| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10080700 |
| E.1.2 | Term | Relapsing multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Core part:
Demonstrate that remibrutinib is superior to teriflunomide in reducing the frequency of confirmed relapses |
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| E.2.2 | Secondary objectives of the trial |
Core Part key secondary objectives:
Assess whether remibrutinib is superior to teriflunomide in
-Delaying disability progression based on the pooled data from both identical pivotal studies
-Reducing new inflammatory activity on MRI, based on MRI cohort data
-Reducing neuronal damage
-Disease-Activity-free status based on pooled data from both identical pivotal studies (MRI Cohort)
Core Part other secondary objectives:
. To assess the effects of remibrutinib relative to teriflunomide on additional clinical and MRI endpoints
. To assess the effect of remibrutinib relative to teriflunomide on the physical and psychological impact of MS
. To assess the safety and tolerability of remibrutinib compared to teriflunomide
. To assess the pharmacokinetics (PK) of remibrutinib
Extension Part:
. To assess long-term safety, tolerability and efficacy parameters in participants treated with remibrutinib
Please see protocol for complete detailed list of objectives |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics
Version: -
Date: 20/10/2021
Title: 1) DNA sampling / Pharmacogenetics
Objectives: 1) DNA sampling / Pharmacogenetics The study includes an optional genetic research component. The purpose of genetic research may be to better understand the safety and efficacy of remibrutinib, or to learn more about human diseases, or to help develop ways to detect, monitor and treat diseases. 2) MRI Cohort Only selected sites will participate in the MRI cohort; it is planned that at least 400 participants will be included in this MRI cohort after signature of an additional (optional) consent. Eligible participants from these selected sites will undergo MRI scanning of the brain (see protocol for details). The purpose is to assess new inflammatory activity on MRI and Disease- Activity free status, based on the MRI cohort data. 3) Additional Biomarker assessment Transcriptomic profiling may be assessed, using RNA from whole blood. mRNA expression patterns and patterns of other RNA species, will be derived from application of various technologies which may include sequencing of cDNA libraries related to the RNA extracted from blood. These analyses will be used to examine the effect of remibrutinib on transient RNA and may support the identification of pathways/markers that characterize the disease or response of treatment with remibrutinib. 4) PK sub-study There are two pharmacokinetic assessments (PK) cohorts, for "rich" and "sparse" sampling. PK assessments are only performed during the Core Part of the study. All PK samples for remibrutinib from both the sparsely sampled and richly sampled subgroup of participants will be used to perform a population pharmacokinetics analysis. See protocol for more information on the sub-studies
Other types of substudies
Specify title, date and version of each substudy with relative objectives: -
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Farmacogenetica
Versione: -
Data: 20/10/2021
Titolo: -
Obiettivi: -
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: -
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| E.3 | Principal inclusion criteria |
1. Signed informed consent obtained prior to any assessment performed (confirm at screening visit)
2. Male or female participants 18 to 55 years of age (inclusive) at screening
3. Diagnosis of RMS according to the 2017 McDonald diagnostic criteria (this would include relapsing-remitting course (RRMS) or secondary progressive (SPMS) course with disease activity) as confirmed at screening visit.
4. At least: 1 documented relapse within the previous year, OR 2 documented relapses within the previous 2 years, prior to screening, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12 months prior to screening
5. EDSS score of 0 to 5.5 (inclusive) at screening and randomization
6. Neurologically stable within 1 month prior to screening and randomization (including no MS relapse in this period)
Please see protocol for complete detailed list of inclusion criteria |
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| E.4 | Principal exclusion criteria |
1. Diagnosis of primary progressive multiple sclerosis (PPMS)
2. Disease duration of more than 10 years in participants with EDSS score of 2 or less at screening
3. History of clinically significant CNS disease other than MS
4. Ongoing substance abuse (drug or alcohol)
5. History of malignancy of any organ system (other than complete resection of localized basal cell carcinoma of the skin or in situ cervical cancer),
6. Participants with history of confirmed Progressive Multifocal Leukoencephalopathy (PML) or Neurological symptoms consistent with PML
7. suicidal ideation or behavior
8. 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
9. Participants who have had a splenectomy
10. Active clinically significant systemic bacterial, viral, parasitic or fungal infections
11. Positive results for syphilis or tuberculosis testing
12. Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids
13. 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.
14. Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody
15. 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.
16. History of severe renal disease or creatinine level
17. Participants at risk of developing or having reactivation of hepatitis
18. 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)
19. History or current diagnosis of significant ECG abnormalities
20. Resting QTcF >=450 msec (male) or >=460 msec (female) at pre treatment (prior to randomization)
21. Use of exclusionary medication prior to screening/randomization as defined in the protocol
22. Use of other investigational drugs
23. Requirement for anticoagulant medication or use of dual anti-platelet therapy
24. Significant bleeding risk or coagulation disorders,
25. History of gastrointestinal bleeding
26. Major surgery within 8 weeks prior to screening
27. History of hypersensitivity to any of the study drugs or excipients
28. Pregnant or nursing (lactating) female participants, prior to randomization
29. Women of childbearing potential not using highly effective contraception
30. Sexually active males not agreeing to use condom
31. Have received any live or live-attenuated vaccines within 6 weeks of randomization or requirement to receive these vaccinations during study
32. Use of strong CYP3A4 inhibitors, or use of moderate or strong CYP3A4 inducers within two weeks prior to randomization
Inclusion to Extension part:
1. patient who complete the Core Part of the study on double-blind study
treatment and conduct the Accelerated Elimination Procedure (AEP)
Please see protocol for complete and more detailed list of exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Core part:
Annualized relapse rate (ARR) of confirmed relapses |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Core part:
¿ Time to 3-month confirmed disability progression (3mCDP) on
Expanded Disability Status Scale (EDSS)
¿ Time to 6-month confirmed disability progression (6mCDP) on EDSS
¿ Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate)
¿ Total number of Gd-enhancing T1 lesions per MRI scan
¿ Neurofilament light chain (NfL) concentration in serum
¿ 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
Core part endpoints for other secondary objectives:
. Time to first confirmed relapse
. Time to 6-month confirmed disability improvement (6mCDI) on EDSS (pooled data)
. Time to 3mCDP and 6mCDP independent of relapse activity (PIRA, pooled data)
. Change from baseline in the Symbol Digit Modalities Test (SDMT) (pooled data)
. Time to 6-month confirmed worsening by at least 20% in the: Timed 25-foot walk test (T25FW) (pooled data) and Timed 9-hole peg test (9HPT) (pooled data)
. Time to composite 6-month confirmed disability progression, as evaluated by 6mCDP or 6-month confirmed worsening by at least 20% in T25FW or 9HPT (pooled data)
. Change from baseline in T2 lesion volume
. Change from baseline in Multiple Sclerosis Impact Scale (MSIS-29)
. Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
. Remibrutinib blood concentrations
Extension part endpoints for other secondary objectives:
. Adverse events, laboratory data, vital signs, electrocardiogram (ECG), Columbia Suicide Severity Rating
. ARR, number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate), time to 6mCDP (EDSS), change in SDMT,
NfL, Patient Reported Outcomes scores
Please see protocol for complete detailed list of endpoints |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to 30 months for the core part endpoints, please refer to the protocol for detailed timepoints for all endpoints |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 88 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Egypt |
| Oman |
| Tunisia |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Croatia |
| Czechia |
| Estonia |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Italy |
| Japan |
| Mexico |
| Morocco |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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