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

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ClinicalTrials.gov Identifier: NCT05147220
Recruitment Status : Recruiting
First Posted : December 7, 2021
Last Update Posted : October 3, 2023
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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

Condition or disease Intervention/treatment Phase
Relapsing Multiple Sclerosis Drug: Remibrutinib Drug: Teriflunomide Phase 3

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible participants will be randomized in a 1:1 ratio
Masking: Double (Participant, Investigator)
Masking Description: In order to maintain blinding, a double-dummy design will be used
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 16, 2021
Estimated Primary Completion Date : April 30, 2026
Estimated Study Completion Date : October 30, 2030

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Remibrutinib - Core
Remibrutinib tablet and matching placebo of teriflunomide capsule
 Drug: Remibrutinib
tablet taken orally
Other Name: LOU064
Active Comparator: Teriflunomide - Core
Teriflunomide capsule and matching placebo remibrutinib tablet
 Drug: Teriflunomide
capsule taken orally
Experimental: Remibrutinib - Extension
Participants on remibrutinib in Core will continue on remibrutinib tablet
 Drug: Remibrutinib
tablet taken orally
Other Name: LOU064
Experimental: Remibrutinib - Extension (on teriflunomide in Core)
Participants on teriflunomide in Core will switch to remibrutinib tablet
 Drug: Remibrutinib
tablet taken orally
Other Name: LOU064


Outcome Measures
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Primary Outcome Measures :
  1. Annualized relapse rate (ARR) of confirmed relapses [Core Part] [ Time Frame: From Baseline, up to 30 month ]
    ARR is the average number of confirmed MS relapses in a year


Secondary Outcome Measures :
  1. Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS) [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    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

  2. Time to 6-month confirmed disability progression (6mCDP) on EDSS [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    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

  3. Annualized rate of new or enlarging T2 lesion [Core Part] [ Time Frame: Baseline up to 30 month ]
    Number of new/newly enlarged T2 lesions per year

  4. Neurofilament light chain (Nfl) [Core Part] [ Time Frame: Baseline up to 30 months ]
    Neurofilament light chain (NfL) concentration in serum

  5. Number of Gd-enhancing T1 lesions per MRI scan [Core Part] [ Time Frame: Baseline up to 30 month ]
    Average number of Gd-enhancing T1 lesions per scan

  6. Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3) [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    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

  7. Time to first confirmed relapse [Core Part] [ Time Frame: Baseline up to 30 month ]
    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.

  8. Time to 6-month confirmed disability improvement (6mCDI) on EDSS [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    Decrease in Expanded Disability Status Scale Score (EDSS) which is sustained for at least 6 months

  9. Change from baseline in the Symbol Digit Modalities Test (SDMT) [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    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

  10. Time to 6-month confirmed worsening by at least 20% in the Timed 25-foot walk test (T25FW) [Core Part] (pooled data) [ Time Frame: Baseline, up to 30 month ]
    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

  11. Time to 6-month confirmed worsening by at least 20% in the Timed 9-hole peg test (9HPT) (pooled data) [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    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)

  12. Time to composite 6-month confirmed disability Progression (CDP) [Core Part] (pooled data) [ Time Frame: Baseline up to 30 month ]
    The composite involves CDP and worsening by at least 20% in T25FW and 9HPT

  13. Change from Baseline in T2 lesion volume [Core Part] [ Time Frame: Baseline up to 30 month ]
    Change from baseline in total T2 lesion volume.

  14. Change from baseline in Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) [Core Part] [ Time Frame: Baseline up to 30 month ]
    20-item, self-administered questionnaire. Global score ranges from 0 to 100 where higher score represents greater fatigue

  15. Change from baseline in Generalized Anxiety Disorder Scale (GAD-7) [Core Part] [ Time Frame: Baseline up to 30 month ]
    7-item, self-administered scale. It has a global score ranging from 0-21. Higher score means higher severity of anxiety symptoms

  16. Change from baseline in Patient Health Questionnaire-9 (PHQ-9) [Core Part] [ Time Frame: Baseline up to 30 month ]
    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

  17. Change from baseline in Brief Pain Inventory- short form (BPI-SF) [Core Part] [ Time Frame: Baseline up to 30 month ]
    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

  18. Change from baseline in Health Utilities Index (HUI-Ill) [Core Part] [ Time Frame: Baseline up to 30 month ]
    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

  19. Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Core Part] [ Time Frame: Baseline up to 30 month ]
    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

  20. Number of participants with Adverse events and Serious adverse events(SAE) [Core Part] [ Time Frame: Baseline up to 30 month ]
    Adverse events and SAEs including clinically significant , laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating

  21. Pharmacokinetics of remibrutinib [Core Part] [ Time Frame: Month 1, Month 6 ]
    Blood concentrations of remibrutinib

  22. Number of participants with Adverse events and Serious adverse events (SAE) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    Adverse events and SAEs including clinically significant, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating

  23. Annualized relapse rate (ARR) of confirmed relapses [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    ARR is the average number of confirmed MS relapses in a year

  24. Annualized rate of new or enlarging T2 lesion [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    Number of new/newly enlarged T2 lesions per year

  25. Time to 6-month confirmed disability progression (6mCDP) on EDSS [Extension Part] [ Time Frame: 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

  26. Change from baseline in the Symbol Digit Modalities Test (SDMT) [Extension Part] [ Time Frame: 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

  27. Neurofilament light chain (NfL) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    Neurofilament light chain (NfL) concentration in serum

  28. Change from baseline in Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    20-item, self-administered questionnaire. Global score ranges from 0 to 100 where higher score represents greater fatigue

  29. Change from baseline in Generalized Anxiety Disorder Scale (GAD-7) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    7-item, self-administered scale. It has a global score ranging from 0-21. Higher score means higher severity of anxiety symptoms

  30. Change from baseline in Patient Health Questionnaire-9 (PHQ-9) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    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

  31. Change from baseline in Brief Pain Inventory- short form (BPI-SF) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    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

  32. Change from baseline in Health Utilities Index (HUI-Ill) [Extension Part] [ Time Frame: Day 1 Extension up to 5 years ]
    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

  33. Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Extension Part] [ Time Frame: 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


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05147220


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05147220    
Other Study ID Numbers: CLOU064C12301
2020-005899-36 ( EudraCT Number )
First Posted: December 7, 2021    Key Record Dates
Last Update Posted: October 3, 2023
Last Verified: September 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Teriflunomide
Remibrutinib
Anti-Inflammatory Agents, Non-Steroidal
 Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Immunosuppressive Agents
Immunologic Factors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action