Efficacy and Safety of Remibrutinib Compared to Teriflunomide in Participants With Relapsing Multiple Sclerosis (RMS)
- Conditions
- Relapsing Multiple Sclerosis
- Interventions
- Registration Number
- NCT05147220
- 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 CLOU064C12301 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 (CLOU064C12302) 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)
-
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
-
Ongoing substance abuse (drug or alcohol)
-
History of malignancy of any organ system (other than complete resection of localized basal cell carcinoma of the skin or in situ cervical cancer),
-
Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or Neurological symptoms consistent with PML
-
suicidal ideation or behavior
-
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
-
Participants who have had a splenectomy
-
Active clinically significant systemic bacterial, viral, parasitic or fungal infections
-
Positive results for syphilis or tuberculosis testing
-
Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids
-
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.
-
Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody
-
History or current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis (including all Child-Pugh classes) or hepatic failure or any chronic liver or biliary disease.
-
History of severe renal disease or creatinine level
-
Participants at risk of developing or having reactivation of hepatitis
-
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)
-
History or current diagnosis of significant ECG abnormalities
-
Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment as per central ECG reading at screening visit
-
Use of other investigational drugs
-
Requirement for anticoagulant medication or use of dual anti-platelet therapy Significant bleeding risk or coagulation disorders,
-
History of gastrointestinal bleeding
-
Major surgery within 8 weeks prior to screening
-
History of hypersensitivity to any of the study drugs or excipients
-
Pregnant or nursing (lactating) female participants, prior to randomization
-
Women of childbearing potential not using highly effective contraception
-
Sexually active males not agreeing to use condom
-
Have received any live or live-attenuated vaccines within 6 weeks of randomization or requirement to receive these vaccinations during study
-
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 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
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
Pharmacokinetics of remibrutinib [Core Part] Month 1, Month 6 Blood concentrations of remibrutinib
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
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 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 event.
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
Change from Baseline in T2 lesion volume [Core Part] Baseline up to 30 months Change from baseline in total T2 lesion volume.
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 [Core Part] Baseline up to 30 months Number of new/newly enlarged T2 lesions per year
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
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
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
Neurofilament light chain (Nfl) [Core Part] Baseline up to 30 months Neurofilament light chain (NfL) concentration in serum
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
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)
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
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 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
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
Neurofilament light chain (NfL) [Extension Part] Day 1 Extension up to 5 years Neurofilament light chain (NfL) concentration in serum
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
Trial Locations
- Locations (72)
US Associates in Research
🇺🇸Miami, Florida, United States
AZ Integrated Neuro and Spine
🇺🇸Phoenix, Arizona, United States
Honor Health Research Institute
🇺🇸Scottsdale, Arizona, United States
Center for Neurosciences
🇺🇸Tucson, Arizona, United States
The Belinga Clinic
🇺🇸Fort Smith, Arkansas, United States
The Research and Education Inst. of Alta Bates Summit Med. Grp
🇺🇸Berkeley, California, United States
The Neuron Clinic
🇺🇸Chula Vista, California, United States
Neur Ctr of N Orange County
🇺🇸Fullerton, California, United States
Glendale Adventist Medical Center
🇺🇸Glendale, California, United States
Hoag Health System
🇺🇸Newport Beach, California, United States
SC3 Research Pasadena
🇺🇸Pasadena, California, United States
Neuro Center
🇺🇸Pomona, California, United States
Mountain Neuro Research Center PC
🇺🇸Basalt, Colorado, United States
Alpine Clinical Research Center
🇺🇸Boulder, Colorado, United States
Christiana Care Health Services
🇺🇸Newark, Delaware, United States
Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
Neurology of Central FL Res Ctr
🇺🇸Altamonte Springs, Florida, United States
Texas Neurology
🇺🇸Dallas, Texas, United States
Arrow Clinical Trials
🇺🇸Daytona Beach, Florida, United States
Homestead Assoc In Research Inc
🇺🇸Homestead, Florida, United States
Reliant Medical Research
🇺🇸Miami, Florida, United States
Neurological Services of Orlando PA
🇺🇸Orlando, Florida, United States
Orlando Health Clinical Trials
🇺🇸Orlando, Florida, United States
Comprehensive Neurology Clinic
🇺🇸Orlando, Florida, United States
Neurology Associates of Ormond Beach
🇺🇸Ormond Beach, Florida, United States
Neurostudies Inc
🇺🇸Port Charlotte, Florida, United States
Accel Research Sites St Pete-Largo
🇺🇸Seminole, Florida, United States
Axiom Clinical Research of Florida
🇺🇸Tampa, Florida, United States
University Of South Florida
🇺🇸Tampa, Florida, United States
Conquest Research
🇺🇸Winter Park, Florida, United States
Velocity Clinical Research
🇺🇸Raleigh, North Carolina, United States
Hawaii Pacific Neuroscience LLC
🇺🇸Honolulu, Hawaii, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Insight Hospital and Medical Center
🇺🇸Chicago, Illinois, United States
Advocate Medical Group
🇺🇸Park Ridge, Illinois, United States
Springfield Clinic
🇺🇸Springfield, Illinois, United States
IU Health Inc
🇺🇸Fort Wayne, Indiana, United States
College Park Family Care Center
🇺🇸Overland Park, Kansas, United States
Norton Neurology MS Services
🇺🇸Louisville, Kentucky, United States
Mid Atlantic Epilepsy and Sleep Ctr
🇺🇸Bethesda, Maryland, United States
International Neurorehab Institute
🇺🇸Lutherville, Maryland, United States
Beth Israel Deaconess Medical Cente
🇺🇸Boston, Massachusetts, United States
Lahey Clinic
🇺🇸Burlington, Massachusetts, United States
Neurology Center of New England PC
🇺🇸Foxboro, Massachusetts, United States
Wayne State University Multiple Sclerosis Clinic
🇺🇸Detroit, Michigan, United States
The MS Center for Innovation in Care
🇺🇸Saint Louis, Missouri, United States
SCL Health
🇺🇸Billings, Montana, United States
Jersey Shore University Medical Ctr
🇺🇸Neptune, New Jersey, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States
NYU Langone Health
🇺🇸Brooklyn, New York, United States
Neurological Associates of Long Island PC
🇺🇸Lake Success, New York, United States
NYU Langone Med Center CV Research
🇺🇸New York, New York, United States
The Neurological Institute PA
🇺🇸Charlotte, North Carolina, United States
Columbus Neuroscience
🇺🇸Westerville, Ohio, United States
Multiple Sclerosis Center of Excellence of OMRF
🇺🇸Oklahoma City, Oklahoma, United States
Providence St Vincent Med Center
🇺🇸Portland, Oregon, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
University Of Pittsburgh Medical Ctr Magee-Womens Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Reading Hospital
🇺🇸Reading, Pennsylvania, United States
Palmetto Clinical Research
🇺🇸Summerville, South Carolina, United States
Univ of Texas Southwest Med Center
🇺🇸Dallas, Texas, United States
Advc Neurology Epilepsy and Sleep
🇺🇸El Paso, Texas, United States
John Peter Smith Hospital
🇺🇸Fort Worth, Texas, United States
Neuro Eye Clinical Trials Inc
🇺🇸Houston, Texas, United States
DHR Health Institute
🇺🇸McAllen, Texas, United States
North TX Inst of Neuro and Headache
🇺🇸Plano, Texas, United States
The University of Utah
🇺🇸Salt Lake City, Utah, United States
MS Center of Greater Washington, P.C.
🇺🇸Vienna, Virginia, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States
University of Wisconsin Madison
🇺🇸Madison, Wisconsin, United States
Neuroscience Group
🇺🇸Neenah, Wisconsin, United States
Novartis Investigative Site
🇬🇧Glasgow, United Kingdom