Trial Outcomes & Findings for Comparison of Rituximab Induction Therapy Followed by Glatiramer Acetate (NCT NCT01569451)

Results Overview

Defined as patients without new lesions on brain MRI using the combined unique lesion approach (CUL), without sustained change in EDSS score over any 3-month period and without relapse. If a clear treatment effect is sustained in the R-GA arm, defined as a ≥ 70% decrease in brain lesions on MRI, using a CUL approach, attributable to MS and ≥ 70% reduction in annual relapse rates, compared to the GA arm, the study will continue under the extension protocol. If induction therapy fails to show superiority, at any point, the study will be stopped.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

53 participants

Primary outcome timeframe

Baseline through 24 months

Results posted on

2018-06-08

Participant Flow

Participant milestones

Participant milestones
Measure	Glatiramer Acetate Therapy (GA) Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Overall Study STARTED	26	27
Overall Study COMPLETED	12	14
Overall Study NOT COMPLETED	14	13

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Comparison of Rituximab Induction Therapy Followed by Glatiramer Acetate

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily	Total n=53 Participants Total of all reporting groups
Age, Continuous	36.64 years STANDARD_DEVIATION 9.15 • n=5 Participants	36.46 years STANDARD_DEVIATION 8.31 • n=7 Participants	36.55 years STANDARD_DEVIATION 8.65 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	19 Participants n=7 Participants	37 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	21 participants n=5 Participants	22 participants n=7 Participants	43 participants n=5 Participants
Race/Ethnicity, Customized Hispanic	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Race/Ethnicity, Customized Unknown	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
Type of relapsing MS RRMS/SPMS	24 participants n=5 Participants	25 participants n=7 Participants	49 participants n=5 Participants
Type of relapsing MS CIS	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Prior treatment with Tysabri Yes	5 participants n=5 Participants	7 participants n=7 Participants	12 participants n=5 Participants
Prior treatment with Tysabri No	21 participants n=5 Participants	20 participants n=7 Participants	41 participants n=5 Participants
Prior treatment with Tysabri (within 6 months) Yes	4 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants
Prior treatment with Tysabri (within 6 months) No	22 participants n=5 Participants	22 participants n=7 Participants	44 participants n=5 Participants
Expanded Disability Status Scale score at baseline	2.63 units on a scale STANDARD_DEVIATION 1.57 • n=5 Participants	2.80 units on a scale STANDARD_DEVIATION 1.78 • n=7 Participants	2.72 units on a scale STANDARD_DEVIATION 1.67 • n=5 Participants
Mean number of GEL at baseline	0.54 lesions STANDARD_DEVIATION 2.16 • n=5 Participants	1.07 lesions STANDARD_DEVIATION 2.53 • n=7 Participants	0.81 lesions STANDARD_DEVIATION 2.35 • n=5 Participants
Number with GEL at baseline	4 participants n=5 Participants	8 participants n=7 Participants	12 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline through 24 months

Population: Out to the last observation for each patient within 24 months (2 years) of follow up.

Defined as patients without new lesions on brain MRI using the combined unique lesion approach (CUL), without sustained change in EDSS score over any 3-month period and without relapse. If a clear treatment effect is sustained in the R-GA arm, defined as a ≥ 70% decrease in brain lesions on MRI, using a CUL approach, attributable to MS and ≥ 70% reduction in annual relapse rates, compared to the GA arm, the study will continue under the extension protocol. If induction therapy fails to show superiority, at any point, the study will be stopped.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Number of Disease-free Patients	5 participants	12 participants

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: Time itself is the outcome. Whenever treatment failure occurs for the first time within the follow up period of 24 months (2 years). Exposure time varies by patient. See exposure time outcome (post hoc).

Time itself is the outcome. Whenever treatment failure occurs for the first time within the follow up period of 24 months (2 years).

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Time to Treatment Failure	11.29 months Interval 5.25 to 23.39	23.32 months Interval 14.64 to There was insufficient data to estimate the upper boundary of the confidence interval.

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: At any time within the follow up period of 24 months (2 years) out to the last observation.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Number of Subjects That Fail Treatment	18 participants	10 participants

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: Out to the last observation for each patient within 24 months (2 years) of follow up.

Change in neurological symptoms in association with EDSS change is defined as relapse.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Number of Relapse-free Subjects	17 participants	21 participants

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: At any time within the follow up period of 24 months (2 years) out to the last observation.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Number of Patients Treated for Relapse With Corticosteroid	9 participants	4 participants

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: At any time within the follow up period of 24 months (2 years) out to the last observation.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Number of Subjects Who Experience Multiple Relapses	3 participants	1 participants

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: At any observation within the follow up period of 24 months (2 years) out to the last observation.

Sustained accumulation of disability is defined as a 1 point change or more on the Expanded Disability Status Scale (EDSS); sustained for at least three months. Physicians assess patients' cerebral, optic, brainstem, pyramidal, sensory, cerebellar, and bowel and bladder neurological symptoms. The physician then subjectively rates the patient on the ordinal EDSS scale. The EDSS scale emphasizes ambulatory ability. The EDSS scale ranges in half integer increments from 0.0 to 10.0. Larger numbers mean more disability, with 0.0 being everything normal and 10.0 being death due to MS.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Number of Patients That Develop Sustained Accumulation of Disability	3 participants	4 participants

SECONDARY outcome

Timeframe: Observations were recorded at baseline and 24 months.

The MSFC consists of Timed 25 Foot Walk Tests, 9 Hole Peg Tests, and the Paced Auditory Serial Addition Test (PASAT), administered by clinicians. The subscales are then converted into Z-scores and averaged to create the MSFC Z-score. Larger values denote improvements.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=25 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Change From Baseline to 24 Months on the Multiple Sclerosis Functional Composite (MSFC) Z-score	0.5226 units on a scale (MSFC Z score) Interval -0.184 to 1.2292	0.2630 units on a scale (MSFC Z score) Interval -0.0882 to 0.6141

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: At any time within the follow up period of 24 months (2 years) out to the last observation.

For PDDS the patient selects an integer 0-8 according to their personal assessment of their degree of ambulatory disability. Larger numbers mean more disability, with 0 being no disability and 8 being bedridden. There is an unclassifiable category as well.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Percentage of Subjects Worsening One Point or More on the Patient Determined Disease Steps (PDDS) Questionnaire	6 Participants	9 Participants

SECONDARY outcome

Timeframe: Baseline through 24 months

Population: At 24 months (2 years); the end of the study follow up period compared with baseline.

Performance scales measures patient assessments of disability in mobility (1-6), hand (1-5), vision (1-5), fatigue (1-5), cognitive (1-5), bladder and bowel, sensory (1-5), and spasticity (1-5). The overall measure of performance is the sum of subscales, ranging from 0 to 41. Larger numbers mean more disability, with 0 being no disability and the maximum number being total disability.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Change in Mean Score on Performance Scales (Baseline to 24 Months)	0.1466 units on a scale Interval -1.4328 to 1.726	0.3477 units on a scale Interval -1.6109 to 2.3062

POST_HOC outcome

Timeframe: Measured in three month intervals from baseline to end of study.

Values represent mean duration of treatment.

Outcome measures

Outcome measures
Measure	Glatiramer Acetate Therapy (GA) n=26 Participants Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=27 Participants Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Exposure Time	1.517 years Standard Deviation 0.766	1.704 years Standard Deviation 0.830

Adverse Events

Glatiramer Acetate Therapy (GA)

Serious events: 3 serious events

Other events: 27 other events

Deaths: 0 deaths

Rituximab + Glatiramer Acetate Therapy (R-GA)

Serious events: 3 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Glatiramer Acetate Therapy (GA) n=27 participants at risk Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=28 participants at risk Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
Blood and lymphatic system disorders Pulmonary	3.7% 1/27 • Number of events 1 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	3.6% 1/28 • Number of events 1 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Gastrointestinal disorders GI related	3.7% 1/27 • Number of events 1 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	0.00% 0/28 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Immune system disorders Relapse related	3.7% 1/27 • Number of events 1 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	0.00% 0/28 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Nervous system disorders Neurological Condition	3.7% 1/27 • Number of events 1 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	0.00% 0/28 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
General disorders Other	7.4% 2/27 • Number of events 2 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	7.1% 2/28 • Number of events 3 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).

Other adverse events

Additional Information

Stefan Sillau

University of Colorado

Phone: 303-724-8657

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Glatiramer Acetate Therapy (GA) n=27 participants at risk Subjects will receive an intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15 according to the infusion protocol. On study day 28, all subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Glatiramer Acetate: 20 mg injected subcutaneously daily	Rituximab + Glatiramer Acetate Therapy (R-GA) n=28 participants at risk Subjects will receive an intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 according to the rituximab infusion protocol. On study day 28, subjects will initiate standard GA therapy, 20 mg injected subcutaneously daily. Rituximab: intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15 Glatiramer Acetate: 20 mg injected subcutaneously daily
General disorders Infusion-related reaction	40.7% 11/27 • Number of events 13 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	67.9% 19/28 • Number of events 42 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Gastrointestinal disorders Gastrointestinal Issues	25.9% 7/27 • Number of events 7 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	32.1% 9/28 • Number of events 15 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
General disorders Influenza like illness	48.1% 13/27 • Number of events 27 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	60.7% 17/28 • Number of events 28 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
General disorders Injection site erythema	7.4% 2/27 • Number of events 3 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	7.1% 2/28 • Number of events 2 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
General disorders Fatigue	37.0% 10/27 • Number of events 20 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	39.3% 11/28 • Number of events 35 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
General disorders Injection-site reaction	25.9% 7/27 • Number of events 11 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	28.6% 8/28 • Number of events 15 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Infections and infestations URI	33.3% 9/27 • Number of events 12 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	28.6% 8/28 • Number of events 13 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Infections and infestations UTI	22.2% 6/27 • Number of events 14 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	25.0% 7/28 • Number of events 13 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Infections and infestations Bronchitis	7.4% 2/27 • Number of events 2 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	10.7% 3/28 • Number of events 3 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Nervous system disorders Headache	37.0% 10/27 • Number of events 13 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	28.6% 8/28 • Number of events 11 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Psychiatric disorders Depression	11.1% 3/27 • Number of events 5 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	17.9% 5/28 • Number of events 5 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Psychiatric disorders Insomnia	3.7% 1/27 • Number of events 1 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	7.1% 2/28 • Number of events 2 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Psychiatric disorders Anxiety	18.5% 5/27 • Number of events 6 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	25.0% 7/28 • Number of events 10 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Musculoskeletal and connective tissue disorders Backpain	0.00% 0/27 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	7.1% 2/28 • Number of events 4 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/27 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).	7.1% 2/28 • Number of events 2 • Within 24 months (2 years) of follow up. Exposure time varied by patient. Out to the last observation for each patient within 24 months (2 years) of follow up. Exposure time varied by patient. See exposure time outcome (post hoc).