Relapsing Multiple Scelrosis
Conditions
Keywords
Relapsing multiple sclerosis, Ofatumumab, adult, OMB157, multiple sclerosis, T1 lesions, T2 lesions, relapse, GD-enhancing MRI, McDonald criteria, RRMS, SPMS
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).
Interventions
Ofatumumab 20 mg prefilled syringes for subcutaneous injection on days 1, 7, 14, week 4 and every 4 weeks thereafter
Placebo capsule, matching in appearance to teriflunomide, taken orally once daily
Teriflunomide 14 mg oral capsule taken once daily
Matching placebo of ofatumumab subcutaneous injections on days 1, 7, 14, week 4 and every 4 weeks thereafter
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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 |
| 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). |
| 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. |
| 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. |
| 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 |
| 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. |
| 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 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. |
| 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. |
| 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. |
| Percent Change in T2 Lesion Volume Relative to Baseline | Baseline, Month 12, Month 24 | Percent change from baseline in total T2 lesion volume |
| 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%. |
| 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. |
| 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. |
| 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). |
| 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). |
| 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. |
| 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) 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. |
Countries
Argentina, Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, India, Italy, Latvia, Lithuania, Mexico, Norway, Peru, Poland, Portugal, Russia, Slovakia, South Africa, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
It was pre-specified in the protocol to combine the data from this study with study NCT02792218 (COMB157G2301) for some outcome measures. Please refer to NCT02792218 for Participant Flow information for participants from other study.
Pre-assignment details
A total of 1280 patients were screened, of whom 955 patients were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| OMB 20 mg Ofatumumab 20 mg s.c. injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter (+ teriflunomide-matching placebo capsule orally once daily) | 481 |
| TER 14 mg Teriflunomide 14 mg capsule orally once daily (+ ofatumumab-matching placebo injections on Days 1, 7, 14, Week 4 and every 4 weeks thereafter) | 474 |
| Total | 955 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 11 |
| Overall Study | Lack of Efficacy | 7 | 9 |
| Overall Study | Lost to Follow-up | 9 | 5 |
| Overall Study | Non-compliance with study treatment | 2 | 1 |
| Overall Study | Patient/guardian decision | 32 | 42 |
| Overall Study | Physician Decision | 14 | 12 |
| Overall Study | Pregnancy | 1 | 3 |
| Overall Study | Protocol deviation | 2 | 0 |
| Overall Study | Technical problems | 0 | 1 |
Baseline characteristics
| Characteristic | TER 14 mg | Total | OMB 20 mg |
|---|---|---|---|
| Age, Continuous | 38.2 Years STANDARD_DEVIATION 9.47 | 38.1 Years STANDARD_DEVIATION 9.37 | 38.0 Years STANDARD_DEVIATION 9.28 |
| Expanded Disability Status Scale (EDSS) | 2.86 Score on a scale STANDARD_DEVIATION 1.373 | 2.88 Score on a scale STANDARD_DEVIATION 1.358 | 2.90 Score on a scale STANDARD_DEVIATION 1.343 |
| Number of gadolinium-enhancing T1 lesions | 1.5 T1 lesions STANDARD_DEVIATION 4.07 | 1.5 T1 lesions STANDARD_DEVIATION 4.07 | 1.6 T1 lesions STANDARD_DEVIATION 4.07 |
| Number of relapses in the past 12 months prior to screening | 1.3 Number of relapses STANDARD_DEVIATION 0.73 | 1.3 Number of relapses STANDARD_DEVIATION 0.74 | 1.3 Number of relapses STANDARD_DEVIATION 0.74 |
| Race/Ethnicity, Customized Asian | 19 Participants | 40 Participants | 21 Participants |
| Race/Ethnicity, Customized Black or African American | 18 Participants | 31 Participants | 13 Participants |
| Race/Ethnicity, Customized Other | 14 Participants | 34 Participants | 20 Participants |
| Race/Ethnicity, Customized Unknown | 6 Participants | 15 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 417 Participants | 835 Participants | 418 Participants |
| Sex: Female, Male Female | 319 Participants | 638 Participants | 319 Participants |
| Sex: Female, Male Male | 155 Participants | 317 Participants | 162 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 481 | 1 / 474 |
| other Total, other adverse events | 348 / 481 | 322 / 474 |
| serious Total, serious adverse events | 42 / 481 | 37 / 474 |
Outcome results
Primary
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).
Time frame: Baseline up to 2.5 years
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OMB 20 mg | Annualized Relapse Rate (ARR) | 0.10 number of relapses in a year |
| TER 14 mg | Annualized Relapse Rate (ARR) | 0.25 number of relapses in a year |
Comparison: Obtained from fitting a negative binomial regression model with log-link to the number of relapses, adjusted for treatment and region as factors, number of relapses in previous year, baseline EDSS, baseline number of Gd-enhancing lesions and the patient's age at baseline as covariates. The natural log of the time-in-study was used as offset to annualize the relapse rate.p-value: <0.00195% CI: [0.309, 0.56]negative binomial regression model
Secondary
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.
Time frame: Baseline up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 18 - from Kaplan Meier estimates | 9.4 percentage of participants |
| OMB 20 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 24 - from Kaplan Meier estimates | 10.9 percentage of participants |
| TER 14 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 18 - from Kaplan Meier estimates | 13.5 percentage of participants |
| TER 14 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 24 - from Kaplan Meier estimates | 15.0 percentage of participants |
Comparison: 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.p-value: 0.00295% CI: [0.486, 0.847]Regression, Cox
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set from combined studies
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data | Month 18 - from Kaplan Meier estimates | 9.4 percentage of participants |
| OMB 20 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 10.9 percentage of participants |
| TER 14 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data | Month 18 - from Kaplan Meier estimates | 13.5 percentage of participants |
| TER 14 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 15.0 percentage of participants |
Comparison: Pooled data - 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.p-value: 0.00395% CI: [0.5, 0.863]Regression, Cox
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 | Month 18 - from Kaplan Meier estimates | 9.3 percentage of participants |
| OMB 20 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 | Month 24 - from Kaplan Meier estimates | 10.5 percentage of participants |
| TER 14 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 | Month 18 - from Kaplan Meier estimates | 13.2 percentage of participants |
| TER 14 mg | 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2302 | Month 24 - from Kaplan Meier estimates | 14.6 percentage of participants |
Comparison: 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.p-value: 0.03895% CI: [0.449, 0.977]Regression, Cox
Secondary
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
Time frame: Baseline, every 6 months up to 2.5 years
Population: Full analysis set from combined studies
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 18 - from Kaplan Meier estimates | 14.3 percentage of participants |
| OMB 20 mg | 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 24 - from Kaplan Meier estimates | 15.4 percentage of participants |
| TER 14 mg | 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 18 - from Kaplan Meier estimates | 13.7 percentage of participants |
| TER 14 mg | 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 24 - from Kaplan Meier estimates | 14.0 percentage of participants |
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set from combined studies
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data | Month 18 - from Kaplan Meier estimates | 10.1 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 11.0 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data | Month 18 - from Kaplan Meier estimates | 7.6 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 8.2 percentage of participants |
Comparison: 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.p-value: 0.09295% CI: [0.952, 1.928]Regression, Cox
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 | Month 18 - from Kaplan Meier estimates | 11.1 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 | Month 24 - from Kaplan Meier estimates | 12.3 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 | Month 18 - from Kaplan Meier estimates | 8.1 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2302 | Month 24 - from Kaplan Meier estimates | 8.1 percentage of participants |
Comparison: 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.p-value: 0.0995% CI: [0.936, 2.477]Regression, Cox
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data | Month 18 - from Kaplan Meier estimates | 5.4 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 5.8 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data | Month 18 - from Kaplan Meier estimates | 4.6 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 4.6 percentage of participants |
Secondary
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.
Time frame: Baseline up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 18- from Kaplan Meier estimates | 7.8 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 24 - from Kaplan Meier estimates | 8.1 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 18- from Kaplan Meier estimates | 10.7 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data | Month 24 - from Kaplan Meier estimates | 12.0 percentage of participants |
Comparison: 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.p-value: 0.00895% CI: [0.481, 0.898]Regression, Cox
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set from combined studies
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data | Month 18- from Kaplan Meier estimates | 7.8 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 8.1 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data | Month 18- from Kaplan Meier estimates | 10.7 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data | Month 24 - from Kaplan Meier estimates | 12.0 percentage of participants |
Comparison: 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.p-value: 0.01295% CI: [0.498, 0.917]Regression, Cox
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 | Month 18- from Kaplan Meier estimates | 8.0 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 | Month 24 - from Kaplan Meier estimates | 8.0 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 | Month 18- from Kaplan Meier estimates | 10.0 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2302 | Month 24 - from Kaplan Meier estimates | 10.9 percentage of participants |
Comparison: 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.p-value: 0.21595% CI: [0.49, 1.174]Regression, Cox
Secondary
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.
Time frame: Baseline up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data | Month 18 - from Kaplan Meier estimates | 20.5 percentage of participants |
| OMB 20 mg | 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data | Month 24 - from Kaplan Meier estimates | 21.4 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data | Month 18 - from Kaplan Meier estimates | 21.7 percentage of participants |
| TER 14 mg | 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data | Month 24 - from Kaplan Meier estimates | 22.6 percentage of participants |
Secondary
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.
Time frame: Baseline, every 6 months up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data | Month 18 - from Kaplan Meier estimates | 2.9 percentage of participants |
| OMB 20 mg | 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data | Month 24 - from Kaplan Meier estimates | 2.9 percentage of participants |
| TER 14 mg | 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data | Month 18 - from Kaplan Meier estimates | 3.3 percentage of participants |
| TER 14 mg | 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data | Month 24 - from Kaplan Meier estimates | 3.3 percentage of participants |
Secondary
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.
Time frame: Baseline, every 3 months up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data | Month 18 - from Kaplan Meier estimates | 11.0 percentage of participants |
| OMB 20 mg | 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data | Month 24 - from Kaplan Meier estimates | 11.4 percentage of participants |
| TER 14 mg | 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data | Month 24 - from Kaplan Meier estimates | 10.6 percentage of participants |
| TER 14 mg | 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data | Month 18 - from Kaplan Meier estimates | 10.4 percentage of participants |
Secondary
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
Time frame: Baseline, Months 12 and 24
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OMB 20 mg | Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline | -0.29 percentage of brain volume loss |
| TER 14 mg | Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline | -0.35 percentage of brain volume loss |
p-value: 0.12895% CI: [-0.02, 0.15]random coefficient model
Secondary
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).
Time frame: Baseline up to 2.5 years
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OMB 20 mg | Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment | 0.096 number of relapses in a year |
| TER 14 mg | Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment | 0.241 number of relapses in a year |
Secondary
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).
Time frame: Baseline up to 2.5 years
Population: Supportive sub-group analysis based on estimations from pooled data from this study and study COMB157G2301.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| OMB 20 mg | Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data | High > median n=443,410 | 0.08 number of relapses in a year |
| OMB 20 mg | Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data | Low <= median n=428,431 | 0.12 number of relapses in a year |
| TER 14 mg | Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data | High > median n=443,410 | 0.21 number of relapses in a year |
| TER 14 mg | Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data | Low <= median n=428,431 | 0.23 number of relapses in a year |
Secondary
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.
Time frame: Baseline, Months 12 and 24
Population: Supportive sub-group analysis based on estimations from pooled data from this study and study COMB157G2301.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| OMB 20 mg | Brain Volume Loss by NfL High-low Subgroups - Pooled Data | High > median n=416,387 | -0.32 percentage of brain volume loss |
| OMB 20 mg | Brain Volume Loss by NfL High-low Subgroups - Pooled Data | Low <= median n=403,407 | -0.24 percentage of brain volume loss |
| TER 14 mg | Brain Volume Loss by NfL High-low Subgroups - Pooled Data | High > median n=416,387 | -0.43 percentage of brain volume loss |
| TER 14 mg | Brain Volume Loss by NfL High-low Subgroups - Pooled Data | Low <= median n=403,407 | -0.29 percentage of brain volume loss |
Secondary
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.
Time frame: Baseline up to 2.5 years
Population: Full analysis set from combined studies.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| OMB 20 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 6 n=921,909 | 1.02 scores |
| OMB 20 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 12 n=879,863 | 1.82 scores |
| OMB 20 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 18 n=849,808 | 2.84 scores |
| OMB 20 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 24 n=492,468 | 3.50 scores |
| OMB 20 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 30 n=156,117 | 3.53 scores |
| TER 14 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 30 n=156,117 | 2.97 scores |
| TER 14 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 6 n=921,909 | 0.64 scores |
| TER 14 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 24 n=492,468 | 2.39 scores |
| TER 14 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 12 n=879,863 | 1.70 scores |
| TER 14 mg | Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data | Month 18 n=849,808 | 2.05 scores |
Secondary
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.
Time frame: Baseline, every 6 months up to 2.5 years
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 12 n=448,438 | -2.47 scores on a scale | Standard Error 0.698 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 24 n=235,238 | -2.93 scores on a scale | Standard Error 0.904 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 18 n=425,409 | -2.29 scores on a scale | Standard Error 0.784 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 30 n=70,54 | -2.49 scores on a scale | Standard Error 1.27 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 6 n=473,461 | -2.20 scores on a scale | Standard Error 0.652 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 30 n=70,54 | 1.44 scores on a scale | Standard Error 1.397 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 6 n=473,461 | -0.46 scores on a scale | Standard Error 0.659 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 12 n=448,438 | -0.49 scores on a scale | Standard Error 0.704 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 18 n=425,409 | 1.53 scores on a scale | Standard Error 0.794 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline | Month 24 n=235,238 | 0.62 scores on a scale | Standard Error 0.905 |
Secondary
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.
Time frame: Baseline, every 6 months up to 2.5 years
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 12 n=448,436 | -5.42 scores on a scale | Standard Error 0.83 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 24 n=234,238 | -6.10 scores on a scale | Standard Error 1.092 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 18 n=423,409 | -6.23 scores on a scale | Standard Error 0.884 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 30 n=70,54 | -6.25 scores on a scale | Standard Error 1.623 |
| OMB 20 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 6 n=473,461 | -5.96 scores on a scale | Standard Error 0.807 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 30 n=70,54 | -4.75 scores on a scale | Standard Error 1.797 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 6 n=473,461 | -3.77 scores on a scale | Standard Error 0.816 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 12 n=448,436 | -3.88 scores on a scale | Standard Error 0.839 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 18 n=423,409 | -2.51 scores on a scale | Standard Error 0.896 |
| TER 14 mg | Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline | Month 24 n=234,238 | -3.12 scores on a scale | Standard Error 1.09 |
Secondary
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.
Time frame: Month 3, 12 and 24
Population: Full analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| OMB 20 mg | Neurofilament Light Chain (NfL) Concentration in Serum | Month 3 n=425,423 | 8.92 pg/mL |
| OMB 20 mg | Neurofilament Light Chain (NfL) Concentration in Serum | Month 12 n=406,406 | 7.06 pg/mL |
| OMB 20 mg | Neurofilament Light Chain (NfL) Concentration in Serum | Month 24 n=345,349 | 6.80 pg/mL |
| TER 14 mg | Neurofilament Light Chain (NfL) Concentration in Serum | Month 3 n=425,423 | 10.02 pg/mL |
| TER 14 mg | Neurofilament Light Chain (NfL) Concentration in Serum | Month 12 n=406,406 | 9.53 pg/mL |
| TER 14 mg | Neurofilament Light Chain (NfL) Concentration in Serum | Month 24 n=345,349 | 8.99 pg/mL |
Comparison: Month 3p-value: <0.00195% CI: [0.85, 0.93]Mixed Models Analysis
Comparison: Month 12p-value: <0.00195% CI: [0.7, 0.79]Mixed Models Analysis
Comparison: Month 24p-value: <0.00195% CI: [0.71, 0.81]Mixed Models Analysis
Secondary
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%.
Time frame: Baseline, Month 12, Month 24
Population: Full analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OMB 20 mg | No Evidence of Disease Activity (NEDA-4) | Month 12 n=433,427 | 23.8 percentage of participants |
| OMB 20 mg | No Evidence of Disease Activity (NEDA-4) | Month 24 n=92,78 | 9.8 percentage of participants |
| TER 14 mg | No Evidence of Disease Activity (NEDA-4) | Month 12 n=433,427 | 17.8 percentage of participants |
| TER 14 mg | No Evidence of Disease Activity (NEDA-4) | Month 24 n=92,78 | 5.1 percentage of participants |
Secondary
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.
Time frame: Baseline, yearly up to 2.5 years
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OMB 20 mg | Number of Gadolinium-enhancing T1 Lesions Per MRI Scan | 0.0317 lesions per scan |
| TER 14 mg | Number of Gadolinium-enhancing T1 Lesions Per MRI Scan | 0.5172 lesions per scan |
p-value: <0.00195% CI: [0.037, 0.101]negative binomial regression model
Secondary
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
Time frame: Baseline, yearly up to 2.5 years
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| OMB 20 mg | Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | Month 12 n=422,410 | 0.94 T2 lesions per year |
| OMB 20 mg | Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | Month 24 n=90,76 | 0.72 T2 lesions per year |
| OMB 20 mg | Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | EOS n=448,442 | 0.64 T2 lesions per year |
| TER 14 mg | Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | Month 12 n=422,410 | 4.41 T2 lesions per year |
| TER 14 mg | Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | Month 24 n=90,76 | 3.72 T2 lesions per year |
| TER 14 mg | Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) | EOS n=448,442 | 4.16 T2 lesions per year |
Comparison: Month 12p-value: <0.00195% CI: [0.17, 0.27]negative binomial regression model
Comparison: Month 24p-value: <0.00195% CI: [0.12, 0.31]negative binomial regression model
Comparison: End of Studyp-value: <0.00195% CI: [0.13, 0.19]negative binomial regression model
Secondary
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.
Time frame: Month 12 up to 2.5 years
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OMB 20 mg | Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS) | 0.13 T2 lesions per year |
| TER 14 mg | Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS) | 3.84 T2 lesions per year |
Secondary
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).
Time frame: Baseline, yearly up to 2.5 years
Population: Supportive sub-group analysis based on estimations from pooled data from this study and study COMB157G2301.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| OMB 20 mg | Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data | High > median n=432,402 | 0.95 T2 lesions per year |
| OMB 20 mg | Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data | Low <= median n=418,421 | 0.39 T2 lesions per year |
| TER 14 mg | Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data | High > median n=432,402 | 5.28 T2 lesions per year |
| TER 14 mg | Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data | Low <= median n=418,421 | 3.02 T2 lesions per year |
Secondary
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).
Time frame: Baseline up to 2.5 years
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OMB 20 mg | Participants With Confirmed Relapse | 16.51 percentage of participants |
| TER 14 mg | Participants With Confirmed Relapse | 32.68 percentage of participants |
Secondary
Percent Change in T2 Lesion Volume Relative to Baseline
Percent change from baseline in total T2 lesion volume
Time frame: Baseline, Month 12, Month 24
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OMB 20 mg | Percent Change in T2 Lesion Volume Relative to Baseline | Month 12 n=447,437 | -2.4 percentage change in lesion volume | Standard Deviation 8.66 |
| OMB 20 mg | Percent Change in T2 Lesion Volume Relative to Baseline | Month 24 n=330,320 | -2.6 percentage change in lesion volume | Standard Deviation 9.34 |
| TER 14 mg | Percent Change in T2 Lesion Volume Relative to Baseline | Month 24 n=330,320 | 17.8 percentage change in lesion volume | Standard Deviation 53.48 |
| TER 14 mg | Percent Change in T2 Lesion Volume Relative to Baseline | Month 12 n=447,437 | 10.1 percentage change in lesion volume | Standard Deviation 38.57 |
Secondary
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.
Time frame: Baseline, Weeks 4, 12, 24, 48, 96
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OMB 20 mg | Pharmacokinetic (PK) Concentrations of Ofatumumab | Baseline n=325 | 0.00325 ug/mL | Standard Deviation 0.031372 |
| OMB 20 mg | Pharmacokinetic (PK) Concentrations of Ofatumumab | Week 4 n=346 | 1.26512 ug/mL | Standard Deviation 0.964645 |
| OMB 20 mg | Pharmacokinetic (PK) Concentrations of Ofatumumab | Week 24 n=243 | 0.38203 ug/mL | Standard Deviation 0.433175 |
| OMB 20 mg | Pharmacokinetic (PK) Concentrations of Ofatumumab | Week 48 n=240 | 0.59087 ug/mL | Standard Deviation 0.59449 |
| OMB 20 mg | Pharmacokinetic (PK) Concentrations of Ofatumumab | Week 96 n=304 | 1.13218 ug/mL | Standard Deviation 0.991141 |
| OMB 20 mg | Pharmacokinetic (PK) Concentrations of Ofatumumab | Week 12 n=257 | 0.20932 ug/mL | Standard Deviation 0.287839 |