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

Phase 3

Completed

• Conditions: Relapsing Multiple Scelrosis
• Interventions: Drug: Ofatumumab subcutaneous injection; Drug: Teriflunomide capsule; Drug: Teriflunomide-matching placebo capsules; Drug: Matching placebo of ofatumumab subcutaneous injections

• Registration Number: NCT02792231
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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).

Study Timeline

• Study First Submitted: 2016-06-02
• Study First Submitted QC: 2016-06-02
• Study First Posted: 2016-06-07
• Study Start: 2016-08-26
• Primary Completion: 2019-07-10
• Disposition First Submitted: 2019-09-24
• Disposition First Submitted QC: 2019-09-24
• Disposition First Posted: 2019-10-08
• Results First Submitted: 2020-09-18
• Results First Submitted QC: 2020-09-18
• Results First Posted: 2020-10-19
• Study Completion: 2020-10-22
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-21
• Last Update Posted: 2021-11-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 955

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
OMG 20 mg	Ofatumumab subcutaneous injection	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
OMG 20 mg	Teriflunomide-matching placebo capsules	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
TER 14 mg	Teriflunomide capsule	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
TER 14 mg	Matching placebo of ofatumumab subcutaneous injections	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

Primary Outcome Measures

Name	Time	Method
Annualized Relapse Rate (ARR)	Baseline up to 2.5 years	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).

Secondary Outcome Measures

Name	Time	Method
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data	Baseline, every 3 months up to 2.5 years	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.
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302	Baseline, every 3 months up to 2.5 years	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.
Number of Gadolinium-enhancing T1 Lesions Per MRI Scan	Baseline, yearly up to 2.5 years	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.
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302	Baseline, every 3 months up to 2.5 years	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.
Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate)	Baseline, yearly up to 2.5 years	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
Participants With Confirmed Relapse	Baseline up to 2.5 years	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).
Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment	Baseline up to 2.5 years	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).
6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data	Baseline, every 3 months up to 2.5 years	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.
6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302	Baseline, every 3 months up to 2.5 years	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.
Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline	Baseline, Months 12 and 24	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
Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS)	Month 12 up to 2.5 years	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.
Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline	Baseline, every 6 months up to 2.5 years	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.
Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data	Baseline up to 2.5 years	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).
Neurofilament Light Chain (NfL) Concentration in Serum	Month 3, 12 and 24	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.
3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data	Baseline up to 2.5 years	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.
Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline	Baseline, every 6 months up to 2.5 years	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.
Pharmacokinetic (PK) Concentrations of Ofatumumab	Baseline, Weeks 4, 12, 24, 48, 96	Summary statistics of pharmacokinetic (PK) concentrations from trough samples collected within a 7-day window prior or at day of dosing.
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data	Baseline, every 3 months up to 2.5 years	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.
6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data	Baseline, every 6 months up to 2.5 years	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
Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data	Baseline up to 2.5 years	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.
6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data	Baseline, every 3 months up to 2.5 years	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.
6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data	Baseline up to 2.5 years	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.
Percent Change in T2 Lesion Volume Relative to Baseline	Baseline, Month 12, Month 24	Percent change from baseline in total T2 lesion volume
Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data	Baseline, yearly up to 2.5 years	Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate).
6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data	Baseline up to 2.5 years	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.
6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data	Baseline, every 3 months up to 2.5 years	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.
6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data	Baseline, every 6 months up to 2.5 years	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.
No Evidence of Disease Activity (NEDA-4)	Baseline, Month 12, Month 24	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%.
Brain Volume Loss by NfL High-low Subgroups - Pooled Data	Baseline, Months 12 and 24	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.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇬🇧 London, United Kingdom