RELAPSING MULTIPLE SCLEROSIS

This study will evaluate the efficacy and safety of fenebrutinib compared with teriflunomide in adult patients with relapsing multiple sclerosis (RMS). The pharmacokinetics (PK) of fenebrutinib will also be evaluated.

Fenebrutinib
Aubagio

Fenebrutinib
Teriflunomide

film-coated tablet
film-coated tablet (will be supplied in hard capsule in this trial for bouble-dummy purpose)

100 mg
14 mg

Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of fenebrutinib compared with teriflunomide on the basis of the following co-primary endpoints:
•Time to onset of composite 12-week confirmed disability progression (cCDP12), defined as the time from baseline to the first occurrence of a progression event according to at least one of the following three criteria; must be confirmed at a regularly scheduled visit that is at least 12 weeks after the initial disability progression:
– An increase from baseline in Expanded Disability Status Scale (EDSS) score of 1.0
point in patients with a baseline EDSS score of 5.5 or an increase of 0.5 points in
patients with a baseline EDSS score of 5.5 (confirmed disability progression [CDP])
– 20% increase from baseline in the Timed 25-Foot Walk Test (T25FWT)
– 20% increase from baseline in time to complete the 9-Hole Peg Test (9-HPT)
• Annualized relapse rate (ARR)
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of fenebrutinib
treatment compared with teriflunomide on the basis of the following endpoints:
•Time to onset of composite 24-week confirmed disability progression (cCDP24)

Patients must meet the following criteria for study entry:
• Signed Informed Consent Form
• Age 18
55 years inclusive at time of signing the Informed Consent Form
• Ability to comply with the study protocol
• EDSS score of 05.5 at screening
• A diagnosis of RMS* in accordance with the revised 2017 McDonald Criteria (Thompson et al. 2018) and one of the following:
 At least two documented clinical relapses within the last 2 years or one documented clinical relapse within 12 months of screening (but not within the 30 days prior to screening)
 Documented evidence of the presence of at least one T1Gd+ lesion on MRI in the 12 months prior to randomization
* RMS may include aSPMS as defined by Lublin 2014.
• Neurologically stable for at least 30 days prior to randomization and baseline assessments
• Ability to complete the 9-HPT for each hand in 240 seconds
• Ability to perform the T25FWT
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% per year during the treatment period, for 8 weeks after the final dose of study medication, and until the teriflunomide elimination protocol is completed (see local label for AUBAGIO). Women must refrain from donating eggs during this same period. A summary of study drug washout procedures can be found in Appendix 11. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment phase, for 8 weeks after the final dose of study drug, and until completion of the teriflunomide elimination protocol (see the local label for AUBAGIO). Men must also refrain from donating sperm during this same period. A summary of study drug washout procedures can be found in Appendix 11. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.

Patients who meet any of the following criteria will be excluded from study entry:
•Disease duration of 10 years from the onset of symptoms and an EDSS score at screening 2.0
•Pregnant or breastfeeding, or intending to become pregnant during the study or within 8 weeks (with ATEP) after the final dose of study drug (see Section 5.4.3.1 for more information regarding pregnancy)
Women of childbearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy tests at all subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test, ideally from the central laboratory.
•Men intending to father a child during the study or within 8 weeks (with ATEP) after final dose of study drug
•A diagnosis of PPMS or non-active SPMS
•Any known or suspected active infection at screening or baseline, or any major episode of infection requiring hospitalization or treatment with IV anti-microbials within 8 weeks prior to and during screening or treatment with oral anti-microbials within 2 weeks prior to and during screening
•History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)
•History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
Basal or squamous cell carcinoma of the skin that has been excised and is considered cured and in situ carcinoma of the cervix treated with apparent success by curative therapy 1 year prior to screening is not exclusionary.
•Known presence of other neurological disorders, including, but not limited to, the following:
– History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack, spontaneous intracranial hemorrhage, or traumatic intracranial hemorrhage) or ischemia of the spinal cord
– History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)
– History or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)
– History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy)
– History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes [MELAS] syndrome)
– Neuromyelitis optica spectrum disorder
– History or known presence of systemic autoimmune disorders potentially causing progressive neurological disease (e.g., lupus, anti-phospholipid antibody syndrome, Sjögren syndrome, Behçet disease)
– History or known presence of sarcoidosis
– History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression)
•Evidence of clinically significant psychiatric, pulmonary, renal, hepatic (including Gilbert syndrome), metabolic, gastrointestinal (GI), or cardiovascular disease (including arrhythmias or QTc prolongation), or endocrine disease (including uncontrolled diabetes, non-gallstone pancreatitis, or chronic pancreatitis) that, in the investigator’s opinion, would preclude patient participation
•Presence of the New York Heart Association Class III and Class IV criteria for congestive heart failure
•Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect patient safety or interpretation of study results, including QT interval corrected through use of Fridericia’s formula (QTcF) 440 ms demonstrated by at least two ECGs 30 minutes apart
•Current treatment with medications that are well known to prolong the QT interval at doses that have a clinically meaningful effect on QT, as determined by the investigator
•History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome); structural heart disease; coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing, prior coronary artery bypass grafting, or coronary lesions 70% diameter stenosis that have not been or cannot be re-vascularized); clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia); family history of sudden, unexplained death; or cardiac ion channel genetic mutations (e.g., congenital long QT syndrome)
•Rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
•Hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with serum albumin 3.0 g/dL
•Patients with severe renal impairment undergoing dialysis and/or estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2 (may be repeated if eGFR 4559 mL/min/1.73 m2)
•Severe hepatic disease impairment (Child-Pugh Class C)
•One or more of the following laboratory results:
– ALT or AST 2 upper limit of normal (ULN; may be repeated if 23 ULN)
– Total bilirubin greater than 1.5 ULN (may be repeated if 1.63 ULN), with the exception of patients with Gilbert syndrome
– Persisting elevations of serum amylase or lipase greater than 2 ULN
•Patients with significantly impaired bone marrow function or significant anemia, leukopenia, neutropenia or thrombocytopenia, and/or any of the following laboratory results:
– Hemoglobin 9.5 g/dL (may be repeated if 99.4 g/dL)
– Absolute white cell count 4000 cells/mm3 (L)
– Platelet count 100 cells 109/L (may be repeated if 80100 109/L)
– Absolute neutrophil 1500 cells/mm3 (L)
•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
•Positive screening tests for active, latent, or inadequately treated hepatitis B (as evidenced by either of the following):
– Positive hepatitis B surface antigen (HBsAg)
– Positive hepatitis B core antibody [total HBcAb] with detectable hepatitis B virus (HPV) DNA
•Positive screening tests for hepatitis C (positive hepatitis C antibodies)
•Evidence of active or latent or inadequately treated infection with tuberculosis (TB) as defined by the following:
– A positive QuantiFERONTB-Gold (QFT) test is found at screening. QFT testing should be performed through the central laboratory
– Patients with a history of Bacille Calmette-Guérin vaccination should be screened using the QFT test.
– An indeterminate QFT test should be repeated.
– A positive QFT test or two successive indeterminate QFT results should be considered positive diagnostic TB test.
– An indeterminate QFT test followed by a negative QFT test should be considered a negative diagnostic TB test.
•Abnormalities in hepatic synthetic function tests (e.g., PT, INR, aPTT) judged by the investigator to be clinically significant
•History of hospitalization or transfusion for a GI bleed
•Known bleeding diathesis
•Any condition possibly affecting oral drug absorption
•History of or currently active primary or secondary (nondrug-related) immunodeficiency, including known history of HIV infection
•Patients with IgG 500 mg/dL
•Inability to complete an MRI scan (contraindications for MRI scan, including but not restricted to, pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI scan) or contraindication to gadolinium (Gd) administration
•Any previous history of transplantation or anti-rejection therapy
•Adrenocorticotropic hormone or systemic corticosteroid therapy within 4 weeks prior to screening
For a patient to be eligible, systemic corticosteroids must not be administered between screening and baseline.
•Receiving an unstable dosing regimen of proton pump inhibitors (PPIs) or H2-receptor agonists (H2RAs) during the screening phase prior to the initiation of study drug and/or no plan to remain at a stable dose for the duration of study treatment Patients must not initiate PPIs or H2RAs within 2 weeks of randomization.
•Receiving an unstable regimen of symptomatic treatment of MS (e.g., fampridine, cannabis). Patients must be treated at a stable dose during the screening phase prior to the initiation of study drug and and/or no plan to remain at a stable dose for the duration of study treatment Patients must not initiate symptomatic treatment of MS within 4 weeks of randomization. Patients must not initiate physiotherapy within 4 weeks of randomization.
•Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
•Sensitivity or intolerance to any ingredient (including excipients) of fenebrutinib or teriflunomide
•Previously discontinued teriflunomide therapy for safety and/or efficacy reasons
•Receipt of a live-attenuated vaccine within 6 weeks prior to randomization Influenza vaccination is permitted if the inactivated vaccine formulation is administered.
•Need for systemic anticoagulation (oral or injectable) or anti-platelet agent other than nonsteroidal anti-inflammatory drugs, aspirin, and other salicylates (aspirin up to 162 mg QD is allowed)
•Previous treatment with fenebrutinib or another BTK inhibitor for any indication
•Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any inactive ingredients in teriflunomide
•Treatment with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, within 7 days or 5 drug-elimination half-lives (whichever is longer) prior to randomization
•Treatment with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug-elimination half-lives (whichever is longer) prior to randomization.
•Previous use of anti-CD20 therapies, including ocrelizumab, unless the last infusion was more than 2 years prior to screening, B-cell count is normal at screening, and treatment discontinuation was not motivated by safety reasons or lack of efficacy
•Previous use of fingolimod, siponimod, or ozanimod within 8 weeks of randomization
•Previous use of natalizumab for more than 1 year and within 6 months of randomization
•Previous treatment with mycophenolate mofetil or methotrexate within 12 weeks of randomization
•Previous use of teriflunomide, unless 24 months from screening or teriflunomide plasma concentrations are 0.02 mg/L at screening
•Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide
•Treatment with any investigational agent (including high-dose biotin) within 24 weeks prior to screening or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
•Requirement for any prohibited concomitant medications
•Chronic use of cholestyramine or activated charcoal
•Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label
If the washout requirements are not described in the applicable local label, then the wash out period must be 5 times the half-life of the medication. The PD effects of the previous medication must also be considered when determining the required time for washout.