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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 : Active, not recruiting
First Posted : November 24, 2010
Results First Posted : July 18, 2017
Last Update Posted : October 14, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE November 23, 2010
First Posted Date  ICMJE November 24, 2010
Results First Submitted Date  ICMJE March 30, 2017
Results First Posted Date  ICMJE July 18, 2017
Last Update Posted Date October 14, 2020
Actual Study Start Date  ICMJE August 31, 2011
Actual Primary Completion Date April 2, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (submitted: November 23, 2010)
Annualized protocol-defined relapse rate [ Time Frame: Week 96 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 17, 2017)
  • 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 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) [ 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  ICMJE
 (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  ICMJE A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Relapsing Multiple Sclerosis
Intervention  ICMJE
  • Drug: Interferon beta-1a
    Other Name: Rebif
  • Drug: Ocrelizumab-matching placebo
  • Drug: Ocrelizumab
    Other Name: RO4964913
  • Drug: Interferon beta-1a-matching placebo
Study Arms  ICMJE
  • 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 *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 1, 2016)
821
Original Estimated Enrollment  ICMJE
 (submitted: November 23, 2010)
1000
Estimated Study Completion Date  ICMJE December 28, 2023
Actual Primary Completion Date April 2, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Chile,   Russian Federation,   Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Czechia,   Estonia,   Finland,   France,   Germany,   Hungary,   Israel,   Italy,   Latvia,   Lithuania,   Mexico,   Netherlands,   Peru,   Poland,   Portugal,   Serbia,   Slovakia,   South Africa,   Spain,   Switzerland,   Tunisia,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Morocco,   New Zealand
 
Administrative Information
NCT Number  ICMJE NCT01247324
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP