A Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Relapsing Multiple Sclerosis (RMS)

• Fenebrutinib (Drug): Participants will receive fenebrutinib.
• Teriflunomide (Drug): Participants will receive teriflunomide.
• Placebo (Drug): Participants will receive teriflunomide-matching placebo or fenebrutinib-matching placebo.

Primary outcomes

• Annualized Relapse Rate (ARR) [Minimum of 96 weeks]

Secondary outcomes

• Time to Onset of Composite 12-week Confirmed Disability Progression (cCDP12) [Minimum of 96 weeks]
• Time to Onset of Composite 24-week Confirmed Disability Progression (cCDP24) [Minimum of 96 weeks]
• Time to Onset of 12-week Confirmed Disability Progression (CDP12) [Minimum of 96 weeks]
• Time to Onset of 24-week Confirmed Disability Progression (CDP24) [Minimum of 96 weeks]
• Total Number of T1 Gadolinium Enhancing (Gd+) Lesions, New and/or Enlarging T2-weighted Lesions, as Detected by Magnetic Resonance Imaging (MRI) [Baseline, Weeks 12, 24, 48 and 96]
• Percentage Change in Total Brain Volume From Week 24 as Assessed by MRI [From Week 24 to Week 96]
• Change in Participant-reported Physical Impacts of Multiple Sclerosis (MS), as Measured by the Multiple Sclerosis Impact Scale (29-item), Version 2 (MSIS-29) Physical Scale [Baseline, Weeks 12, 24, 36, 48, 60, 72, 84 and 96]
• Time to Onset of 12-week Confirmed 4-point Worsening in Symbol Digit Modality Test (SDMT) Score [Minimum of 96 weeks]
• Percent Change From Baseline to Week 48 in the Concentration of Blood Neurofilament Light Chain (NfL) [Baseline, Week 48]
• Time to Onset of Composite 12-week Confirmed Progression Independent of Relapse Activity (cPIRA12) [Minimum of 96 weeks]
• Percentage of Participants With Adverse Events (AEs) [Up to 4.5 years]
• Plasma Concentrations of Fenebrutinib at Specified Timepoints [Up to 4.5 years]

Sex: All, ages: 18 Years to 55 Years

Inclusion Criteria:

* Expanded Disability Status Scale (EDSS) score of 0 - 5.5 at screening
* A diagnosis of RMS in accordance with the revised 2017 McDonald Criteria
* Ability to complete the 9-Hole Peg Test (9-HPT) for each hand in < 240 seconds
* Ability to perform the Timed 25-Foot Walk Test (T25FWT) in < 150 seconds
* For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating eggs
* For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating sperm

OLE Inclusion Criteria:

* Completed the DBT phase of the study (remaining on study treatment; no other disease-modifying therapy (DMT) administered) and who, in the opinion of the investigator, may benefit from treatment with fenebrutinib
* Participants randomized to the teriflunomide treatment arm during the DBT phase must undergo the accelerated teriflunomide elimination procedure (ATEP) prior to the first administration of open-label fenebrutinib
* For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating eggs
* For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and refrain from donating sperm

Exclusion Criteria:

* Disease duration of > 10 years from the onset of symptoms and an EDSS score at screening < 2.0
* Female participants who are pregnant or breastfeeding, or intending to become pregnant
* Male participants who intend to father a child during the study
* A diagnosis of primary progressive multiple sclerosis (PPMS) or non-active secondary progressive multiple sclerosis (SPMS)
* Any known or suspected active infection at screening, including but not limited to a positive screening test for hepatitis B (HBV) and hepatitis C (HCV), an active or latent or inadequately treated infection with tuberculosis (TB), a confirmed or suspected progressive multifocal leukoencephalopathy (PML)
* History of cancer including hematologic malignancy and solid tumors within 10 years of screening
* Known presence of other neurological disorders, that could interfere with the diagnosis of MS or assessments of efficacy or safety during the study and clinically significant cardiovascular, psychiatric, pulmonary, renal, hepatic, endocrine, metabolic or gastrointestinal (GI) disease
* Rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
* Hypoproteinemia
* Acute liver disease
* Chronic liver disease unless considered stable for > 6 months
* Presence of cirrhosis (Child-Pugh Class A, B, or C) or Gilbert's Syndrome
* Participants with significantly impaired bone marrow function or significant anemia, leukopenia, neutropenia or thrombocytopenia
* Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
* History of alcohol or other drug abuse within 12 months prior to screening
* History of or currently active primary or secondary (non-drug-related) immunodeficiency, including known history of human immunodeficiency virus (HIV) infection
* Inability to complete an MRI scan
* Adrenocorticotropic hormone or systemic corticosteroid therapy within 4 weeks prior to screening (inhaled and topical corticosteroids are allowed)
* Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
* Any previous treatment with immunomodulatory or immunosuppressive medication without an appropriate washout period

OLE Exclusion Criteria:

* Acute liver disease
* Chronic liver disease unless considered stable for > 6 months
* Cirrhosis (Child-Pugh Class A, B, or C)
* Gilbert's syndrome

58 more sites not listed.

• Clinical Trials, Study director, Hoffmann-La Roche

NIH grants: 2019