A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis

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ClinicalTrials.gov Identifier: NCT01247324

Recruitment Status : Completed

First Posted : November 24, 2010

Results First Posted : July 18, 2017

Last Update Posted : March 4, 2024

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Sponsor:

Information provided by (Responsible Party):

Hoffmann-La Roche

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Relapsing Multiple Sclerosis
Interventions	Drug: Interferon beta-1a Drug: Ocrelizumab-matching placebo Drug: Ocrelizumab Drug: Interferon beta-1a-matching placebo
Enrollment	821

Participant Flow

Recruitment Details

1051 participants were screened for entry into study. 821 participants were entered into double-blind treatment period. Participants who completed the 96-week double-blind treatment had option to enter a single group, active treatment open label extension, providing they fulfilled the eligibility criteria and at study completion date, all participants are provided opportunity to rollover and continue treatment and/or safety follow-up under new extension protocol MN43964 (NCT05269004).

Pre-assignment Details

In error, the study completion status for 5 participants in WA21092 was registered as 'Sponsor Termination' in the study eCRF. However, all 5 participants were successfully enrolled into MN43964 and thus have completed the WA21092 study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Period Title: Overall Study
Started	411	410
Entered Open-Label Extension	326	352
Completed	226	239
Not Completed	185	171
Reason Not Completed
Death	6	10
Physician Decision	2	3
Non-compliance with study drug	3	0
Lack of Efficacy	24	14
Non-compliance	3	2
Pregnancy	5	10
Protocol Violation	1	1
Reason not specified	42	32
Consent withdrawn by participant	41	56
Adverse Event	49	35
Lost to Follow-up	3	6
Study Terminated by Sponsor	4	1
Missing	2	1

Baseline Characteristics

Arm/Group Title		Interferon Beta-1a 44 mcg SC	Ocrelizumab	Total
Arm/Group Description		Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...	Total of all reporting groups
Arm/Group Description		Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.	Total of all reporting groups
Overall Number of Baseline Participants		411	410	821
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Intent-to-treat (ITT) population included all randomized participants in the study.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	411 participants	410 participants	821 participants
		36.9 (9.3)	37.1 (9.3)	37.0 (9.3)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	411 participants	410 participants	821 participants
	Female	272 66.2%	270 65.9%	542 66.0%
	Male	139 33.8%	140 34.1%	279 34.0%

Outcome Measures

1.Primary Outcome


Title	Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks
Description	ARR was protocol-defined and calculated as the total number of relapse...
Description	ARR was protocol-defined and calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of exposure to that treatment.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all randomized participants in the study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	411	410
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: relapses/participant year of treatment
	0.292 (0.235 to 0.361)	0.156 (0.122 to 0.200)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	Adjusted by Geographical Region (US vs. Rest of World) and baseline EDSS (<4.0 vs. >=4.0).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Negative Binomial Model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.536
	Confidence Interval	(2-Sided) 95% 0.4 to 0.719
	Estimation Comments	Rate ratio was calculated as Ocrelizumab ARR/Interferon beta-1a 44 mcg SC ARR.

2.Secondary Outcome


Title	Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period
Description	Disability progression was defined as an increase in the Expanded Disa...
Description	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Time Frame	Week 108

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	411	410
Median (Full Range) Unit of Measure: weeks
	NA ^[1] (0 to 103)	NA ^[1] (0 to 108)

[1]

Median of time to onset of CDP was not achieved due to low number of participants with events. The full-range values are censored observations.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	Time to onset CDP at week 12
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	= 0.0139
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95% 0.37 to 0.90
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment
Description	The total number of T1 gadolinium-enhancing lesions for all participan...
Description	The total number of T1 gadolinium-enhancing lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	411	410
Measure Type: Number Unit of Measure: lesions
	337	21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Negative Binomial Model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.058
	Confidence Interval	95% 0.032 to 0.104
	Estimation Comments	Adjusted by baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. rest-of-world). Adjusted rate ratio was calculated as Ocrelizumab adjusted rate/Interferon beta-1a 44 mcg SC adjusted rate.

4.Secondary Outcome


Title	Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
Description	The total number of new and/or enlarging T2 lesions for all participan...
Description	The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 24, 48, and 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	411	410
Measure Type: Number Unit of Measure: lesions
	1916	430

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Negative Binomial Model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.229
	Confidence Interval	95% 0.174 to 0.300
	Estimation Comments	Adjusted by baseline T2 lesion (present or not), baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. rest-of-world). Adjusted rate ratio was calculated as Ocrelizumab adjusted rate/Interferon beta-1a 44 mcg SC adjusted rate.

5.Secondary Outcome


Title	Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks
Description	Disability improvement was assessed only for the subgroup of participa...
Description	Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, number of participants analyzed signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	306	310
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	12.42 (8.94 to 16.64)	20.00 (15.69 to 24.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	= 0.0106
	Comments	[Not Specified]
	Method	CMH Chi-Squared test (stratified)
	Comments	CMH (Cochran-Mantel-Haenszel) Chi-Squared test Stratified by Geographical Region (US vs. Rest of World) and Baseline EDSS (<4.0 vs. >=4.0)

Method of Estimation	Estimation Parameter	Relative risk (stratified)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95% 1.11 to 2.33
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period
Description	Disability progression was defined as an increase in the Expanded Disa...
Description	Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). This outcome measure was considered confirmatory only when results of both studies WA21092 and WA21093 were combined. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Time Frame	Week 108

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	411	410
Median (Full Range) Unit of Measure: weeks
	NA ^[1] (0 to 103)	NA ^[1] (0 to 108)

[1]

Median of time to onset of CDP was not achieved due to low number of participants with events. The full-range values are censored observations.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	Time to onset CDP at week 24
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	= 0.0278
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95% 0.34 to 0.95
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Number of T1 Hypointense Lesions During the Double-Blind Treatment
Description	The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) ...
Description	The total number of new T1-Hypo-Intense Lesions (Chronic Black Holes) for all participants in the treatment group was calculated as the sum of the individual number of new lesions at Weeks 24, 48, and 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	411	410
Measure Type: Number Unit of Measure: lesions
	1307	564

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Negative Binomial Model
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted rate ratio
	Estimated Value	0.428
	Confidence Interval	95% 0.328 to 0.557
	Estimation Comments	Adjusted by baseline T1-hypointense lesion count, baseline EDSS (<4.0 vs. >=4.0) and geographical region (US vs. rest-of-world). Adjusted rate ratio was calculated as Ocrelizumab adjusted rate/Interferon beta-1a 44 mcg SC adjusted rate.

8.Secondary Outcome


Title	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96
Description	MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-H...
Description	MSFC score consists of: A) Timed 25-Foot walk; B) 9-Hole Peg Test (9-HPT); and C) Paced Auditory Serial Addition Test (PASAT-3 version). The MSFCS is based on the concept that scores for these three dimensions (arm, leg, and cognitive function) are combined to create a single score (the MSFC) that can be used to detect change over time in a group of participants with MS. Since the three primary measures differ in what they actually measure, a common composite score for the three different measures i.e., Z- score was selected for the purpose. MSFC Score = {Z arm, average + Z leg, average + Z cognitive} / 3.0. The results from each of these three tests are transformed into Z-scores and averaged to yield a composite score for each participant at each time point. A score of +1 indicates that, on average, an individual scored 1 standard deviation (SD) better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, n signifies the number of participants evaluable at specified time points.


Arm/Group Title		Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:		Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:		Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed		411	410
Mean (Standard Error) Unit of Measure: Z-score
Unadjusted Baseline mean	Number Analyzed	359 participants	360 participants
Unadjusted Baseline mean		0.028 (0.034)	-0.012 (0.040)
Adjusted Week 96 mean	Number Analyzed	308 participants	322 participants
Adjusted Week 96 mean		0.174 (0.031)	0.213 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	= 0.3261
	Comments	[Not Specified]
	Method	mixed-effect model of repeated measures
	Comments	Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix.

Method of Estimation	Estimation Parameter	Difference in Adjusted Means
	Estimated Value	0.039
	Confidence Interval	(2-Sided) 95% -0.039 to 0.116
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.039
	Estimation Comments	Difference in adjusted means was calculated as Ocrelizumab adjusted mean at Week 96/ Interferon beta-1a 44 mcg SC adjusted mean at Week 96.

9.Secondary Outcome


Title	Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96
Description	Brain volume was recorded as an absolute "normalized" value ...
Description	Brain volume was recorded as an absolute "normalized" value at the baseline visit then recorded at subsequent visits as a percentage change relative to the absolute value at the baseline visit. Therefore, brain volume at Week 24 was calculated as the brain volume at the baseline visit multiplied by 1 + ([percentage change in brain volume from baseline visit to Week 24]/100). Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix: Percentage Change = Brain Volume at Week 24 + Geographical Region (US vs. ROW) + Baseline EDSS (< 4.0 vs. >= 4.0) + Week + Treatment + TreatmentWeek (repeated values over Week) + Brain Volume at Week 24Week.
Time Frame	From Week 24 up to Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, number of participants analyzed signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	267	281
Mean (Standard Error) Unit of Measure: percent change
	-0.741 (0.046)	-0.572 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	= 0.0042
	Comments	[Not Specified]
	Method	mixed-effect model of repeated measures
	Comments	Estimates are from analysis based on mixed-effect model of repeated measures (MMRM) using unstructured covariance matrix.

Method of Estimation	Estimation Parameter	Difference in Adjusted Means
	Estimated Value	0.168
	Confidence Interval	(2-Sided) 95% 0.053 to 0.283
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.058
	Estimation Comments	Difference in the rate of brain volume loss: 22.8%. Difference in adjusted means was calculated as Ocrelizumab adjusted mean at Week 96/ Interferon beta-1a 44 mcg SC adjusted mean at Week 96.

10.Secondary Outcome


Title	Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96
Description	The SF-36 is a multi-purpose, short-form health survey with 36 questio...
Description	The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t- scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Descriptive statistics at baseline include participants with assessment at baseline and at least one post- baseline value. ITT population included all randomized participants in the study. Here, n signifies the number of participants evaluable at specified time points.


Arm/Group Title		Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:		Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:		Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed		411	410
Mean (Standard Error) Unit of Measure: t-score
Unadjusted Baseline mean	Number Analyzed	338 participants	357 participants
Unadjusted Baseline mean		45.399 (0.529)	45.065 (0.507)
Adjusted mean change at week 96	Number Analyzed	276 participants	315 participants
Adjusted mean change at week 96		-0.657 (0.475)	0.036 (0.456)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	= 0.2193
	Comments	[Not Specified]
	Method	mixed-effect model of repeated measures
	Comments	Estimates are from analysis based on mixed-effect model of repeated measures using unstructured covariance matrix.

Method of Estimation	Estimation Parameter	Difference in Adjusted Means
	Estimated Value	0.693
	Confidence Interval	(2-Sided) 95% -0.414 to 1.800
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.564
	Estimation Comments	Difference in adjusted means was calculated as Ocrelizumab adjusted mean at Week 96/ Interferon beta-1a 44 mcg SC adjusted mean at Week 96.

11.Secondary Outcome


Title	Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96
Description	NEDA was defined only for participants with a baseline EDSS score >...
Description	NEDA was defined only for participants with a baseline EDSS score >=2.0. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Participants who completed the 96- week treatment period were considered as having evidence of disease activity if at least one protocol- defined relapse (PDR), a confirmed disability progression (CDP) event or at least one MRI scan showing MRI activity (defined as Gd-enhancing T1 lesions, or new or enlarging T2 lesions) was reported during the 96-week treatment period, otherwise the participant was considered as having NEDA.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants in the study. Here, number of participants analyzed signifies number of participants who were evaluable for this outcome measure.


Arm/Group Title	Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	291	289
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	27.1 (22.1 to 32.6)	47.4 (41.5 to 53.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a 44 mcg SC, Ocrelizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	CMH Chi-Squared test (stratified)
	Comments	Analyzed using CMH test, stratified by Geographical Region (US vs. rest-of-world) and baseline EDSS (<4.0 vs. >=4.0).

Method of Estimation	Estimation Parameter	Relative risk (stratified)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95% 1.39 to 2.17
	Estimation Comments	[Not Specified]

12.Secondary Outcome


Title	Number of Participants With Adverse Events (AEs)
Description	AEs included infusion related reactions (IRRs) and serious MS relapses...
Description	AEs included infusion related reactions (IRRs) and serious MS relapses, but excluded non-serious MS relapses. Serious Adverse Events (SAEs) included serious MS relapses and serious IRRs.
Time Frame	Baseline up to 588 weeks

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received any study drug.


Arm/Group Title	Interferon Beta-1a + Placebo (Double Blind Period)	Ocrelizumab + Placebo (Double Blind Period)	Interferon Beta-1a + Placebo (Open Label Extension)	Ocrelizumab + Placebo (Open Label Extension)
Arm/Group Description:	Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...	During the OLE phase, all participa...	During the OLE phase, all participa...
Arm/Group Description:	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.	During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.	During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
Overall Number of Participants Analyzed	409	408	326	352
Measure Type: Number Unit of Measure: Participants
	331	327	302	319

13.Secondary Outcome


Title	Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC)
Description	AUC represents total drug exposure for one dosing interval after the 4...
Description	AUC represents total drug exposure for one dosing interval after the 4th dose.
Time Frame	Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96

Outcome Measure Data

Analysis Population Description

The pharmacokinetics (PK) population included all participants in the ocrelizumab group who had at least 1 measurable concentration value.


Arm/Group Title	Ocrelizumab
Arm/Group Description:	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed	393
Mean (Standard Deviation) Unit of Measure: micrograms per milliliter*day
	3513 (955)

14.Secondary Outcome


Title	Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab
Description	Number of participants positive for anti-drug antibodies (ADAs) to ocr...
Description	Number of participants positive for anti-drug antibodies (ADAs) to ocrelizumab is the number of post- baseline evaluable participants determined to have treatment-induced ADA or treatment-enhanced ADA during the study period.
Time Frame	Baseline up to week 96

Outcome Measure Data

Analysis Population Description

Baseline evaluable participants with an ADA assay result from a baseline sample(s). The safety population included all participants who received any study drug. Here, n signifies the number of participants evaluable at the specified time points.


Arm/Group Title		Interferon Beta-1a 44 mcg SC	Ocrelizumab
Arm/Group Description:		Interferon beta-1a 44 mcg SC inject...	Ocrelizumab 600 mg intravenous (IV)...
Arm/Group Description:		Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).	Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.
Overall Number of Participants Analyzed		409	408
Measure Type: Number Unit of Measure: Participants
Positive sample at baseline	Number Analyzed	397 participants	396 participants
Positive sample at baseline		2	1
Positive for ADA post-baseline	Number Analyzed	401 participants	402 participants
Positive for ADA post-baseline		2	1

Adverse Events

Time Frame	Baseline to approximately 588 weeks
Adverse Event Reporting Description	The safety population includes all enrolled patients who have received at least one dose of any study drug. In the open-label extension (OLE) period, all participants from the double blind period (DBP) had the option to receive ocrelizumab.

Arm/Group Title	Interferon Beta -1a + Placebo (Double Blind Period)		Ocrelizumab + Placebo (Double Blind Period)		Interferon Beta-1a + Placebo (Open Label Extension)		Ocrelizumab + Placebo (Open Label Extension)
Arm/Group Description	Interferon beta-1a 44 mcg SC inject...		Ocrelizumab 600 mg intravenous (IV)...		During the OLE phase, all participa...		During the OLE phase, all participa...
Arm/Group Description	Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).		Ocrelizumab 600 mg intravenous (IV) as 300 mg infusions on Days 1 and 15 for the first dose and as a single infusion of 600 mg for all subsequent infusions every 24 weeks, with placebo injections matching interferon beta-1a SC three times per week.		During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.		During the OLE phase, all participants received ocrelizumab 600-mg IV infusion every 24 weeks.
All-Cause Mortality
	Interferon Beta -1a + Placebo (Double Blind Period)		Ocrelizumab + Placebo (Double Blind Period)		Interferon Beta-1a + Placebo (Open Label Extension)		Ocrelizumab + Placebo (Open Label Extension)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/409 (0.24%)		0/408 (0.00%)		6/326 (1.84%)		11/352 (3.13%)
Serious Adverse Events Serious Adverse Events
	Interferon Beta -1a + Placebo (Double Blind Period)		Ocrelizumab + Placebo (Double Blind Period)		Interferon Beta-1a + Placebo (Open Label Extension)		Ocrelizumab + Placebo (Open Label Extension)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/409 (7.82%)		28/408 (6.86%)		109/326 (33.44%)		116/352 (32.95%)
Blood and lymphatic system disorders
ANAEMIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	2/352 (0.57%)	2
IRON DEFICIENCY ANAEMIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
LEUKOPENIA ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	2/326 (0.61%)	2	0/352 (0.00%)	0
Cardiac disorders
ACUTE CORONARY SYNDROME ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
ACUTE MYOCARDIAL INFARCTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	3/326 (0.92%)	3	0/352 (0.00%)	0
ANGINA PECTORIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	4/352 (1.14%)	4
ANGINA UNSTABLE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
ATRIAL FIBRILLATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	2/352 (0.57%)	4
ATRIAL FLUTTER ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	2	0/326 (0.00%)	0	1/352 (0.28%)	1
ATRIOVENTRICULAR BLOCK COMPLETE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CARDIAC ARREST ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CARDIAC FAILURE CONGESTIVE ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
CONGESTIVE CARDIOMYOPATHY ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
CORONARY ARTERY DISEASE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
CORONARY ARTERY OCCLUSION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
LEFT VENTRICULAR DYSFUNCTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
MYOCARDIAL INFARCTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	4/352 (1.14%)	5
PERICARDITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Congenital, familial and genetic disorders
HYPERTROPHIC CARDIOMYOPATHY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PHIMOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Ear and labyrinth disorders
VESTIBULAR DISORDER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
Eye disorders
CATARACT ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
RETINAL ARTERY OCCLUSION ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
RETINAL DETACHMENT ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
UVEITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
VISION BLURRED ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Gastrointestinal disorders
ABDOMINAL INCARCERATED HERNIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ABDOMINAL PAIN ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
COLITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CROHN'S DISEASE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	2/352 (0.57%)	2
DIARRHOEA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	2
DYSPHAGIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
FUNCTIONAL GASTROINTESTINAL DISORDER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
GASTRIC PERFORATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
GASTRITIS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	2	0/326 (0.00%)	0	0/352 (0.00%)	0
GASTROINTESTINAL INFLAMMATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	2
GASTROINTESTINAL ULCER HAEMORRHAGE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
IMPAIRED GASTRIC EMPTYING ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
INGUINAL HERNIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	2/352 (0.57%)	2
INTRA-ABDOMINAL FLUID COLLECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
LARGE INTESTINAL STENOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PANCREATITIS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	2	0/326 (0.00%)	0	0/352 (0.00%)	0
PEPTIC ULCER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
SMALL INTESTINAL OBSTRUCTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
SUBILEUS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PANCREATITIS ACUTE ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
General disorders
CHEST PAIN ^† 1	0/409 (0.00%)	0	2/408 (0.49%)	2	1/326 (0.31%)	1	0/352 (0.00%)	0
INFLAMMATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PYREXIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	5/352 (1.42%)	5
Hepatobiliary disorders
CHOLECYSTITIS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	1/326 (0.31%)	1	1/352 (0.28%)	1
CHOLECYSTITIS CHRONIC ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
CHOLELITHIASIS ^† 1	0/409 (0.00%)	0	2/408 (0.49%)	2	1/326 (0.31%)	1	0/352 (0.00%)	0
GALLBLADDER MUCOCOELE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
LIVER DISORDER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
LIVER INJURY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PORTAL VEIN THROMBOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	2
Immune system disorders
DRUG HYPERSENSITIVITY ^† 1	1/409 (0.24%)	1	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
Infections and infestations
ABDOMINAL ABSCESS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ABSCESS LIMB ^† 1	2/409 (0.49%)	2	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
ANAL ABSCESS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
APPENDICITIS ^† 1	2/409 (0.49%)	2	0/408 (0.00%)	0	1/326 (0.31%)	1	3/352 (0.85%)	3
APPENDICITIS PERFORATED ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
BILIARY SEPSIS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
BRONCHITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
CELLULITIS ^† 1	1/409 (0.24%)	1	2/408 (0.49%)	2	0/326 (0.00%)	0	0/352 (0.00%)	0
CHOLECYSTITIS INFECTIVE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
CHRONIC SINUSITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	2
COVID-19 ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	6/326 (1.84%)	6	8/352 (2.27%)	8
COVID-19 PNEUMONIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	17/326 (5.21%)	18	20/352 (5.68%)	23
CYSTITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
DENGUE FEVER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
DEVICE RELATED INFECTION ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	1/352 (0.28%)	1
ENCEPHALITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ENDOCARDITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	2
ENTEROCOLITIS INFECTIOUS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
GASTROENTERITIS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
GENITAL HERPES SIMPLEX ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	1/352 (0.28%)	1
HERPES SIMPLEX ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
HERPES SIMPLEX MENINGITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
INFECTED DERMAL CYST ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
INFECTIVE THROMBOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
INFLUENZA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	2/352 (0.57%)	2
INJECTION SITE CELLULITIS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
LYME DISEASE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	2/326 (0.61%)	2	0/352 (0.00%)	0
MASTOIDITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	2
MENINGITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
NEUROBORRELIOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PELVIC INFLAMMATORY DISEASE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PERIORBITAL CELLULITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PERIRECTAL ABSCESS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
PERITONITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PILONIDAL DISEASE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PNEUMONIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	11/326 (3.37%)	16	6/352 (1.70%)	7
PNEUMONIA ASPIRATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PNEUMONIA BACTERIAL ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
POST-ACUTE COVID-19 SYNDROME ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PULMONARY SEPSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PULMONARY TUBERCULOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PYELONEPHRITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
PYELONEPHRITIS ACUTE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
RESPIRATORY SYNCYTIAL VIRUS INFECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
RESPIRATORY TRACT INFECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
SALPINGITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	2/352 (0.57%)	3
SALPINGO-OOPHORITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
SEPSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
SEPTIC ARTHRITIS STAPHYLOCOCCAL ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
SEPTIC SHOCK ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
SINUSITIS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
SYSTEMIC CANDIDA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
TONSILLITIS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
TOOTH ABSCESS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
TUBERCULOSIS BLADDER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
TUBO-OVARIAN ABSCESS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
URINARY TRACT INFECTION ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	4/326 (1.23%)	5	1/352 (0.28%)	1
VIRAL INFECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
WOUND INFECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Injury, poisoning and procedural complications
ACETABULUM FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ALCOHOL POISONING ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
ANKLE FRACTURE ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	2/326 (0.61%)	2	2/352 (0.57%)	2
COMMINUTED FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CONCUSSION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	2/326 (0.61%)	2	0/352 (0.00%)	0
CRANIOCEREBRAL INJURY ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
FEMORAL NECK FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
FEMUR FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	2/326 (0.61%)	2	1/352 (0.28%)	1
FIBULA FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	2/326 (0.61%)	2	0/352 (0.00%)	0
FOOT FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
FRACTURE DISPLACEMENT ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HAND FRACTURE ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
HUMERUS FRACTURE ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
INFUSION RELATED REACTION ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	1/352 (0.28%)	1
JOINT DISLOCATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
MULTIPLE INJURIES ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
MUSCLE RUPTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
MUSCLE STRAIN ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
OVERDOSE ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PERIPROSTHETIC FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
POST LUMBAR PUNCTURE SYNDROME ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
POST PROCEDURAL HAEMATOMA ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
POSTOPERATIVE RESPIRATORY FAILURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PROCEDURAL PAIN ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
RADIUS FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
SUBDURAL HAEMATOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
TENDON DISLOCATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
TENDON RUPTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
TIBIA FRACTURE ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
UPPER LIMB FRACTURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
WEIGHT DECREASED ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
Metabolism and nutrition disorders
GLUCOSE TOLERANCE IMPAIRED ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HYPERGLYCAEMIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HYPERNATRAEMIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	2	0/352 (0.00%)	0
TYPE 2 DIABETES MELLITUS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
BACK PAIN ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
CERVICAL SPINAL STENOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HAEMARTHROSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
INTERVERTEBRAL DISC PROTRUSION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
JAW CYST ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
MUSCLE SPASMS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
MUSCULOSKELETAL DISCOMFORT ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
OSTEOARTHRITIS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	1/326 (0.31%)	2	2/352 (0.57%)	2
RHABDOMYOLYSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
RHEUMATOID ARTHRITIS ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
SPINAL RETROLISTHESIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
THORACIC SPINAL STENOSIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
TRIGGER FINGER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA OF COLON ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
BASAL CELL CARCINOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
BREAST CANCER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
BREAST NEOPLASM ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
CERVIX CARCINOMA STAGE II ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
CHOLESTEATOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
COLON CANCER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
DERMATOFIBROSARCOMA PROTUBERANS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ENDOMETRIAL ADENOCARCINOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
INVASIVE BREAST CARCINOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
INVASIVE DUCTAL BREAST CARCINOMA ^† 1	0/409 (0.00%)	0	2/408 (0.49%)	2	2/326 (0.61%)	2	1/352 (0.28%)	1
MALIGNANT MELANOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	2/352 (0.57%)	2
MANTLE CELL LYMPHOMA ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
MENINGIOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
OESOPHAGEAL ADENOCARCINOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PAPILLARY THYROID CANCER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PROSTATE CANCER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
RENAL CANCER ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
SALIVARY GLAND ADENOMA ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
SQUAMOUS CELL CARCINOMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
UTERINE LEIOMYOMA ^† 1	2/409 (0.49%)	2	0/408 (0.00%)	0	3/326 (0.92%)	4	1/352 (0.28%)	1
Nervous system disorders
CARPAL TUNNEL SYNDROME ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CEREBRAL ISCHAEMIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
CEREBROVASCULAR ACCIDENT ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CERVICAL RADICULOPATHY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
DIZZINESS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	1/352 (0.28%)	1
DYSARTHRIA ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
EPILEPSY ^† 1	1/409 (0.24%)	1	1/408 (0.25%)	1	1/326 (0.31%)	1	1/352 (0.28%)	1
FACIAL PARESIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
HEADACHE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
HEMIPARESIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
MIGRAINE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
MULTIPLE SCLEROSIS RELAPSE ^† 1	3/409 (0.73%)	3	0/408 (0.00%)	0	3/326 (0.92%)	3	5/352 (1.42%)	5
MYELOPATHY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PARTIAL SEIZURES WITH SECONDARY GENERALISATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
POLYNEUROPATHY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
RUPTURED CEREBRAL ANEURYSM ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
SCIATICA ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
SEIZURE ^† 1	0/409 (0.00%)	0	2/408 (0.49%)	2	0/326 (0.00%)	0	1/352 (0.28%)	3
SYNCOPE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
TRIGEMINAL NEURALGIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
APHASIA ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
Pregnancy, puerperium and perinatal conditions
ABORTION SPONTANEOUS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ANEMBRYONIC GESTATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
CERVICAL INCOMPETENCE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PRE-ECLAMPSIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
Product Issues
DEVICE DISLOCATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Psychiatric disorders
AFFECTIVE DISORDER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ANXIETY ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
COMPLETED SUICIDE ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
DEPRESSION ^† 1	0/409 (0.00%)	0	2/408 (0.49%)	2	0/326 (0.00%)	0	0/352 (0.00%)	0
MENTAL STATUS CHANGES ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
PSYCHOGENIC TREMOR ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
SUICIDAL IDEATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	2/352 (0.57%)	2
SUICIDE ATTEMPT ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	1/326 (0.31%)	1	2/352 (0.57%)	2
Renal and urinary disorders
ACUTE KIDNEY INJURY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	2	0/352 (0.00%)	0
NEPHROLITHIASIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
URETEROLITHIASIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
URINARY RETENTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Reproductive system and breast disorders
ABNORMAL UTERINE BLEEDING ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
BENIGN PROSTATIC HYPERPLASIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
CERVICAL POLYP ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
DYSMENORRHOEA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ENDOMETRIAL HYPERTROPHY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
ENDOMETRIOSIS ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
GENITAL PROLAPSE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HEAVY MENSTRUAL BLEEDING ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	1/352 (0.28%)	1
MENOPAUSAL SYMPTOMS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
OVARIAN CYST ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	2/326 (0.61%)	2	1/352 (0.28%)	2
OVARIAN CYST RUPTURED ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PROSTATITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
UTERINE PROLAPSE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
MENORRHAGIA ^† 1	0/409 (0.00%)	0	1/408 (0.25%)	1	0/326 (0.00%)	0	0/352 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	2/352 (0.57%)	2
ASTHMA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	1/352 (0.28%)	1
CHRONIC OBSTRUCTIVE PULMONARY DISEASE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	2/326 (0.61%)	2	1/352 (0.28%)	2
DYSPNOEA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HYPERVENTILATION ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
NASAL SEPTUM DEVIATION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PLEURAL EFFUSION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
PULMONARY EMBOLISM ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	4/326 (1.23%)	4	1/352 (0.28%)	1
SINUS CONGESTION ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
Skin and subcutaneous tissue disorders
ERYTHEMA MULTIFORME ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
ERYTHEMA NODOSUM ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
HIDRADENITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	1/326 (0.31%)	1	0/352 (0.00%)	0
Surgical and medical procedures
MAMMOPLASTY ^† 1	1/409 (0.24%)	1	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
Vascular disorders
SHOCK HAEMORRHAGIC ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
VARICOSE VEIN ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	0/326 (0.00%)	0	1/352 (0.28%)	1
1 Term from vocabulary, MedDRA v25.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Interferon Beta -1a + Placebo (Double Blind Period)		Ocrelizumab + Placebo (Double Blind Period)		Interferon Beta-1a + Placebo (Open Label Extension)		Ocrelizumab + Placebo (Open Label Extension)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	257/409 (62.84%)		241/408 (59.07%)		285/326 (87.42%)		286/352 (81.25%)
Gastrointestinal disorders
DIARRHOEA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	22/326 (6.75%)	25	16/352 (4.55%)	18
NAUSEA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	12/326 (3.68%)	13	19/352 (5.40%)	22
General disorders
FATIGUE ^† 1	29/409 (7.09%)	33	21/408 (5.15%)	22	34/326 (10.43%)	52	36/352 (10.23%)	45
INFLUENZA LIKE ILLNESS ^† 1	85/409 (20.78%)	97	14/408 (3.43%)	14	0/326 (0.00%)	0	0/352 (0.00%)	0
INJECTION SITE ERYTHEMA ^† 1	73/409 (17.85%)	75	0/408 (0.00%)	0	0/326 (0.00%)	0	0/352 (0.00%)	0
PYREXIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	24/326 (7.36%)	35	25/352 (7.10%)	29
Infections and infestations
BRONCHITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	46/326 (14.11%)	65	51/352 (14.49%)	91
CONJUNCTIVITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	11/326 (3.37%)	11	19/352 (5.40%)	26
COVID-19 ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	96/326 (29.45%)	117	96/352 (27.27%)	110
CYSTITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	21/326 (6.44%)	25	16/352 (4.55%)	21
GASTROENTERITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	18/326 (5.52%)	22	16/352 (4.55%)	25
HERPES ZOSTER ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	18/326 (5.52%)	20	13/352 (3.69%)	18
INFLUENZA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	30/326 (9.20%)	33	24/352 (6.82%)	30
NASOPHARYNGITIS ^† 1	40/409 (9.78%)	52	42/408 (10.29%)	60	68/326 (20.86%)	138	73/352 (20.74%)	156
ORAL HERPES ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	18/326 (5.52%)	59	21/352 (5.97%)	63
PHARYNGITIS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	17/326 (5.21%)	20	16/352 (4.55%)	23
PNEUMONIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	19/326 (5.83%)	24	15/352 (4.26%)	15
RESPIRATORY TRACT INFECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	24/326 (7.36%)	29	24/352 (6.82%)	31
SINUSITIS ^† 1	25/409 (6.11%)	28	18/408 (4.41%)	22	41/326 (12.58%)	68	49/352 (13.92%)	75
UPPER RESPIRATORY TRACT INFECTION ^† 1	35/409 (8.56%)	44	59/408 (14.46%)	82	89/326 (27.30%)	181	90/352 (25.57%)	182
URINARY TRACT INFECTION ^† 1	56/409 (13.69%)	81	52/408 (12.75%)	92	80/326 (24.54%)	236	101/352 (28.69%)	296
VIRAL INFECTION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	19/326 (5.83%)	32	17/352 (4.83%)	24
Injury, poisoning and procedural complications
INFUSION RELATED REACTION ^† 1	31/409 (7.58%)	47	126/408 (30.88%)	236	83/326 (25.46%)	172	71/352 (20.17%)	179
FALL ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	19/326 (5.83%)	22	8/352 (2.27%)	11
Musculoskeletal and connective tissue disorders
ARTHRALGIA ^† 1	30/409 (7.33%)	35	27/408 (6.62%)	31	46/326 (14.11%)	57	29/352 (8.24%)	43
BACK PAIN ^† 1	20/409 (4.89%)	24	24/408 (5.88%)	27	32/326 (9.82%)	40	36/352 (10.23%)	46
MUSCLE SPASMS ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	19/326 (5.83%)	24	11/352 (3.13%)	12
PAIN IN EXTREMITY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	27/326 (8.28%)	34	24/352 (6.82%)	34
Nervous system disorders
HEADACHE ^† 1	54/409 (13.20%)		33/408 (8.09%)		46/326 (14.11%)	57	40/352 (11.36%)	47
HYPOAESTHESIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	19/326 (5.83%)	40	16/352 (4.55%)	23
MULTIPLE SCLEROSIS RELAPSE ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	82/326 (25.15%)	163	84/352 (23.86%)	158
PARAESTHESIA ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	17/326 (5.21%)	28	18/352 (5.11%)	23
Psychiatric disorders
ANXIETY ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	15/326 (4.60%)	17	23/352 (6.53%)	28
DEPRESSION ^† 1	26/409 (6.36%)	26	27/408 (6.62%)	31	24/326 (7.36%)	28	45/352 (12.78%)	55
INSOMNIA ^† 1	15/409 (3.67%)	15	21/408 (5.15%)	22	0/326 (0.00%)	0	0/352 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
COUGH ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	26/326 (7.98%)	32	30/352 (8.52%)	46
Skin and subcutaneous tissue disorders
RASH ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	19/326 (5.83%)	23	8/352 (2.27%)	12
Vascular disorders
HYPERTENSION ^† 1	0/409 (0.00%)	0	0/408 (0.00%)	0	23/326 (7.06%)	24	20/352 (5.68%)	23
1 Term from vocabulary, MedDRA v25.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Medical Communications
Organization:	Hoffmann-La Roche
Phone:	800-821-8590
EMail:	genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Arnold DL, Sprenger T, Bar-Or A, Wolinsky JS, Kappos L, Kolind S, Bonati U, Magon S, van Beek J, Koendgen H, Bortolami O, Bernasconi C, Gaetano L, Traboulsee A. Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS. Mult Scler. 2022 Oct;28(12):1927-1936. doi: 10.1177/13524585221097561. Epub 2022 Jun 7.

Krishnan AP, Song Z, Clayton D, Gaetano L, Jia X, de Crespigny A, Bengtsson T, Carano RAD. Joint MRI T1 Unenhancing and Contrast-enhancing Multiple Sclerosis Lesion Segmentation with Deep Learning in OPERA Trials. Radiology. 2022 Mar;302(3):662-673. doi: 10.1148/radiol.211528. Epub 2021 Dec 14.

Giovannoni G, Kappos L, de Seze J, Hauser SL, Overell J, Koendgen H, Manfrini M, Wang Q, Wolinsky JS. Risk of requiring a walking aid after 6.5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials. Eur J Neurol. 2022 Apr;29(4):1238-1242. doi: 10.1111/ene.14823. Epub 2021 May 5.

Hauser SL, Kappos L, Arnold DL, Bar-Or A, Brochet B, Naismith RT, Traboulsee A, Wolinsky JS, Belachew S, Koendgen H, Levesque V, Manfrini M, Model F, Hubeaux S, Mehta L, Montalban X. Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology. 2020 Sep 29;95(13):e1854-e1867. doi: 10.1212/WNL.0000000000010376. Epub 2020 Jul 20.

Kappos L, Wolinsky JS, Giovannoni G, Arnold DL, Wang Q, Bernasconi C, Model F, Koendgen H, Manfrini M, Belachew S, Hauser SL. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020 Sep 1;77(9):1132-1140. doi: 10.1001/jamaneurol.2020.1568.

Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.

Layout table for additonal information

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT01247324
Other Study ID Numbers:	WA21092 2010-020337-99 ( EudraCT Number )
First Submitted:	November 23, 2010
First Posted:	November 24, 2010
Results First Submitted:	March 30, 2017
Results First Posted:	July 18, 2017
Last Update Posted:	March 4, 2024

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