Trial Outcomes & Findings for Dasatinib in Treating Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma (NCT NCT00423735)

Last Updated: 2019-07-24

Results Overview

This study utilized a two-stage phase II design (Stage 1B and 2). The primary endpoint of 6-month progression-free survival (6mPFS) would be assessed based on the patients combined from 1B and 2 if the study continued to Stage 2. Null hypothesis = 11%; alternative hypothesis = 25%. Simon's minmax 2-stage design was used with type I and type II error both set at 10%. If the first stage met its criteria (see secondary outcome measure), then accrual would continue, otherwise there would be no further accrual and the alternative hypothesis would be rejected. Following Stage 2 accrual completion and 6 months of follow-up, if 9 or more patients were alive without progression by 6 months, the null hypothesis would be rejected in favor of the alternative.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

64 participants

Primary outcome timeframe

Registration to 6 months

Results posted on

2019-07-24

Participant Flow

Per protocol criteria, the study did not continue to Stage 2 and therefore no patients were accrued to this arm.

Participant milestones

Participant milestones
Measure	Stage 1: Dasatinib 200mg/Day Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity	Stage 1B: Dasatinib up to 400mg/Day Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.
Overall Study STARTED	29	35
Overall Study COMPLETED	21	29
Overall Study NOT COMPLETED	8	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage 1: Dasatinib 200mg/Day Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity	Stage 1B: Dasatinib up to 400mg/Day Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Dasatinib up to 400mg/Day Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.
Overall Study Ineligible / No protocol treatment	8	6	0

Baseline Characteristics

Dasatinib in Treating Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Dasatinib up to 400mg/Day Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Total n=50 Participants Total of all reporting groups
Age, Continuous	51 years n=5 Participants	54 years n=7 Participants	—	54 years n=4 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	12 Participants n=7 Participants	—	23 Participants n=4 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	17 Participants n=7 Participants	—	27 Participants n=4 Participants

PRIMARY outcome

Timeframe: Registration to 6 months

Population: Eligible patients who started protocol treatment.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Number of Patients Achieving 6-month Progression-free Survival (6mPFS)	1 participants	2 participants	—

SECONDARY outcome

Timeframe: Registration to 6 months

Population: Eligible patients who started protocol treatment.

Study design and efficacy determination uses the hybrid endpoint of 6mPFS or complete/partial response of any duration prior to or at 6 months. Null hypothesis = 11%; alternative hypothesis = 25%. Simon's minmax 2-stage design was used with type I and type II error both set at 10%. Stage 1 and 1B: If 2 or fewer patients were alive and progression-free at 6 months or achieved complete/partial response, then there would be no further accrual and the alternative hypothesis would be rejected. Otherwise accrual would continue to a total of 50 analyzable patients to address the primary endpoint. Complete Response: Complete disappearance of all enhancing tumor on consecutive CT or MRI scans at least 1 month apart; off corticosteroids; neurologically stable/improved. Partial Response: ≥ 50% decrease in size of enhancing tumor on consecutive CT or MRI scans at least 1 month apart; corticosteroids stable/reduced; neurologically stable/improved.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Number of Patients Achieving Objective Response (Partial or Complete Response) OR 6-month Progression-free Survival (6mPFS)	1 participants	2 participants	—

SECONDARY outcome

Timeframe: Analysis occurs after all patients have been on study for at least 6 months. (Patients are followed from registration to death or study termination whichever occurs first.)

Population: Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 6 months. Arms are not compared.

Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. The study is not designed for a comparison of the treatment arms to each other.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Overall Survival	6.5 months Interval 3.5 to 9.5	8.9 months Interval 5.0 to 11.3	—

SECONDARY outcome

Timeframe: From registration to 6 months

Population: Eligible patients who started study treatment

Best response is assessed using standard criteria for patients with malignant gliomas (Macdonald 1990) as reported by the site. Complete response (CR): Complete disappearance of all enhancing tumor on consecutive CT or MRI scans at least 1 month apart; off corticosteroids; neurologically stable/improved. Partial response (PR): ≥ 50% decrease in size of enhancing tumor on consecutive CT or MRI scans at least 1 month apart; corticosteroids stable/reduced; neurologically stable/improved. Stable disease (SD): Does not qualify for CR, PR, or PD. Progressive disease (PD): ≥ 25% increase in the size of enhancing tumor or any new tumor; neurologically worse; steroids stable/increased. The best tumor response is defined as the best radiographic response for patients evaluable for radiographic response prior to progression, up to six months. The study is not designed for a comparison of the treatment arms to each other.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Treatment Response Rates at Six Months CR or PR	0.0 percentage of participants	0.0 percentage of participants	—
Treatment Response Rates at Six Months Stable	19.0 percentage of participants	27.6 percentage of participants	—
Treatment Response Rates at Six Months Progression	76.2 percentage of participants	69.0 percentage of participants	—
Treatment Response Rates at Six Months No scan done and no clinical progression reported	4.8 percentage of participants	3.4 percentage of participants	—

SECONDARY outcome

Timeframe: Analysis occurs after all patients have been on study for at least 6 months. (Patients are followed from registration to death or study termination whichever occurs first.)

Population: Eligible patients who started study treatment

Progression-free survival time is measured from randomization to the date of first progression or death, else the last follow-up date on which the patient was reported alive, and is estimated by the Kaplan-Meier method. Progression is defined as ≥ 25% increase in the size of enhancing tumor or any new tumor, neurologically worse, or steroids stable/increased. The study is not designed for a comparison of the treatment arms to each other.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Progression-free Survival	1.7 months Interval 1.0 to 2.0	1.8 months Interval 1.2 to 2.0	—

SECONDARY outcome

Timeframe: Analysis occurs after all patients have been on study for at least 6 months. (Patients are followed from registration to death or study termination whichever occurs first.)

Population: Eligible patients who started protocol treatment

The rate of patients' worst overall grade of adverse event is reported. Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. The study is not designed for a comparison of the treatment arms to each other.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=21 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=29 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Rate of Adverse Events Grade 1	0.0 percentage of participants	10.3 percentage of participants	—
Rate of Adverse Events Grade 2	14.3 percentage of participants	17.2 percentage of participants	—
Rate of Adverse Events Grade 3	57.1 percentage of participants	44.8 percentage of participants	—
Rate of Adverse Events Grade 4	14.3 percentage of participants	3.4 percentage of participants	—
Rate of Adverse Events Grade 5	14.3 percentage of participants	17.2 percentage of participants	—

SECONDARY outcome

Timeframe: From registration to 6 months

Population: Eligible patients who started study treatment and whose response was assessed

The following markers were examined: p-SRC, PDGFR, EPHA2, c-KIT. Patients were categorized based on the number of positive molecular markers they had: 2 vs. 3 and 4. Correlation of marker category and best tumor response was tested using Fisher's exact test. The best tumor response is defined as the best radiographic response for patients evaluable for radiographic response prior to progression up to six months. Patients are combined from the two treatment arms.

Outcome measures

Outcome measures
Measure	Stage 1: Dasatinib 200mg/Day n=12 Participants Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.	Stage 1B: Dasatinib up to 400mg/Day n=36 Participants Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity.	Stage 2: Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity
Correlation of Molecular Markers and Tumor Response 2 postivie molecular markers	4 Participants	13 Participants	—
Correlation of Molecular Markers and Tumor Response 3 or 4 positive molecular markers	8 Participants	23 Participants	—

SECONDARY outcome

Timeframe: Analysis occurs after all patients have been on study for at least 6 months. (Patients are followed from registration to death or study termination whichever occurs first.)

Sufficient pharmacokinetic data was not obtained.

Outcome measures

Outcome data not reported

Adverse Events

Stage 1: Dasatinib 200mg/Day

Serious events: 8 serious events

Other events: 21 other events

Deaths: 0 deaths

Stage 1B: Dasatinib up to 400mg/Day

Serious events: 14 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Wendy Seiferheld

Radiation Therapy Oncology Group (RTOG)

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Stage 1: Dasatinib 200mg/Day n=21 participants at risk Patients receive oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity dasatinib: Given orally	Stage 1B: Dasatinib up to 400mg/Day n=29 participants at risk Patients begin with oral 100mg dasatinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. Patients could escalate 50mg/day at each new cycle up to 400mg/day if they had not progressed to date and had not experienced dose-limiting toxicity. dasatinib: Given orally
Blood and lymphatic system disorders Hemoglobin	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Cardiac disorders Angina pectoris	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Gastrointestinal disorders Anal haemorrhage	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Gastrointestinal disorders Colitis NOS	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Gastrointestinal disorders Diarrhoea NOS	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Gastrointestinal disorders Lower gastrointestinal hemorrhage	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Gastrointestinal disorders Nausea	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Gastrointestinal disorders Vomiting NOS	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
General disorders Chest pain	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
General disorders Constitutional Symptoms - Other:	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
General disorders Disease progression NOS	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	13.8% 4/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
General disorders Fatigue	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
General disorders Pyrexia	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
General disorders Rigors	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Infections and infestations Infection - Other:	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Investigations Lymphopenia	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Metabolism and nutrition disorders Anorexia	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	6.9% 2/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Metabolism and nutrition disorders Dehydration	9.5% 2/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Metabolism and nutrition disorders Hyperglycaemia NOS	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Metabolism and nutrition disorders Hyperkalaemia	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Metabolism and nutrition disorders Hypoglycemia NOS	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Musculoskeletal and connective tissue disorders Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-lower	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Nervous system disorders Convulsions NOS	9.5% 2/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	10.3% 3/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Nervous system disorders Depressed level of consciousness	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Nervous system disorders Headache	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	6.9% 2/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Nervous system disorders Peripheral motor neuropathy	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	6.9% 2/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Nervous system disorders Syncope	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Psychiatric disorders Confusional state	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	6.9% 2/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Renal and urinary disorders Renal failure NOS	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Skin and subcutaneous tissue disorders Dermatitis exfoliative NOS	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Skin and subcutaneous tissue disorders Dermatology/skin - Other:	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Vascular disorders Hematoma	4.8% 1/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	0.00% 0/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Vascular disorders Hypotension NOS	0.00% 0/21 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).	3.4% 1/29 Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).