Efficacy and Safety of Ofatumumab Compared to Placebo in Patients With Relapsing Multiple Sclerosis Followed by Extended Treatment With Open-label Ofatumumab

Study Overview
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Brief Summary
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The study provided efficacy, safety, and pharmacokinetics (PK) data for patients with relapsing multiple sclerosis (RMS) in Japan and the other countries

Detailed Description
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This study had 2 parts: A controlled Core and an open-label Extension. Core part: A 24-week, randomized, double-blind, placebo controlled, parallel-group, multicenter study evaluated the efficacy, safety and tolerability and PK of ofatumumab in patients with RMS. Extension part: The Core part was followed by an Extension part in which all patients received open-label ofatumumab. In the Extension part, patients were treated for at least 24 weeks and no longer than 48 weeks. Sixty-four patients were randomized in a 2:1 ratio to ofatumumab or placebo in the Core part; half of the study patients were from Japan and the other half from the other countries.

Official Title
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A 24-week, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Ofatumumab in Patients With Relapsing Multiple Sclerosis Followed by an Extended Treatment of at Least 24 Weeks With Open-label Ofatumumab

Conditions
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Relapsing Multiple Sclerosis

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: Matching placebo of ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of multiple sclerosis (MS) Relapsing MS (RMS) At least 1 appearance of a new neurological abnormality or worsening of pre-existing neurological abnormality during the previous 2 years prior to Screening AND an MRI activity (Gd-enhancing T1 lesions or new or enlarging T2 lesions) in brain during the previous 1 year prior to randomization EDSS score of 0 to 5.5 Exclusion Criteria: Primary progressive MS or SPMS without disease activity 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: OMB 20 mg<br>Ofatumumab 20 mg subcutaneous injection on Days 1,7, 14 and every 4 weeks for 24 weeks in Core. Core placebo patients received loading dose at Weeks 25 and 26 and then all Extension patients received dose every 4 Weeks up to Week 48. | Drug: Ofatumumab<br>* Provided in pre-filled syringes for subcutaneous injection (s.c.) administration containing 20 mg ofatumumab (50 mg/mL, 0.4 mL content)<br>|
| Placebo Comparator: Placebo<br>Placebo subcutaneous injection matching to ofatumumab every 4 weeks for 24 weeks in Core | Drug: Matching placebo of ofatumumab<br>* Matching placebo in pre-filled syringes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Gadolinium-enhancing T1 Lesions Per MRI Scan - Core Part | Total number of Gd-enhancing T1 lesions across scans at Week 12, 16, 20, and 24 were adjusted for the different numbers of scans. This was calculated as a rate for population, rather than at patient level, using a negative binomial regression model with log link. The model included each patient's total number of Gd-enhancing T1 lesions as the response variable, and treatment, region, and subgroup of baseline number of Gd-enhancing T1 lesions (0 or >=1) as explanatory variables, and logarithm of the patient's number of scans as the offset variable. | Baseline up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Gadolinium-enhancing T1 Lesions Per MRI Scan - Japan vs Non-Japan - Core Part | Total number of Gd-enhancing T1 lesions across scans at Week 12, 16, 20, and 24 were adjusted for the different numbers of scans. This was calculated as a rate for population, rather than at patient level, using a negative binomial regression model with log link. The model included each patient's total number of Gd-enhancing T1 lesions as the response variable, and treatment, region, subgroup of baseline number of Gd-enhancing T1 lesions (0 or >=1), and the treatment-by-region interaction term as explanatory variables, and the patient's number of scans as the offset variable. | Baseline up to Week 24 | 
| Number of New or Enlarging T2 Lesions on MRI Scans (Annualized T2 Lesion Rate) - Core Part | Number of new/enlarging T2 lesions on the last available MRI scan in the Core Part (up to Week 24) relative to baseline, adjusted for different follow-up times. This was calculated as a rate for population, rather than at patient level, using a negative binomial regression model with log-link. The model included each patient's last available number of new or enlarging T2 lesions relative to baseline as the response variable, and treatment, region, subgroup of baseline number of Gd-enhancing T1 lesions (0 or >=1), and baseline volume of T2 lesions as explanatory variables, and the patient's follow-up time as the offset variable. | Baseline up to Week 24 | 
| Annualized Relapse Rate (ARR) - Core Part | ARR was the number of confirmed MS relapses in a year. 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). ARR was calculated as a rate for population, rather than at patient-level, using a negative binomial regression model with log-link. The model included each patient's number of confirmed relapses as the response variable, and treatment and region as explanatory variables, and the patient's follow-up time as the offset variable. | Baseline up to Week 24 | 
| Pharmacokinetic (PK) Concentrations of Ofatumumab - Core Part | Blood samples were collected at the scheduled visit. Summary statistics of PK concentrations from trough samples. | Pre-dose at Baseline, Days 2, 5, 7, 14, Weeks 4, 12, 24 | 
| B-cell Counts - Japan vs Non-Japan - Core Part | Blood samples were collected at the scheduled visits. The CD19+ B-cell counts were measured by the central laboratory. | Baseline, Days 2, 5, 7, 14, Weeks 4, 12, 24 | 
| Number of Gadolinium-enhancing T1 Lesions Per MRI Scan - Extension Part | Total number of Gd-enhancing T1 lesions per scan during the Extension Part (up to Week 48) calculated as a rate for population, rather than at patient-level. It was calculated as sum of each patient's total number of Gd-enhancing T1 lesions across scans at Week 36 and 48, divided by sum of each patient's total number of scans. | Week 24 up to Week 48 | 
| Number of New or Enlarging T2 Lesions on MRI Scans (Annualized T2 Lesion Rate) - Extension Part | Number of new/enlarging T2 lesions on the last available MRI scan in the Extension Part (up to Week 48) relative to Week 24, adjusted for different follow-up times. Annualized rate of new or enlarging T2 lesions was calculated by dividing the sum of each patient's number of new or enlarging T2 lesions relative to Week 24 by the sum of each patient's number of MRI assessment days during the Extension part, and then multiplying it by 365.25. | Week 24 up to Week 48 | 
| Annualized Relapse Rate (ARR) - Extension Part | ARR was the number of confirmed MS relapses in a year. 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). ARR (time-based) was calculated by summing each patient's number of confirmed relapses observed during the Extension part, divided by the total number of each patient's days in a study of all patients during the Extension part, and multiplied by 365.25. | Week 24 up to Week 48 | 
| Pharmacokinetic (PK) Concentrations of Ofatumumab - Extension Part | Blood samples were collected at the scheduled visits. Summary statistics of PK concentrations from trough samples. | Weeks 24, 28, 36, 48 | 
| B-cell Counts - Extension Part | Blood samples were collected at the scheduled visits. The CD19+ B-cell counts were measured by the central laboratory. | Weeks 24, 36 and 48 | 
| Participants With Confirmed Relapse - Core and Extension Parts | 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 Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, double-blind, placebo controlled, ofatumumab, relapsing multiple sclerosis, Japanese patients, RMS, adult, OMB157