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

• ClinicalTrials.gov Identifier: NCT01247324
• Recruitment Status: Completed
• First Posted: November 24, 2010
• Results First Posted: July 18, 2017
• Last Update Posted: March 4, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: November 23, 2010
• First Posted Date: November 24, 2010
• Results First Submitted Date: March 30, 2017
• Results First Posted Date: July 18, 2017
• Last Update Posted Date: March 4, 2024
• Actual Study Start Date: August 31, 2011
• Actual Primary Completion Date: April 2, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 17, 2017)

Annualized Relapse Rate (ARR) in Participants With Relapsing Multiple Sclerosis (MS) at 96 Weeks [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: November 23, 2010): Annualized protocol-defined relapse rate [ Time Frame: Week 96 ]

Current Secondary Outcome Measures (submitted: February 13, 2024)

• Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks During the Double-Blind Treatment Period [ Time Frame: Week 108 ]
  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.
• Number of T1 Gadolinium (Gd)-Enhancing Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) During the Double-Blind Treatment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Week 108 ]
  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 [ Time Frame: 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 [ Time Frame: 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.
• Percent Change in Brain Volume as Detected by Brain Magnetic Resonance Imaging (MRI) From Week 24 to Week 96 [ Time Frame: 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.
• Change From Baseline in Short Form Health Survey-36 (SF-36) Physical Component Summary (PCS) Score at Week 96 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: Baseline up to 588 weeks ]
  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) [ 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 ]
  AUC represents total drug exposure for one dosing interval after the 4th dose.
• Number of Participants With Anti-Drug Antibodies (ADAs) to Ocrelizumab [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: November 23, 2010)

• Time to onset of sustained disability progression as confirmed by pre-defined increase in EDSS for at least 12 weeks [ Time Frame: 96 weeks ]
• Time to onset of sustained disability progression as confirmed by pre-defined increase in EDSS for at least 24 weeks [ Time Frame: 96 weeks ]
• Proportion of relapse-free patients [ Time Frame: Week 96 ]
• Total number of T1 gadolinium-enhanced lesions as detected by brain magnetic resonance imaging (MRI) [ Time Frame: Week 96 ]
• Change in total T2 lesion volume as detected by brain MRI [ Time Frame: from baseline to Week 96 ]
• Change in Multiple Sclerosis Functional Composite Scale (MSFCS) score [ Time Frame: from baseline to Week 96 ]
• Change in brain volume as detected by MRI [ Time Frame: from Week 24 to Week 96 ]
• Safety: Incidence of adverse events [ Time Frame: 3.5 years ]
• Pharmacokinetics/dynamics: C, AUC, Cl, V [ Time Frame: 3.5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis
• Official Title: A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate the Efficacy and Safety of Ocrelizumab in Comparison to Interferon Beta-1a (Rebif®) in Patients With Relapsing Multiple Sclerosis
• 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). Planned duration of double-blind treatment is 96 weeks. Participants who complete the 96-week double-blind treatment will have an option to enter a single-group, active-treatment, open-label extension period, providing they fulfill the eligibility criteria.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Relapsing Multiple Sclerosis

Intervention

• Drug: Interferon beta-1a
  Other Name: Rebif
• Drug: Ocrelizumab-matching placebo
• Drug: Ocrelizumab
  Other Name: RO4964913
• Drug: Interferon beta-1a-matching placebo

Study Arms

• Active Comparator: Interferon beta-1a 44 mcg SC
  Interferon beta-1a 44 mcg SC injections three times per week (with placebo infusions matching ocrelizumab infusions every 24 weeks).
  Interventions:

  • Drug: Interferon beta-1a
  • Drug: Ocrelizumab-matching placebo
• Experimental: Ocrelizumab
  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.
  Interventions:

  • Drug: Ocrelizumab
  • Drug: Interferon beta-1a-matching placebo

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 1, 2016): 821
• Original Estimated Enrollment (submitted: November 23, 2010): 1000
• Actual Study Completion Date: December 31, 2022
• Actual Primary Completion Date: April 2, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 participants with EDSS 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 (e.g., 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, Czechia, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Peru, Poland, Portugal, Russian Federation, Serbia, Slovakia, South Africa, Spain, Switzerland, Tunisia, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic, Morocco, New Zealand

Administrative Information

• NCT Number: NCT01247324
• Other Study ID Numbers: WA21092; 2010-020337-99 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Disclosures Group, Hoffmann-La Roche
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: February 2024