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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05156281

Collaborator

(none)

800

Enrollment

Locations

Arms

95.3

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

800 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Eligible participants will be randomized in a 1:1 ratioEligible 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 :

Dec 13, 2021

Anticipated Primary Completion Date :

Oct 31, 2025

Anticipated Study Completion Date :

Nov 23, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Remibrutinib - Core Remibrutinib tablet and matching placebo of teriflunomide capsule	Drug: Remibrutinib tablet taken orally Other Names: 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 Names: LOU064
Experimental: Remibrutinib - Extension (on teriflunomide in Core) Participants on teriflunomide in Core will switch to remibrutinib tablet	Drug: Remibrutinib tablet taken orally Other Names: LOU064

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Time to 3-month confirmed disability progression (3mCDP) on Expanded Disability Status Scale (EDSS) [Core Part] (pooled data) [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
Time to 6-month confirmed disability progression (6mCDP) on EDSS [Core Part] (pooled data) [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
Annualized rate of new or enlarging T2 lesion [Core Part] [Baseline up to 30 month]
Number of new/newly enlarged T2 lesions per year
Neurofilament light chain (Nfl) [Core Part] [Baseline up to 30 months]
Neurofilament light chain (NfL) concentration in serum
Number of Gd-enhancing T1 lesions per MRI scan [Core Part] [Baseline up to 30 month]
Average number of Gd-enhancing T1 lesions per scan
Percentage of participants with No Evidence of Disease Activity-3 (NEDA-3) [Core Part] (pooled data) [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
Time to first confirmed relapse [Core Part] [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.
Time to 6-month confirmed disability improvement (6mCDI) on EDSS [Core Part] (pooled data) [Baseline up to 30 month]
Decrease in Expanded Disability Status Scale Score (EDSS) which is sustained for at least 6 months
Change from baseline in the Symbol Digit Modalities Test (SDMT) [Core Part] (pooled data) [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
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 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
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 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)
Time to composite 6-month confirmed disability Progression (CDP) [Core Part] (pooled data) [Baseline up to 30 month]
The composite involves CDP and worsening by at least 20% in T25FW and 9HPT
Change from Baseline in T2 lesion volume [Core Part] [Baseline up to 30 month]
Change from baseline in total T2 lesion volume.
Change from baseline in Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) [Core Part] [Baseline up to 30 month]
20-item, self-administered questionnaire. Global score ranges from 0 to 100 where higher score represents greater fatigue
Change from baseline in Generalized Anxiety Disorder Scale (GAD-7) [Core Part] [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
Change from baseline in Patient Health Questionnaire-9 (PHQ-9) [Core Part] [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
Change from baseline in Brief Pain Inventory- short form (BPI-SF) [Core Part] [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
Change from baseline in Health Utilities Index (HUI-Ill) [Core Part] [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
Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29) [Core Part] [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
Number of participants with Adverse events and Serious adverse events(SAE) [Core Part] [Baseline up to 30 month]
Adverse events and SAEs including clinically significant , laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
Pharmacokinetics of remibrutinib [Core Part] [Month 1, Month 6]
Blood concentrations of remibrutinib
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 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
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 [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
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
Neurofilament light chain (NfL) [Extension Part] [Day 1 Extension up to 5 years]
Neurofilament light chain (NfL) concentration in serum
Change from baseline in Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS) [Extension Part] [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
Change from baseline in Generalized Anxiety Disorder Scale (GAD-7) [Extension Part] [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
Change from baseline in Patient Health Questionnaire-9 (PHQ-9) [Extension Part] [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
Change from baseline in Brief Pain Inventory- short form (BPI-SF) [Extension Part] [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
Change from baseline in Health Utilities Index (HUI-Ill) [Extension Part] [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
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Hanford	California	United States	93230
2	Novartis Investigative Site	Bradenton	Florida	United States	34209
3	Novartis Investigative Site	Maitland	Florida	United States	32751
4	Novartis Investigative Site	Miami	Florida	United States	33136
5	Novartis Investigative Site	Pembroke Pines	Florida	United States	33024
6	Novartis Investigative Site	Pensacola	Florida	United States	32514
7	Novartis Investigative Site	Port Orange	Florida	United States	32127
8	Novartis Investigative Site	Vero Beach	Florida	United States	32960
9	Novartis Investigative Site	Suwanee	Georgia	United States	30024
10	Novartis Investigative Site	Columbus	Ohio	United States	43235
11	Novartis Investigative Site	Dayton	Ohio	United States	45408
12	Novartis Investigative Site	Greer	South Carolina	United States	29650
13	Novartis Investigative Site	El Paso	Texas	United States	79935
14	Novartis Investigative Site	Houston	Texas	United States	77094
15	Novartis Investigative Site	Seattle	Washington	United States	98133
16	Novartis Investigative Site	Crab Orchard	West Virginia	United States	25827
17	Novartis Investigative Site	Sofia		Bulgaria	1413
18	Novartis Investigative Site	Levis	Quebec	Canada	G6W 0M5
19	Novartis Investigative Site	Nantes	Cedex 1	France	44093
20	Novartis Investigative Site	CAEN Cedex		France	14033
21	Novartis Investigative Site	Grenoble		France	38042
22	Novartis Investigative Site	Lille Cedex		France	59037
23	Novartis Investigative Site	Nice Cedex		France	06202
24	Novartis Investigative Site	Toulouse Cedex 9		France	31059
25	Novartis Investigative Site	Pozzilli	IS	Italy	86077
26	Novartis Investigative Site	Katowice		Poland	40 571
27	Novartis Investigative Site	Zabrze		Poland	41-800
28	Novartis Investigative Site	Banska Bystrica		Slovakia	975 17
29	Novartis Investigative Site	Celje		Slovenia	3000
30	Novartis Investigative Site	Ljubljana		Slovenia	1000
31	Novartis Investigative Site	Maribor		Slovenia	2000
32	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
33	Novartis Investigative Site	Gijon	Asturias	Spain	33394
34	Novartis Investigative Site	Hospitalet de Llobregat	Barcelona	Spain	08907
35	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
36	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
37	Novartis Investigative Site	Madrid		Spain	28009
38	Novartis Investigative Site	Madrid		Spain	28040
39	Novartis Investigative Site	Valencia		Spain	46026
40	Novartis Investigative Site	Stockholm		Sweden	141 86
41	Novartis Investigative Site	Kocaeli		Turkey	41380
42	Novartis Investigative Site	Samsun		Turkey	55139