Efficacy and Safety of Remibrutinib Compared to Teriflunomide in Participants With Relapsing Multiple Sclerosis

Study Overview
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Brief Summary
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To compare the efficacy and safety of remibrutinib versus teriflunomide in patients with relapsing multiple sclerosis

Detailed Description
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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.

Official Title
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A Randomized, Double-blind, Double-dummy, Parallel-group Study, Comparing the Efficacy and Safety of Remibrutinib Versus Teriflunomide in Participants With Relapsing Multiple Sclerosis, Followed by Extended Treatment With Open-label Remibrutinib

Conditions
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Relapsing Multiple Sclerosis

Intervention / Treatment
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* Drug: Remibrutinib
* Drug: Teriflunomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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 or hepatic failure or participants with moderate or severe hepatic impairment (Child-Pugh class C) 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 (prior to randomization) 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 strong CYP3A4 inducers within two weeks prior to randomization Inclusion to Extension part: • patient 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible participants will be randomized in a 1:1 ratio
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remibrutinib - Core<br>Remibrutinib tablet and matching placebo of teriflunomide capsule | Drug: Remibrutinib<br>* tablet taken orally<br>* Other names: LOU064;|
| Active Comparator: Teriflunomide - Core<br>Teriflunomide capsule and matching placebo remibrutinib tablet | Drug: Teriflunomide<br>* capsule taken orally<br>|
| Experimental: Remibrutinib - Extension<br>Participants on remibrutinib in Core will continue on remibrutinib tablet | Drug: Remibrutinib<br>* tablet taken orally<br>* Other names: LOU064;|
| Experimental: Remibrutinib - Extension (on teriflunomide in Core)<br>Participants on teriflunomide in Core will switch to remibrutinib tablet | Drug: Remibrutinib<br>* tablet taken orally<br>* Other names: LOU064;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized relapse rate (ARR) of confirmed relapses [Core Part] | ARR is the average number of confirmed MS relapses in a year | From Baseline, up to 30 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS) [Core Part] (pooled data) | 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 | Baseline up to 30 month | 
| Time to 6-month confirmed disability progression (6mCDP) on EDSS [Core Part] (pooled data) | 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 | Baseline up to 30 month | 
| Annualized rate of new or enlarging T2 lesion [Core Part] | Number of new/newly enlarged T2 lesions per year | Baseline up to 30 month | 
| Neurofilament light chain (Nfl) [Core Part] | Neurofilament light chain (NfL) concentration in serum | Baseline up to 30 months | 
| Number of Gd-enhancing T1 lesions per MRI scan [Core Part] | Average number of Gd-enhancing T1 lesions per scan | Baseline up to 30 month | 
| Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3) [Core Part] (pooled data) | 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 | Baseline up to 30 month | 
| Time to first confirmed relapse [Core Part] | 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. | Baseline up to 30 month | 
| Time to 6-month confirmed disability improvement (6mCDI) on EDSS [Core Part] (pooled data) | Decrease in Expanded Disability Status Scale Score (EDSS) which is sustained for at least 6 months | Baseline up to 30 month | 
| Change from baseline in the Symbol Digit Modalities Test (SDMT) [Core Part] (pooled data) | 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 | Baseline up to 30 month | 
| Time to 6-month confirmed worsening by at least 20% in the Timed 25-foot walk test (T25FW) [Core Part] (pooled data) | 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 | Baseline, up to 30 month | 
| Time to 6-month confirmed worsening by at least 20% in the Timed 9-hole peg test (9HPT) (pooled data) [Core Part] (pooled data) | 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) | Baseline up to 30 month | 
| Time to composite 6-month confirmed disability Progression (CDP) [Core Part] (pooled data) | The composite involves CDP and worsening by at least 20% in T25FW and 9HPT | Baseline up to 30 month | 
| Change from Baseline in T2 lesion volume [Core Part] | Change from baseline in total T2 lesion volume. | Baseline up to 30 month | 
| Change from baseline in Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) [Core Part] | 20-item, self-administered questionnaire. Global score ranges from 0 to 100 where higher score represents greater fatigue | Baseline up to 30 month | 
| Change from baseline in Generalized Anxiety Disorder Scale (GAD-7) [Core Part] | 7-item, self-administered scale. It has a global score ranging from 0-21. Higher score means higher severity of anxiety symptoms | Baseline up to 30 month | 
| Change from baseline in Patient Health Questionnaire-9 (PHQ-9) [Core Part] | 9-item, self-administered scale. Scores can range from 0 to 27. PHQ-9 scores of 5, 10, 15, and 20 represent mild, moderate, moderately severe, and severe depression, respectively | Baseline up to 30 month | 
| Change from baseline in Brief Pain Inventory- short form (BPI-SF) [Core Part] | 15-item, self-administered questionnaire to assess the severity of pain and the impact of pain on daily functions. Includes seven-item interference scale. It has a 10-point response option, ranging from 0 (does not interfere) to 10 (completely interferes). Global score ranges from 0 to 10, where lower scores represent lower pain | Baseline up to 30 month | 
| Change from baseline in Health Utilities Index (HUI-Ill) [Core Part] | 15-item, self-administered index that measures eight health-related quality of life areas including vision, hearing, speech, ambulation/mobility, pain, dexterity, emotion, and cognition | Baseline up to 30 month | 
| Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Core Part] | 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 | Baseline up to 30 month | 
| Number of participants with Adverse events and Serious adverse events(SAE) [Core Part] | Adverse events and SAEs including clinically significant , laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating | Baseline up to 30 month | 
| Pharmacokinetics of remibrutinib [Core Part] | Blood concentrations of remibrutinib | Month 1, Month 6 | 
| Number of participants with Adverse events and Serious adverse events (SAE) [Extension Part] | Adverse events and SAEs including clinically significant, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating | Day 1 Extension up to 5 years | 
| Annualized relapse rate (ARR) of confirmed relapses [Extension Part] | ARR is the average number of confirmed MS relapses in a year | Day 1 Extension up to 5 years | 
| Annualized rate of new or enlarging T2 lesion [Extension Part] | Number of new/newly enlarged T2 lesions per year | Day 1 Extension up to 5 years | 
| Time to 6-month confirmed disability progression (6mCDP) on EDSS [Extension Part] | 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 | Day 1 Extension up to 5 years | 
| Change from baseline in the Symbol Digit Modalities Test (SDMT) [Extension Part] | 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 | Day 1 Extension up to 5 years | 
| Neurofilament light chain (NfL) [Extension Part] | Neurofilament light chain (NfL) concentration in serum | Day 1 Extension up to 5 years | 
| Change from baseline in Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) [Extension Part] | 20-item, self-administered questionnaire. Global score ranges from 0 to 100 where higher score represents greater fatigue | Day 1 Extension up to 5 years | 
| Change from baseline in Generalized Anxiety Disorder Scale (GAD-7) [Extension Part] | 7-item, self-administered scale. It has a global score ranging from 0-21. Higher score means higher severity of anxiety symptoms | Day 1 Extension up to 5 years | 
| Change from baseline in Patient Health Questionnaire-9 (PHQ-9) [Extension Part] | 9-item, self-administered scale. Scores can range from 0 to 27. PHQ-9 scores of 5, 10, 15, and 20 represent mild, moderate, moderately severe, and severe depression, respectively | Day 1 Extension up to 5 years | 
| Change from baseline in Brief Pain Inventory- short form (BPI-SF) [Extension Part] | 15-item, self-administered questionnaire to assess the severity of pain and the impact of pain on daily functions. Includes seven-item interference scale. It has a 10-point response option, ranging from 0 (does not interfere) to 10 (completely interferes). Global score ranges from 0 to 10, where lower scores represent lower pain | Day 1 Extension up to 5 years | 
| Change from baseline in Health Utilities Index (HUI-Ill) [Extension Part] | 15-item, self-administered index that measures eight health-related quality of life areas including vision, hearing, speech, ambulation/mobility, pain, dexterity, emotion, and cognition | Day 1 Extension up to 5 years | 
| Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Extension Part] | 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 | Day 1 Extension up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, RMS, RRMS, active secondary progressive multiple sclerosis SPMS, remibrutinib, LOU064, teriflunomide, adult, relapse, Expanded Disability Status Scale, T2 lesions, T1 lesions, GD- enhancing MRI, Neurofilament light chain, McDonald diagnostic criteria