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Clinical Trial Results:
An Open-label, Single-arm Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Patients With Early Stage Relapsing Remitting Multiple Sclerosis

Summary
EudraCT number	2016-002937-31
Trial protocol	NO SE AT DK DE PT BE HU PL SK ES BG SI NL GB FR HR IT
Global end of trial date	27 Apr 2023

Results information
Results version number	v2(current)
This version publication date	15 Feb 2025
First version publication date	12 May 2024
Other versions	v1
Version creation reason

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

MA30143

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Hoffmann-La Roche

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, 4058

Public contact

Roche Trial Information Hotline, Hoffmann-La Roche, +41 61 6878333,

Scientific contact

Medical Communications, Hoffmann-La Roche, +1 8008218590, 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

27 Apr 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Apr 2023

Global end of trial reached?

Yes

Global end of trial date

27 Apr 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the effectiveness and safety of ocrelizumab in patients with early stage relapsing remitting multiple sclerosis.

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) guidelines according to the regulations and procedures described in the protocol.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Mar 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 14

Country: Number of subjects enrolled

Australia: 55

Country: Number of subjects enrolled

Austria: 11

Country: Number of subjects enrolled

Belgium: 39

Country: Number of subjects enrolled

Bulgaria: 28

Country: Number of subjects enrolled

Brazil: 21

Country: Number of subjects enrolled

Canada: 67

Country: Number of subjects enrolled

Switzerland: 21

Country: Number of subjects enrolled

Germany: 78

Country: Number of subjects enrolled

Denmark: 11

Country: Number of subjects enrolled

Spain: 36

Country: Number of subjects enrolled

France: 69

Country: Number of subjects enrolled

United Kingdom: 52

Country: Number of subjects enrolled

Croatia: 36

Country: Number of subjects enrolled

Hungary: 15

Country: Number of subjects enrolled

Italy: 60

Country: Number of subjects enrolled

Kuwait: 5

Country: Number of subjects enrolled

Lebanon: 6

Country: Number of subjects enrolled

Mexico: 72

Country: Number of subjects enrolled

Netherlands: 24

Country: Number of subjects enrolled

Norway: 6

Country: Number of subjects enrolled

Poland: 153

Country: Number of subjects enrolled

Portugal: 27

Country: Number of subjects enrolled

Romania: 19

Country: Number of subjects enrolled

Slovakia: 28

Country: Number of subjects enrolled

Slovenia: 12

Country: Number of subjects enrolled

Sweden: 10

Country: Number of subjects enrolled

Türkiye: 47

Country: Number of subjects enrolled

United States: 203

Worldwide total number of subjects

1225

EEA total number of subjects

662

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)

1225

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A prospective, multicenter, open-label, single-arm effectiveness and safety study enrolled 1225 eligible treatment-naive patients with early stage RMSR. The study consisted of screening period up 4 weeks and open-label treatment with ocrelizumab period up to 192 week.

Screening details

The efficacy analyses were performed on the main study cohort enrolled as per original study protocol, and safety analyses on all enrolled participants.

Period 1 title

Overall Study

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Main Study - Ocrelizumab

Arm description

Ocrelizumab was administered intravenously (IV) as two 300-milligram (mg) infusions on Days 1 and 15, followed by one 600-mg infusion dose every 24 weeks (+/- 14 days) for a maximum of 8 doses throughout the 192 weeks treatment period.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Ocrelizumab was administered IV as two 300-mg infusions on Days 1 and 15, followed by one 600-mg infusion dose every 24 weeks (+/- 14 days).

Number of subjects in period 1	Main Study - Ocrelizumab
Started	1225
Completed	1010
Not completed	215
Adverse event, serious fatal	12
Site Closure	3
Physician decision	13
planned pregnancy	17
Consent withdrawn by subject	77
Changed to Commercial Ocrelizumab	4
Adverse event, non-fatal	25
Pregnancy	7
Terminated By Sponsor	14
Lost to follow-up	17
disease progression	1
Protocol deviation	15
Lack of efficacy	10

Period 2 title

Substudy (Week 24 to Week 144)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Substudy - Conventional Infusion

Arm description

Ocrelizumab was administered as 600 mg IV infused over approximately 3.5 hours every 24 weeks throughout the treatment period.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion, Concentrate and solvent for solution for infusion, Concentrate and solvent for solution for infusion

Routes of administration

Subcutaneous use, Subcutaneous use, Subcutaneous use

Dosage and administration details

Ocrelizumab was administered as 600 mg IV infused over approximately 3.5 hours every 24 weeks.

Substudy - Shorter Infusion

Arm description

Ocrelizumab was administered as 600 mg IV infused over approximately 2 hours and saline for remaining 1.5 hours, every 24 weeks throughout the treatment period.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

RO4964913

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Ocrelizumab was administered as 600 mg IV infused over approximately 2 hours every 24 weeks.

Number of subjects in period 2 ^[1]	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Started	373	372
Completed	0	2
Not completed	373	370
Consent withdrawn by subject	5	7
Substudy stopped by sponsor	355	352
Reason Not Specified	13	8
Withdrawal due to infusion related reaction (IRR)	-	3

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 consented to participate in the sub-study were enrolled.

Baseline characteristics

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Reporting group title

Main Study - Ocrelizumab

Reporting group description

Reporting group values	Main Study - Ocrelizumab	Total
Number of subjects	1225	1225
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	0	0
From 65-84 years	1225	1225
85 years and over	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	32.7 ( 9.1 )	-
Sex: Female, Male
Units:
Female	784	784
Male	441	441
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	11	11
Asian	19	19
Native Hawaiian or Other Pacific Islander	2	2
Black or African American	34	34
White	1007	1007
More than one race	37	37
Unknown or Not Reported	115	115
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	145	145
Not Hispanic or Latino	960	960
Unknown or Not Reported	120	120

End points

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Reporting group title

Main Study - Ocrelizumab

Reporting group description

Reporting group title

Substudy - Conventional Infusion

Reporting group description

Ocrelizumab was administered as 600 mg IV infused over approximately 3.5 hours every 24 weeks throughout the treatment period.

Reporting group title

Substudy - Shorter Infusion

Reporting group description

Ocrelizumab was administered as 600 mg IV infused over approximately 2 hours and saline for remaining 1.5 hours, every 24 weeks throughout the treatment period.

Primary: Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS)

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End point title

Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS) ^[1]

End point description

The EDSS-Expanded Disability Status Scale is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 and a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from the initial progression event was seen i.e. the change in EDSS must have been sustained at all available visits for a minimum of 24 weeks/48 weeks. Treatment efficacy was measured for this First Enrollment Cohort ITT population. 9999=Median (corresponds to a probability of 50%) and 95% CI was not reached due to low number of participants with the event at the end of the study.

End point type

Primary

End point timeframe

Baseline up to 4 years

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: weeks
median (confidence interval 95%)
CPD Sustained for at Least 24 weeks	9999 (9999 to 9999)
CDP Sustained for at Least 48 weeks	9999 (9999 to 9999)

No statistical analyses for this end point

Primary: Percentage of Participants with 24-Week and 48-Week Confirmed Disability Improvement (CDI) During the Year 1 Treatment Period, as Measured Using EDSS

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End point title

Percentage of Participants with 24-Week and 48-Week Confirmed Disability Improvement (CDI) During the Year 1 Treatment Period, as Measured Using EDSS ^[2]

End point description

CDI is defined as an improvement of ≥1 point on the EDSS score confirmed at a regular scheduled visit at least 24/48 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Treatment efficacy was measured for this First Enrollment Cohort ITT population. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.

End point type

Primary

End point timeframe

At Weeks 24 and 48 during Year 1

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	309
Units: Percentage %
number (confidence interval 95%)
CDI Sustained for 24 weeks: At Week 24 (n=293)	95.11 (92.03 to 97.03)
CDI Sustained for 24 weeks: At Week 48 (n=205)	83.50 (78.81 to 87.24)
CDI Sustained for 48 weeks: At Week 48 (n=213)	87.54 (83.28 to 90.77)

No statistical analyses for this end point

Primary: Percentage of Participants with 24-Week and 48-Week CDI During the Year 2 Treatment Period, as Measured Using EDSS

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End point title

Percentage of Participants with 24-Week and 48-Week CDI During the Year 2 Treatment Period, as Measured Using EDSS ^[3]

End point description

CDI is defined as an improvement of 1 point on the EDSS score confirmed at a regular scheduled visit at least 24/48 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Treatment efficacy was measured for this First Enrollment Cohort ITT population. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.

End point type

Primary

End point timeframe

At Weeks 48, 72 and 96 during Year 2

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	252
Units: Percentage of Participants
number (confidence interval 95%)
CDI Sustained for 24 weeks: At Week 48 (n=252)	100.0 (100.00 to 100.00)
CDI Sustained for 48 weeks: At Week 48 (n=252)	100.0 (100.0 to 100.0)
CDI Sustained for 24 weeks: At Week 72 (n=243)	97.20 (94.22 to 98.66)
CDI Sustained for 48 weeks: At Week 72 (n=244)	97.60 (94.74 to 98.91)
CDI Sustained for 24 weeks: At Week 96 (n=166)	90.29 (85.71 to 93.46)
CDI Sustained for 48 weeks: At Week 96 (n=169)	92.55 (88.41 to 92.55)

No statistical analyses for this end point

Primary: Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 2, as Measured Using EDSS

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End point title

Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 2, as Measured Using EDSS ^[4]

End point description

EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Disability progression as measured by EDSS is defined as ≥1 point increase in EDSS score from a baseline EDSS score of 1-5 inclusive, a 0.5-increase from a baseline EDSS score higher than 5 & a 1.5-increase from a baseline EDSS score from 0 to 1 exclusive. Disability progression was considered confirmed if a sustained change in EDSS for a minimum of 24 weeks (-2 weeks) from initial progression event was seen i.e. change in EDSS must have been sustained at all available visits (during Year 1) for a minimum of 24 weeks/48 weeks. Percentage of participants who did not have CPD sustained for 24 & 48 weeks are reported here. Treatment efficacy was measured for First Enrollment Cohort ITT population. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed for CDP at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Primary

End point timeframe

Year 2 (Weeks 72 and 96)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Particiopants
number (confidence interval 95%)
CDP Sustained for 24 weeks: At Week 72 (n=615)	93.97 (91.87 to 95.54)
CDP Sustained for 48 weeks: At Week 72 (n=622)	95.18 (93.25 to 96.56)
CDP Sustained for 24 weeks: Week 96 (n=587)	91.65 (89.26 to 93.52)
CDP Sustained for 48 weeks: Week 96 (n=598)	93.47 (91.30 to 95.12)

No statistical analyses for this end point

Primary: Percentage of Participants With 24-Week and 48-Week CDI at Year 4, as Measured Using EDSS

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End point title

Percentage of Participants With 24-Week and 48-Week CDI at Year 4, as Measured Using EDSS ^[5]

End point description

CDI is defined as an improvement of 1 point on the EDSS score confirmed at a regular scheduled visit at least 24 weeks after the initial documentation of neurological worsening (measured only participants with a baseline EDSS of ≥2.0). EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death). Treatment efficacy was measured for this First Enrollment Cohort ITT population. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed for CDP at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Primary

End point timeframe

At Weeks 144, 168 and 192 during Year 4

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
number (confidence interval 95%)
CDI Sustained for 24 weeks: At Week 144 (n=218)	100.00 (100.00 to 100.00)
CDI Sustained for 48 weeks: At Week 144 (n=218)	100.00 (100.00 to 100.00)
CDI Sustained for 24 weeks: At Week 168 (n=215)	99.54 (96.77 to 99.93)
CDI Sustained for 48 weeks: At Week 168 (n=216)	100.00 (100.00 to 100.00)
CDI Sustained for 24 weeks: At Week 192 (n=163)	93.77 (89.51 to 96.34)
CDI Sustained for 48 weeks: At Week 192 (n=172)	98.01 (94.77 to 99.25)

No statistical analyses for this end point

Primary: Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 4, as Measured Using EDSS

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End point title

Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 4, as Measured Using EDSS ^[6]

End point description

End point type

Primary

End point timeframe

Year 4 (Weeks 168 and 192)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
number (confidence interval 95%)
CDP Sustained for 24 weeks: At Week 168 (n=516)	85.98 (83.04 to 88.44)
CDP Sustained for 48 weeks: At Week 168 (n=528)	87.98 (85.20 to 90.27)
CDP Sustained for 24 weeks: At Week 192 (n=402)	84.18 (81.08 to 86.81)
CDP Sustained for 48 weeks: At Week 192 (n=414)	86.48 (83.54 to 88.93)

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 24

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End point title

Mean Change From Baseline in EDSS Score at Week 24 ^[7]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

From Baseline to Week 24

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	671
Units: Change in Total EDSS Score
arithmetic mean (standard deviation)	-0.14 ( 0.68 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 120

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End point title

Mean Change From Baseline in EDSS Score at Week 120 ^[8]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Baseline, Week 120

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	579
Units: Change in Total EDSS Score
arithmetic mean (standard deviation)	-0.10 ( 0.94 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 96

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End point title

Mean Change From Baseline in EDSS Score at Week 96 ^[9]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Baseline, Week 96

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	637
Units: Change in Total EDSS Score
arithmetic mean (standard error)	-0.12 ( 0.95 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 72

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End point title

Mean Change From Baseline in EDSS Score at Week 72 ^[10]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

From Baseline to Week 72

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	651
Units: Change in Total EDSS Score
arithmetic mean (standard deviation)	-0.09 ( 0.89 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 48

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End point title

Mean Change From Baseline in EDSS Score at Week 48 ^[11]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

From Baseline to Week 48

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	659
Units: Change in Total EDSS
arithmetic mean (standard deviation)	-0.14 ( 0.77 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 144

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End point title

Mean Change From Baseline in EDSS Score at Week 144 ^[12]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Baseline, Week 144

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	561
Units: Change in Total EDSS Score
arithmetic mean (standard error)	-0.10 ( 1.00 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 168

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End point title

Mean Change From Baseline in EDSS Score at Week 168 ^[13]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Baseline, Week 168

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	560
Units: Change in Total EDSS Score
arithmetic mean (standard error)	-0.05 ( 1.05 )

No statistical analyses for this end point

Primary: Mean Change From Baseline in EDSS Score at Week 192

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End point title

Mean Change From Baseline in EDSS Score at Week 192 ^[14]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Baseline, Week 192

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	562
Units: Change in Total EDSS Score
arithmetic mean (standard deviation)	-0.06 ( 1.06 )

No statistical analyses for this end point

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS

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End point title

Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS ^[15]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Year 2 (Week 96)

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	632
Units: Percentage of Participants
number (not applicable)
Week 96 Stable (Change <= 0.5 and >= -0.5)	76.6
Week 96 Improved (<-0.5)	11.6
Week 96 Improved (<-0.5)	11.6

No statistical analyses for this end point

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS

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End point title

Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS ^[16]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Year 1 (Week 48)

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	659
Units: Percentage of Participants
number (not applicable)
Week 48 Stable (Change <= 0.5 and >= -0.5)	73.3
Week 48 Improved (<-0.5)	17.5
Week 48 Improved (<-0.5)	17.5

No statistical analyses for this end point

Primary: Annualized Relapse Rate

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End point title

Annualized Relapse Rate ^[17]

End point description

Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. The adjusted annualized relapse rate is reported which is: Adjusted by age at disease diagnosis, Baseline EDSS, Presence of T1 Gd-enhanced lesion at screening and Presence of relapses in the last year prior to enrollment. Log-transformed exposure time is included as an offset variable. The report contains data up to week 192 of the treatment period of each individual participant. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort.

End point type

Primary

End point timeframe

Baseline up to 4 years

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: events per participant per year
least squares mean (confidence interval 95%)	0.02 (0.015 to 0.027)

No statistical analyses for this end point

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 3, As Measured Using EDSS

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End point title

Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 3, As Measured Using EDSS ^[18]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Year 3

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	557
Units: Percentage of Participants
number (not applicable)
Worsened (>0.5)	9.3
Stable (Change <= 0.5 and >= -0.5)	81.5
Improved (<-0.5)	9.2

No statistical analyses for this end point

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 4, As Measured Using EDSS

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End point title

Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 4, As Measured Using EDSS ^[19]

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Overall number analyzed is the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Year 4

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	562
Units: Percentage of Participants
number (not applicable)
Worsened (>0.5)	18.0
Stable (Change <= 0.5 and >= -0.5)	59.3
Improved (<-0.5)	22.8

No statistical analyses for this end point

Primary: Percentage of Participants Event-Free for CDP Sustained for at Least 24 and 48 Weeks at Year 1, as Measured Using EDSS

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End point title

Percentage of Participants Event-Free for CDP Sustained for at Least 24 and 48 Weeks at Year 1, as Measured Using EDSS ^[20]

End point description

End point type

Primary

End point timeframe

Year 1 (Weeks 24 and 48)

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
number (confidence interval 95%)
CDP Sustained for 24 weeks: At Week 24 (n=668)	99.55 (98.62 to 99.86)
CDP Sustained for 24 weeks: At Week 48 (n=645)	97.30 (95.75 to 98.29)
CDP Sustained for 48 weeks: At Week 48 (n=649)	98.05 (96.67 to 98.87)

No statistical analyses for this end point

Primary: Percentage of Participants without Protocol-Defined Event of Disease Activity

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End point title

Percentage of Participants without Protocol-Defined Event of Disease Activity ^[21]

End point description

Protocol-defined event of disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis [MS], as determined using EDSS/Functional Systems Score [FSS] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8 (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint

End point type

Primary

End point timeframe

Baseline up to 4 years

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of participants
number (confidence interval 95%)
Week 24 (n=646)	95.98 (94.20 to 97.23)
Week 48 (n=590)	88.94 (86.30 to 91.09)
Week 72 (n=549)	83.94 (80.92 to 86.52)
Week 96 (n=517)	80.38 (77.14 to 83.21)
Week 120 (n=488)	77.38 (73.99 to 80.39)
Week 144 (n=463)	75.76 (72.28 to 78.86)
Week 168 (n=436)	72.79 (69.18 to 76.05)
Week 192 (n=340)	70.67 (66.97 to 74.04)

No statistical analyses for this end point

Primary: Percentage of Participants without Relapse

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End point title

Percentage of Participants without Relapse ^[22]

End point description

Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Primary

End point timeframe

Baseline up to 4 years

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
number (confidence interval 95%)
Week 24 (n=661)	98.52 (97.26 to 99.20)
Week 48 (n=649)	97.91 (96.50 to 98.76)
Week 72 (n=631)	96.25 (94.49 to 97.45)
Week 96 (n=610)	95.32 (93.41 to 96.69)
Week 120 (n=593)	93.90 (91.78 to 95.49)
Week 144 (n=570)	93.09 (90.85 to 94.79)
Week 168 (n=554)	92.43 (90.10 to 94.23)
Week 192 (n=439)	91.56 (89.12 to 93.48)

No statistical analyses for this end point

Primary: Sub Study: Number of Participants with IRRs Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy

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End point title

Sub Study: Number of Participants with IRRs Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy ^[23]

End point description

ITT Population included all randomized participants in shorter infusion sub study.

End point type

Primary

End point timeframe

Week 24 through Week 144

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical analysis was planned for this endpoint.

End point values	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Number of subjects analysed	373	372
Units: Participants	101	107

No statistical analyses for this end point

Secondary: Percentage of Participants Who Are Relapse Free

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End point title

Percentage of Participants Who Are Relapse Free

End point description

Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment.

End point type

Secondary

End point timeframe

Week 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	624
Units: Percentage of Participants
median (confidence interval 95%)	92.00 (89.7 to 94.0)

No statistical analyses for this end point

Secondary: Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD)

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End point title

Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD)

End point description

NEPAD is defined as no progression on all of the three components of NEP (CDP, T25FWT, 9HPT), no new relapse and no enlarging or new T2 or T1 Gd-enhancing lesion. CDP will be assessed using EDSS. Relapse is defined as occurrence of new or worsening neurological symptoms attributable to MS, as determined using EDSS/FSS assessment. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Weeks 96, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
number (confidence interval 95%)
Week 192 (n=277)	58.89 (54.96 to 62.60)
Week 192	58.89 (54.96 to 62.60)

No statistical analyses for this end point

Secondary: Percentage of Participants With No Evidence of Protocol Defined Disease Activity

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End point title

Percentage of Participants With No Evidence of Protocol Defined Disease Activity

End point description

Protocol-defined disease activity is defined as having at least one of the following: (1). protocol defined relapse (occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis [MS], as determined using EDSS/Functional Systems Score [FSS] assessment). (2). CDP, as determined using EDSS. (3). a T1 Gd-enhanced lesion after Week 8. (4). a new and/or enlarging T2 hyperintense lesion on magnetic resonance imaging (MRI) after Week 8 compared to the Week 8 MRI scan. Event-free rate. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Weeks 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
median (confidence interval 95%)
Week 96	80.38 (77.14 to 83.21)
Week 144	75.76 (72.28 to 78.86)
Week 192	70.67 (66.97 to 74.04)

No statistical analyses for this end point

Secondary: Change from Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score

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End point title

Change from Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score

End point description

The change in the mean score of T25FW is reported below. The time taken to walk 25 feet, typically measured in seconds. The longer it takes to walk, the higher score, which indicates deterioration. Lower times indicate better performance and greater mobility. Higher times indicate worse performance and greater impairment. Subsequently, the lower the mean change in the score over time, the better performance. Treatment efficacy was measured for this First Enrollment Cohort ITT population. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at the specified timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: seconds
arithmetic mean (standard deviation)
Week 24 (n=650)	-0.31 ( 6.62 )
Week 48 (n=647)	-0.49 ( 6.88 )
Week 72 (n=627)	-0.56 ( 6.99 )
Week 96 (n=617)	-0.62 ( 6.95 )
Week 120 (n=560)	-0.44 ( 7.94 )
Week 144 (n=562)	-0.97 ( 6.25 )
Week 168 (n=554)	-0.83 ( 6.64 )
Week 192 (n=543)	0.09 ( 9.37 )

No statistical analyses for this end point

Secondary: Change from Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score

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End point title

Change from Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score

End point description

Mean change in 9HPT-score is reported. Participants are instructed to place pegs one by one into each of nine holes arranged in a board stabilized with a plastic nonslip sheet on a solid table, and then to remove these pegs from the holes. Both the dominant and non-dominant hands are tested twice (two consecutive trials for each hand). The participants are required to complete two successful trials for each hand. The amount of time (in seconds) required to place and remove all nine pegs is recorded for each trial. The number of seconds it takes to complete the test, the higher raw scores, which indicates deterioration. The lower mean change in the score over time, the better the performance. Treatment efficacy was measured for this First Enrollment Cohort ITT population. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at the specified timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Weeks 24, 48, 72, 96, 120, 144, 168, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: seconds
arithmetic mean (standard deviation)
Week 24 (n=650)	-0.47 ( 14.44 )
Week 48 (n=648)	-1.22 ( 11.54 )
Week 72 (n=628)	-1.78 ( 8.09 )
Week 96 (n=618)	-1.67 ( 10.91 )
Week 120 (n=551)	-0.87 ( 15.21 )
Week 144 (n=560)	-1.91 ( 8.70 )
Week 168 (n=555)	-1.84 ( 10.68 )
Week 192 (n=544)	-0.73 ( 17.55 )

No statistical analyses for this end point

Secondary: Change from Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score

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End point title

Change from Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score

End point description

PASAT measures cognitive function. A total of 60 single digit numbers are presented by an audiotape/CD-rom at a constant rate in every 3 seconds (PASAT-3). Participants are required to add each new number to the one immediately before it. Due to the relative complexity of this test, a practice trial with a set of 10 numbers should be performed before the original test. Participants are allowed up to 3 practice trials. Two sets of numbers (forms A & B) are developed to be used alternatively in every visit to minimize memorizing. Number of correct answers is recorded. PASAT score range: 0-60. Higher values=better outcome in cognitive processing speed. Subsequently, higher values in mean changes from baseline=improvement in cognitive function. First Enrollment Cohort ITT population. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at the specified timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Weeks 24, 48, 72, 96, 120, 144, 168, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: score on a scale
arithmetic mean (standard deviation)
Week 24 (n=251)	4.18 ( 9.26 )
Week 48 (n=453)	5.40 ( 9.52 )
Week 72 (n=320)	6.33 ( 11.59 )
Week 96 (n=435)	7.66 ( 10.93 )
Week 120 (n=290)	7.69 ( 12.95 )
Week 144 (n=372)	8.45 ( 10.02 )
Week 168 (n=285)	8.47 ( 11.79 )
Week 192 (n=344)	9.64 ( 11.56 )

No statistical analyses for this end point

Secondary: Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI

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End point title

Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI

End point description

Number of Lesions are categorized as followed: 1, 2, 3, >1, >3

End point type

Secondary

End point timeframe

Weeks 24, 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Number of Lesions
Week 24 Number of Lesions 0	659
Week 24 Number of Lesions 1	6
Week 24 Number of Lesions 2	2
Week 24 Number of Lesions >1	2
Week 48 Number of Lesions 0	650
Week 48 Number of Lesions 1	7
Week 96 Number of Lesions 0	629
Week 96 Number of Lesions 1	1
Week 144 Number of Lesions 0	567
Week 144 Number of Lesions 1	1
Week 144 Number of Lesions 3	1
Week 144 Number of Lesions >1	1
Week 192 Number of Lesions 0	545
Week 192 Number of Lesions 1	1

No statistical analyses for this end point

Secondary: Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI

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End point title

Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI

End point description

Number of Lesions are categorized as followed: 1, 2, 3, >1, >3

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Number of Lesions
Week 24 Number of Lesions 0	651
Week 24 Number of Lesions 1	13
Week 24 Number of Lesions 2	3
Week 24 Number of Lesions >1	3
Week 48 Number of Lesions 0	644
Week 48 Number of Lesions 1	11
Week 48 Number of Lesions 2	3
Week 48 Number of Lesions 3	2
Week 48 Number of Lesions >1	5
Week 96 Number of Lesions 0	624
Week 96 Number of Lesions 1	8
Week 96 Number of Lesions 2	1
Week 96 Number of Lesions >1	1
Week 144 Number of Lesions 0	564
Week 144 Number of Lesions 1	6
Week 144 Number of Lesions 2	1
Week 144 Number of Lesions 3	1
Week 144 Number of Lesions >1	2
Week 192 Number of Lesions 0	546
Week 192 Number of Lesions 1	4
Week 192 Number of Lesions 2	1
Week 192 Number of Lesions >1	1

No statistical analyses for this end point

Secondary: Change from baseline in total T1 hypointense lesion volume as Detected by Brain MRI

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End point title

Change from baseline in total T1 hypointense lesion volume as Detected by Brain MRI

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Change in Volume
arithmetic mean (standard deviation)
Week 48	-310.63 ( 708.07 )
Week 96	-405.61 ( 755.99 )
Week 144	-359.76 ( 761.84 )
Week 192	-307.64 ( 797.87 )

No statistical analyses for this end point

Secondary: Secondary: Change from Baseline in Multiple Sclerosis Functional Composite Score (MSFC) Total

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End point title

Secondary: Change from Baseline in Multiple Sclerosis Functional Composite Score (MSFC) Total

End point description

MSFC combines the following: Timed 25 Foot Walk Test [T25FWT] for leg function &ambulation measured in seconds (sec). The longer it takes to walk, higher the score indicating deterioration; 9 Hole Peg Test [9HPT] for arm & handf unction measured in sec. Higher score=more time taken to complete test indicating deterioration. Paced Auditory Serial Addition Test [PASAT] for cognitive function (score range: 0-60, higher score=better cognitive processing speed). MSFC composite={[Average(1/9-HPT)-Baseline Mean(1/9-HPT)/Baseline Std Dev(1/9-HPT)]+[-(Average T25FWT-Baseline Mean T25FWT)/Baseline Std-Dev T25FWT]+[(PASAT-3-BaselineMean PASAT-3)/Baseline Std Dev PASAT-3]}/ 3.0. MSFC is based on the concept that scores for these 3 dimensions are combined to create a single score to detect change over time in a group of MS patients. Higher composite score=better overall function. Lower score=worse overall function. Higher mean change in total MSFC score=functional improvement at cohort level.

End point type

Secondary

End point timeframe

Weeks 24, 48, 72, 96, 120, 144, 168, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: score on a scale
arithmetic mean (standard deviation)
Week 24 (n=595)	0.09 ( 0.67 )
Week 48 (n=601)	0.11 ( 0.54 )
Week 78 (n=588)	0.12 ( 0.45 )
Week 96 (n=566)	0.14 ( 0.53 )
Week 120 (n=511)	0.16 ( 0.61 )
Week 144 (n=513)	0.16 ( 0.48 )
Week 168 (n=498)	0.18 ( 0.56 )
Week 192 (n=492)	0.19 ( 0.72 )

No statistical analyses for this end point

Secondary: Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI

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End point title

Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 8, 24, 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Number of Lesions
Baseline Week 8 0	633
Baseline Week 8 1	6
Week 24 0	635
Week 24 1	6
Week 48 0	631
Week 48 1	6
Week 96 0	611
Week 96 1	7
Week 144 0	550
Week 144 1	5
Week 192 0	530
Week 192 1	5

No statistical analyses for this end point

Secondary: Change From Baseline in Brain Volume as Detected by Brain MRI

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End point title

Change From Baseline in Brain Volume as Detected by Brain MRI

End point description

Percentage change from Normalized brain volume in cm3 (cubic centimeter)values are reported

End point type

Secondary

End point timeframe

From Baseline to Weeks 24, 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage Change in Volume (cm3)
arithmetic mean (standard deviation)
Week 24	-0.189 ( 0.564 )
Week 48	-0.479 ( 0.733 )
Week 96	-0.909 ( 0.930 )
Week 144	-1.283 ( 1.156 )
Week 192	-1.535 ( 1.311 )

No statistical analyses for this end point

Secondary: Employment Status: Work Productivity and Activity Impairment Questionnaire (WAPI) Score

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End point title

Employment Status: Work Productivity and Activity Impairment Questionnaire (WAPI) Score

End point description

WPAI scale measures impact of health problems on work productivity and regular activities: Absenteeism (Work Time Missed) measuring % of work time missed due to health issues; Presenteeism:Calculated as the percentage of impairment while working due to health problems. Overall Work Impairment:Calculated by combining absenteeism and presenteeism using the formula:Overall Work Impairment=Absenteeism+(1−Absenteeism)×Presenteeism Overall Work Impairment=Absenteeism(1−Absenteeism)×Presenteeism. This formula accounts for both the time missed and the reduced productivity while at work. Activity Impairment: Calculated as the percentage of impairment in regular activities outside of work. Range: Each component is scored as 0%-100%). Higher % indicate greater impairment and worse outcomes.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 48, 96, 120, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: WAPI Sub-Score
arithmetic mean (standard deviation)
Work productivity Baseline (n=369)	26.33 ( 31.84 )
Work productivity Week 24 (n=401)	17.65 ( 25.04 )
Work productivity Week 48 (n=404)	18.83 ( 25.92 )
Work productivity Week 96 (n=420)	16.46 ( 23.10 )
Work productivity Week 144 (n=368)	16.78 ( 23.85 )
Work productivity Week 192 (n=369)	15.80 ( 22.25 )
Activity Impairment Baseline (n=640)	23.23 ( 24.79 )
Activity Impairment Week 24 (n=634)	18.09 ( 22.15 )
Presenteeism Week 48 (n=635)	18.85 ( 23.37 )
Activity Impairment Week 96 (n=605)	17.79 ( 22.92 )
Activity Impairment Week 144 (n=563)	17.80 ( 23.74 )
Activity Impairment Week 192 (n=521)	18.18 ( 23.25 )

No statistical analyses for this end point

Secondary: SymptoMScreen Composite Score

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End point title

SymptoMScreen Composite Score

End point description

The SMSS consists of 12 items which are assessed on a seven-point Likert scale that ranges from 0 (not at all affected) to 6 (total limitation) [7]. The total score ranges from 0 to 72, with higher scores indicating more severe symptom endorsement. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Change in SymptoMScreen Composite Score
arithmetic mean (standard deviation)
Week 24 (n=651)	-0.1 ( 0.9 )
Week 48 (n=648)	-0.1 ( 1.0 )
Week 96 (n=621)	0.0 ( 1.1 )
Week 144 (n=568)	0.0 ( 1.1 )
Week 192 (n=538)	0.0 ( 1.1 )

No statistical analyses for this end point

Secondary: Quality of Life: Multiple Sclerosis Impact Scale (MSIS)-29 Questionnaire Score

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End point title

Quality of Life: Multiple Sclerosis Impact Scale (MSIS)-29 Questionnaire Score

End point description

The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a questionnaire to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient’s perspective, which includes 29 items self-reported measures associated with a physical scale and 9 items with a psychological scale. MSIS-29 scales are generated by summing items and it's ranging from 29-145'. The higher total MSIS-29 scores indicate a greater degree of disability. The mean change in MSIS-29 scores from baseline is reported. The decreasing values in the mean change from baseline indicate functional improvement from participants’ perspective. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Change in MSIS-29 Score
arithmetic mean (standard deviation)
Week 24 (n=656)	-2.43 ( 12.13 )
Week 48 (n=650)	-2.15 ( 13.04 )
Week 96 (n=627)	-1.26 ( 14.31 )
Week 144 (n=571)	-0.73 ( 14.83 )
Week 192 (n=543)	-0.63 ( 16.04 )

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

End point type

Secondary

End point timeframe

Baseline up to 4 years

End point values	Main Study - Ocrelizumab
Number of subjects analysed	1225
Units: Percentage of Participants
number (not applicable)
Adverse Events	95.8
Serious Adverse Events	15.0

No statistical analyses for this end point

Secondary: Percentage of Participants without Treatment Discontinuation

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End point title

Percentage of Participants without Treatment Discontinuation

End point description

First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort.

End point type

Secondary

End point timeframe

Baseline up to 4 years

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: percentage of participants
number (confidence interval 95%)
Week 24 (n=671)	98.97 (97.85 to 99.51)
Week 48 (n=661)	97.49 (96.00 to 98.45)
Week 72 (n=652)	96.02 (94.25 to 97.25)
Week 96 (n=635)	93.51 (91.38 to 95.13)
Week 120 (n=625)	92.04 (89.73 to 93.84)
Week 144 (n=605)	89.23 (86.65 to 91.34)
Week 168 (n=589)	87.17 (84.41 to 89.47)
Week 192 (n=464)	83.85 (80.85 to 86.42)

No statistical analyses for this end point

Secondary: Percentage of Participants without protocol-defined event of Evidence of Progression (NEP)

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End point title

Percentage of Participants without protocol-defined event of Evidence of Progression (NEP)

End point description

NEP is defined as no progression sustained for at least 24 weeks on all of the following three components (CDP; 20 percent [%] increase from baseline in timed 25 Foot Walk Test [T25FWT]; 20% increase from baseline in timed 9 hole peg test [9HPT]). CDP will be assessed using EDSS. First Enrollment Cohort ITT population. Treatment efficacy was measured for this First Enrollment Cohort. Number analyzed per timepoint are unique number of participants out of all the participants who were assessed at that timepoint. Different participants may have contributed data for each timepoint.

End point type

Secondary

End point timeframe

Weeks 96, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	678
Units: Percentage of Participants
number (confidence interval 95%)
Week 96 (n=511)	79.60 (76.33 to 82.48)
Week 192 (n=325)	69.16 (65.40 to 72.60)

No statistical analyses for this end point

Secondary: Number of Participants With IRR Overall and by Dose at Randomization

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End point title

Number of Participants With IRR Overall and by Dose at Randomization

End point description

ITT Population included all randomized participants in shorter infusion sub study. Number analyzed is the number of participants who received an infusion.

End point type

Secondary

End point timeframe

From Week 24 to Week 144

End point values	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Number of subjects analysed	373	372
Units: Participants
All Randomized Doses (Overall) (n=373, 372)	155	172
1st Randomized Dose (n=373, 372)	101	107
2nd Randomized Dose (n=367, 355)	84	96
3rd Randomized Dose (n=305, 300)	62	82
4th Randomized Dose (n=147, 136)	14	17
5th Randomized Dose (n=23, 21)	1	3
6th Randomized Dose (n=6, 4)	0	0

No statistical analyses for this end point

Secondary: Change from baseline in Cognitive Performance as Measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) - Symbol Digits Modalities Test (SDMT)

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End point title

Change from baseline in Cognitive Performance as Measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) - Symbol Digits Modalities Test (SDMT)

End point description

BICAMS is assessing cognitive processing speed and verbal and visual memory. SDMT assesses processing speed/working memory. The SDMT presents a series of nine symbols, each paired with a single digit in a key at the top of a standard sheet of paper. Participants are asked to voice the digit associated with each symbol as rapidly as possible for 90 sec. There is a single outcome measure - the number correct over the 90 second time span. The higher the results, the better processing speed/working memory. Treatment efficacy was measured for this First Enrollment Cohort ITT population. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	602
Units: responses over 90 seconds
arithmetic mean (standard deviation)
Change atWeek 48 (n=602)	2.48 ( 10.12 )
Change atWeek 96 (n=563)	1.89 ( 9.98 )
Change atWeek 144 (n=506)	3.33 ( 9.31 )
Change at Week 192 (n=506)	4.38 ( 10.38 )

No statistical analyses for this end point

Secondary: Substudy: IRRs Leading to Treatment Discontinuation

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End point title

Substudy: IRRs Leading to Treatment Discontinuation

End point description

ITT Population included all randomized participants in shorter infusion sub study.

End point type

Secondary

End point timeframe

From Week 24 to Week 144

End point values	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Number of subjects analysed	373	372
Units: symptoms	0	0

No statistical analyses for this end point

Secondary: Substudy: Severity of IRRs

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End point title

Substudy: Severity of IRRs

End point description

The number of participants with IRRs by most extreme intensity were reported (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 =life-threatening, grade 5 = fatal). Multiple IRRs in one participant are counted only once at the most extreme (highest) intensity observed. ITT Population included all randomized participants in shorter infusion sub study. Number analyzed is the number of participants with IRR.

End point type

Secondary

End point timeframe

From Week 24 to Week 144

End point values	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Number of subjects analysed	373	372
Units: Participants
Grade 1 (Mild)	88	92
Grade 2 (Moderate)	66	76
Grade 3 (Severe)	1	4
Grade 4 (Life-Threatening)	0	0
Grade 5 (Fatal)	0	0

No statistical analyses for this end point

Secondary: Substudy: Number of IRR Symptoms

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End point title

Substudy: Number of IRR Symptoms

End point description

ITT Population included all randomized participants in shorter infusion sub study. Overall number of participants analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with an infusion.

End point type

Secondary

End point timeframe

From Week 24 to Week 144

End point values	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Number of subjects analysed	373	372
Units: symptoms
1st randomized dose Overall Participants with IRR	471	458

No statistical analyses for this end point

Secondary: Change from baseline in Cognitive Performance as Measured by BICAMS -California Verbal Learning Test-II (CVLT-II)

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End point title

Change from baseline in Cognitive Performance as Measured by BICAMS -California Verbal Learning Test-II (CVLT-II)

End point description

BICAMS assesses cognitive processing speed and verbal and visual memory. The CLVT-II is an assessment of verbal learning and memory which measures recall and recognition scores, encoding strategies, learning rates and error types. A list learning task with 16 words from 4 semantic categories are read over a series of 5 list presentations. Recall is assessed after learning and at a 20-minute delay. The maximum possible score is 80 and a minimum is 0. A higher score indicated better recall. Treatment efficacy was measured for this First Enrollment Cohort ITT population. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	130
Units: score on a scale
arithmetic mean (standard deviation)
Change at Week 48 (n=130)	2.02 ( 8.29 )
Change at Week 96 (n=119)	2.71 ( 9.25 )
Change at Week 144 (n=97)	3.99 ( 7.60 )
Change at Week 192 (n=108)	4.28 ( 13.76 )

No statistical analyses for this end point

Secondary: Change from baseline in Cognitive Performance as Measured by BICAMS - Brief Visuospatial Memory Test-Revised (BVMT-R)

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End point title

Change from baseline in Cognitive Performance as Measured by BICAMS - Brief Visuospatial Memory Test-Revised (BVMT-R)

End point description

BICAMS assesses cognitive processing speed and verbal and visual memory. BVMT-R assesses visuospatial memory. In this test, six abstract designs are presented for 10 sec. The display is removed from view and patients render the stimuli via pencil on paper manual responses. Each design receives from 0 to 2 points representing accuracy and location. There are three learning trials, and the outcome measure is the total number of points earned over the three learning trials, thus the scale range is 0-36. The higher the result, the better visual/spatial memory. Treatment efficacy was measured for this First Enrollment Cohort ITT population. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at the specified timepoints.

End point type

Secondary

End point timeframe

Baseline, Weeks 48, 96, 144, 192

End point values	Main Study - Ocrelizumab
Number of subjects analysed	643
Units: points on a scale
arithmetic mean (standard deviation)
Baseline (n=643)	23.69 ( 6.44 )
Change at Week 48 (n=587)	-0.71 ( 5.31 )
Change at Week 96 (n=566)	0.82 ( 5.68 )
Change at Week 144 (n=489)	3.15 ( 5.37 )
Change at Week 192 (n=489)	1.06 ( 7.09 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Main study: Up to 4 Years Sub-study: Week 24 to Week 144

Adverse event reporting additional description

Safety population included all enrolled participants who received any dose or part of a dose of ocrelizumab. Three participants from the 'Substudy - Conventional Infusion' arm received shorter infusions of ocrelizumab. Hence, these participants are represented in the 'Substudy - Shorter Infusion' arm for safety assessment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Ocrelizumab

Reporting group description

Ocrelizumab was administered IV as two 300-mg infusions on Days 1 and 15, followed by one 600-mg infusion dose every 24 weeks (+/- 14 days) for a maximum of 8 doses throughout the 192 weeks treatment period.

Reporting group title

Substudy - Conventional Infusion

Reporting group description

Ocrelizumab was administered as 600 mg IV infused over approximately 3.5 hours every 24 weeks throughout the treatment period.

Reporting group title

Substudy - Shorter Infusion

Reporting group description

Ocrelizumab was administered as 600 mg IV infused over approximately 2 hours and saline for remaining 1.5 hours, every 24 weeks throughout the treatment period.

Serious adverse events	Ocrelizumab	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Total subjects affected by serious adverse events
subjects affected / exposed	184 / 1225 (15.02%)	21 / 370 (5.68%)	19 / 375 (5.07%)
number of deaths (all causes)	13	2	1
number of deaths resulting from adverse events	4	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BENIGN BREAST NEOPLASM
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEOPLASM PROGRESSION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MALIGNANT MELANOMA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INVASIVE DUCTAL BREAST CARCINOMA
subjects affected / exposed	3 / 1225 (0.24%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTRADUCTAL PAPILLOMA OF BREAST
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PAPILLARY THYROID CANCER
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UTERINE LEIOMYOMA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL CELL CARCINOMA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
PHLEBITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
ABORTION INDUCED
subjects affected / exposed	4 / 1225 (0.33%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
ABORTION
subjects affected / exposed	3 / 1225 (0.24%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABORTION SPONTANEOUS
subjects affected / exposed	7 / 1225 (0.57%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	2 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMORRHAGE IN PREGNANCY
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ectopic pregnancy
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
PAIN
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Reproductive system and breast disorders
OVARIAN CYST
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CERVICAL DYSPLASIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOMETRIOSIS
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UTERINE POLYP
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VULVOVAGINAL PAIN
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
NASAL SEPTUM DEVIATION
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NASAL TURBINATE HYPERTROPHY
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	2 / 1225 (0.16%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
MENTAL STATUS CHANGES
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MAJOR DEPRESSION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEPRESSIVE SYMPTOM
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEPRESSION
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COMPLETED SUICIDE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BIPOLAR DISORDER
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANXIETY
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST-TRAUMATIC STRESS DISORDER
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SOMATIC SYMPTOM DISORDER
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUICIDAL IDEATION
subjects affected / exposed	2 / 1225 (0.16%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUICIDE ATTEMPT
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
TRANSAMINASES INCREASED
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CAPILLARY PERMEABILITY INCREASED
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
FIBULA FRACTURE
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FRACTURE DISPLACEMENT
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANKLE FRACTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CONCUSSION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	6 / 1225 (0.49%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	7 / 7	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIGAMENT RUPTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIGAMENT SPRAIN
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LOWER LIMB FRACTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MULTIPLE INJURIES
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OVERDOSE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RADIUS FRACTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SKIN LACERATION
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TENDON RUPTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WRIST FRACTURE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
CRI DU CHAT SYNDROME
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
PERICARDITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PALPITATIONS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
DYSTONIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CERVICOBRACHIAL SYNDROME
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEADACHE
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MIGRAINE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MULTIPLE SCLEROSIS RELAPSE
subjects affected / exposed	9 / 1225 (0.73%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEURALGIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TRIGEMINAL NEURALGIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TOXIC ENCEPHALOPATHY
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEIZURE
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RADICULOPATHY
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
VISUAL IMPAIRMENT
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ANAL FISTULA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL PERFORATION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL SPASM
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COLITIS ULCERATIVE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS ACUTE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BILE DUCT STONE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLELITHIASIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
ERYTHEMA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
URINARY RETENTION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEPHROLITHIASIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
THYROID CYST
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRITIS
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
APPENDICITIS
subjects affected / exposed	5 / 1225 (0.41%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EPIDIDYMITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FALLOPIAN TUBE ABSCESS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	23 / 1225 (1.88%)	2 / 370 (0.54%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	6 / 23	0 / 2	0 / 1
deaths causally related to treatment / all	2 / 7	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19 PNEUMONIA
subjects affected / exposed	17 / 1225 (1.39%)	0 / 370 (0.00%)	2 / 375 (0.53%)
occurrences causally related to treatment / all	6 / 18	0 / 0	0 / 2
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 1
GASTROENTERITIS
subjects affected / exposed	3 / 1225 (0.24%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OTITIS MEDIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ORCHITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIC SEPSIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENINGITIS VIRAL
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MENINGITIS BACTERIAL
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HEPATITIS A
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENITAL HERPES
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROENTERITIS VIRAL
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PENILE ABSCESS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERITONSILLAR ABSCESS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	5 / 1225 (0.41%)	0 / 370 (0.00%)	2 / 375 (0.53%)
occurrences causally related to treatment / all	2 / 5	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TYPHOID FEVER
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SUBACUTE ENDOCARDITIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RENAL ABSCESS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS
subjects affected / exposed	4 / 1225 (0.33%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA MYCOPLASMAL
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	8 / 1225 (0.65%)	0 / 370 (0.00%)	1 / 375 (0.27%)
occurrences causally related to treatment / all	3 / 8	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VAGINAL INFECTION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VARICELLA
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VIRAL INFECTION
subjects affected / exposed	2 / 1225 (0.16%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS INADEQUATE CONTROL
subjects affected / exposed	1 / 1225 (0.08%)	0 / 370 (0.00%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	1 / 1225 (0.08%)	1 / 370 (0.27%)	0 / 375 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Ocrelizumab	Substudy - Conventional Infusion	Substudy - Shorter Infusion
Total subjects affected by non serious adverse events
subjects affected / exposed	1110 / 1225 (90.61%)	251 / 370 (67.84%)	276 / 375 (73.60%)
Injury, poisoning and procedural complications
INFUSION RELATED REACTION
subjects affected / exposed	674 / 1225 (55.02%)	154 / 370 (41.62%)	172 / 375 (45.87%)
occurrences all number	1930	297	350
Nervous system disorders
HEADACHE
subjects affected / exposed	295 / 1225 (24.08%)	46 / 370 (12.43%)	37 / 375 (9.87%)
occurrences all number	639	80	50
PARAESTHESIA
subjects affected / exposed	98 / 1225 (8.00%)	20 / 370 (5.41%)	15 / 375 (4.00%)
occurrences all number	124	25	17
DIZZINESS
subjects affected / exposed	88 / 1225 (7.18%)	12 / 370 (3.24%)	10 / 375 (2.67%)
occurrences all number	102	12	10
HYPOAESTHESIA
subjects affected / exposed	91 / 1225 (7.43%)	17 / 370 (4.59%)	11 / 375 (2.93%)
occurrences all number	113	20	14
General disorders and administration site conditions
FATIGUE
subjects affected / exposed	201 / 1225 (16.41%)	28 / 370 (7.57%)	28 / 375 (7.47%)
occurrences all number	274	32	29
PYREXIA
subjects affected / exposed	98 / 1225 (8.00%)	7 / 370 (1.89%)	8 / 375 (2.13%)
occurrences all number	139	12	9
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed	91 / 1225 (7.43%)	18 / 370 (4.86%)	9 / 375 (2.40%)
occurrences all number	116	18	10
NAUSEA
subjects affected / exposed	87 / 1225 (7.10%)	8 / 370 (2.16%)	10 / 375 (2.67%)
occurrences all number	109	11	10
Respiratory, thoracic and mediastinal disorders
OROPHARYNGEAL PAIN
subjects affected / exposed	113 / 1225 (9.22%)	7 / 370 (1.89%)	9 / 375 (2.40%)
occurrences all number	156	7	13
COUGH
subjects affected / exposed	126 / 1225 (10.29%)	13 / 370 (3.51%)	18 / 375 (4.80%)
occurrences all number	160	15	19
Skin and subcutaneous tissue disorders
RASH
subjects affected / exposed	84 / 1225 (6.86%)	9 / 370 (2.43%)	8 / 375 (2.13%)
occurrences all number	109	9	8
Psychiatric disorders
INSOMNIA
subjects affected / exposed	81 / 1225 (6.61%)	12 / 370 (3.24%)	9 / 375 (2.40%)
occurrences all number	85	12	9
DEPRESSION
subjects affected / exposed	75 / 1225 (6.12%)	11 / 370 (2.97%)	11 / 375 (2.93%)
occurrences all number	88	13	14
ANXIETY
subjects affected / exposed	62 / 1225 (5.06%)	10 / 370 (2.70%)	8 / 375 (2.13%)
occurrences all number	69	11	8
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	132 / 1225 (10.78%)	17 / 370 (4.59%)	15 / 375 (4.00%)
occurrences all number	169	21	20
MUSCLE SPASMS
subjects affected / exposed	68 / 1225 (5.55%)	11 / 370 (2.97%)	11 / 375 (2.93%)
occurrences all number	76	12	12
BACK PAIN
subjects affected / exposed	115 / 1225 (9.39%)	12 / 370 (3.24%)	14 / 375 (3.73%)
occurrences all number	147	15	16
PAIN IN EXTREMITY
subjects affected / exposed	133 / 1225 (10.86%)	18 / 370 (4.86%)	14 / 375 (3.73%)
occurrences all number	172	24	14
Infections and infestations
PHARYNGITIS
subjects affected / exposed	63 / 1225 (5.14%)	8 / 370 (2.16%)	9 / 375 (2.40%)
occurrences all number	81	8	9
COVID-19
subjects affected / exposed	291 / 1225 (23.76%)	14 / 370 (3.78%)	13 / 375 (3.47%)
occurrences all number	344	14	13
SINUSITIS
subjects affected / exposed	109 / 1225 (8.90%)	8 / 370 (2.16%)	13 / 375 (3.47%)
occurrences all number	144	12	14
ORAL HERPES
subjects affected / exposed	63 / 1225 (5.14%)	5 / 370 (1.35%)	9 / 375 (2.40%)
occurrences all number	142	18	11
INFLUENZA
subjects affected / exposed	96 / 1225 (7.84%)	8 / 370 (2.16%)	9 / 375 (2.40%)
occurrences all number	119	8	9
BRONCHITIS
subjects affected / exposed	62 / 1225 (5.06%)	6 / 370 (1.62%)	8 / 375 (2.13%)
occurrences all number	84	6	11
NASOPHARYNGITIS
subjects affected / exposed	320 / 1225 (26.12%)	58 / 370 (15.68%)	50 / 375 (13.33%)
occurrences all number	646	81	70
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	196 / 1225 (16.00%)	28 / 370 (7.57%)	35 / 375 (9.33%)
occurrences all number	301	34	41
URINARY TRACT INFECTION
subjects affected / exposed	184 / 1225 (15.02%)	20 / 370 (5.41%)	24 / 375 (6.40%)
occurrences all number	319	30	30

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Were there any global substantial amendments to the protocol? Yes

22 Nov 2016

28 Mar 2017

27 Jul 2018

30 Jul 2018

30 Dec 2018

23 Apr 2019

28 Apr 2020

17 Sep 2020

23 Mar 2021

V10

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 Trial Results: An Open-label, Single-arm Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Patients With Early Stage Relapsing Remitting Multiple Sclerosis

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End points

End points

Primary: Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS)

Primary: Time to Onset of Confirmed Disability Progression (CDP) Sustained for at Least 24 Weeks and 48 Weeks as Measured Using Expanded Disability Status Scale (EDSS)

Primary: Percentage of Participants with 24-Week and 48-Week Confirmed Disability Improvement (CDI) During the Year 1 Treatment Period, as Measured Using EDSS

Primary: Percentage of Participants with 24-Week and 48-Week Confirmed Disability Improvement (CDI) During the Year 1 Treatment Period, as Measured Using EDSS

Primary: Percentage of Participants with 24-Week and 48-Week CDI During the Year 2 Treatment Period, as Measured Using EDSS

Primary: Percentage of Participants with 24-Week and 48-Week CDI During the Year 2 Treatment Period, as Measured Using EDSS

Primary: Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 2, as Measured Using EDSS

Primary: Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 2, as Measured Using EDSS

Primary: Percentage of Participants With 24-Week and 48-Week CDI at Year 4, as Measured Using EDSS

Primary: Percentage of Participants With 24-Week and 48-Week CDI at Year 4, as Measured Using EDSS

Primary: Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 4, as Measured Using EDSS

Primary: Percentage of Participants Event-free for CDP Sustained for at Least 24 and 48 Weeks at Year 4, as Measured Using EDSS

Primary: Mean Change From Baseline in EDSS Score at Week 24

Primary: Mean Change From Baseline in EDSS Score at Week 24

Primary: Mean Change From Baseline in EDSS Score at Week 120

Primary: Mean Change From Baseline in EDSS Score at Week 120

Primary: Mean Change From Baseline in EDSS Score at Week 96

Primary: Mean Change From Baseline in EDSS Score at Week 96

Primary: Mean Change From Baseline in EDSS Score at Week 72

Primary: Mean Change From Baseline in EDSS Score at Week 72

Primary: Mean Change From Baseline in EDSS Score at Week 48

Primary: Mean Change From Baseline in EDSS Score at Week 48

Primary: Mean Change From Baseline in EDSS Score at Week 144

Primary: Mean Change From Baseline in EDSS Score at Week 144

Primary: Mean Change From Baseline in EDSS Score at Week 168

Primary: Mean Change From Baseline in EDSS Score at Week 168

Primary: Mean Change From Baseline in EDSS Score at Week 192

Primary: Mean Change From Baseline in EDSS Score at Week 192

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 2, As Measured Using EDSS

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability Compared to Baseline at Year 1, As Measured Using EDSS

Primary: Annualized Relapse Rate

Primary: Annualized Relapse Rate

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 3, As Measured Using EDSS

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 3, As Measured Using EDSS

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 4, As Measured Using EDSS

Primary: Percentage of Participants Who Have Improved, Stable, or Worsened Disability at Year 4, As Measured Using EDSS

Primary: Percentage of Participants Event-Free for CDP Sustained for at Least 24 and 48 Weeks at Year 1, as Measured Using EDSS

Primary: Percentage of Participants Event-Free for CDP Sustained for at Least 24 and 48 Weeks at Year 1, as Measured Using EDSS

Primary: Percentage of Participants without Protocol-Defined Event of Disease Activity

Primary: Percentage of Participants without Protocol-Defined Event of Disease Activity

Primary: Percentage of Participants without Relapse

Primary: Percentage of Participants without Relapse

Primary: Sub Study: Number of Participants with IRRs Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy

Primary: Sub Study: Number of Participants with IRRs Occurring During or Within 24 Hours Following the First Infusion After Randomization to the Shorter Infusion Substudy

Secondary: Percentage of Participants Who Are Relapse Free

Secondary: Percentage of Participants Who Are Relapse Free

Secondary: Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD)

Secondary: Percentage of Participants With no Evidence of Progression Sustained for At Least 24 Weeks and no Active Disease (NEPAD)

Secondary: Percentage of Participants With No Evidence of Protocol Defined Disease Activity

Secondary: Percentage of Participants With No Evidence of Protocol Defined Disease Activity

Secondary: Change from Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score

Secondary: Change from Baseline in MSFC Composite Timed 25 Foot Walk Test (T25FW) Score

Secondary: Change from Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score

Secondary: Change from Baseline in MSFC Composite 9 Hole Peg Test (9HPT) Score

Secondary: Change from Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score

Secondary: Change from Baseline in MSFC Composite (Paced Auditory Serial Addition Test [PASAT]) Score

Secondary: Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI

Secondary: Total Number of T1 Gd-Enhancing Lesions as Detected by Brain MRI

Secondary: Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI

Secondary: Total Number of New and/or Enlarging T2 Lesion as Detected by Brain MRI

Secondary: Change from baseline in total T1 hypointense lesion volume as Detected by Brain MRI

Secondary: Change from baseline in total T1 hypointense lesion volume as Detected by Brain MRI

Secondary: Secondary: Change from Baseline in Multiple Sclerosis Functional Composite Score (MSFC) Total

Secondary: Secondary: Change from Baseline in Multiple Sclerosis Functional Composite Score (MSFC) Total

Secondary: Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI

Secondary: Total Number of Fluid-Attenuated Inversion-Recovery (FLAIR) Lesion as Detected by Brain MRI

Secondary: Change From Baseline in Brain Volume as Detected by Brain MRI

Secondary: Change From Baseline in Brain Volume as Detected by Brain MRI

Clinical Trial Results:
An Open-label, Single-arm Study to Evaluate the Effectiveness and Safety of Ocrelizumab in Patients With Early Stage Relapsing Remitting Multiple Sclerosis