analysis.	2.6% 13/509 • Number of events 15 Only eligible patients are included in the toxicity analysis.	4.1% 10/246 • Number of events 10 Only eligible patients are included in the toxicity analysis.	4.9% 12/247 • Number of events 12 Only eligible patients are included in the toxicity analysis.	6.4% 41/638 • Number of events 52 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypocalcemia	2.9% 38/1306 • Number of events 38 Only eligible patients are included in the toxicity analysis.	3.8% 35/931 • Number of events 36 Only eligible patients are included in the toxicity analysis.	3.7% 34/931 • Number of events 35 Only eligible patients are included in the toxicity analysis.	5.0% 25/501 • Number of events 25 Only eligible patients are included in the toxicity analysis.	2.8% 14/509 • Number of events 15 Only eligible patients are included in the toxicity analysis.	4.5% 11/246 • Number of events 11 Only eligible patients are included in the toxicity analysis.	5.3% 13/247 • Number of events 14 Only eligible patients are included in the toxicity analysis.	6.0% 38/638 • Number of events 40 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypoglycemia	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	6.6% 61/931 • Number of events 73 Only eligible patients are included in the toxicity analysis.	1.7% 16/931 • Number of events 19 Only eligible patients are included in the toxicity analysis.	3.4% 17/501 • Number of events 21 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 8 Only eligible patients are included in the toxicity analysis.	5.3% 13/246 • Number of events 16 Only eligible patients are included in the toxicity analysis.	4.0% 10/247 • Number of events 10 Only eligible patients are included in the toxicity analysis.	6.3% 40/638 • Number of events 47 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypokalemia	5.4% 70/1306 • Number of events 70 Only eligible patients are included in the toxicity analysis.	11.5% 107/931 • Number of events 127 Only eligible patients are included in the toxicity analysis.	12.4% 115/931 • Number of events 135 Only eligible patients are included in the toxicity analysis.	10.6% 53/501 • Number of events 70 Only eligible patients are included in the toxicity analysis.	12.6% 64/509 • Number of events 80 Only eligible patients are included in the toxicity analysis.	14.2% 35/246 • Number of events 49 Only eligible patients are included in the toxicity analysis.	12.1% 30/247 • Number of events 40 Only eligible patients are included in the toxicity analysis.	21.6% 138/638 • Number of events 191 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypomagnesemia	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hyponatremia	5.9% 77/1306 • Number of events 78 Only eligible patients are included in the toxicity analysis.	8.1% 75/931 • Number of events 90 Only eligible patients are included in the toxicity analysis.	6.7% 62/931 • Number of events 68 Only eligible patients are included in the toxicity analysis.	8.2% 41/501 • Number of events 43 Only eligible patients are included in the toxicity analysis.	8.3% 42/509 • Number of events 47 Only eligible patients are included in the toxicity analysis.	7.7% 19/246 • Number of events 20 Only eligible patients are included in the toxicity analysis.	7.3% 18/247 • Number of events 20 Only eligible patients are included in the toxicity analysis.	10.3% 66/638 • Number of events 80 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Hypophosphatemia	1.5% 20/1306 • Number of events 20 Only eligible patients are included in the toxicity analysis.	1.4% 13/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	2.3% 21/931 • Number of events 21 Only eligible patients are included in the toxicity analysis.	2.4% 12/501 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	3.1% 20/638 • Number of events 20 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Obesity	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Metabolism and nutrition disorders Tumor lysis syndrome	1.1% 14/1306 • Number of events 14 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Arthralgia	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Avascular necrosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.3% 8/638 • Number of events 11 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Back pain	0.61% 8/1306 • Number of events 8 Only eligible patients are included in the toxicity analysis.	1.2% 11/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.3% 12/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	3.0% 15/501 • Number of events 17 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 6 Only eligible patients are included in the toxicity analysis.	2.8% 18/638 • Number of events 19 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Bone pain	0.38% 5/1306 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.6% 8/509 • Number of events 8 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.3% 8/638 • Number of events 8 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Buttock pain	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Chest wall pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Joint effusion	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	1.2% 16/1306 • Number of events 16 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.4% 7/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.9% 12/638 • Number of events 12 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Muscle weakness right-sided	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Muscle weakness trunk	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Muscle weakness upper limb	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Myalgia	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Osteoporosis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.79% 4/509 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.94% 6/638 • Number of events 7 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Pain in extremity	1.1% 14/1306 • Number of events 14 Only eligible patients are included in the toxicity analysis.	3.7% 34/931 • Number of events 38 Only eligible patients are included in the toxicity analysis.	2.4% 22/931 • Number of events 25 Only eligible patients are included in the toxicity analysis.	2.8% 14/501 • Number of events 16 Only eligible patients are included in the toxicity analysis.	3.5% 18/509 • Number of events 25 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	3.8% 24/638 • Number of events 32 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Soft tissue necrosis lower limb	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Musculoskeletal and connective tissue disorders Soft tissue necrosis upper limb	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Treatment related secondary malignancy	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Abducens nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Arachnoiditis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Ataxia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.94% 6/638 • Number of events 6 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Cerebrospinal fluid leakage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Cognitive disturbance	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Depressed level of consciousness	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Dizziness	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Dysphasia	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Encephalopathy	0.38% 5/1306 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	2.5% 16/638 • Number of events 19 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Extrapyramidal disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Facial muscle weakness	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Facial nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Headache	0.77% 10/1306 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.7% 16/931 • Number of events 19 Only eligible patients are included in the toxicity analysis.	2.3% 21/931 • Number of events 24 Only eligible patients are included in the toxicity analysis.	2.2% 11/501 • Number of events 17 Only eligible patients are included in the toxicity analysis.	4.5% 23/509 • Number of events 26 Only eligible patients are included in the toxicity analysis.	2.4% 6/246 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 7 Only eligible patients are included in the toxicity analysis.	3.0% 19/638 • Number of events 30 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Hydrocephalus	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Hypoglossal nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders IVth nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Intracranial hemorrhage	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Ischemia cerebrovascular	0.23% 3/1306 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Leukoencephalopathy	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Memory impairment	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Nervous system disorders - Other, specify	0.61% 8/1306 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.6% 10/638 • Number of events 10 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Neuralgia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.79% 4/509 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Oculomotor nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Peripheral motor neuropathy	2.9% 38/1306 • Number of events 38 Only eligible patients are included in the toxicity analysis.	7.3% 68/931 • Number of events 105 Only eligible patients are included in the toxicity analysis.	5.6% 52/931 • Number of events 89 Only eligible patients are included in the toxicity analysis.	8.6% 43/501 • Number of events 76 Only eligible patients are included in the toxicity analysis.	7.7% 39/509 • Number of events 64 Only eligible patients are included in the toxicity analysis.	11.0% 27/246 • Number of events 46 Only eligible patients are included in the toxicity analysis.	8.9% 22/247 • Number of events 41 Only eligible patients are included in the toxicity analysis.	12.4% 79/638 • Number of events 141 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Peripheral sensory neuropathy	2.2% 29/1306 • Number of events 29 Only eligible patients are included in the toxicity analysis.	6.1% 57/931 • Number of events 94 Only eligible patients are included in the toxicity analysis.	4.4% 41/931 • Number of events 78 Only eligible patients are included in the toxicity analysis.	4.0% 20/501 • Number of events 42 Only eligible patients are included in the toxicity analysis.	7.5% 38/509 • Number of events 56 Only eligible patients are included in the toxicity analysis.	8.5% 21/246 • Number of events 29 Only eligible patients are included in the toxicity analysis.	3.6% 9/247 • Number of events 14 Only eligible patients are included in the toxicity analysis.	8.5% 54/638 • Number of events 85 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Recurrent laryngeal nerve palsy	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Seizure	0.92% 12/1306 • Number of events 12 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.2% 11/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.6% 13/509 • Number of events 16 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.8% 7/247 • Number of events 7 Only eligible patients are included in the toxicity analysis.	3.1% 20/638 • Number of events 24 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Sinus pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Somnolence	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Syncope	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Tremor	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Trigeminal nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Vagus nerve disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Nervous system disorders Vasovagal reaction	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Agitation	0.54% 7/1306 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.2% 6/501 • Number of events 6 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.3% 8/638 • Number of events 8 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Anxiety	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Confusion	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 6/509 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Depression	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Insomnia	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Personality change	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.94% 6/638 • Number of events 7 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Psychiatric disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Psychosis	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Psychiatric disorders Suicidal ideation	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Acute kidney injury	0.54% 7/1306 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.60% 3/501 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Bladder spasm	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Cystitis noninfective	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Hematuria	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Proteinuria	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Renal and urinary disorders - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Renal calculi	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Renal colic	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Renal hemorrhage	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Urinary retention	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Urinary tract obstruction	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Renal and urinary disorders Urinary tract pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Reproductive system and breast disorders Pelvic pain	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Reproductive system and breast disorders Penile pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Reproductive system and breast disorders Scrotal pain	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Reproductive system and breast disorders Testicular pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Apnea	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.63% 4/638 • Number of events 4 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Bronchial obstruction	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary hemorrhage	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.2% 11/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	2.4% 6/246 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Cough	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.4% 13/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	1.7% 16/931 • Number of events 16 Only eligible patients are included in the toxicity analysis.	2.0% 10/501 • Number of events 14 Only eligible patients are included in the toxicity analysis.	2.0% 10/509 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.4% 9/638 • Number of events 9 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.00% 5/501 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.94% 6/638 • Number of events 6 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	1.4% 9/638 • Number of events 10 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.1% 15/1306 • Number of events 15 Only eligible patients are included in the toxicity analysis.	3.2% 30/931 • Number of events 32 Only eligible patients are included in the toxicity analysis.	2.7% 25/931 • Number of events 26 Only eligible patients are included in the toxicity analysis.	2.2% 11/501 • Number of events 14 Only eligible patients are included in the toxicity analysis.	2.8% 14/509 • Number of events 14 Only eligible patients are included in the toxicity analysis.	3.7% 9/246 • Number of events 14 Only eligible patients are included in the toxicity analysis.	4.0% 10/247 • Number of events 10 Only eligible patients are included in the toxicity analysis.	4.4% 28/638 • Number of events 34 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Laryngeal edema	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Laryngeal mucositis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Laryngeal obstruction	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pharyngeal mucositis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pharyngeal stenosis	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.69% 9/1306 • Number of events 9 Only eligible patients are included in the toxicity analysis.	1.4% 13/931 • Number of events 13 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.98% 5/509 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	1.6% 4/247 • Number of events 5 Only eligible patients are included in the toxicity analysis.	1.4% 9/638 • Number of events 9 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.46% 6/1306 • Number of events 6 Only eligible patients are included in the toxicity analysis.	2.3% 21/931 • Number of events 23 Only eligible patients are included in the toxicity analysis.	2.1% 20/931 • Number of events 21 Only eligible patients are included in the toxicity analysis.	1.4% 7/501 • Number of events 8 Only eligible patients are included in the toxicity analysis.	2.0% 10/509 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 6 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 6 Only eligible patients are included in the toxicity analysis.	3.4% 22/638 • Number of events 24 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.86% 8/931 • Number of events 8 Only eligible patients are included in the toxicity analysis.	1.6% 15/931 • Number of events 16 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	1.7% 11/638 • Number of events 12 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Sinus disorder	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Sore throat	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Stridor	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Tracheal fistula	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Voice alteration	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Erythema multiforme	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Pain of skin	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Photosensitivity	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.21% 2/931 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Purpura	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.31% 2/638 • Number of events 2 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.31% 4/1306 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 11 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.80% 4/501 • Number of events 4 Only eligible patients are included in the toxicity analysis.	2.4% 12/509 • Number of events 13 Only eligible patients are included in the toxicity analysis.	1.2% 3/246 • Number of events 3 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 6 Only eligible patients are included in the toxicity analysis.	2.4% 15/638 • Number of events 18 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	0.15% 2/1306 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 12 Only eligible patients are included in the toxicity analysis.	0.43% 4/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.79% 4/509 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.41% 1/246 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	1.6% 10/638 • Number of events 12 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Skin ulceration	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.39% 2/509 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Stevens-Johnson syndrome	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.75% 7/931 • Number of events 7 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.59% 3/509 • Number of events 3 Only eligible patients are included in the toxicity analysis.	1.6% 4/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	1.2% 3/247 • Number of events 3 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 5 Only eligible patients are included in the toxicity analysis.
Surgical and medical procedures Surgical and medical procedures - Other, specify	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Vascular disorders Capillary leak syndrome	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.
Vascular disorders Hematoma	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.54% 5/931 • Number of events 5 Only eligible patients are included in the toxicity analysis.	0.20% 1/501 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.16% 1/638 • Number of events 1 Only eligible patients are included in the toxicity analysis.
Vascular disorders Hypertension	2.3% 30/1306 • Number of events 31 Only eligible patients are included in the toxicity analysis.	1.9% 18/931 • Number of events 18 Only eligible patients are included in the toxicity analysis.	3.1% 29/931 • Number of events 31 Only eligible patients are included in the toxicity analysis.	1.6% 8/501 • Number of events 8 Only eligible patients are included in the toxicity analysis.	2.6% 13/509 • Number of events 15 Only eligible patients are included in the toxicity analysis.	2.4% 6/246 • Number of events 12 Only eligible patients are included in the toxicity analysis.	2.0% 5/247 • Number of events 6 Only eligible patients are included in the toxicity analysis.	4.7% 30/638 • Number of events 35 Only eligible patients are included in the toxicity analysis.
Vascular disorders Hypotension	0.77% 10/1306 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.8% 17/931 • Number of events 18 Only eligible patients are included in the toxicity analysis.	1.1% 10/931 • Number of events 10 Only eligible patients are included in the toxicity analysis.	1.4% 7/501 • Number of events 7 Only eligible patients are included in the toxicity analysis.	1.6% 8/509 • Number of events 8 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.40% 1/247 • Number of events 1 Only eligible patients are included in the toxicity analysis.	2.8% 18/638 • Number of events 21 Only eligible patients are included in the toxicity analysis.
Vascular disorders Thromboembolic event	1.3% 17/1306 • Number of events 17 Only eligible patients are included in the toxicity analysis.	0.97% 9/931 • Number of events 9 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.20% 1/509 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.81% 2/247 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.78% 5/638 • Number of events 6 Only eligible patients are included in the toxicity analysis.
Vascular disorders Vascular disorders - Other, specify	0.08% 1/1306 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.64% 6/931 • Number of events 6 Only eligible patients are included in the toxicity analysis.	0.32% 3/931 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.40% 2/501 • Number of events 2 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.81% 2/246 • Number of events 4 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.47% 3/638 • Number of events 3 Only eligible patients are included in the toxicity analysis.
Vascular disorders Vasculitis	0.00% 0/1306 Only eligible patients are included in the toxicity analysis.	0.00% 0/931 Only eligible patients are included in the toxicity analysis.	0.11% 1/931 • Number of events 1 Only eligible patients are included in the toxicity analysis.	0.00% 0/501 Only eligible patients are included in the toxicity analysis.	0.00% 0/509 Only eligible patients are included in the toxicity analysis.	0.00% 0/246 Only eligible patients are included in the toxicity analysis.	0.00% 0/247 Only eligible patients are included in the toxicity analysis.	0.00% 0/638 Only eligible patients are included in the toxicity analysis.

Additional Information

Results Reporting Coordinator

Children's Oncology Group

Phone: 626-447-0064

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Must obtain prior Sponsor approval.
Publication restrictions are in place

Restriction type: OTHER