Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis.

Study Overview
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Brief Summary
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To compare the efficacy and safety of ofatumumab administered subcutaneously (sc) every 4 weeks versus teriflunomide administered orally once daily in patients with relapsing multiple sclerosis

Detailed Description
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This was a randomized, double-blind, double-dummy, active comparatorcontrolled, parallel-group, multi-center study with variable treatment duration in approximately 900 patients with relapsing multiple sclorosis (RMS). The maximal treatment duration in the study for an individual patient was 2.5 years. Eligible patients were randomized to receive either experimental ofatumumab subcutaneous (s.c.) injections every 4 weeks or active comparator teriflunomide orally once daily. The dose regimen for ofatumumab for this study was a loading dose regimen of 20 mg at Day 1, Day 7 and Day 14, followed by a maintenance dose regimen of 20 mg administered every 4 weeks starting at Week 4. In order to blind for the different formulations, double-dummy masking was used, i.e., all patients will take injections (containing either active ofatumumab or placebo) and oral capsules (containing either active teriflunomide or placebo).

Official Title
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A Randomized, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Ofatumumab Versus Teriflunomide in Patients With Relapsing Multiple Sclerosis.

Conditions
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Relapsing Multiple Scelrosis

Intervention / Treatment
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* Drug: Ofatumumab subcutaneous injection
* Drug: Teriflunomide-matching placebo capsules
* Drug: Teriflunomide capsule
* Drug: Matching placebo of ofatumumab subcutaneous injections


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 to 55 years at Screening Diagnosis of multiple sclerosis (MS) Relapsing MS: relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) with disease activity Documentation of at least: 1 relapse during the previous 1 year OR 2 relapses during the previous 2 years OR a positive gadolinium-enhancing MRI scan during the year prior to randomization Disability status at Screening with an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 Neurologically stable within 1 month prior to randomization Exclusion Criteria: Patients with primary progressive MS or SPMS without disease activity Disease duration of more than 10 years in patients with an EDSS score of 2 or less Patients with an active chronic disease of the immune system other than MS Patients at risk of developing or having reactivation of hepatitis Patients with active systemic infections or with neurological findings consistent with PML

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OMG 20 mg<br>Ofatumumab 20 mg pre-filled syringes for subcutaneous injectionon on days 1 ,7 ,14, week 4 and every 4 weeks thereafter and a teriflunomide-matching placebo, taken orally once daily | Drug: Ofatumumab subcutaneous injection<br>* Ofatumumab 20 mg prefilled syringes for subcutaneous injection on days 1, 7, 14, week 4 and every 4 weeks thereafter<br>Drug: Teriflunomide-matching placebo capsules<br>* Placebo capsule, matching in appearance to teriflunomide, taken orally once daily<br>|
| Active Comparator: TER 14 mg<br>Teriflunomide 14 mg oral capsule taken once daily and matching placebo for subcutaneous injections to ofatumumab on days 1, 7, 14, week 4 and every 4 weeks thereafter | Drug: Teriflunomide capsule<br>* Teriflunomide 14 mg oral capsule taken once daily<br>Drug: Matching placebo of ofatumumab subcutaneous injections<br>* Matching placebo of ofatumumab subcutaneous injections on days 1, 7, 14, week 4 and every 4 weeks thereafter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Relapse Rate (ARR) | ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). Comparisons were made to the previous rating (the last EDSS rating that did not occur during a relapse). | Baseline up to 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data | A 3-month confirmed disability worsening (3mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 3 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 | A 3-month confirmed disability worsening (3mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 3 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data | A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 | A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data | A 6-month confirmed disability improvement (6mCDI) was defined as a decrease from baseline EDSS sustained for at least 6 months. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 | A 6-month confirmed disability improvement (6mCDI) was defined as a decrease from baseline EDSS sustained for at least 6 months. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| Number of Gadolinium-enhancing T1 Lesions Per MRI Scan | Total number of Gd-enhancing T1 lesions across all scans per patient adjusted for different number of scans due to variable follow-up time in study. | Baseline, yearly up to 2.5 years | 
| Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | Number of new/enlarging T2 lesions on last available MRI scan compared to baseline adjusted for different time of scans versus baseline due to variable follow up time in study | Baseline, yearly up to 2.5 years | 
| Neurofilament Light Chain (NfL) Concentration in Serum | The NfL concentration (geometric mean concentration) was estimated by treatment and time point with using a repeated measures model on the basis of all evaluable log-transformed NfL values. | Month 3, 12 and 24 | 
| Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline | Percent change from baseline in brain volume loss (BVL) on all MRI scans adjusted for different time of scan versus baseline due to variable follow up time in study | Baseline, Months 12 and 24 | 
| Participants With Confirmed Relapse | A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). | Baseline up to 2.5 years | 
| Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment | ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). Comparisons were made to the previous rating (the last EDSS rating that did not occur during a relapse). | Baseline up to 2.5 years | 
| 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | A 3-month confirmed disability worsening (3mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 3 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline up to 2.5 years | 
| 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline up to 2.5 years | 
| 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data | A 6-month confirmed cognitive decline was defined as a decrease from baseline of at least 4 points in SDMT score sustained for at least 6 months. Processing speed was measured by the Symbol Digit Modalities Test (SDMT) score. SDMT measures the time to pair abstract symbols with specific numbers. The test requires visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items in 90 seconds. (max=110, min=0). Higher scores indicate improvement. Lower scores indicate worsening. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint | Baseline, every 6 months up to 2.5 years | 
| 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data | A 6-month confirmed disability worsening (6mCDW) was defined as an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months. For patients with a baseline EDSS of 0, the criterion for disability worsening was an increase in EDSS of ≥1.5, for patients with a baseline EDSS of 1 to 5 or ≥5.5, the criterion for disability worsening was an increase in EDSS of ≥1 or ≥0.5, respectively. A 6-month confirmed cognitive decline (6mCCD) was defined as a 4-point worsening on Symbol Digit Modalities Test (SDMT) sustained for at least 6 months. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline up to 2.5 years | 
| Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Processing speed is being measured by the Symbol Digit Modalities Test (SDMT) score. SDMT measures the time to pair abstract symbols with specific numbers. The test requires visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items in 90 seconds. (max=110, min=0). Higher scores indicate improvement. Lower scores indicate worsening. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline up to 2.5 years | 
| 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data | The patient is directed to walk 25 feet quickly and safely as possible from one marked end to the other. The time is calculated from the initiation of the patient instructed to begin, until the patient has reached the 25-foot mark. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data | 9-Hole Peg Test is a test of upper limb function. Participants place 9 pegs on pegboard and remove pegs and this is timed for each hand. Time recorded in seconds. Longer time indicates poorer upper limb function. 20% improvement is defined as 20% shorter time in seconds. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 6 months up to 2.5 years | 
| 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data | A 6-month confirmed disability improvement (6mCDI) sustained until EOS was defined as a decrease from baseline EDSS sustained until EOS. For patients with a baseline EDSS of 0 to 1.5, no disability improvement was possible based on the protocol definition of an improvement; for patients with a baseline EDSS of ≥2 to 6 or ≥6.5 to 9.5, the criterion for disability improvement was a decrease in EDSS of ≤1 or ≤0.5, respectively. This study was not powered for the analysis of this endpoint individually. It was pre-specified in the study protocol to combine the data from this study with study COMB157G2301 to address this endpoint. | Baseline, every 3 months up to 2.5 years | 
| Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS) | Number of new/enlarging T2 lesions on the last available MRI scan compared to Month 12 adjusted for different time of scans versus Month 12 due to variable follow up time in study. | Month 12 up to 2.5 years | 
| Percent Change in T2 Lesion Volume Relative to Baseline | Percent change from baseline in total T2 lesion volume | Baseline, Month 12, Month 24 | 
| No Evidence of Disease Activity (NEDA-4) | NEDA-4 was defined as no 3-month confirmed disability worsening, no confirmed MS relapse, no new or enlarging T2 lesions compared to baseline, and the annualized rate of brain atrophy >-0.04%. | Baseline, Month 12, Month 24 | 
| Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | MSIS-29 is a 29-item, self-administered questionnaire that includes 2 domains, physical and psychological. Responses are captured on a 4-point scale ranging from not at all (1) to extremely (4), where higher scores reflect greater impact on day to day life. | Baseline, every 6 months up to 2.5 years | 
| Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | MSIS-29 is a 29-item, self-administered questionnaire that includes 2 domains, physical and psychological. Responses are captured on a 4-point scale ranging from not at all (1) to extremely (4), where higher scores reflect greater impact on day to day life. | Baseline, every 6 months up to 2.5 years | 
| Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data | ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study. A confirmed MS relapse was defined as one accompanied by a clinically-relevant change in the EDSS performed by the Independent EDSS rater, i.e. an increase of at least 0.5 points on the EDSS score, or an increase of 1 point on two functional scores or 2 points on one functional score (excluding changes involving bowel/bladder or cerebral functional system). | Baseline up to 2.5 years | 
| Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data | Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate). | Baseline, yearly up to 2.5 years | 
| Brain Volume Loss by NfL High-low Subgroups - Pooled Data | Percent change from baseline in brain volume loss (BVL) on all MRI scans adjusted for different time of scan versus baseline due to variable follow up time in study. | Baseline, Months 12 and 24 | 
| Pharmacokinetic (PK) Concentrations of Ofatumumab | Summary statistics of pharmacokinetic (PK) concentrations from trough samples collected within a 7-day window prior or at day of dosing. | Baseline, Weeks 4, 12, 24, 48, 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ofatumumab, Relapsing multiple sclerosis, adult, OMB157, multiple sclerosis, T1 lesions, T2 lesions, relapse, GD-enhancing MRI, McDonald criteria, RRMS, SPMS