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

Relapsing Multiple Sclerosis Clinical Trial

— REMODEL-1  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05147220
• Other study ID #: CLOU064C12301
• Secondary ID: 2020-005899-36
• Status: Recruiting
• Phase: Phase 3
• Start date: December 16, 2021
• Est. completion date: October 30, 2030

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: October 30, 2030
• Est. primary completion date: April 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Relapsing Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Remibrutinib
tablet taken orally
• Teriflunomide
capsule taken orally

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Santiago del Estero
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Linz	Oberoesterreich
Belgium	Novartis Investigative Site	Antwerpen
Belgium	Novartis Investigative Site	Ath
Belgium	Novartis Investigative Site	Brasschaat
Belgium	Novartis Investigative Site	Brugge
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Jette	Brussel
Belgium	Novartis Investigative Site	Lier
Belgium	Novartis Investigative Site	Melsbroek
Belgium	Novartis Investigative Site	Pelt
Bulgaria	Novartis Investigative Site	Pleven
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Chile	Novartis Investigative Site	Santiago	Region Metropolitana
Chile	Novartis Investigative Site	Santiago	Region Metropolitana
China	Novartis Investigative Site	Baotou	Inner Mongolia
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing	Beijing
China	Novartis Investigative Site	Changchun	Jilin
China	Novartis Investigative Site	Changsha	Hunan
China	Novartis Investigative Site	Chongqing
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Guangzhou City	Guangdong
China	Novartis Investigative Site	Hohhot	Inner Mongolia
China	Novartis Investigative Site	Nanchang	Jiangxi
China	Novartis Investigative Site	Tianjin
China	Novartis Investigative Site	Zhengzhou	Henan
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Cali	Valle Del Cauca
Colombia	Novartis Investigative Site	Cali	Valle Del Cauca
Colombia	Novartis Investigative Site	Puerto Colombia	Atlantico
Croatia	Novartis Investigative Site	Osijek
Croatia	Novartis Investigative Site	Rijeka	HRV
Croatia	Novartis Investigative Site	Zadar
Croatia	Novartis Investigative Site	Zagreb
Denmark	Novartis Investigative Site	Slagelse
Georgia	Novartis Investigative Site	Tbilisi
Georgia	Novartis Investigative Site	Tbilisi
Georgia	Novartis Investigative Site	Tbilisi
Georgia	Novartis Investigative Site	Tbilisi
Georgia	Novartis Investigative Site	Tbilisi
Georgia	Novartis Investigative Site	Tbilisi
Guatemala	Novartis Investigative Site	Guatemala
Hong Kong	Novartis Investigative Site	Sha Tin
India	Novartis Investigative Site	Chandigarh	Punjab
India	Novartis Investigative Site	DehraDun	Uttarakhand
India	Novartis Investigative Site	Hyderabad	Telangana
India	Novartis Investigative Site	Lucknow	Uttar Pradesh
India	Novartis Investigative Site	Ludhiana	Punjab
India	Novartis Investigative Site	Mangalore
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	Nashik	Maharashtra
India	Novartis Investigative Site	New Delhi	Delhi
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Dublin 4
Israel	Novartis Investigative Site	Ashkelon
Israel	Novartis Investigative Site	Hadera
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Sefad
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Montichiari	BS
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Novara
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Verona	VR
Jordan	Novartis Investigative Site	Amman
Latvia	Novartis Investigative Site	Riga	LV
Latvia	Novartis Investigative Site	Riga
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	El Chouf	LBN
Lebanon	Novartis Investigative Site	Tripoli
Lithuania	Novartis Investigative Site	Klaipeda
Lithuania	Novartis Investigative Site	Siauliai	LTU
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuala Terengganu	Terengganu
Malaysia	Novartis Investigative Site	Seberang Jaya	Pulau Pinang
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Hertogenbosch
Netherlands	Novartis Investigative Site	Rotterdam
Poland	Novartis Investigative Site	Bydgoszcz	Woj Kujawsko-pomorskie
Poland	Novartis Investigative Site	Kielce
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Piotrkow Trybunalski
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Rzeszow
Poland	Novartis Investigative Site	Szczecin
Poland	Novartis Investigative Site	Wroclaw	Dolnoslaskie
Saudi Arabia	Novartis Investigative Site	Jeddah
Saudi Arabia	Novartis Investigative Site	Jeddah
Saudi Arabia	Novartis Investigative Site	Khorais Street	Riyadh
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice	Slovak Republic
Slovakia	Novartis Investigative Site	Nitra
Slovakia	Novartis Investigative Site	Trnava
Spain	Novartis Investigative Site	Alcorcon	Madrid
Spain	Novartis Investigative Site	Baracaldo	Vizcaya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Cadiz	Andalucia
Spain	Novartis Investigative Site	Castilleja De La Cuesta	Sevilla
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	El Palmar	Murcia
Spain	Novartis Investigative Site	Getafe	Madrid
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Las Palmas de Gran Canaria
Spain	Novartis Investigative Site	Leon
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Salt	Cataluna
Spain	Novartis Investigative Site	Sant Joan Despi	Barcelona
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Vigo	Pontevedra
Switzerland	Novartis Investigative Site	Basel
Switzerland	Novartis Investigative Site	Bern
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
United Arab Emirates	Novartis Investigative Site	Abu Dhabi
United Arab Emirates	Novartis Investigative Site	Dubai
United Kingdom	Novartis Investigative Site	Westbruy On Trym	Bristol
United Kingdom	Novartis Investigative Site	Winchester	Hampshire
United States	Neurology of Central FL Res Ctr	Altamonte Springs	Florida
United States	Mountain Neuro Research Center PC .	Basalt	Colorado
United States	The Research and Education Inst. of Alta Bates Summit Med. Grp	Berkeley	California
United States	Mid Atlantic Epilepsy and Sleep Ctr	Bethesda	Maryland
United States	SCL Health	Billings	Montana
United States	Beth Israel Deaconess Medical Cente	Boston	Massachusetts
United States	Alpine Clinical Research Center	Boulder	Colorado
United States	Lahey Clinic	Burlington	Massachusetts
United States	The Neurological Institute PA	Charlotte	North Carolina
United States	Insight Hospital and Medical Center	Chicago	Illinois
United States	Rush University Medical Center CFTY720D2312	Chicago	Illinois
United States	The Neuron Clinic .	Chula Vista	California
United States	Novartis Investigative Site	Dallas	Texas
United States	Texas Neurology	Dallas	Texas
United States	Novartis Investigative Site	El Paso	Texas
United States	The Belinga Clinic .	Fort Smith	Arkansas
United States	Allied Physicians, Inc. .	Fort Wayne	Indiana
United States	John Peter Smith Hospital	Fort Worth	Texas
United States	Neurology Center of New England PC .	Foxboro	Massachusetts
United States	Neur Ctr of N Orange County	Fullerton	California
United States	Glendale Adventist Medical Center Research	Glendale	California
United States	Hawaii Pacific Neuroscience LLC	Honolulu	Hawaii
United States	Neuro Eye Clinical Trials Inc	Houston	Texas
United States	Neurological Associates of Long Island PC	Lake Success	New York
United States	Norton Neurology MS Services	Louisville	Kentucky
United States	International Neurorehab Institute .	Lutherville	Maryland
United States	University of Wisconsin Madison	Madison	Wisconsin
United States	DHR Health Institute .	McAllen	Texas
United States	Homestead Associates in Research Inc	Miami	Florida
United States	Reliant Medical Research	Miami	Florida
United States	US Associates in Research	Miami	Florida
United States	Neuroscience Group	Neenah	Wisconsin
United States	Jersey Shore University Medical Ctr	Neptune	New Jersey
United States	NYU Langone Med Center CV Research .	New York	New York
United States	Christiana Care Health Services	Newark	Delaware
United States	Hoag Health System	Newport Beach	California
United States	Multiple Sclerosis Center of Excellence of OMRF	Oklahoma City	Oklahoma
United States	Comprehensive Neurology Clinic	Orlando	Florida
United States	Neurological Services of Orlando, PA	Orlando	Florida
United States	Orlando Health Clinical Trials .	Orlando	Florida
United States	Neurology Associates of Ormond Beach	Ormond Beach	Florida
United States	College Park Family Care Center	Overland Park	Kansas
United States	Advocate Medical Group	Park Ridge	Illinois
United States	SC3 Research Pasadena	Pasadena	California
United States	Thomas Jefferson University Hospital Dept. of Neurology	Philadelphia	Pennsylvania
United States	AZ Integrated Neuro and Spine Integrated MS Center	Phoenix	Arizona
United States	University of Pittsburgh Medical Ctr Magee - Womens Hospital	Pittsburgh	Pennsylvania
United States	North TX Inst of Neuro and Headache	Plano	Texas
United States	Neurostudies Inc	Port Charlotte	Florida
United States	Providence St Vincent Med Center	Portland	Oregon
United States	Velocity Clinical Research Drug Shipment	Raleigh	North Carolina
United States	Reading Hospital Tower Health Med Group Neuro	Reading	Pennsylvania
United States	The MS Center for Innovation in Care .	Saint Louis	Missouri
United States	The University of Utah .	Salt Lake City	Utah
United States	Velocity Clinical Research	Savannah	Georgia
United States	Honor Health Research Institute .	Scottsdale	Arizona
United States	Swedish Medical Center Swedish Neuroscience Research	Seattle	Washington
United States	Accel Research Sites St Pete-Largo	Seminole	Florida
United States	Springfield Clinic Research	Springfield	Illinois
United States	Palmetto Clinical Research .	Summerville	South Carolina
United States	Axiom Clinical Research of Florida	Tampa	Florida
United States	University of South Florida .	Tampa	Florida
United States	Center for Neurosciences	Tucson	Arizona
United States	MS Center of Greater Washington, P.C.	Vienna	Virginia
United States	Washington Hospital Center Research Site Shipment	Washington	District of Columbia
United States	Novartis Investigative Site	Westerville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Bulgaria,  Chile,  China,  Colombia,  Croatia,  Denmark,  Georgia,  Guatemala,  Hong Kong,  India,  Ireland,  Israel,  Italy,  Jordan,  Latvia,  Lebanon,  Lithuania,  Malaysia,  Netherlands,  Poland,  Saudi Arabia,  Slovakia,  Spain,  Switzerland,  Taiwan,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 months
Secondary	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 months
Secondary	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 months
Secondary	Annualized rate of new or enlarging T2 lesion [Core Part]	Number of new/newly enlarged T2 lesions per year	Baseline up to 30 months
Secondary	Neurofilament light chain (Nfl) [Core Part]	Neurofilament light chain (NfL) concentration in serum	Baseline up to 30 months
Secondary	Number of Gd-enhancing T1 lesions per MRI scan [Core Part]	Average number of Gd-enhancing T1 lesions per scan	Baseline up to 30 months
Secondary	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 months
Secondary	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 months
Secondary	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 months
Secondary	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.	Baseline up to 30 months
Secondary	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 months
Secondary	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 months
Secondary	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 months
Secondary	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 months
Secondary	Change from Baseline in T2 lesion volume [Core Part]	Change from baseline in total T2 lesion volume.	Baseline up to 30 months
Secondary	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 months
Secondary	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 months
Secondary	Pharmacokinetics of remibrutinib [Core Part]	Blood concentrations of remibrutinib	Month 1, Month 6
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Neurofilament light chain (NfL) [Extension Part]	Neurofilament light chain (NfL) concentration in serum	Day 1 Extension up to 5 years
Secondary	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