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Clinical Trial Results:
Phase II, Multicenter, Randomized, Parallel-Group, Partially Blinded, Placebo and Avonex Controlled Dose Finding Study to Evaluate the Efficacy As Measured by Brain MRI Lesions, and Safety of 2 Dose Regimens of Ocrelizumab in Patients With RRMS

Summary
EudraCT number	2007-006338-32
Trial protocol	FR GB DE ES CZ SK DK BE NL FI BG IT
Global end of trial date	08 Nov 2023

Results information
Results version number	v2(current)
This version publication date	10 Nov 2024
First version publication date	22 Mar 2015
Other versions	v1
Version creation reason
Summary report(s)	WA21493 (CSR synopsis)

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ACT4422g

ISRCTN number

US NCT number

NCT00676715

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4058

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

Medical Communications, F. Hoffmann-La Roche AG, +41 616878333, genentech@druginfo.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Nov 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Nov 2023

Was the trial ended prematurely?

Main objective of the trial

This was a Avonex (interferon beta-1a) controlled dose finding study to evaluate the efficacy as measured by brain MRI lesions, and safety of 2 dose regimens of ocrelizumab in participants with relapsing remitting multiple sclerosis (RRMS).

Protection of trial subjects

All study participants were required to read and sign an informed consent form (ICF).

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Jul 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

84 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Bulgaria: 11

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

Czechia: 14

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Mexico: 8

Country: Number of subjects enrolled

Russian Federation: 17

Country: Number of subjects enrolled

Romania: 4

Country: Number of subjects enrolled

Serbia: 34

Country: Number of subjects enrolled

Slovakia: 14

Country: Number of subjects enrolled

Ukraine: 26

Country: Number of subjects enrolled

United States: 47

Worldwide total number of subjects

218

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

218

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 220 participants were randomized, of which 218 received study treatment. Participants took part in the study at 79 investigative sites across 18 countries from July 17, 2008, to November 08, 2023.

Screening details

The study consisted of a 96-week Treatment Period (TP) followed by a Treatment-free period (TFP). Participants who completed both TP & TFP (at least Week 120) were invited to participate in the optional Open-label Extension (OLE) period.

Period 1 title

Treatment Period (TP)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Avonex/Ocrelizumab 600 mg (Active Comparator) group was open-label.

Are arms mutually exclusive

Yes

Placebo / Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received placebo as intravenous (IV) infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 300 milligrams (mg), IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, once every 24 weeks (Q24W).

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab was administered 300 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by, 600 mg, IV, on Day 1 of Cycle 2 and 600 mg, IV, on Day 1 of Cycles 3 and 4.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo was administered on Day 1, and Day 15 in Cycle 1 (1 Cycle = 168 days)

Ocrelizumab 600 mg / Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab was administered 300 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by, 600 mg, IV, on Day 1 of Cycle 2 and 600 mg, IV, on Day 1 of Cycles 3 and 4.

Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycle 3 and ocrelizumab, 600 mg, IV, on Day 1 of Cycle 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab was administered 300 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by, 600 mg, IV, on Day 1 of Cycle 2 and 600 mg, IV, on Day 1 of Cycles 3 and 4.

Investigational medicinal product name

Ocrelizumab 1000 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab was administered 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by, 1000 mg, IV, on Day 1 of Cycle 2 and placebo IV on Day 15 of Cycle 2 followed by ocrelizumab, 1000 mg, IV, on Day 1 of Cycles 3 and 4.

Avonex / Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received Avonex 30 micrograms (mcg) as intramuscular (IM) injection once every week of Cycle 1 ( 1 Cycle = 168 days ), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600 mg, Q24W.

Arm type

Active comparator

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab administered 300 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by, 600 mg, IV, on Day 1 of Cycle 2 and 600 mg, IV, on Day 1 of Cycles 3 and 4.

Investigational medicinal product name

Avonex

Investigational medicinal product code

Other name

Interferon beta-1a

Pharmaceutical forms

Powder and solvent for concentrate for solution for infusion

Routes of administration

Intramuscular use

Dosage and administration details

Avonex was administered 30 mcg as IM injection every week of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2 and 600 mg, IV, on Day 1 of Cycles 3 and 4.

Number of subjects in period 1	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Started	54	55	55	54
Completed	48	46	43	46
Not completed	6	9	12	8
Adverse event, serious fatal	-	-	1	-
Insufficient therapeutic response	1	1	2	1
Failure to return	1	-	-	-
Administrative	-	-	-	1
Adverse event, non-fatal	-	3	2	2
Violation of selection criteria at entry	-	-	1	-
Refused treatment/did not cooperate	1	2	3	1
Withdrew consent	3	3	3	3

Period 2 title

Treatment-free Period (TFP)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo/ Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received placebo as intravenous (IV) infusion on Days 1 and 15 of Cycle 1 (1Cycle=168 days), followed by ocrelizumab, 300 milligrams (mg), IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, once every 24 weeks (Q24W).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Ocrelizumab 600 mg/Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Ocrelizumab 1000 mg/ Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Avonex/ Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received Avonex 30 micrograms (mcg) as intramuscular (IM) injection every week of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Placebo/ Ocrelizumab 600 mg	Ocrelizumab 600 mg/Ocrelizumab 600 mg	Ocrelizumab 1000 mg/ Ocrelizumab 600 mg	Avonex/ Ocrelizumab 600 mg
Started	48	46	43	46
Completed	35	32	30	35
Not completed	14	16	20	14
Adverse event, serious fatal	1	1	1	-
Consent withdrawn by subject	3	3	4	5
Adverse event, non-fatal	-	-	1	-
Lost to follow-up	2	2	6	2
Reason not provided	8	10	8	7
Joined	1	2	7	3
Participants Joined from TP.	1	2	7	3

Period 3 title

Open Label Extension (OLE)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo/ Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received placebo as intravenous (IV) infusion on Days 1 and 15 of Cycle 1 (1Cycle=168 days), followed by ocrelizumab, 300 milligrams (mg), IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, once every 24 weeks (Q24W).

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab 300mg was administered IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of 600mg, Q24W.

Ocrelizumab 600 mg/Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab 300mg was administered IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of 600mg, Q24W.

Ocrelizumab 1000 mg/ Ocrelizumab 600 mg

Arm description

In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab 300mg was administered IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of 600mg, Q24W.

Avonex/ Ocrelizumab 600 mg

Arm description

Arm type

Active comparator

Investigational medicinal product name

Ocrelizumab 600 mg

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Ocrelizumab 300mg was administered IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of 600mg, Q24W.

Number of subjects in period 3 ^[1]	Placebo/ Ocrelizumab 600 mg	Ocrelizumab 600 mg/Ocrelizumab 600 mg	Ocrelizumab 1000 mg/ Ocrelizumab 600 mg	Avonex/ Ocrelizumab 600 mg
Started	29	32	19	24
Completed	22	21	11	14
Not completed	7	11	8	10
Adverse event, serious fatal	2	-	2	2
Consent withdrawn by subject	2	4	3	3
Adverse event, non-fatal	-	3	1	-
Lost to follow-up	-	-	1	1
Reason not provided	3	4	1	4

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Participants who have completed both the Treatment Period and the Treatment-Free Period will be invited to participate in the OLE. Participants will be re-consented for participation and enter the OLE screening period where they will undergo an evaluation for continued eligibility. Participants who are not eligible, or choose not to enter the OLE will complete the trial after their B-cells have repleted.

Baseline characteristics

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Reporting group title

Placebo / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Ocrelizumab 600 mg / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Avonex / Ocrelizumab 600 mg

Reporting group description

Reporting group values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg	Total
Number of subjects	54	55	55	54	218
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	38.0 ( 8.8 )	35.6 ( 8.5 )	38.5 ( 8.7 )	38.1 ( 9.3 )	-
Gender, Male/Female
Units: participants
Female	36	35	38	32	141
Male	18	20	17	22	77
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	0	0	1
Asian	1	0	0	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	3	2	1	6
White	52	51	53	53	209
More than one race	0	0	0	0	0
Unknown or Not Reported	1	0	0	0	1
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	6	6	7	7	26
Not Hispanic or Latino	48	49	48	47	192
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

Placebo / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Ocrelizumab 600 mg / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Avonex / Ocrelizumab 600 mg

Reporting group description

Reporting group title

Placebo/ Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received placebo as intravenous (IV) infusion on Days 1 and 15 of Cycle 1 (1Cycle=168 days), followed by ocrelizumab, 300 milligrams (mg), IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, once every 24 weeks (Q24W).

Reporting group title

Ocrelizumab 600 mg/Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Reporting group title

Ocrelizumab 1000 mg/ Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Reporting group title

Avonex/ Ocrelizumab 600 mg

Reporting group description

Reporting group title

Placebo/ Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received placebo as intravenous (IV) infusion on Days 1 and 15 of Cycle 1 (1Cycle=168 days), followed by ocrelizumab, 300 milligrams (mg), IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, once every 24 weeks (Q24W).

Reporting group title

Ocrelizumab 600 mg/Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 ( 1 Cycle = 168 days), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Reporting group title

Ocrelizumab 1000 mg/ Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Reporting group title

Avonex/ Ocrelizumab 600 mg

Reporting group description

Primary: Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic R4esonance Imaging (MRI) Scans of the Brain

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End point title

Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic R4esonance Imaging (MRI) Scans of the Brain

End point description

Mean of total number of gadolinium-enhancing T1 lesions observed on MRI scans of the brain at Weeks 12, 16, 20, 24 was determined using average imputation method. The intent-to-treat population includes all randomized participants who had received any study drug. Here, number analysed signifies the participants who were evaluable for the outcome.

End point type

Primary

End point timeframe

Week 12 to Week 24

End point values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Number of subjects analysed	54	51	52	52
Units: lesions
arithmetic mean (standard deviation)	5.6 ( 12.53 )	0.6 ( 1.52 )	0.2 ( 0.65 )	6.9 ( 16.01 )

Placebo vs Ocrelizumab 600 mg

Statistical analysis description

Van Elteren test is stratified by region and presence of baseline gadolinium-enhancing lesions (absent or present).

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 600 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Avonex

Statistical analysis description

Van Elteren test is stratified by region and presence of baseline gadolinium-enhancing lesions (absent or present).

Comparison groups

Placebo / Ocrelizumab 600 mg v Avonex / Ocrelizumab 600 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7496

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Ocrelizumab 1000 mg

Statistical analysis description

Van Elteren test is stratified by region and presence of baseline gadolinium-enhancing lesions (absent or present).

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Van Elteren Test (stratified)

Confidence interval

Secondary: Annualized Protocol Defined Relapse Rate at Week 24

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End point title

Annualized Protocol Defined Relapse Rate at Week 24

End point description

Adjusted annualized relapse rate for geographical region is reported here. The relapse rate was calculated as the total number of relapses for each participant divided by the total number of patient-years. The intent-to-treat population includes all randomized participants who had received any study drug.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Number of subjects analysed	54	55	55	54
Units: relapses per year
number (confidence interval 95%)	0.557 (0.370 to 0.839)	0.127 (0.054 to 0.299)	0.213 (0.110 to 0.414)	0.364 (0.220 to 0.602)

Placebo vs Ocrelizumab 600 mg

Statistical analysis description

Poisson model was fitted for adjusting for geographic region only.

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 600 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0019

Method

Poisson model

Confidence interval

Placebo vs Avonex

Statistical analysis description

Poisson model was fitted for adjusting for geographic region only.

Comparison groups

Placebo / Ocrelizumab 600 mg v Avonex / Ocrelizumab 600 mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1814

Method

Poisson model

Confidence interval

Placebo vs Ocrelizumab 1000 mg

Statistical analysis description

Poisson model was fitted for adjusting for geographic region only.

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0136

Method

Poisson model

Confidence interval

Secondary: Percentage of Participants Who Remained Relapse Free at Week 24

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End point title

Percentage of Participants Who Remained Relapse Free at Week 24

End point description

Percentage of participants who remained relapse free at Week 24 were reported. The intent-to-treat population includes all randomized participants who had received any study drug. Percentages have been rounded off to the first decimal.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Number of subjects analysed	54	55	55	54
Units: percentage of participants
number (confidence interval 95%)	75.9 (64.5 to 87.3)	85.5 (76.1 to 94.8)	87.3 (78.5 to 96.1)	77.8 (66.7 to 88.9)

Placebo vs Ocrelizumab 600 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 600 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1978

Method

Cochran-Mantel-Haenszel chi-square test

Parameter type

Relative risk (RR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.34

Placebo vs Avonex

Comparison groups

Placebo / Ocrelizumab 600 mg v Avonex / Ocrelizumab 600 mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8206

Method

CMH chi-square tes

Parameter type

Relative risk (RR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

1.84

Placebo vs Ocrelizumab 1000 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

P-value

= 0.131

Method

CMH chi-square test

Parameter type

Relative risk (RR)

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

1.22

Secondary: Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24

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End point title

Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24

End point description

Change from baseline in total volume of T2 lesions on MRI scans of the brain at Week 24 was reported. The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Number of subjects analysed	54	55	55	54
Units: cubic millimeter (mm^3)
arithmetic mean (standard deviation)
Baseline (n= 47, 51, 53, 49)	8950.84 ( 9776.261 )	13972.61 ( 19930.158 )	13178.30 ( 14271.383 )	13209.11 ( 17206.511 )
Change at Week 24 (n= 43, 45, 46, 46)	-112.31 ( 1464.206 )	-878.84 ( 2756.839 )	-600.89 ( 2105.964 )	1040.06 ( 4510.140 )

Placebo vs Ocrelizumab 600 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 600 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1391

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Avonex

Comparison groups

Placebo / Ocrelizumab 600 mg v Avonex / Ocrelizumab 600 mg

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

P-value

= 0.474

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Ocrelizumab 1000 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1596

Method

Van Elteren Test (stratified)

Confidence interval

Secondary: Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain

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End point title

Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain

End point description

Total number of new gadolinium-enhancing T1 lesions observed by MRI scans of the brain were reported. The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Weeks 4 to Week 24

End point values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Number of subjects analysed	54	51	52	52
Units: lesions
arithmetic mean (standard deviation)	5.1 ( 11.99 )	0.8 ( 1.95 )	0.8 ( 2.16 )	6.2 ( 13.79 )

Placebo vs Ocrelizumab 600 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 600 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Avonex

Comparison groups

Placebo / Ocrelizumab 600 mg v Avonex / Ocrelizumab 600 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4985

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Ocrelizumab 1000 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Van Elteren Test (stratified)

Confidence interval

Secondary: Total Number of Gadolinium-Enhancing T1 Lesions

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End point title

Total Number of Gadolinium-Enhancing T1 Lesions

End point description

Total number of gadolinium-enhancing T1 lesions from Week 4 to Week 24 were reported. The intent-to-treat population includes all randomized participants who had received any study drug. Overall number of participants analyzed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Weeks 4 to Week 24

End point values	Placebo / Ocrelizumab 600 mg	Ocrelizumab 600 mg / Ocrelizumab 600 mg	Ocrelizumab 1000 mg / Ocrelizumab 600 mg	Avonex / Ocrelizumab 600 mg
Number of subjects analysed	54	51	52	52
Units: lesions
arithmetic mean (standard deviation)	8.7 ( 17.54 )	2.5 ( 5.10 )	1.8 ( 5.26 )	10.3 ( 22.15 )

Placebo vs Ocrelizumab 600 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 600 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0004

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Ocrelizumab 600 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Avonex / Ocrelizumab 600 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2725

Method

Van Elteren Test (stratified)

Confidence interval

Placebo vs Ocrelizumab 1000 mg

Comparison groups

Placebo / Ocrelizumab 600 mg v Ocrelizumab 1000 mg / Ocrelizumab 600 mg

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Van Elteren Test (stratified)

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Up to 787 Weeks

Adverse event reporting additional description

The safety population included all participants who received any study drug and underwent at least one assessment of safety. As per planned analysis adverse events from both the TP and TFP were combined and reported.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Placebo/Ocrelizumab 600mg

Reporting group description

In the Treatment Period, participants received placebo as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Reporting group title

Ocrelizumab 600mg/Ocrelizumab 600mg

Reporting group description

In the Treatment Period, participants received ocrelizumab 300 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 600 mg, IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W

Reporting group title

Ocrelizumab 600 mg Open Label Extension (OLE)

Reporting group description

Participants who opted to enroll in the OLE received two IV infusions of ocrelizumab, 300mg on Days 1 and 15 of Cycle 5, followed by a single infusion of ocrelizumab, 600mg, once Q24W

Reporting group title

Avonex/Ocrelizumab 600 mg

Reporting group description

In the Treatment Period, participants received Avonex 30 mcg as IM injection once every week of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 300 mg, IV, on Days 1 and 15 of Cycle 2. Participants then received ocrelizumab, 600 mg, IV, on Day 1 of Cycles 3 and 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Reporting group title

Ocrelizumab 1000mg/Ocrelizumab 600mg

Reporting group description

In the Treatment Period, participants received ocrelizumab 1000 mg as IV infusion on Days 1 and 15 of Cycle 1 (1 Cycle = 168 days), followed by ocrelizumab, 1000 mg IV, on Day 1 and placebo IV on Day 15 of Cycle 2. Participants then received ocrelizumab, 1000 mg, IV, on Day 1 of Cycle 3 and ocrelizumab, 600 mg, IV, on Day 1 of Cycle 4. Participants who completed the TP then entered the TFP which was of variable duration. Participants who completed the TP and the TFP (at least through Week 120) and opted to enroll in the OLE period received ocrelizumab, 300mg, IV, on Days 1 and 15 of Cycle 5 followed by a single infusion of ocrelizumab, 600mg, Q24W.

Serious adverse events	Placebo/Ocrelizumab 600mg	Ocrelizumab 600mg/Ocrelizumab 600mg	Ocrelizumab 600 mg Open Label Extension (OLE)	Avonex/Ocrelizumab 600 mg	Ocrelizumab 1000mg/Ocrelizumab 600mg
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 54 (20.37%)	17 / 55 (30.91%)	28 / 103 (27.18%)	16 / 54 (29.63%)	16 / 55 (29.09%)
number of deaths (all causes)	3	1	6	2	3
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BREAST CANCER
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG NEOPLASM MALIGNANT
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
HYPERTENSION
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
PREGNANCY
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
DRUG WITHDRAWAL SYNDROME
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
DEATH
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
HYPERSENSITIVITY
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
OVARIAN MASS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UTERINE PROLAPSE
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	2 / 103 (1.94%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Psychiatric disorders
DEPRESSION
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE PSYCHOSIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUSPECTED SUICIDE ATTEMPT
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANXIETY
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUICIDAL IDEATION
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
AMYLASE INCREASED
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BLOOD POTASSIUM INCREASED
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SMEAR CERVIX ABNORMAL
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
INFUSION RELATED REACTION
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INJURY
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
SUBDURAL HAEMATOMA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
CARDIAC ARREST
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	2 / 54 (3.70%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEIZURE
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NERVOUS SYSTEM DISORDER
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MULTIPLE SCLEROSIS PSEUDO RELAPSE
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	2 / 103 (1.94%)	1 / 54 (1.85%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCLE SPASTICITY
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
IMMUNE THROMBOCYTOPENIA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
RETINAL ARTERY OCCLUSION
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN UPPER
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA STRANGULATED
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUBILEUS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SALIVARY DUCT INFLAMMATION
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COLITIS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LARGE INTESTINE POLYP
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OESOPHAGITIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS CHRONIC
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
ERYTHEMA NODOSUM
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
URETEROLITHIASIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
ADRENAL CYST
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
RHEUMATOID ARTHRITIS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ROTATOR CUFF SYNDROME
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	1 / 54 (1.85%)	1 / 55 (1.82%)	2 / 103 (1.94%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
BRONCHITIS
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	1 / 103 (0.97%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAL ABSCESS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
TRACHEOBRONCHITIS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	2 / 103 (1.94%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
PNEUMONIA
subjects affected / exposed	2 / 54 (3.70%)	1 / 55 (1.82%)	4 / 103 (3.88%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	1 / 2	1 / 1	2 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 54 (1.85%)	1 / 55 (1.82%)	4 / 103 (3.88%)	2 / 54 (3.70%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
GINGIVITIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 PNEUMONIA
subjects affected / exposed	3 / 54 (5.56%)	3 / 55 (5.45%)	6 / 103 (5.83%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 3	1 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORAL HERPES
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS ACUTE
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEPATITIS A
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 103 (0.97%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	3 / 103 (2.91%)	0 / 54 (0.00%)	3 / 55 (5.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COMPLICATED APPENDICITIS
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
subjects affected / exposed	1 / 54 (1.85%)	0 / 55 (0.00%)	1 / 103 (0.97%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENCEPHALITIS
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 103 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo/Ocrelizumab 600mg	Ocrelizumab 600mg/Ocrelizumab 600mg	Ocrelizumab 600 mg Open Label Extension (OLE)	Avonex/Ocrelizumab 600 mg	Ocrelizumab 1000mg/Ocrelizumab 600mg
Total subjects affected by non serious adverse events
subjects affected / exposed	52 / 54 (96.30%)	47 / 55 (85.45%)	85 / 103 (82.52%)	45 / 54 (83.33%)	45 / 55 (81.82%)
Vascular disorders
HYPERTENSION
subjects affected / exposed	4 / 54 (7.41%)	6 / 55 (10.91%)	4 / 103 (3.88%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences all number	4	7	4	2	0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	3 / 54 (5.56%)	2 / 55 (3.64%)	3 / 103 (2.91%)	1 / 54 (1.85%)	2 / 55 (3.64%)
occurrences all number	5	2	3	1	3
CHILLS
subjects affected / exposed	0 / 54 (0.00%)	2 / 55 (3.64%)	1 / 103 (0.97%)	3 / 54 (5.56%)	1 / 55 (1.82%)
occurrences all number	0	2	1	3	1
PYREXIA
subjects affected / exposed	3 / 54 (5.56%)	8 / 55 (14.55%)	11 / 103 (10.68%)	2 / 54 (3.70%)	3 / 55 (5.45%)
occurrences all number	3	8	12	2	4
FATIGUE
subjects affected / exposed	5 / 54 (9.26%)	7 / 55 (12.73%)	8 / 103 (7.77%)	4 / 54 (7.41%)	11 / 55 (20.00%)
occurrences all number	8	7	12	4	14
INFLUENZA LIKE ILLNESS
subjects affected / exposed	1 / 54 (1.85%)	2 / 55 (3.64%)	3 / 103 (2.91%)	11 / 54 (20.37%)	2 / 55 (3.64%)
occurrences all number	1	2	3	15	2
OEDEMA PERIPHERAL
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	2 / 103 (1.94%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences all number	3	1	2	0	0
Immune system disorders
HYPOGAMMAGLOBULINAEMIA
subjects affected / exposed	1 / 54 (1.85%)	3 / 55 (5.45%)	4 / 103 (3.88%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences all number	1	3	4	0	0
SEASONAL ALLERGY
subjects affected / exposed	1 / 54 (1.85%)	1 / 55 (1.82%)	3 / 103 (2.91%)	0 / 54 (0.00%)	3 / 55 (5.45%)
occurrences all number	1	1	3	0	3
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA
subjects affected / exposed	0 / 54 (0.00%)	0 / 55 (0.00%)	2 / 103 (1.94%)	3 / 54 (5.56%)	1 / 55 (1.82%)
occurrences all number	0	0	2	3	1
Respiratory, thoracic and mediastinal disorders
RHINORRHOEA
subjects affected / exposed	0 / 54 (0.00%)	3 / 55 (5.45%)	3 / 103 (2.91%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences all number	0	3	3	2	0
COUGH
subjects affected / exposed	1 / 54 (1.85%)	3 / 55 (5.45%)	5 / 103 (4.85%)	4 / 54 (7.41%)	3 / 55 (5.45%)
occurrences all number	1	5	7	4	3
DYSPNOEA
subjects affected / exposed	2 / 54 (3.70%)	1 / 55 (1.82%)	2 / 103 (1.94%)	1 / 54 (1.85%)	3 / 55 (5.45%)
occurrences all number	3	1	3	1	3
Psychiatric disorders
DEPRESSION
subjects affected / exposed	2 / 54 (3.70%)	7 / 55 (12.73%)	5 / 103 (4.85%)	4 / 54 (7.41%)	5 / 55 (9.09%)
occurrences all number	2	8	5	5	5
INSOMNIA
subjects affected / exposed	2 / 54 (3.70%)	3 / 55 (5.45%)	4 / 103 (3.88%)	1 / 54 (1.85%)	9 / 55 (16.36%)
occurrences all number	3	4	4	1	12
ANXIETY
subjects affected / exposed	3 / 54 (5.56%)	5 / 55 (9.09%)	4 / 103 (3.88%)	6 / 54 (11.11%)	3 / 55 (5.45%)
occurrences all number	3	7	4	6	3
Injury, poisoning and procedural complications
SKIN LACERATION
subjects affected / exposed	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 103 (0.97%)	0 / 54 (0.00%)	4 / 55 (7.27%)
occurrences all number	0	1	1	0	4
INFUSION RELATED REACTION
subjects affected / exposed	29 / 54 (53.70%)	25 / 55 (45.45%)	23 / 103 (22.33%)	20 / 54 (37.04%)	29 / 55 (52.73%)
occurrences all number	63	60	39	33	60
FALL
subjects affected / exposed	1 / 54 (1.85%)	1 / 55 (1.82%)	2 / 103 (1.94%)	0 / 54 (0.00%)	3 / 55 (5.45%)
occurrences all number	1	1	2	0	3
THERMAL BURN
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	0 / 103 (0.00%)	0 / 54 (0.00%)	3 / 55 (5.45%)
occurrences all number	4	1	0	0	3
CONTUSION
subjects affected / exposed	2 / 54 (3.70%)	3 / 55 (5.45%)	3 / 103 (2.91%)	1 / 54 (1.85%)	3 / 55 (5.45%)
occurrences all number	3	3	3	1	3
LIGAMENT SPRAIN
subjects affected / exposed	2 / 54 (3.70%)	1 / 55 (1.82%)	1 / 103 (0.97%)	1 / 54 (1.85%)	5 / 55 (9.09%)
occurrences all number	2	1	1	1	6
Cardiac disorders
PALPITATIONS
subjects affected / exposed	1 / 54 (1.85%)	1 / 55 (1.82%)	3 / 103 (2.91%)	1 / 54 (1.85%)	3 / 55 (5.45%)
occurrences all number	1	1	3	1	3
Nervous system disorders
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	26 / 54 (48.15%)	19 / 55 (34.55%)	28 / 103 (27.18%)	29 / 54 (53.70%)	21 / 55 (38.18%)
occurrences all number	70	39	68	58	72
HEADACHE
subjects affected / exposed	15 / 54 (27.78%)	9 / 55 (16.36%)	7 / 103 (6.80%)	12 / 54 (22.22%)	10 / 55 (18.18%)
occurrences all number	33	16	11	19	14
DIZZINESS
subjects affected / exposed	5 / 54 (9.26%)	4 / 55 (7.27%)	2 / 103 (1.94%)	1 / 54 (1.85%)	4 / 55 (7.27%)
occurrences all number	6	4	2	1	6
PARAESTHESIA
subjects affected / exposed	1 / 54 (1.85%)	4 / 55 (7.27%)	0 / 103 (0.00%)	1 / 54 (1.85%)	5 / 55 (9.09%)
occurrences all number	1	4	0	1	5
SYNCOPE
subjects affected / exposed	3 / 54 (5.56%)	0 / 55 (0.00%)	0 / 103 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences all number	4	0	0	0	0
HYPOAESTHESIA
subjects affected / exposed	1 / 54 (1.85%)	2 / 55 (3.64%)	3 / 103 (2.91%)	3 / 54 (5.56%)	5 / 55 (9.09%)
occurrences all number	1	3	3	4	5
MIGRAINE
subjects affected / exposed	5 / 54 (9.26%)	4 / 55 (7.27%)	4 / 103 (3.88%)	1 / 54 (1.85%)	2 / 55 (3.64%)
occurrences all number	6	6	5	1	2
SCIATICA
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	3 / 103 (2.91%)	1 / 54 (1.85%)	1 / 55 (1.82%)
occurrences all number	3	1	3	1	1
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	2 / 54 (3.70%)	3 / 55 (5.45%)	2 / 103 (1.94%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences all number	2	3	2	0	0
Eye disorders
VISION BLURRED
subjects affected / exposed	0 / 54 (0.00%)	2 / 55 (3.64%)	3 / 103 (2.91%)	0 / 54 (0.00%)	3 / 55 (5.45%)
occurrences all number	0	3	3	0	3
Gastrointestinal disorders
HAEMORRHOIDS
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	2 / 103 (1.94%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences all number	3	1	2	0	2
NAUSEA
subjects affected / exposed	1 / 54 (1.85%)	2 / 55 (3.64%)	5 / 103 (4.85%)	4 / 54 (7.41%)	7 / 55 (12.73%)
occurrences all number	1	3	5	5	10
DIARRHOEA
subjects affected / exposed	3 / 54 (5.56%)	4 / 55 (7.27%)	5 / 103 (4.85%)	2 / 54 (3.70%)	5 / 55 (9.09%)
occurrences all number	3	6	7	2	6
CONSTIPATION
subjects affected / exposed	3 / 54 (5.56%)	3 / 55 (5.45%)	4 / 103 (3.88%)	2 / 54 (3.70%)	4 / 55 (7.27%)
occurrences all number	3	3	4	2	4
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	3 / 54 (5.56%)	2 / 55 (3.64%)	3 / 103 (2.91%)	4 / 54 (7.41%)	4 / 55 (7.27%)
occurrences all number	3	3	3	4	4
SKIN LESION
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	2 / 103 (1.94%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences all number	3	1	2	0	0
ALOPECIA
subjects affected / exposed	1 / 54 (1.85%)	4 / 55 (7.27%)	1 / 103 (0.97%)	1 / 54 (1.85%)	2 / 55 (3.64%)
occurrences all number	1	4	1	2	2
Renal and urinary disorders
RENAL CYST
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	2 / 103 (1.94%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences all number	3	1	2	0	1
NEPHROLITHIASIS
subjects affected / exposed	0 / 54 (0.00%)	3 / 55 (5.45%)	4 / 103 (3.88%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences all number	0	5	5	0	1
Musculoskeletal and connective tissue disorders
PAIN IN EXTREMITY
subjects affected / exposed	7 / 54 (12.96%)	2 / 55 (3.64%)	8 / 103 (7.77%)	2 / 54 (3.70%)	8 / 55 (14.55%)
occurrences all number	11	2	10	2	10
MYALGIA
subjects affected / exposed	0 / 54 (0.00%)	3 / 55 (5.45%)	3 / 103 (2.91%)	3 / 54 (5.56%)	2 / 55 (3.64%)
occurrences all number	0	3	3	3	2
ARTHRALGIA
subjects affected / exposed	8 / 54 (14.81%)	9 / 55 (16.36%)	13 / 103 (12.62%)	5 / 54 (9.26%)	5 / 55 (9.09%)
occurrences all number	15	10	18	8	8
BACK PAIN
subjects affected / exposed	9 / 54 (16.67%)	5 / 55 (9.09%)	6 / 103 (5.83%)	7 / 54 (12.96%)	4 / 55 (7.27%)
occurrences all number	11	7	7	9	5
MUSCULAR WEAKNESS
subjects affected / exposed	2 / 54 (3.70%)	4 / 55 (7.27%)	4 / 103 (3.88%)	1 / 54 (1.85%)	3 / 55 (5.45%)
occurrences all number	2	5	4	1	4
Infections and infestations
SINUSITIS
subjects affected / exposed	5 / 54 (9.26%)	4 / 55 (7.27%)	5 / 103 (4.85%)	2 / 54 (3.70%)	3 / 55 (5.45%)
occurrences all number	7	4	6	2	4
GASTROENTERITIS VIRAL
subjects affected / exposed	0 / 54 (0.00%)	5 / 55 (9.09%)	1 / 103 (0.97%)	0 / 54 (0.00%)	1 / 55 (1.82%)
occurrences all number	0	7	1	0	1
BRONCHITIS
subjects affected / exposed	7 / 54 (12.96%)	4 / 55 (7.27%)	10 / 103 (9.71%)	2 / 54 (3.70%)	6 / 55 (10.91%)
occurrences all number	12	4	17	2	11
VULVOVAGINAL MYCOTIC INFECTION
subjects affected / exposed	1 / 54 (1.85%)	3 / 55 (5.45%)	2 / 103 (1.94%)	0 / 54 (0.00%)	2 / 55 (3.64%)
occurrences all number	1	3	2	0	2
HERPES ZOSTER
subjects affected / exposed	1 / 54 (1.85%)	3 / 55 (5.45%)	2 / 103 (1.94%)	1 / 54 (1.85%)	1 / 55 (1.82%)
occurrences all number	1	3	2	1	1
INFLUENZA
subjects affected / exposed	7 / 54 (12.96%)	4 / 55 (7.27%)	10 / 103 (9.71%)	4 / 54 (7.41%)	7 / 55 (12.73%)
occurrences all number	8	4	14	5	11
NASOPHARYNGITIS
subjects affected / exposed	10 / 54 (18.52%)	15 / 55 (27.27%)	20 / 103 (19.42%)	9 / 54 (16.67%)	12 / 55 (21.82%)
occurrences all number	15	32	41	25	25
VAGINAL INFECTION
subjects affected / exposed	1 / 54 (1.85%)	3 / 55 (5.45%)	3 / 103 (2.91%)	0 / 54 (0.00%)	0 / 55 (0.00%)
occurrences all number	1	3	3	0	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	10 / 54 (18.52%)	14 / 55 (25.45%)	15 / 103 (14.56%)	7 / 54 (12.96%)	11 / 55 (20.00%)
occurrences all number	17	25	32	10	26
PNEUMONIA
subjects affected / exposed	3 / 54 (5.56%)	1 / 55 (1.82%)	7 / 103 (6.80%)	1 / 54 (1.85%)	3 / 55 (5.45%)
occurrences all number	5	1	10	1	4
GASTROENTERITIS
subjects affected / exposed	1 / 54 (1.85%)	3 / 55 (5.45%)	5 / 103 (4.85%)	1 / 54 (1.85%)	2 / 55 (3.64%)
occurrences all number	1	3	5	1	2
ORAL HERPES
subjects affected / exposed	4 / 54 (7.41%)	3 / 55 (5.45%)	6 / 103 (5.83%)	4 / 54 (7.41%)	2 / 55 (3.64%)
occurrences all number	17	7	18	5	3
CYSTITIS
subjects affected / exposed	4 / 54 (7.41%)	2 / 55 (3.64%)	4 / 103 (3.88%)	0 / 54 (0.00%)	5 / 55 (9.09%)
occurrences all number	5	4	4	0	6
COVID-19
subjects affected / exposed	12 / 54 (22.22%)	7 / 55 (12.73%)	26 / 103 (25.24%)	2 / 54 (3.70%)	5 / 55 (9.09%)
occurrences all number	13	8	30	4	5
PHARYNGITIS
subjects affected / exposed	6 / 54 (11.11%)	3 / 55 (5.45%)	5 / 103 (4.85%)	3 / 54 (5.56%)	1 / 55 (1.82%)
occurrences all number	7	6	6	4	1
RESPIRATORY TRACT INFECTION
subjects affected / exposed	8 / 54 (14.81%)	5 / 55 (9.09%)	8 / 103 (7.77%)	3 / 54 (5.56%)	2 / 55 (3.64%)
occurrences all number	18	8	9	5	5
RESPIRATORY TRACT INFECTION VIRAL
subjects affected / exposed	2 / 54 (3.70%)	3 / 55 (5.45%)	3 / 103 (2.91%)	1 / 54 (1.85%)	1 / 55 (1.82%)
occurrences all number	2	6	4	1	1
URINARY TRACT INFECTION
subjects affected / exposed	14 / 54 (25.93%)	10 / 55 (18.18%)	23 / 103 (22.33%)	10 / 54 (18.52%)	15 / 55 (27.27%)
occurrences all number	29	24	58	17	39
VIRAL INFECTION
subjects affected / exposed	3 / 54 (5.56%)	0 / 55 (0.00%)	1 / 103 (0.97%)	1 / 54 (1.85%)	0 / 55 (0.00%)
occurrences all number	3	0	1	1	0
PYELONEPHRITIS
subjects affected / exposed	3 / 54 (5.56%)	0 / 55 (0.00%)	3 / 103 (2.91%)	1 / 54 (1.85%)	1 / 55 (1.82%)
occurrences all number	4	0	3	1	1
Metabolism and nutrition disorders
VITAMIN D DEFICIENCY
subjects affected / exposed	2 / 54 (3.70%)	3 / 55 (5.45%)	5 / 103 (4.85%)	0 / 54 (0.00%)	2 / 55 (3.64%)
occurrences all number	2	3	5	0	2

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Were there any global substantial amendments to the protocol? Yes

11 Jun 2008

The following changes were made as per amendment B: •Collection of persisting gadolinium-enhancing T1 lesions was added. •The transition to Cycle 2 for participants enrolled into Group D was clarified. •An exclusion criterion relating to potential hypersensitivity as a result of human serum albumin contained in the Avonex vials was added. •A risk-benefit reassessment/stopping rule was added. •Consistency was provided in the Expanded Disability Status Scale (EDSS) increase for assessment of disability progression within the protocol. •The difference between treatment withdrawal and study withdrawal was clarified. •The window for study Magnetic Resonance Imaging (MRI) scans was clarified; it was also clarified that the sites would not receive reports from the central MRI reading center. •The requirement of blood samples in order to have baseline values for participants in Group D prior to first Ocrelizumab (OCR) dose was added. •The assessment of protocol-defined relapses was clarified. •A standardized questionnaire for the telephone interview was provided. •The frequency of John Cunningham Virus (JCV) plasma sampling was increased. •Procedures for sample analysis for suspected progressive multifocal leukoencephalopathy (PML) were provided. •An exploratory investigation of patient-reported outcome (PRO) scales for potential implementation in Phase III was added. •Retreatment criteria were provided. •The requirement for clinical evaluations prior to re-dosing with OCR was clarified. •Reporting of clinical relapses and secondary progressive Multiple Sclerosis (MS) as Adverse Events (AEs) was included. •Consistent terminology for the grading of infusion reaction intensity was provided.

15 Oct 2011

The following changes were made as per amendment C: the addition of an Open Label Extension (OLE) period of the study following the Treatment free period (TFP).

03 Apr 2012

The following changes were made as per Amendment D: the window for the Week 144 visit to allow participants the opportunity to enter the OLE following the TFP was increased from 24 weeks to 96 weeks.

22 Dec 2015

The following changes as per amendment E •The duration of OLE period was extended for the participants having completed their 4 years of open-label ocrelizumab treatment. •The permittance of alternative MS treatments and prolongation of the monitoring period for participants switching to other MS therapies post-ocrelizumab was clarified. •Voluntary collection of pregnancy outcomes and infant health information on the first year of life was added. •The telephone interview script was updated to clarify the purpose of the telephone interview. •The activities of the independent Data Monitoring Committee (iDMC) for the OLE period were clarified. •Minor changes and clarifications were made to the schedule of assessments for the OLE period of the study to improve consistency

04 Aug 2016

The following changes were made as per amendment F: •The version of ocrelizumab that would be administered across the program was changed such that each vial contains 300 mg ocrelizumab. Updated guidance on the storage of infusion bags and a requirement on the use of an infusion set with an infusion set with an in-line filter was added. •The safety section was updated to align the safety language with the Investigator’s Brochure, reflecting the outcome from the Phase III clinical studies.

01 Feb 2017

The following change was made as per amendment G: OLE period of the study was extended to provide participants with the opportunity to continue receiving benefit from ocrelizumab treatment based on positive Phase III relapse multiple sclerosis (RMS) data.

27 Sep 2017

The following changes were made as per amendment H: •The protocol safety wording was updated for the following risks associated with ocrelizumab treatment: infusion-related reaction (IRR) risk, infection risk, delayed return of peripheral B cells, decrease in immunoglobulins, malignancy including breast cancer risk, progressive multifocal leukoencephalopathy (PML), including the guidance for PML diagnosis, neutropenia, serious infections related to decrease in immunoglobulins, hypersensitivity reactions, and impaired response to immunization. The following risks associated with ocrelizumab treatment have been removed after the latest benefit–risk assessments: cardiovascular disorders and immunogenicity. •Adverse Events of Special Interest (AESIs) were required to be reported by the Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). •With antihistamines considered as part of the pretreatment regimen, the risks associated with antihistamine use were added (Warnings and Precautions). •Contraception requirements for male participants and female partner pregnancy reporting were removed. •Contraception requirements, duration of contraception, and procedures for pregnant women during OLE period were updated.

15 Aug 2018

The following changes were made as per amendment I: •The OLE treatment period was extended to 31 December 2020 to provide additional long-term efficacy and safety data. •Language was updated pertaining to impairment of vaccination response. •Retreatment with ocrelizumab for participants with active tuberculosis and for pregnant or breastfeeding female participants was clarified. •Information regarding exposure in utero to ocrelizumab and administration of live or live-attenuated vaccines to neonates and infants were added. •Language related specially to Case Report Forms (CRFs) was deleted to allow for conversion to electronic capture.

09 Feb 2020

The following changes were made as per amendment J: •For the first participant entering OLE period, the maximum duration was modified to 11 years. •The safety risks for ocrelizumab were updated. •The pharmacokinetic/anti-drug antibody (ADA) collection/analysis was removed because immunogenicity incidence with ocrelizumab is very low (<1%) with no safety risks identified, so continuous monitoring in this population is unnecessary. •The plasma and urine sample collection for John Cunningham virus (JCV) was removed because there is no evidence that JCV antibody index (or similar) informs the risk of PML for participants on ocrelizumab. •Guidance for diagnosis of PML was updated. •Guidance for reporting abortions was updated. •Reference to Medical Monitor was changed where applicable and the emergency contact information was updated.

31 Jul 2020

The following change was made as per amendment K: The option of a shorter study drug infusion regimen was added to reduce burden on participants and infusion centers during the OLE period.

17 Nov 2021

The following changes were made as per amendment L: •The benefit-risk assessment for concomitant use of SARS-CoV-2 vaccines was updated. •Language was added to clarify that participants who complete or who discontinue the OLE period treatment early, for any reason, would be followed up for a maximum of 48 weeks after the last infusion of ocrelizumab. Continued B-cell monitoring for participants whose B cells are not repleted (i.e., returned to baseline levels or the lower limit of normal, whichever is lower) was removed because no increased safety risk was identified in the ocrelizumab clinical development program following cessation of treatment. •Language was added to clarify that participants who switch to commercial ocrelizumab after entering B-cell monitoring or enter into treatment with another Disease modifying therapy (DMT) would be discontinued from B-cell monitoring and from the study.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Phase II, Multicenter, Randomized, Parallel-Group, Partially Blinded, Placebo and Avonex Controlled Dose Finding Study to Evaluate the Efficacy As Measured by Brain MRI Lesions, and Safety of 2 Dose Regimens of Ocrelizumab in Patients With RRMS

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic R4esonance Imaging (MRI) Scans of the Brain

Primary: Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic R4esonance Imaging (MRI) Scans of the Brain

Secondary: Annualized Protocol Defined Relapse Rate at Week 24

Secondary: Annualized Protocol Defined Relapse Rate at Week 24

Secondary: Percentage of Participants Who Remained Relapse Free at Week 24

Secondary: Percentage of Participants Who Remained Relapse Free at Week 24

Secondary: Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24

Secondary: Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24

Secondary: Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain

Secondary: Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain

Secondary: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: Total Number of Gadolinium-Enhancing T1 Lesions

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Phase II, Multicenter, Randomized, Parallel-Group, Partially Blinded, Placebo and Avonex Controlled Dose Finding Study to Evaluate the Efficacy As Measured by Brain MRI Lesions, and Safety of 2 Dose Regimens of Ocrelizumab in Patients With RRMS

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic R4esonance Imaging (MRI) Scans of the Brain

Primary: Total Number of Gadolinium-Enhancing T1 Lesions Observed on Magnetic R4esonance Imaging (MRI) Scans of the Brain

Secondary: Annualized Protocol Defined Relapse Rate at Week 24

Secondary: Annualized Protocol Defined Relapse Rate at Week 24

Secondary: Percentage of Participants Who Remained Relapse Free at Week 24

Secondary: Percentage of Participants Who Remained Relapse Free at Week 24

Secondary: Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24

Secondary: Change From Baseline in Total Volume of T2 Lesions on MRI Scans of the Brain at Week 24

Secondary: Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain

Secondary: Total Number of New Gadolinium-Enhancing T1 Lesions Observed by MRI Scans of the Brain

Secondary: Total Number of Gadolinium-Enhancing T1 Lesions

Secondary: Total Number of Gadolinium-Enhancing T1 Lesions

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Phase II, Multicenter, Randomized, Parallel-Group, Partially Blinded, Placebo and Avonex Controlled Dose Finding Study to Evaluate the Efficacy As Measured by Brain MRI Lesions, and Safety of 2 Dose Regimens of Ocrelizumab in Patients With RRMS