Efficacy and Safety of Remibrutinib Compared to Teriflunomide in Participants With Relapsing Multiple Sclerosis (RMS)
- Conditions
- Relapsing Multiple Sclerosis
- Interventions
- Registration Number
- NCT05156281
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
To compare the efficacy and safety of remibrutinib versus teriflunomide in patients with relapsing multiple sclerosis (RMS)
- Detailed Description
The study CLOU064C12302 consists of an initial Core Part (CP) (maximum duration per participant of up to 30 months), followed by an Extension Part (EP, of up to 5 years duration) for eligible participants.
The Core Part is a randomized, double-blind, double-dummy, active comparator-controlled, fixed-dose, parallel-group, multi-center study in approximately 800 participants with relapsing multiple sclerosis (RMS).
The Extension Part is an open-label, single-arm, fixed-dose design in which eligible participants are treated with remibrutinib for up to 5 years.
A second study of identical design (CLOU064C12301) will be conducted simultaneously. Both studies will be conducted globally and data from the two studies will be pooled for some of the endpoints.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 800
- 18 to 55 years of age
- Diagnosis of RMS according to the 2017 McDonald diagnostic criteria
- At least: 1 documented relapse within the previous year. OR 2 documented relapses within the previous 2 years, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12 months.
- EDSS score of 0 to 5.5 (inclusive)
- Neurologically stable within 1 month
-
Diagnosis of primary progressive multiple sclerosis (PPMS)
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Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening
-
History of clinically significant CNS disease other than MS
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Ongoing substance abuse (drug or alcohol)
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History of malignancy of any organ system (other than complete resection of localized basal cell carcinoma of the skin or in situ cervical cancer),
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Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or Neurological symptoms consistent with PML
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suicidal ideation or behavior
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Evidence of clinically significant cardiovascular, neurological, psychiatric, pulmonary , renal, hepatic, endocrine, metabolic, hematological disorders or gastrointestinal disease that can interfere with interpretation of the study results or protocol adherence
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Participants who have had a splenectomy
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Active clinically significant systemic bacterial, viral, parasitic or fungal infections
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Positive results for syphilis or tuberculosis testing
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Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids
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Active, chronic disease of the immune system (including stable disease treated with immune therapy (e.g. Leflunomide, Methotrexate)) other than MS (e.g. rheumatoid arthritis, systemic lupus erythematosus, etc.) with the exception of well-controlled diabetes or thyroid disorder.
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Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody
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History or current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or participants with moderate or severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary disease.
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History of severe renal disease or creatinine level
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Participants at risk of developing or having reactivation of hepatitis
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Hematology parameters at screening:
- Hemoglobin: < 10 g/dl (<100g/L)
- Platelets: < 100000/mm3 (<100 x 109/L)
- Absolute lymphocyte count < 800/mm3 (<0.8 x 109/L)
- White blood cells: <3 000/mm3 (<3.0 x 109/L)
- Neutrophils: < 1 500/mm3 (<1.5 x 109/L)
- B-cell count < 50% lower limit of normal (LLN) or total IgG & total IgM < LLN (only required for participants who had a history of receiving B-cell therapies, such as rituximab, ocrelizumab or ofatumumab, prior to screening)
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History or current diagnosis of significant ECG abnormalities
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Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment (prior to randomization)
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Use of other investigational drugs
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Requirement for anticoagulant medication or use of dual anti-platelet therapy Significant bleeding risk or coagulation disorders,
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History of gastrointestinal bleeding
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Major surgery within 8 weeks prior to screening
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History of hypersensitivity to any of the study drugs or excipients
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Pregnant or nursing (lactating) female participants, prior to randomization
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Women of childbearing potential not using highly effective contraception
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Sexually active males not agreeing to use condom
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Have received any live or live-attenuated vaccines within 6 weeks of randomization or requirement to receive these vaccinations during study
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Use of strong CYP3A4 inhibitors or use of moderate or strong CYP3A4 inducers within two weeks prior to randomization
Inclusion to Extension part:
• Participants who complete the Core Part of the study on double-blind study treatment and conduct the Accelerated Elimination Procedure (AEP)
Other inclusion and exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Remibrutinib - Extension (on teriflunomide in Core) Remibrutinib Participants on teriflunomide in Core will switch to remibrutinib tablet Teriflunomide - Core Teriflunomide Teriflunomide capsule and matching placebo remibrutinib tablet Remibrutinib - Core Remibrutinib Remibrutinib tablet and matching placebo of teriflunomide capsule Remibrutinib - Extension Remibrutinib Participants on remibrutinib in Core will continue on remibrutinib tablet
- Primary Outcome Measures
Name Time Method Annualized relapse rate (ARR) of confirmed relapses [Core Part] From Baseline, up to 30 months ARR is the average number of confirmed MS relapses in a year
- Secondary Outcome Measures
Name Time Method Annualized rate of new or enlarging T2 lesion [Core Part] Baseline up to 30 months Number of new/newly enlarged T2 lesions per year
Number of Gd-enhancing T1 lesions per MRI scan [Core Part] Baseline up to 30 months Average number of Gd-enhancing T1 lesions per scan
Time to 6-month confirmed worsening by at least 20% in the Timed 25-foot walk test (T25FW) [Core Part] (pooled data) Baseline, up to 30 months The patient walking speed to cover 25-foot distance is recorded in seconds. Longer time indicates poorer lower limb function. 20% worsening is defined as 20% increase from baseline T25FW score
Number of participants with Adverse events and Serious adverse events (SAE) [Extension Part] Day 1 Extension up to 5 years Adverse events and SAEs including clinically significant, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
Annualized rate of new or enlarging T2 lesion [Extension Part] Day 1 Extension up to 5 years Number of new/newly enlarged T2 lesions per year
Time to 6-month confirmed disability progression (6mCDP) on EDSS [Core Part] (pooled data) Baseline up to 30 months Time to 6-month confirmed disability progression (6mCDP) is defined as an increase in Expanded Disability Status Scale (EDSS) which is sustained for at least 6 months
Neurofilament light chain (Nfl) [Core Part] Baseline up to 30 months Neurofilament light chain (NfL) concentration in serum
Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS) [Core Part] (pooled data) Baseline up to 30 months Time to 3-month confirmed disability progression (3mCDP) is defined as an increase in Expanded Disability Status Scale (EDSS) which is sustained for at least 3 months
Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3) [Core Part] (pooled data) Baseline up to 30 months Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), as assessed by absence of confirmed MS relapses, 6mCDP and new/enlarging T2 lesions on MRI
Time to 3-months confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP) independent of relapse activity (PIRA) [Core Part] (pooled data) Baseline up to 30 months Time to 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP) is defined as an increase in Expanded Disability Status Scale (EDSS) which is sustained for at least 3 months or 6 months, respectively, without an on-study relapse before or on the day of a progression eve
Annualized relapse rate (ARR) of confirmed relapses [Extension Part] Day 1 Extension up to 5 years ARR is the average number of confirmed MS relapses in a year
Time to first confirmed relapse [Core Part] Baseline up to 30 months Change in the Expanded Disability Status Scale (EDSS), an increase of at least 0.5 points on the EDSS (total) score, or an increase of at least 1 point on at least two functional scores (FSs), or an increase of at least 2 points on at least one FS, excluding changes involving bowel/bladder or cerebral FS, compared to the previous available rating.
Time to 6-month confirmed disability improvement (6mCDI) on EDSS [Core Part] (pooled data) Baseline up to 30 months Decrease in Expanded Disability Status Scale Score (EDSS) which is sustained for at least 6 months
Change from Baseline in T2 lesion volume [Core Part] Baseline up to 30 months Change from baseline in total T2 lesion volume.
Pharmacokinetics of remibrutinib [Core Part] Month 1, Month 6 Blood concentrations of remibrutinib
Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Extension Part] Day 1 Extension up to 5 years 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 to 6-month confirmed worsening by at least 20% in the Timed 9-hole peg test (9HPT) (pooled data) [Core Part] (pooled data) Baseline up to 30 months The patient's right and left arm function to peg 9 holes measured in seconds. Longer time indicates poorer upper limb function. 20% worsening is defined as 20% increase from baseline 9HPT score in at least one hand (average of two trials per hand)
Time to composite 6-month confirmed disability Progression (CDP) [Core Part] (pooled data) Baseline up to 30 months The composite involves CDP and worsening by at least 20% in T25FW and 9HPT
Change from baseline in the Symbol Digit Modalities Test (SDMT) [Extension Part] Day 1 Extension up to 5 years Symbol Digit Modalities Test (SDMT), an array of symbols paired with empty spaces, measures processing in speed; participants verbally match the number for each symbol as rapidly as possible. The score is the number of correctly coded items in 90 seconds. Higher scores indicate improvement. Lower scores indicate worsening
Change from baseline in the Symbol Digit Modalities Test (SDMT) [Core Part] (pooled data) Baseline up to 30 months Symbol Digit Modalities Test (SDMT), an array of symbols paired with empty spaces, measures processing in speed; participants verbally match the number for each symbol as rapidly as possible. The score is the number of correctly coded items in 90 seconds. Higher scores indicate improvement. Lower scores indicate worsening
Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Core Part] Baseline up to 30 months 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
Number of participants with Adverse events and Serious adverse events(SAE) [Core Part] Baseline up to 30 months Adverse events and SAEs including clinically significant, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
Time to 6-month confirmed disability progression (6mCDP) on EDSS [Extension Part] Day 1 Extension up to 5 years Time to 6-month confirmed disability progression (6mCDP) is defined as an increase in Expanded Disability Status Scale (EDSS) which is sustained for at least 6 months
Neurofilament light chain (NfL) [Extension Part] Day 1 Extension up to 5 years Neurofilament light chain (NfL) concentration in serum
Trial Locations
- Locations (60)
Neurocare Plus
🇺🇸Houston, Texas, United States
Ctr for Neurology and Spine
🇺🇸Phoenix, Arizona, United States
Vladimir Royter MD APMC
🇺🇸Hanford, California, United States
VA Greater LA Healthcare System
🇺🇸Los Angeles, California, United States
Regina Berkovich MD PhD Inc
🇺🇸West Hollywood, California, United States
CU Anschutz Med Campus
🇺🇸Aurora, Colorado, United States
Colorado Springs Neurological Associates
🇺🇸Colorado Springs, Colorado, United States
Colorado Neurological Research PC
🇺🇸Denver, Colorado, United States
New England Institute for Clinical Research
🇺🇸Stamford, Connecticut, United States
Georgetown University Hospital Research
🇺🇸Washington, District of Columbia, United States
SFM Clinical Research LLC
🇺🇸Boca Raton, Florida, United States
Nova Clinical Research LLC
🇺🇸Bradenton, Florida, United States
Univ of Florida College of Medicine
🇺🇸Gainesville, Florida, United States
Memorial Hospital
🇺🇸Hollywood, Florida, United States
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
Neurology Associates PA
🇺🇸Maitland, Florida, United States
Gables Neurology
🇺🇸Miami, Florida, United States
UM Department Of Neurology
🇺🇸Miami, Florida, United States
Aqualane Clinical Research
🇺🇸Naples, Florida, United States
Advent Health Orlando
🇺🇸Orlando, Florida, United States
Humanity Clinical Research
🇺🇸Pembroke Pines, Florida, United States
Emerald Coast Neurology
🇺🇸Pensacola, Florida, United States
Brain and Spine Institute
🇺🇸Port Orange, Florida, United States
Vero Beach Neurology
🇺🇸Vero Beach, Florida, United States
Conquest Research
🇺🇸Winter Park, Florida, United States
Georgia Neurology and Sleep Medicine Assoc
🇺🇸Suwanee, Georgia, United States
Methodist Neuroscience Institute
🇺🇸Merrillville, Indiana, United States
University of Kansas Hospital
🇺🇸Kansas City, Kansas, United States
Baptist Physicians Lexington
🇺🇸Nicholasville, Kentucky, United States
Ochsner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States
Comprehensive Neurology
🇺🇸Frederick, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Memorial Healthcare
🇺🇸Owosso, Michigan, United States
Kansas City VA Medical Center
🇺🇸Kansas City, Missouri, United States
South Shore Neurologic Associates
🇺🇸Patchogue, New York, United States
True North Neurology
🇺🇸Port Jefferson Station, New York, United States
University Of NC At Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Piedmont HealthCare
🇺🇸Charlotte, North Carolina, United States
The Boster Ctr for MS
🇺🇸Columbus, Ohio, United States
Neurology Diagnostics Inc
🇺🇸Dayton, Ohio, United States
Penn State Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Medical Uni of South Carolina
🇺🇸Charleston, South Carolina, United States
Premier Neurology
🇺🇸Greenville, South Carolina, United States
Metrolina Neurological Associates PA
🇺🇸Indian Land, South Carolina, United States
Sibyl Wray MD Neurology PC
🇺🇸Knoxville, Tennessee, United States
Neurology Consultants Of Dallas PA
🇺🇸Dallas, Texas, United States
Med Research Inc
🇺🇸El Paso, Texas, United States
Lone Star Neurology
🇺🇸Frisco, Texas, United States
University of Texas Health Science Center San Antonio
🇺🇸San Antonio, Texas, United States
Lonestar Neurology of San Antonio
🇺🇸San Antonio, Texas, United States
Texas Institute for Neurological Disorders
🇺🇸Sherman, Texas, United States
Baylor Scott and White
🇺🇸Temple, Texas, United States
Virginia Mason Medical Centre
🇺🇸Seattle, Washington, United States
University of Washington MS Clinic
🇺🇸Seattle, Washington, United States
Elligo Health Research
🇺🇸Crab Orchard, West Virginia, United States
Aurora BayCare Medical Center
🇺🇸Green Bay, Wisconsin, United States
Ascension St Francis Center
🇺🇸Milwaukee, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Novartis Investigative Site
🇬🇧London, United Kingdom
Caribbean Center for Clinical Research, Inc
🇵🇷Guaynabo, Puerto Rico