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Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02792218
Recruitment Status : Completed
First Posted : June 7, 2016
Results First Posted : October 19, 2020
Last Update Posted : October 1, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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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

Condition or disease Intervention/treatment Phase
Relapsing Multiple Sclerosis Drug: Ofatumumab subcutaneous injection Drug: Teriflunomide-matching placebo capsules Drug: Teriflunomide capsule Drug: Matching placebo of ofatumumab subcutaneous injections Phase 3

Detailed Description:

This was a randomized, double-blind, double-dummy, active comparator-controlled, 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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 930 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Ofatumumab Versus Teriflunomide in Patients With Relapsing Multiple Sclerosis
Actual Study Start Date : September 20, 2016
Actual Primary Completion Date : July 5, 2019
Actual Study Completion Date : July 20, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: OMB 20 mg
Ofatumumab 20 mg pre-filled syringes for subcutaneous injectionon on days 1 ,7 ,14, week 4 and every 4 weeks thereafter and a teriflunomide- matching placebo, taken orally once daily
 Drug: Ofatumumab subcutaneous injection
Ofatumumab 20 mg pre-filled syringes for subcutaneous injection on days 1, 7, 14, week 4 and every 4 weeks thereafter

Drug: Teriflunomide-matching placebo capsules
Placebo capsule, matching in appearance to teriflunomide, taken orally once daily
Active Comparator: TER 14 mg
Teriflunomide 14 mg oral capsule taken once daily and matching placebo for subcutaneous injections to ofatumumab on days 1, 7, 14, week 4 and every 4 weeks thereafter
 Drug: Teriflunomide capsule
Teriflunomide 14 mg oral capsule taken once daily

Drug: Matching placebo of ofatumumab subcutaneous injections
Matching placebo of ofatumumab subcutaneous injections on days 1, 7, 14, week 4 and every 4 weeks thereafter


Outcome Measures
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Primary Outcome Measures :
  1. Annualized Relapse Rate (ARR) [ Time Frame: 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 :
  1. 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  2. 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS - Study COMB157G2301 [ Time Frame: 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 COMB157G2302 to address this endpoint.

  3. 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  4. 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS - Study COMB157G2301 [ Time Frame: 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 COMB157G2302 to address this endpoint.

  5. 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  6. 6-month Confirmed Disability Improvement (6mCDI ) Based on EDSS - Study COMB157G2301 [ Time Frame: 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 COMB157G2302 to address this endpoint.

  7. Number of Gd-enhancing T1 Lesions Per MRI Scan [ Time Frame: 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.

  8. Number of New or Enlarging T2 Lesions on MRI Per Year (Annualized Lesion Rate) [ Time Frame: 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

  9. Neurofilament Light Chain (NfL) Concentration in Serum [ Time Frame: 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.

  10. Annualized Rate of Brain Volume Loss Based on Assessments of Percent Brain Volume Change From Baseline [ Time Frame: 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

  11. Percentage of Participants With Confirmed Relapse [ Time Frame: 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).

  12. Annualized Relapse Rate (ARR) >8 Weeks After Onset of Treatment [ Time Frame: 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).

  13. 3-month Confirmed Disability Worsening (3mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  14. 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS > 8 Weeks After Onset of Treatment - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  15. 6-month Confirmed Cognitive Decline on Symbol Digit Modalities Test (SDMT) - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint

  16. 6-month Confirmed Disability Worsening (6mCDW) or 6-month Confirmed Cognitive Decline (6mCCD) - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  17. Change in Cognitive Performance Measured by the Symbol Digit Modalities Test (SDMT) - Pooled Data [ Time Frame: 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.

  18. 6-month Confirmed Worsening of at Least 20% in the Timed 25-Foot Walk (T25FW) - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  19. 6-month Confirmed Worsening of at Least 20% in the 9-Hole Peg Test (9HPT) - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  20. 6-month Confirmed Disability Improvement (6mCDI) Sustained Until End of Study (EOS) as Measured by EDSS - Pooled Data [ Time Frame: 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 COMB157G2302 to address this endpoint.

  21. Number of New or Enlarging T2 Lesions on MRI Per Year From Month 12 Until End of Study (EOS) [ Time Frame: 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.

  22. Percent Change in T2 Lesion Volume Relative to Baseline [ Time Frame: Baseline, Month 12, Month 24 ]
    Percent change from baseline in total T2 lesion volume

  23. No Evidence of Disease Activity (NEDA-4) [ Time Frame: 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%.

  24. Multiple Sclerosis Impact Scale (MSIS-29) Physical Impact Score Change From Baseline [ Time Frame: 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.

  25. Multiple Sclerosis Impact Scale (MSIS-29) Psychological Impact Score Change From Baseline [ Time Frame: 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.

  26. Annualized Relapse Rates (ARR) by NfL High-low Subgroups - Pooled Data [ Time Frame: 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).

  27. Number of New or Enlarging T2 Lesions Per Year by NfL High-low Subgroups - Pooled Data [ Time Frame: Baseline, yearly up to 2.5 years ]
    Number of new or enlarging T2 lesions on MRI per year (annualized lesion rate).

  28. Annual Rate of Percent Change in Brain Volume Loss by NfL High-low Subgroups - Pooled Data [ Time Frame: 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.

  29. Pharmacokinetic (PK) Concentrations of Ofatumumab [ Time Frame: 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.


Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 to 55 years of age
  • Diagnosis of multiple sclerosis (MS)
  • Relapsing MS: relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS)
  • At least 1 relapse during the previous 1 year or 2 relapses during the previous 2 years or a positive gadolinium-enhancing MRI scan in previous year
  • Expanded disability status scale (EDSS) score of 0 to 5.5

Exclusion Criteria:

  • Primary progressive MS
  • 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02792218


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] August 6, 2018
Statistical Analysis Plan  [PDF] October 17, 2019

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02792218    
Other Study ID Numbers: COMB157G2301
2015-005418-31 ( EudraCT Number )
First Posted: June 7, 2016    Key Record Dates
Results First Posted: October 19, 2020
Last Update Posted: October 1, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Relapsing multiple sclerosis
Ofatumumab
adult
OMB157
multiple sclerosis
T1 lesions
 T2 lesions
relapse
GD-enhancing MRI
McDonald criteria
RRMS
SPMS
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Teriflunomide
Ofatumumab
Antibodies, Monoclonal
 Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Immunosuppressive Agents