Study of Evobrutinib in Participants With RMS (evolutionRMS 2)

• ClinicalTrials.gov Identifier: NCT04338061
• Recruitment Status: Terminated
• First Posted: April 8, 2020
• Last Update Posted: April 29, 2024
• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Collaborator: EMD Serono Research & Development Institute, Inc.
• Information provided by (Responsible Party): Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: April 6, 2020
• First Posted Date: April 8, 2020
• Last Update Posted Date: April 29, 2024
• Actual Study Start Date: July 2, 2020
• Actual Primary Completion Date: October 2, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 30, 2023)

• DBTP: Annualized Relapse Rate (ARR) [ Time Frame: Up to 156 weeks ]
  The annualized relapse rates up to 156 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days).
• DBE Period: ARR [ Time Frame: Up to 96 weeks ]
  The annualized relapse rates up to 96 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days).
• OLE Period: Number of Participants with Adverse Events and Serious Adverse Events (SAE)s [ Time Frame: Baseline OLE up to 96 weeks ]

Original Primary Outcome Measures (submitted: April 6, 2020)

Annualized Relapse Rate (ARR) [ Time Frame: At Week 96 ]

The annualized relapse rates over 96 weeks will be calculated based on qualified relapses. Qualifying relapse is defined as occurrence of new or worsening neurological symptoms attributable to Multiple Sclerosis (MS) (for more than 24 hours, no fever, infection, injury, adverse events, and preceded by a stable or improving neurological state for greater than or equal to (=>) 30 days).

Current Secondary Outcome Measures (submitted: June 30, 2023)

• DBTP: Time to First Occurrence of 12-Week Confirmed Disability Progression (CDP) as measured by Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Up to 156 weeks ]
• DBTP: Time to First Occurrence of 24-Week CDP as measured by EDSS Progression [ Time Frame: Up to 156 weeks ]
• DBTP: Time to First Occurrence of 24-Week Confirmed Disability Improvement (CDI) as measured by EDSS Improvement [ Time Frame: Up to 156 weeks ]
• DBTP: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Physical Function (PF) Short Form Score [ Time Frame: Baseline up to 96 weeks ]
• DBTP: Change From Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Short Form Score [ Time Frame: Baseline up to 96 weeks ]
• DBTP: Total Number of Gadolinium-Enhancing (Gd+) T1 Lesions Assessed by all Available Magnetic Resonance Imaging (MRI) Scans [ Time Frame: Up to Week 156 ]
• DBTP: Total Number of New or Enlarging T2 Lesions Assessed by the Last Available Magnetic Resonance Imaging (MRI) Scan Relative to Baseline MRI Scan [ Time Frame: Up to Week 156 ]
• DBTP: Neurofilament light chain (NfL) Serum Concentration [ Time Frame: At Week 12 ]
• DBTP: Number of Participants With Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) [ Time Frame: Baseline up to 156 weeks ]
  An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment.
• DBTP: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings [ Time Frame: Baseline up to 156 weeks ]
  Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported.
• DBTP: Absolute Concentrations of Immunoglobulin (Ig) Levels [ Time Frame: Baseline up to 156 weeks ]
• DBTP: Change From Baseline in Immunoglobulin (Ig) Levels [ Time Frame: Baseline up to 156 weeks ]
• DBE Period: Time to First Occurrence of 12-Week CDP as measured by EDSS Progression [ Time Frame: Up to 96 weeks ]
• DBE Period: Time to First Occurrence of 24-Week CDP as measured by EDSS Progression [ Time Frame: Up to 96 weeks ]
• DBE Period: Time to First Occurrence of 24-Week CDI as measured by EDSS Improvement [ Time Frame: Up to 96 weeks ]
• DBE Period: Change From Baseline in PROMIS MS PF Short Form Score [ Time Frame: Baseline up to 96 weeks ]
• DBE Period: Change From Baseline in PROMIS MS Fatigue Short Form Score [ Time Frame: Baseline up to 96 weeks ]
• DBE Period: Total Number of Gd+ T1 Lesions Assessed by all Available MRI Scans [ Time Frame: Up to Week 96 ]
• DBE Period: Total Number of New or Enlarging T2 Lesions Assessed on the Last Available MRI Scans Relative to Baseline MRI Scan [ Time Frame: Up to Week 96 ]
• DBE Period: Number of Participants With Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) [ Time Frame: Baseline up to 96 weeks ]
  An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment.
• DBE Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings [ Time Frame: Baseline up to 96 weeks ]
  Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported.
• DBE Period: Absolute Concentrations of Immunoglobulin (Ig) Levels [ Time Frame: Baseline up to 96 weeks ]
• DBE Period: Change From Baseline in Immunoglobulin (Ig) Levels [ Time Frame: Baseline up to 96 weeks ]
• OLE Period: ARR based on protocol-defined qualified relapses [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE Period: Time to first occurrence of 24-week CDP as measured by EDSS [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE Period: Time to first occurrence of 24-week CDI as measured by EDSS [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE Period: Symbol Digital Modalities Test Over time [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE Period: PROMISnq PF (MS) 15a score change over time [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE Period: PROMIS Fatigue (MS) 8a Score Change Over Time [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE Period: Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Electrocardiogram (ECG) and Laboratory Findings [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE: Total Number of New or Enlarging T2 Lesions Assessed on the Last Available Magnetic Resonance Imaging (MRI) Scans [ Time Frame: Baseline OLE up to 96 weeks ]
• OLE: Change from Baseline in T2 lesion Volume Over Time [ Time Frame: Baseline OLE up to 96 weeks ]

Original Secondary Outcome Measures (submitted: April 6, 2020)

• Time to First Occurrence of 12-Week Confirmed Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Baseline up to 96 weeks ]
• Time to First Occurrence of 24-Week Confirmed Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Baseline up to 96 weeks ]
• Change from Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Physical Function (PF) Short Form Score [ Time Frame: Baseline, Week 96 ]
• Change from Baseline in Patient Reported Outcomes Measurement Information System (PROMIS) MS Fatigue Short Form Score [ Time Frame: Baseline, Week 96 ]
• Total Number of Gadolinium-Enhancing (Gd+) T1 Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans [ Time Frame: At Weeks 24, 48, and 96 ]
• Total Number of New or Enlarging T2 Lesions Assessed by Magnetic Resonance Imaging (MRI) Scans [ Time Frame: At Weeks 24, 48, and 96 ]
• Number of Participants With Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) [ Time Frame: Baseline up to Week 100 ]
  An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal relationship with this treatment.
• Number of Participants With Clinically Significant Change From Baseline in Vital Signs, Laboratory Parameters and Electrocardiogram Findings [ Time Frame: Baseline up to Week 100 ]
  Number of participants with clinically significant change from baseline in vital signs, laboratory parameters and electrocardiogram findings will be reported.
• Absolute Concentrations of Immunoglobulin (Ig) Levels [ Time Frame: Baseline up to Week 100 ]
• Change From Baseline in Immunoglobulin (Ig) Levels [ Time Frame: Baseline up to Week 100 ]

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

Descriptive Information

• Brief Title: Study of Evobrutinib in Participants With RMS (evolutionRMS 2)
• Official Title: A Phase III, Multicenter, Randomized, Parallel Group, Double Blind, Double Dummy, Active Controlled Study of Evobrutinib Compared With Teriflunomide, in Participants With Relapsing Multiple Sclerosis to Evaluate Efficacy and Safety (evolutionRMS 2)
• Brief Summary: The study is to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio®), administered orally once daily in participants with Relapsing Multiple Sclerosis (RMS). Participants who complete the double-blind treatment period (DBTP) and double-blind extension period (DBEP) prior to approval of a separate long-term follow-up study in their country will get an option for evobrutinib treatment continuation through a 96-week open-label extension (OLE) period.
• Detailed Description: Not Provided
• 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 Sclerosis

Intervention

• Drug: Evobrutinib
  Evobrutinib twice daily (BID) in DBTP.
  Other Name: M2951
• Drug: Placebo (match to Teriflunomide)
  Placebo match to Teriflunomide once daily in DBTP.
• Drug: Teriflunomide
  Teriflunomide once daily in DBTP.
• Drug: Placebo (match to Evobrutinib)
  Placebo match to Evobrutinib BID in DBTP.

Study Arms

• Experimental: Evobrutinib + Teriflunomide matched Placebo: DB Period
  Interventions:

  • Drug: Evobrutinib
  • Drug: Placebo (match to Teriflunomide)
• Active Comparator: Teriflunomide + Evobrutinib matched Placebo: DB Period
  Interventions:

  • Drug: Teriflunomide
  • Drug: Placebo (match to Evobrutinib)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 28, 2023): 1124
• Original Estimated Enrollment (submitted: April 6, 2020): 930
• Actual Study Completion Date: March 19, 2024
• Actual Primary Completion Date: October 2, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants are diagnosed with RMS (relapsing-remitting multiple sclerosis [RRMS] or secondary progressive multiple sclerosis [SPMS] with relapses) in accordance with 2017 Revised McDonald criteria (Thompson 2018)
• Participants with one or more documented relapses within the 2 years before Screening with either: a. one relapse which occurred within the last year prior to randomization, OR b. the presence of at least 1 gadolinium-enhancing (Gd+) T1 lesion within 6 months prior to randomization
• Participants have Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at Screening and Baseline (Day 1). Participants with an EDSS score <= 2 at Screening and Baseline (Day 1) are only eligible for participation if their disease duration (time since onset of symptoms) is no more than 10 years
• Participants are neurologically stable for >= 30 days prior to both screening and baseline (Day 1)
• Female participants must be neither pregnant nor breast-feeding or must lack child-bearing potential (as defined by either: post-menopausal or surgically sterile), or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure
• Male participants must refrain from donating sperm and/or abstain from intercourse with women of child-bearing potential or use an effective method of contraception for the duration of the study and at least 2 years after study intervention due to the long elimination period for teriflunomide of 2 years, unless the participant undergoes an accelerated elimination procedure
• Participants have given written informed consent prior to any study-related procedure
• Other protocol defined inclusion criteria could apply.

Exclusion Criteria:

• Participants diagnosed with Progressive MS, in accordance with the 2017 Revised McDonald criteria as follows: a). Participants with Primary Progressive MS. b) Participants with secondary progressive MS without evidence of relapse
• Disease duration more than (>) 10 years in participants with an EDSS =< 2.0 at screening and Baseline (Day 1)
• Immunologic disorder other than MS, or any other condition requiring oral, intravenous (IV), intramuscular, or intra-articular corticosteroid therapy, with the exception of well-controlled Type 2 diabetes mellitus or well controlled thyroid disease
• Other protocol defined exclusion criteria could apply.

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: Belarus, Brazil, Bulgaria, Canada, France, Germany, Greece, India, Italy, Latvia, Lithuania, Malaysia, Moldova, Republic of, Norway, Philippines, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Saudi Arabia, Singapore, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, Ukraine, United States

Administrative Information

• NCT Number: NCT04338061
• Other Study ID Numbers: MS200527_0082; 2019-004980-36 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• Access Criteria: Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
• URL: http://bit.ly/IPD21

• Current Responsible Party: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Original Study Sponsor: Same as current
• Collaborators: EMD Serono Research & Development Institute, Inc.

Investigators

• Study Director: Medical Responsible; Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

• PRS Account: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Verification Date: April 2024