Relapsing Multiple Sclerosis
Conditions
Brief summary
This randomized, double-blind, double-dummy, parallel-group study will evaluate the efficacy and safety of ocrelizumab in comparison with interferon beta-1a (Rebif) in participants with relapsing multiple sclerosis. Participants will be randomized to receive either ocrelizumab 600 mg or matching placebo 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; or interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).
Interventions
DRUGInterferon beta-1a
DRUGOcrelizumab
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple sclerosis, in accordance with the revised McDonald criteria (2010) * At least 2 documented clinical attacks within the last 2 years prior to screening or one clinical attack in the years prior to screening (but not within 30 days prior to screening) * Neurologic stability for greater than or equal to (\>/=) 30 days prior to both screening and baseline * Expanded Disability Status Scale (EDSS) score 0 to 5.5 inclusive
Exclusion criteria
* Primary progressive multiple sclerosis * Disease duration of more than 10 years in patients with EDSS score less than or equal to (\</=) 2.0 at screening * Contraindications for MRI * Known presence of other neurological disorders which may mimic multiple sclerosis * Pregnancy or lactation * Requirement for chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study * History of or currently active primary or secondary immunodeficiency * History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies * Active infection, or history of or known presence of recurrent or chronic infection (for example, hepatitis B or C, Human Immunodeficiency Virus \[HIV\], syphilis, tuberculosis) * History of progressive multifocal leukoencephalopathy * Contraindications to or intolerance of oral or IV corticosteroids * Contraindications to Rebif or incompatibility with Rebif use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks In Double Blind Period | Week 96 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment | Baseline up to week 96 | 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. |
| Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment | Baseline up to week 96 | 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. |
| Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks In Double Blind Period | Week 96 | 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 to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period | Week 104 | 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. |
| Number of T1 Hypointense Lesions During the Double-Blind Treatment | Baseline up to week 96 | 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. |
| Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period | Baseline, Week 96 | 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 to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period | Week 104 | 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. 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. |
| Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period | Baseline, Week 96 | 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. |
| Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96 In Double Blind Period | Week 96 | 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. |
| Number of Participants With Adverse Events (AEs) | Baseline up to Week 96 | 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. |
| Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC) In Double Blind Period | Pre-infusion at Weeks 1, 24, 48, 72; and 30 minutes post-infusion at Week 72; at any time during Weeks 84 and 96 | AUC represents total drug exposure for one dosing interval after the 4th dose. |
| Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period | Baseline up to Week 96 | 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. |
| Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 In Double Blind Period | From week 24 up to week 96 | 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 + Treatment\*Week (repeated values over Week) + Brain Volume at Week 24\*Week. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). |
Countries
Argentina, Belarus, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Croatia, Czechia, France, Germany, Ireland, Italy, Mexico, Norway, Poland, Russia, Slovakia, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 1045 participants were screened for entry into the study. Of these, 210 participants failed screening; the main reasons were failure to meet the inclusion/exclusion criteria or unacceptable laboratory values. A total of 835 participants were enrolled in the study.
Pre-assignment details
All participants were provided an opportunity to rollover and continue treatment and/or safety follow-up under the new extension protocol MN43964. In error, the study completion status for 5 participants was registered as 'Sponsor Termination' in the study eCRF. All 5 participants opted not to be enrolled into MN43964 and decided to pursue treatment outside the context of a clinical trial. In conclusion, the 5 participants should be considered as having completed the WA21093 study.
Participants by arm
| Arm | Count |
|---|---|
| Interferon Beta-1a + Ocrelizumab Placebo (Double Blind Period) Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks). | 418 |
| Ocrelizumab + Interferon Beta-1a Placebo (Double Blind Period) Ocrelizumab 600 mg or matching placebo 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. | 417 |
| Total | 835 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 40 | 42 |
| Overall Study | Death | 5 | 6 |
| Overall Study | Lack of Efficacy | 22 | 10 |
| Overall Study | Lost to Follow-up | 15 | 12 |
| Overall Study | Missing | 1 | 3 |
| Overall Study | Non-Compliance | 3 | 7 |
| Overall Study | Non-Compliance With Study Drug | 1 | 1 |
| Overall Study | Other | 30 | 33 |
| Overall Study | Physician Decision | 11 | 16 |
| Overall Study | Pregnancy | 6 | 4 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Study Terminated By Sponsor | 3 | 2 |
| Overall Study | Withdrawal by Subject | 51 | 54 |
Baseline characteristics
| Characteristic | Interferon Beta-1a + Ocrelizumab Placebo (Double Blind Period) | Ocrelizumab + Interferon Beta-1a Placebo (Double Blind Period) | Total |
|---|---|---|---|
| Age, Continuous | 37.4 years STANDARD_DEVIATION 9 | 37.2 years STANDARD_DEVIATION 9.1 | 37.3 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 280 Participants | 271 Participants | 551 Participants |
| Sex: Female, Male Male | 138 Participants | 146 Participants | 284 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 417 | 1 / 417 | 5 / 297 | 6 / 350 |
| other Total, other adverse events | 357 / 417 | 360 / 417 | 266 / 297 | 317 / 350 |
| serious Total, serious adverse events | 40 / 417 | 29 / 417 | 71 / 297 | 121 / 350 |
Outcome results
Primary
Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks In Double Blind Period
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
Population: Intent-to-treat (ITT) population included all randomized participants in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks In Double Blind Period | 0.290 relapses/participant year of treatment |
| Ocrelizumab | Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks In Double Blind Period | 0.155 relapses/participant year of treatment |
Comparison: Adjusted by Geographical Region (US vs. Rest of World) and baseline EDSS (\<4.0 vs. \>=4.0).p-value: <0.000195% CI: [0.397, 0.714]Negative Binomial Model
Secondary
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period
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
Population: ITT population included all randomized participants in the study. Here, n signifies the number of participants evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Interferon Beta-1a 44 mcg SC | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period | Unadjusted Baseline mean (n= 342, 358) | -0.001 Z-score | Standard Error 0.033 |
| Interferon Beta-1a 44 mcg SC | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period | Adjusted Week 96 mean (n= 269, 308) | 0.169 Z-score | Standard Error 0.029 |
| Ocrelizumab | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period | Unadjusted Baseline mean (n= 342, 358) | 0.026 Z-score | Standard Error 0.034 |
| Ocrelizumab | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score to Week 96 In Double Blind Period | Adjusted Week 96 mean (n= 269, 308) | 0.276 Z-score | Standard Error 0.028 |
p-value: =0.00495% CI: [0.034, 0.18]mixed-effect model of repeated measures
Secondary
Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Interferon Beta-1a 44 mcg SC | Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period | Unadjusted Baseline mean (n= 319, 355) | 44.552 t-score | Standard Error 0.544 |
| Interferon Beta-1a 44 mcg SC | Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period | Adjusted mean change at week 96(n=276, 315) | -0.833 t-score | Standard Error 0.472 |
| Ocrelizumab | Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period | Unadjusted Baseline mean (n= 319, 355) | 44.307 t-score | Standard Error 0.541 |
| Ocrelizumab | Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 In Double Blind Period | Adjusted mean change at week 96(n=276, 315) | 0.326 t-score | Standard Error 0.444 |
p-value: =0.040495% CI: [0.051, 2.268]mixed-effect model of repeated measures
Secondary
Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC) In Double Blind Period
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
Population: The pharmacokinetics (PK) population included all participants in the ocrelizumab group who had at least 1 measurable concentration value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Beta-1a 44 mcg SC | Exposure to Ocrelizumab (Area Under the Concentration - Time Curve, AUC) In Double Blind Period | 3513 micrograms per milliter*day | Standard Deviation 955 |
Secondary
Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment
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
Population: ITT population included all randomized participants in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment | 2103 lesions |
| Ocrelizumab | Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double Blind Treatment | 380 lesions |
p-value: <0.000195% CI: [0.13, 0.225]Negative Binomial Model
Secondary
Number of Participants With Adverse Events (AEs)
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 Week 96
Population: The safety population included all participants who received any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Interferon Beta-1a 44 mcg SC | Number of Participants With Adverse Events (AEs) | Serious Adverse Events | 40 participants |
| Interferon Beta-1a 44 mcg SC | Number of Participants With Adverse Events (AEs) | Adverse Events | 357 participants |
| Ocrelizumab | Number of Participants With Adverse Events (AEs) | Serious Adverse Events | 29 participants |
| Ocrelizumab | Number of Participants With Adverse Events (AEs) | Adverse Events | 360 participants |
| Interferon Beta-1a + Placebo (Open Label Extension) | Number of Participants With Adverse Events (AEs) | Adverse Events | 281 participants |
| Interferon Beta-1a + Placebo (Open Label Extension) | Number of Participants With Adverse Events (AEs) | Serious Adverse Events | 71 participants |
| Ocrelizumab + Placebo (Open Label Extension) | Number of Participants With Adverse Events (AEs) | Adverse Events | 333 participants |
| Ocrelizumab + Placebo (Open Label Extension) | Number of Participants With Adverse Events (AEs) | Serious Adverse Events | 121 participants |
Secondary
Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Interferon Beta-1a 44 mcg SC | Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period | Positive sample at baseline (n= 407, 402) | 2 participants |
| Interferon Beta-1a 44 mcg SC | Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period | Positive for ADA post-baseline (n= 403, 405) | 5 participants |
| Ocrelizumab | Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period | Positive sample at baseline (n= 407, 402) | 4 participants |
| Ocrelizumab | Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab In Double Blind Period | Positive for ADA post-baseline (n= 403, 405) | 2 participants |
Secondary
Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment
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
Population: ITT population included all randomized participants in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment | 465 lesions |
| Ocrelizumab | Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment | 21 lesions |
p-value: <0.000195% CI: [0.029, 0.089]Negative Binomial Model
Secondary
Number of T1 Hypointense Lesions During the Double-Blind Treatment
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
Population: ITT population included all randomized participants in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Number of T1 Hypointense Lesions During the Double-Blind Treatment | 1484 lesions |
| Ocrelizumab | Number of T1 Hypointense Lesions During the Double-Blind Treatment | 567 lesions |
p-value: <0.000195% CI: [0.272, 0.47]Negative Binomial Model
Secondary
Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96 In Double Blind Period
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
Population: ITT population included all randomized participants in the study. Here, number of participants analysed signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96 In Double Blind Period | 24.1 percentage of participants |
| Ocrelizumab | Percentage of Participants Who Have No Evidence of Disease Activity (NEDA) up to Week 96 In Double Blind Period | 43.9 percentage of participants |
p-value: <0.000195% CI: [1.41, 2.32]CMH Chi-Squared test (stratified)
Secondary
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks In Double Blind Period
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks In Double Blind Period | 18.83 percentage of participants |
| Ocrelizumab | Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks In Double Blind Period | 21.38 percentage of participants |
p-value: =0.401995% CI: [0.84, 1.56]CMH Chi-Squared test (stratified)
Secondary
Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 In Double Blind Period
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 + Treatment\*Week (repeated values over Week) + Brain Volume at Week 24\*Week. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis).
Time frame: From week 24 up to week 96
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Beta-1a 44 mcg SC | Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 In Double Blind Period | -0.75 percent change | Standard Error 0.051 |
| Ocrelizumab | Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 In Double Blind Period | -0.638 percent change | Standard Error 0.049 |
p-value: =0.0995% CI: [-0.018, 0.241]mixed-effect model of repeated measures
Secondary
Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period
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. 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 104
Population: ITT population included all randomized participants in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period | NA weeks |
| Ocrelizumab | Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period | NA weeks |
Comparison: Time to onset of CDP at week 12p-value: =0.016995% CI: [0.42, 0.92]Log Rank
Secondary
Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period
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 104
Population: ITT population included all randomized participants in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Interferon Beta-1a 44 mcg SC | Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period | NA weeks |
| Ocrelizumab | Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks During the Double-Blind Treatment Period | NA weeks |
Comparison: Time to onset of CDP at week 24p-value: =0.03795% CI: [0.4, 0.98]Log Rank