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

• ClinicalTrials.gov Identifier: NCT02792231
• Recruitment Status: Completed
• First Posted: June 7, 2016
• Results First Posted: October 19, 2020
• Last Update Posted: May 12, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 2, 2016
• First Posted Date: June 7, 2016
• Results First Submitted Date: September 18, 2020
• Results First Posted Date: October 19, 2020
• Last Update Posted Date: May 12, 2021
• Actual Study Start Date: August 26, 2016
• Actual Primary Completion Date: July 10, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2020)

Annualized Relapse Rate (ARR) (Confirmed Relapses) [ 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).

Original Primary Outcome Measures (submitted: June 2, 2016)

Annualized relapse rate (ARR) [ Time Frame: up to 2.5 years ]

ARR is the number of confirmed relapses in a year calculated based on cumulative number of relapses by patient adjusted for time-in-study by patient

Current Secondary Outcome Measures (submitted: September 18, 2020)

• 3-month Confirmed Disability Worsening) (3mCDW) Based on EDSS [ Time Frame: Baseline, every 3 months up to 2.5 years ]
  A 3-month confirmed disability worsening is an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at last 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
• 6-month Confirmed Disability Worsening (6mCDW) Based on EDSS [ 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.
• 6-month Confirmed Disability Improvement) (6mCDI ) Based on EDSS [ Time Frame: Baseline, every 3 months up to 2.5 years ]
  A 6-month confirmed disability improvement is a decrease from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months.
• 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
• 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
• Neurofilament Light Chain (NfL) Concentration in Serum [ Time Frame: Month 3, 12, 24 ]
  The NfL concentration (geometric mean concentration) will be 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 [ 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

Original Secondary Outcome Measures (submitted: June 2, 2016)

• Time to 3-month confirmed disability worsening on EDSS [ Time Frame: Baseline, every 3 months up to 2.5 years ]
  A 3-month confirmed disability worsening is an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at last 3 months.
• Time to 6-month confirmed disability worsening on EDSS [ Time Frame: Baseline, every 3 months up to 2.5 years ]
  A 6-month confirmed disability worsening is an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at last 6 months.
• Time to 6-month confirmed disability improvement on EDSS [ Time Frame: Baseline, every 3 months up to 2.5 years ]
  A 6-month confirmed disability improvement is a decrease from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6 months.
• Number of gadolinium (Gd)-enhancing lesions per MRI scan [ Time Frame: Baseline, yearly up to 2.5 years ]
  Total number of Gd-enhancing 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) [ 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
• Rate of brain volume loss based on assessments of percentage brain volume change from baseline [ Time Frame: Baseline, yearly up to 2.5 years ]
  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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis.
• 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.
• 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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Relapsing Multiple Scelrosis

Intervention

• Drug: Ofatumumab subcutaneous injection
  Ofatumumab 20 mg prefilled 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
• 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

Study Arms

• Experimental: OMG 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

  Interventions:

  • Drug: Ofatumumab subcutaneous injection
  • Drug: Teriflunomide-matching placebo capsules
• 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
  Interventions:

  • Drug: Teriflunomide capsule
  • Drug: Matching placebo of ofatumumab subcutaneous injections

• Publications *: Hauser SL, Bar-Or A, Cohen JA, Comi G, Correale J, Coyle PK, Cross AH, de Seze J, Leppert D, Montalban X, Selmaj K, Wiendl H, Kerloeguen C, Willi R, Li B, Kakarieka A, Tomic D, Goodyear A, Pingili R, Häring DA, Ramanathan K, Merschhemke M, Kappos L; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020 Aug 6;383(6):546-557. doi: 10.1056/NEJMoa1917246.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 20, 2020): 957
• Original Estimated Enrollment (submitted: June 2, 2016): 900
• Actual Study Completion Date: October 22, 2020
• Actual Primary Completion Date: July 10, 2019 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, India, Italy, Latvia, Lithuania, Mexico, Norway, Peru, Poland, Portugal, Russian Federation, Slovakia, South Africa, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT02792231
• Other Study ID Numbers: COMB157G2302; 2015-005419-33 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis

• PRS Account: Novartis
• Verification Date: May 2021