| Eligibility |
Inclusion Criteria:
- Participants are eligible to be included in the study only if all of the following
criteria apply: Age I 01. The participant must be 18 to 55 years of age, inclusive, at
the time of signing the informed consent. Type of participant and disease
characteristics I 02. The participant must have been diagnosed with RMS according to
the 2017 revision of the McDonald diagnostic criteria. I 03. The participant has an
EDSS score =5.5 at the first Screening Visit I 04. The participant must have at least
1 of the following prior to screening: =1 documented relapse within the previous year
OR =2 documented relapses within the previous 2 years, OR =1 documented Gd-enhancing
brain lesion on an MRI scan within the previous year. Note: The initial clinical
demyelinating episode of MS should be counted as a relapse for the first 2 criteria.
Weight I 05. Not applicable. Sex I 06. Male or Female Contraceptive use by men or
women should be consistent with local regulations regarding the methods of
contraception for those participating in clinical studies. Male participants wishing
to conceive a child and female participants becoming pregnant or wishing to become
pregnant must permanently discontinue the study intervention and follow the local
teriflunomide label recommendation. A) Male participants Male participants are
eligible to participate if they agree to the following during the intervention period
and until the accelerated elimination procedure is performed. • Refrain from donating
sperm Plus either: • Be abstinent from heterosexual intercourse as their preferred and
usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain
abstinent OR • Must agree to use contraception/barrier method as detailed below -
Agree to use a male condom and should also be advised of the benefit for a female
partner to use a highly effective method of contraception as a condom may break or
leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who
is not currently pregnant B) Female participants • A female participant is eligible to
participate if she is not pregnant or breastfeeding, and at least one of the following
conditions apply: - Is not a WOCBP OR - Is a WOCBP and agrees to use a contraceptive
method that is highly effective (with a failure rate of <1% per year), with low user
dependency, as described in Appendix 4 during the intervention period and until the
accelerated elimination procedure is completed after the last dose of study
intervention. - A WOCBP must have a negative highly sensitive pregnancy test (urine or
serum, as required by local regulations) within 24 hours before the first dose of
study intervention. - If a urine test cannot be confirmed as negative (eg, an
ambiguous result), a serum pregnancy test is required. In such cases, the participant
must be excluded from participation if the serum pregnancy result is positive. •
Additional requirements for pregnancy testing during the study and after study
intervention are located in the schedule of activities (SoA). • The Investigator is
responsible for review of medical history, menstrual history, and recent sexual
activity to decrease the risk for inclusion of a woman with an early undetected
pregnancy, if allowed by local regulations. Informed Consent I 07. The participant
must have given written informed consent prior to undertaking any study-related
procedure. This includes consent to comply with the requirements and restrictions
listed in the informed consent form (ICF) and in this protocol. In countries where the
legal age of maturity is greater than 18 years, a specific ICF for such legally minor
participants must also be signed by the participant's legally authorized
representative.
Exclusion Criteria:
- Participants are excluded from the study if any of the following criteria apply:
Medical conditions E 01. The participant has been diagnosed with PPMS according to the
2017 revision of the McDonald diagnostic criteria or with nonrelapsing SPMS. E 02. The
participant has a history of infection or may be at risk for infection: • A history of
T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid
organ, stem cell, and bone marrow transplantation) and/or antirejection therapy. • The
participant has received any live (attenuated) vaccine (including but not limited to
varicella zoster, oral polio, and nasal influenza) within 2 months before the first
treatment visit. • The participant has a lymphocyte count less than the lower limit of
normal (LLN) at the Screening Visit. • A history of diagnosis of progressive
multifocal leukoencephalopathy (PML) or evidence of findings suggestive of PML on the
screening MRI. • A history of infection with human immunodeficiency virus (HIV). • A
history of active or latent tuberculosis (TB) (unless the participant has completed a
full course of anti-tuberculosis therapy or it is documented by a specialist that the
participant has been adequately treated and can begin treatment with an
immunosuppressive agent); screening tuberculosis testing should be performed at
screening and again during the study, if clinically indicated. Blood testing (eg,
QuantiFERON TB Gold test) is preferred; skin testing (eg, tuberculin skin test) will
be allowed if blood testing is not available or the blood test result is
indeterminate. • Persistent chronic or active recurring infection requiring treatment
with antibiotics, antivirals, or antifungals. • Fever within 4 weeks of the Screening
Visit (=38°C; however, if due to brief and mild ear, nose, throat viral infection
participant may be included based on the Investigator's judgment). • At screening, the
participant is positive for hepatitis B surface antigen and/or hepatitis B core
antibody and/or is positive for hepatitis C antibody. Serologies consistent with
resolved infection or vaccination may not exclude potential participants from the
trial. • Any other active infections that would adversely affect participation or IMP
administration in this study, as judged by the Investigator. E 03. The presence of
psychiatric disturbance or substance abuse as evidenced by: • A history of any
psychiatric disease, behavioral condition, or depression requiring hospitalization
within 2 years prior to the Screening Visit. • A documented history of attempted
suicide over the 6 months prior to the Screening Visit, presents with suicidal
ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS)
during the study, OR if in the Investigator's judgment, the participant is at risk for
a suicide attempt. • A history of alcohol or drug abuse within 1 year prior to the
Screening Visit. E 04. The following findings obtained during the screening visit
considered in the Investigator's judgment to be clinically significant: • Any
screening laboratory values outside normal limits • Abnormal ECG E 05. Conditions that
may predispose the participant to excessive bleeding: • A bleeding disorder or known
platelet dysfunction at any time prior to the Screening Visit • A platelet count <150
000/µL at the Screening Visit • The participant has had major surgery within 4 weeks
prior to the Screening Visit, which could affect the participant's safety or affect
immune response (as judged by the Investigator) or has planned any elective major
surgery during the study. E 06. Conditions that would adversely affect participation
in the study or make the primary efficacy endpoint non-evaluable: • Sensitivity to any
of the study interventions, or components thereof, or has a drug or other allergy
that, in the opinion of the Investigator, contraindicates participation in the study.
• A short life expectancy due to pre-existing health condition(s) as determined by
their treating neurologist. • A history or presence of significant other concomitant
illness according to the Investigator's judgment such as, but not limited to
cardiovascular (including Stage III or IV cardiac failure according to New York Heart
Association [NYHA] classification), or renal (ie, undergoing dialysis), neurological,
endocrine, gastrointestinal, hepatic (ie, underlying hepatobiliary disease, screening
ALT >3 X upper limit of normal (ULN), or albumin =2.5 g/dL [25 g/L]), metabolic,
pulmonary, or lymphatic disease that would adversely affect participation in this
study. • Any malignancy within 5 years prior to the Screening visit (except for
effectively treated carcinoma in situ of the cervix or adequately treated
non-metastatic squamous or basal cell carcinoma of the skin) will also be
exclusionary. • Any other medical condition(s) or concomitant disease(s) making them
nonevaluable for the primary efficacy endpoint or that would adversely affect
participation in this study, as judged by the Investigator. Prior/concomitant therapy
E 07. The participant has received any of the following medications/treatments within
the specified time frame before any baseline assessment (no washout is required for
interferon beta or glatiramer acetate treatments): Systemic corticosteroids,
adrenocorticotropic hormone : 1 month prior to screening MRI scan. Dimethyl fumarate
(DMF), siponimod :1 month prior to randomization. Intravenous immunoglobulin,
fingolimod: 2 months prior to randomization. Teriflunomide (<3 months treatment),
mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprine
and methotrexate, mycophenolate: 3 months prior to randomization (no time restriction
if accelerated elimination procedure is done). Teriflunomide (=3 months treatment),
lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence of
cardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), other
strongly immunosuppressive treatments with very long-lasting effects: any time.
Natalizumab: 6 months prior to randomization. B-cell-depleting therapies such as
ocrelizumab and rituximab: 6 months prior to randomization or until return of B-cell
counts to normal levels, whichever is longer. Highly
immunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 body
surface area, cyclophosphamide, cladribine: 2 years prior to randomization.
Alemtuzumab: 4 years prior to randomization. Other MS-disease modifying treatments: 5
half-lives or until end of pharmacodynamics activity, whichever is longer. E 08. The
participant is receiving strong inducers or inhibitors of cytochrome P450 (CYP) 3A or
CYP2C8 hepatic enzymes as listed in Appendix 8A. E 09. The participant is receiving
anticoagulant/antiplatelet therapies, including: • Acetylsalicylic acid (aspirin) •
Antiplatelet drugs (eg, clopidogrel) • Warfarin (vitamin K antagonist) • Heparin,
including low molecular weight heparin (antithrombin agents) • Dabigatran (direct
thrombin inhibitor) • Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors)
Note: All above drugs need to be stopped at least 5 half-lives before study drug
administration except for aspirin, which needs to be stopped at least 8 days before. E
10. A history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any
of the inactive ingredients in Aubagio (this includes anaphylaxis, angioedema, and
serious skin reactions) Prior/concurrent clinical study experience E 11. The
participant was previously exposed to any BTK inhibitor, including SAR442168. E 12.
The participant has taken other investigational drugs within 3 months or 5 half-lives,
whichever is longer, before the Screening Visit. Diagnostic assessments E 13. The
participant has had a relapse in the 30 days prior to randomization. E 14. The
participant has contraindication for MRI, ie, presence of pacemaker, metallic implants
in high-risk areas (ie, artificial heart valves, aneurysm/vessel clips), presence of
metallic material (eg, shrapnel) in high risk areas, known history of allergy to any
contrast medium, or history of claustrophobia that would prevent completion of all
protocol-scheduled MRI scans Note: People with a contraindication to Gd can be
enrolled into the study but cannot receive Gd contrast dyes during their MRI scans.
Other exclusions E 15. Individuals accommodated in an institution because of
regulatory or legal order; prisoners or participants who are legally
institutionalized. E 16. Any country-related specific regulation that would prevent
the participant from entering the study. E 17. Participant not suitable for
participation, whatever the reason, as judged by the Investigator, including medical
or clinical conditions, or participants potentially at risk of noncompliance to study
procedures or not able to follow the schedule of protocol assessments due to other
reasons (exception: participants who are not able to complete electronic clinical
outcome assessments may be given paper clinical outcome assessments to complete). E
18. Participants are dependent on the Sponsor or Investigator (in conjunction with
Section 1.61 of the International Council for Harmonisation (ICH) Good Clinical
Practice (GCP) Ordinance E6). E 19. Participants are employees of the clinical study
site or other individuals directly involved in the conduct of the study, or immediate
family members of such individuals. E 20. Any other situation during study
implementation/course that may raise ethics considerations. Note: a one-time retest at
screening may be performed if an abnormal laboratory test value is considered
temporary. 5.3 LIFESTYLE CONSIDERATIONS 5.3.1 Meals and dietary restrictions SAR442168
shall be taken with a meal. When possible, the meal (eg, breakfast, lunch, or dinner)
should be consistent in terms of time of day throughout the study. The typical time of
day at which IMP is administered will be collected at each visit. The participant must
refrain from consumption of grapefruit or grapefruit juice from 5 days prior to
intervention administration and throughout the treatment phase. 5.3.2 Caffeine,
alcohol, and tobacco For each visit with PK/PD assessment, participants will abstain
from ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola
drinks, and chocolate) for 2 hours before the start of treatment until after
collection of the final PK and/or PD sample later that day. For each visit with PK/PD
assessment, participants will abstain from alcohol for 24 hours before the start of
treatment until after collection of the final PK and/or PD sample later that day.
During the entire study, the IMP should be used with caution in participants who
consume substantial quantities of alcohol. 5.3.3 Activity No special restrictions. 5.4
SCREEN FAILURES Screen failures are defined as participants who consent to participate
in the clinical study but are not subsequently randomly assigned to the study
intervention. A minimal set of screen failure information is required to ensure
transparent reporting of screen failure participants to meet the Consolidated
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to
queries from regulatory authorities. Minimal information includes demography, screen
failure details, eligibility criteria, and any SAE. Individuals who do not meet the
criteria for participation in this study (screen failure) may be rescreened up to 2
times. Rescreened individuals should be assigned a different participant number.
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