Trial Outcomes & Findings for Tocilizumab for KSHV-Associated Multicentric Castleman Disease (NCT NCT01441063)

Last Updated: 2020-10-27

Results Overview

Overall clinical benefit response is defined as Complete Response (CR): Full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks; and Partial Response (PR): At least 50% of the abnormalities probably or definitely attributed to KSHV-MCD must improve by the minimum amounts specified to attain PR. Only abnormalities present in a specific patient at baseline may count toward the achievement of a PR (e.g. if six of indicator abnormalities are present at baseline, at least three must meet the specified criteria to be considered a PR) assessed using a modified Kaposi sarcoma herpes virus-associated multicentric Castleman disease (KSHV- MCD) Clinical Benefit Response Criteria and the National Cancer Institute (NCI) KSHV-MCD criteria.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

8 participants

Primary outcome timeframe

every 2 weeks for up to 12 weeks

Results posted on

2020-10-27

Participant Flow

Participant milestones

Participant milestones
Measure	Tocilizumab Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered. Zidovudine: Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours) Tocilizumab: Tocilizumab 8mg/kg every 2 weeks Valganciclovir (VGC): Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle. KSHV-MCD = Kaposi sarcoma herpes virus-associated multicentric Castleman Disease
Tocilizumab Alone STARTED	8
Tocilizumab Alone COMPLETED	5
Tocilizumab Alone NOT COMPLETED	3
Tocilizumab + Zidovudine /Valganciclovir STARTED	3
Tocilizumab + Zidovudine /Valganciclovir COMPLETED	2
Tocilizumab + Zidovudine /Valganciclovir NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Tocilizumab Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered. Zidovudine: Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours) Tocilizumab: Tocilizumab 8mg/kg every 2 weeks Valganciclovir (VGC): Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle. KSHV-MCD = Kaposi sarcoma herpes virus-associated multicentric Castleman Disease
Tocilizumab Alone Required AZT/VGC addition	3
Tocilizumab + Zidovudine /Valganciclovir Worsening KSHV-MCD symptoms	1

Baseline Characteristics

Tocilizumab for KSHV-Associated Multicentric Castleman Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tocilizumab n=8 Participants Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered. Zidovudine: Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours) Tocilizumab: Tocilizumab 8mg/kg every 2 weeks Valganciclovir (VGC): Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=93 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants
Age, Continuous	47.61 years STANDARD_DEVIATION 13.41 • n=93 Participants
Sex: Female, Male Female	1 Participants n=93 Participants
Sex: Female, Male Male	7 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	4 Participants n=93 Participants
Race (NIH/OMB) White	3 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Region of Enrollment United States	8 participants n=93 Participants

PRIMARY outcome

Timeframe: every 2 weeks for up to 12 weeks

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With an Overall Clinical Benefit Response Cumulative Response	63 percentage of participants Interval 25.0 to 92.0	100 percentage of participants Interval 31.0 to 100.0
Percentage of Participants With an Overall Clinical Benefit Response Partial Response	50 percentage of participants Interval 16.0 to 84.0	67 percentage of participants Interval 13.0 to 98.0
Percentage of Participants With an Overall Clinical Benefit Response Complete Response	13 percentage of participants Interval 0.0 to 53.0	33 percentage of participants Interval 2.0 to 87.0

SECONDARY outcome

Timeframe: up to 12 weeks

Clinical response is defined as a Complete Response (CR): Full resolution of all signs and symptoms attributable to MCD, lasting 1 cycle (3-4 weeks depending on regimen; Symptom Free Disease (SFD:) Full resolution of all signs and symptoms attributable to MCD, not yet lasting 1 cycle (3-4 weeks depending on regimen); and Partial Response (PR): Improvement in at least 50% of signs and symptoms by at least 1 grade (NCI-Common Terminology Criteria for Adverse Events (CTCAE v4), with no increased MCD related increases, lasting 1 cycle (3-4 weeks depending on regimen) assessed by the National Cancer Institute Kaposi sarcoma herpes virus-associated multicentric Castleman disease (NCI KSHV-MCD) Response Criteria.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With a Clinical Response Cumulative Response	75 percentage of participants Interval 35.0 to 97.0	100 percentage of participants Interval 31.0 to 100.0
Percentage of Participants With a Clinical Response Complete Response	25 percentage of participants Interval 3.0 to 65.0	33 percentage of participants Interval 2.0 to 87.0
Percentage of Participants With a Clinical Response Symptom Free Disease	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0
Percentage of Participants With a Clinical Response Partial Response	50 percentage of participants Interval 16.0 to 84.0	67 percentage of participants Interval 13.0 to 98.0

SECONDARY outcome

Timeframe: up to 12 weeks

A biochemical response is defined as a Complete Response (CR): Normalization of abnormalities attributed to MCD in the following labs: Complete blood count (CBC), Chem 20, C-Reactive protein (CRP), lasting 1 cycle (3-4 weeks depending on regimen); Partial Response (PR): 50% improvement in all labs abnormalities attributable to MCD, lasting 1 cycle (3-4 weeks depending on regimen), and was assessed by the National Cancer Institute (NCI) Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD) Response Criteria.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With a Biochemical Response Partial Response	38 percentage of participants Interval 9.0 to 76.0	33 percentage of participants Interval 2.0 to 87.0
Percentage of Participants With a Biochemical Response Cumulative Response	50 percentage of participants Interval 16.0 to 84.0	100 percentage of participants Interval 31.0 to 100.0
Percentage of Participants With a Biochemical Response Complete Response	13 percentage of participants Interval 0.0 to 53.0	67 percentage of participants Interval 13.0 to 98.0

SECONDARY outcome

Timeframe: up to 12 weeks

A radiographic response is defined as a Complete Response (CR): Normalization of all lymph nodes to \<1.5 cm in greatest transverse dimension, decrease to \< 1 cm of lymph nodes 1.1-1.5 cm at baseline (or 75% decrease in the sum of products of diameters (SPD)), Spleen \< 12 cm greatest dimension, no pleural effusions; Complete Response unconfirmed (CRu): Residual lymph node mass \>1.5 cm or splenomegaly \> 12 cm that has decrease by \>75% and does not change over one year; and Partial Response (PR): For lymph nodes, \>50% decrease in SPD of 6 dominant nodes, for spleen 50% decrease in longest transverse dimension assessed by the National Cancer Institute (NCI) Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD) Response Criteria.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With a Radiographic Response Cumulative Response	13 percentage of participants Interval 0.0 to 53.0	0 percentage of participants Interval 0.0 to 0.0
Percentage of Participants With a Radiographic Response Complete Response	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0
Percentage of Participants With a Radiographic Response Complete Response unconfirmed	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0
Percentage of Participants With a Radiographic Response Partial Response	13 percentage of participants Interval 0.0 to 53.0	0 percentage of participants Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Baseline, week 7, and at off study visit, approximately 2 weeks following last study treatment for those with KS, up to 14 weeks.

The ACTG Criteria is defined as a Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), and Symptom Free Disease (SFD). The terms Improved (I), Stable (S), Mixed (M) Response, and Worse (W) are also used to further describe participants who have SD or PR.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria Complete Response	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0
Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria Partial Response	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0
Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria Progressive Disease	100 percentage of participants Interval 16.0 to 100.0	0 percentage of participants Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of antiretrovirals (ART) and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Ritonavir will be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Lopinavir will be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Atazanavir will be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Efavirenz will be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: each cycle, up to 6 years, 8 months and 24 days.

Here is the percentage of participants with Grade 3 or greater serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe or medically significant, Grade 4 is life threatening, and Grade 5 is death.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With Grade 3 or Greater Serious Adverse Events	25 percentage of participants Interval 3.0 to 65.0	67 percentage of participants Interval 12.0 to 98.0

SECONDARY outcome

Timeframe: each cycle, up to 6 years, 8 months and 24 days.

Here is the percentage of participants with \<Grade 3 non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. Grade 1 is mild and Grade 2 is moderate.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With <Grade 3 Non- Serious Adverse Events Cumulative <Grade 3 Adverse Events	100 percentage of participants Interval 63.0 to 100.0	100 percentage of participants Interval 31.0 to 100.0
Percentage of Participants With <Grade 3 Non- Serious Adverse Events Grade 2	100 percentage of participants Interval 63.0 to 100.0	100 percentage of participants Interval 31.0 to 100.0
Percentage of Participants With <Grade 3 Non- Serious Adverse Events Grade 1	63 percentage of participants Interval 24.0 to 91.0	100 percentage of participants Interval 31.0 to 100.0

SECONDARY outcome

Timeframe: Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	8 Participants	3 Participants

SECONDARY outcome

Timeframe: Cycle 1, Day 1 and Cycle 2-6 Day 1

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that are cytochrome P3A4 (CYP3A4) substrates in patients with symptomatic Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 4 months

Progression-free survival is defined as participants who progress or die by 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants Progression-free Survival at 4 Months	25 percentage of participants Interval 4.0 to 56.0	33 percentage of participants Interval 0.0 to 77.0

SECONDARY outcome

Timeframe: 4 months

Overall survival is defined as the percentage of participants alive at 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.

Outcome measures

Outcome measures
Measure	Tocilizumab Monotherapy n=8 Participants All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 Participants 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC)	100 Percentage of participants	100 Percentage of participants

Adverse Events

Tocilizumab Monotherapy

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Tocilizumab Combination Therapy

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tocilizumab Monotherapy n=8 participants at risk All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 participants at risk 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
General disorders Fever	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.

Other adverse events

Additional Information

Dr. Robert Yarchoan

National Cancer Institute

Phone: 240-760-6075

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Tocilizumab Monotherapy n=8 participants at risk All participants (e.g. 8/8) who received Tocilizumab. Participants who fail monotherapy, may receive Tocilizumab Combination Therapy (Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).	Tocilizumab Combination Therapy n=3 participants at risk 3/8 participants who failed on Tocilizumab and received Tocilizumab + Zidovudine (AZT) and Valganciclovir (VGC).
Gastrointestinal disorders Abdominal pain	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Alanine aminotransferase increased	37.5% 3/8 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Alkaline phosphatase increased	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Blood and lymphatic system disorders Anemia	100.0% 8/8 • Number of events 20 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Anorexia	37.5% 3/8 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Aspartate aminotransferase increased	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Gastrointestinal disorders Bloatness	37.5% 3/8 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Blood bilirubin increased	12.5% 1/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations CD4 lymphocytes decreased	50.0% 4/8 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Musculoskeletal and connective tissue disorders Chest wall pain	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
General disorders Chills	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Cholesterol high	37.5% 3/8 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Gastrointestinal disorders Constipation	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Respiratory, thoracic and mediastinal disorders Cough	62.5% 5/8 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Creatinine increased	37.5% 3/8 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Gastrointestinal disorders Diarrhea	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Nervous system disorders Dizziness	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Nervous system disorders Dysgeusia	0.00% 0/8 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Gastrointestinal disorders Dyspepsia	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
General disorders Edema limbs	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
General disorders Fatigue	75.0% 6/8 • Number of events 11 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
General disorders Fever	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Haptoglobin decreased	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Nervous system disorders Headache	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Vascular disorders Hot flashes	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hypercalcemia	0.00% 0/8 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hyperglycemia	50.0% 4/8 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hypertriglyceridemia	50.0% 4/8 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hyperuricemia	12.5% 1/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hypoalbuminemia	62.5% 5/8 • Number of events 7 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hypomagnesemia	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hyponatremia	37.5% 3/8 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Hypophosphatemia	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Infections and infestations Infections and infestations - Other, respiratory	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Infections and infestations Infections and infestations - Other, C. Diff.	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Infections and infestations Infections and infestations - Other, left psoas abcess	12.5% 1/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Infections and infestations Infections and infestations - Other, specify	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Psychiatric disorders Insomnia	37.5% 3/8 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/8 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Lipase increased	50.0% 4/8 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Lymphocyte count decreased	62.5% 5/8 • Number of events 9 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	100.0% 3/3 • Number of events 7 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/8 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Respiratory, thoracic and mediastinal disorders Nasal congestion	25.0% 2/8 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Gastrointestinal disorders Nausea	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	100.0% 3/3 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Neutrophil count decreased	50.0% 4/8 • Number of events 7 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	100.0% 3/3 • Number of events 7 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Skin and subcutaneous tissue disorders Night Sweats	0.00% 0/8 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
General disorders Pain	37.5% 3/8 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Musculoskeletal and connective tissue disorders Pain in extremity	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Platelet count decreased	37.5% 3/8 • Number of events 7 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	66.7% 2/3 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Respiratory, thoracic and mediastinal disorders Postnasal drip	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Renal and urinary disorders Proteinuria	25.0% 2/8 • Number of events 2 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Skin and subcutaneous tissue disorders Pruritus	25.0% 2/8 • Number of events 3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Skin and subcutaneous tissue disorders Rash acneiform	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Serum amylase increased	25.0% 2/8 • Number of events 4 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	33.3% 1/3 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Cardiac disorders Sinus tachycardia	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Infections and infestations Sinusitis	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations TSH elevated	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Metabolism and nutrition disorders Triglyceride	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations Weight loss	12.5% 1/8 • Number of events 1 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	0.00% 0/3 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Investigations White blood cell decreased	37.5% 3/8 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.	100.0% 3/3 • Number of events 5 • Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.