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

Phase 3Active Not RecruitingNCT05147220

Novartis Pharmaceuticals1,001 enrolled

Overview

To compare the efficacy and safety of remibrutinib versus teriflunomide in patients with relapsing multiple sclerosis (RMS)

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

1,001

Conditions

Relapsing Multiple Sclerosis

Interventions

RemibrutinibDRUG

tablet taken orally

TeriflunomideDRUG

capsule taken orally

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

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 (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

Locations (208)

Outcomes

Primary Outcomes

Annualized relapse rate (ARR) of confirmed relapses [Core Part]

ARR is the average number of confirmed MS relapses in a year

Time frame: From Baseline, up to 30 months

Secondary Outcomes

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

Time frame: Baseline up to 30 months

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

Time frame: Baseline up to 30 months

Annualized rate of new or enlarging T2 lesion [Core Part]

Number of new/newly enlarged T2 lesions per year

Time frame: Baseline up to 30 months

Neurofilament light chain (Nfl) [Core Part]

Neurofilament light chain (NfL) concentration in serum

Time frame: 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

Time frame: Baseline up to 30 months

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

Data from ClinicalTrials.gov

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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

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

...and 198 more locations

Time frame: Baseline up to 30 months

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.

Time frame: Baseline up to 30 months

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

Time frame: Baseline up to 30 months

Time to 3-months confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP) independent of relapse activity (PIRA) [Core Part] (pooled data)

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 frame: Baseline up to 30 months

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

Time frame: Baseline up to 30 months

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

Time frame: Baseline, up to 30 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)

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 frame: Baseline up to 30 months

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

Time frame: Baseline up to 30 months

Change from Baseline in T2 lesion volume [Core Part]

Change from baseline in total T2 lesion volume.

Time frame: Baseline up to 30 months

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

Time frame: Baseline up to 30 months

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

Time frame: Baseline up to 30 months

Pharmacokinetics of remibrutinib [Core Part]

Blood concentrations of remibrutinib

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Day 1 Extension up to 5 years

Change from baseline in the Symbol Digit Modalities Test (SDMT) [Extension Part]

Time frame: Day 1 Extension up to 5 years

Neurofilament light chain (NfL) [Extension Part]

Neurofilament light chain (NfL) concentration in serum

Time frame: Day 1 Extension up to 5 years

Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Extension Part]

Time frame: Day 1 Extension up to 5 years