| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing Multiple Sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsing Multiple Sclerosis |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048393 |
| E.1.2 | Term | Multiple sclerosis relapse |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
| To demonstrate superior efficacy with evobrutinib compared to Avonex in terms of Annualized Relapse Rate (ARR) |
|
| E.2.2 | Secondary objectives of the trial |
a.To demonstrate the efficacy of evobrutinib relative to that of Avonex on disability progression
b.To demonstrate the efficacy of evobrutinib relative to that of Avonex on patient reported symptoms and functional status
c.To demonstrate the efficacy of evobrutinib relative to that of Avonex on magnetic resonance imaging (MRI) lesion parameters
d.To characterize the safety and tolerability of evobrutinib.
e. OLE period: To evaluate the long-term safety, efficacy, and HRQoL of evobrutinib for an additional up to 144 weeks. |
|
| 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 |
Pharmacokinetic (PK) and Pharmacodynamic (PD) substudies will be performed in selected sites.
For the PK substudy, participants (N = 75) must meet the inclusion/exclusion criteria and must complete all safety and efficacy activities as described for other study participants. For the PK substudy participants, additional whole blood samples (37) of approximately 2 mL will be collected for measurement of plasma concentrations of evobrutinib. Participation in the substudy is mandatory at the selected sites.
For PD substudy, participants (N = 75), blood samples will be collected for measurement of BTK Occupancy, cellular function, and cytokines (approximately 50 mL per visit) from participants at selected sites. Participation in the substudy is mandatory at the selected sites.
|
|
| E.3 | Principal inclusion criteria |
1.18 to 55 years of age at the time of signing the informed consent.
2.Are diagnosed with RMS (relapsing-remitting multiple sclerosis [RRMS] or secondary progressive multiple sclerosis [SPMS] with relapses) in accordance with 2017 Revised McDonald criteria
3.One or more documented relapses within the 2 years before Screening
4. Have an EDSS score of 0 to 5.5 at Baseline
5. Are neurologically stable for ≥ 30 days prior to both Screening and Baseline
6. Are female or male
a. Female participants are not pregnant or breastfeeding, and at least one of the following conditions
applies:
o Not a Woman of Child Bearing Potential OR
o If a Woman of Child Bearing Potential, use a highly effective contraceptive method AND a barrier method
7. Capable of giving signed informed consent
8. Participants must be contactable by email or telephone throughout the study. |
|
| E.4 | Principal exclusion criteria |
1.Participants diagnosed with Progressive MS, in accordance with the 2017 Revised McDonald criteria
2.Disease duration > 10 years in participants with an EDSS ≤ 2.0 at Screening
3.Immunologic disorder other than MS or any other condition requiring oral, intravenous, intramuscular, or intra-articular corticosteroid therapy, with the exception of well-controlled Type 2 diabetes mellitus or well controlled thyroid disease
4.History or current diagnosis of other neurological disorders that may mimic MS
5.History or current diagnosis of PML
6.Active, clinically significant viral, bacterial, or fungal infection, or any major episode of infection
7.History of or current diagnosis of active tuberculosis (TB) OR currently undergoing treatment for latent TB infection or untreated LTBI. TB skin test with purified protein derivative will not be performed at Screening
8.Indeterminate QuantiFERON-TB test results may be repeated once. If results continue to be indeterminate, T-SPOT will be used. If T-SPOT.TB is not available, the Medical Monitor should be contacted
9.Individuals with a diagnosis of hemochromatosis, Wilson’s disease, alpha-1-antitrypsin deficiency, or any other chronic liver disease including Gilbert’s disease
10. Individuals with elevated transferrin saturation (> 50% transferrin saturation in males;
and > 40% transferrin saturation in females) and/or with elevated ferritin levels > 500 μg/L
11.Individuals with sickle cell anemia, thalassemia and/or any chronic blood disorder requiring blood transfusions
12.History of splenectomy at any time, or any major surgery within 2 months prior to Screening
13.History of myocardial infarction or cerebrovascular event within 6 months prior to Screening, or current active angina pectoris, history of or current congestive heart failure NYHA Class III or Class IV, uncontrolled seizures, prolonged untreated hypertension, active GI bleeding, others
14.A history of attempted suicide within 6 months prior to Screening or a positive response to items 4 or 5 of the Columbia-Suicide Severity Rating Scale at Screening
15.An episode of major depression within the last 6 months prior to Screening
16.History of cancer with the exceptions per protocol
17.Clinically significant abnormality on screening ECG
18.An active infective process or any other clinically significant abnormality on Screening Chest X-ray
19.Contraindication to Avonex or incompatibility with Avonex use
20.IV or oral glucocorticoids within 4 weeks prior to randomization
21.Treatment with monthly IV methylprednisolone
22.Treatment with beta-interferons or glatiramer acetate within 4 weeks prior to randomization
23.Treatment with dimethyl fumarate within 4 weeks prior to randomization
24.Treatment with teriflunomide within 12 weeks or after the accelerated elimination procedure 12 days prior to randomization
25.Use of lymphocyte trafficking blockers within 48 weeks prior to randomization
26.Use of IV Ig or plasmapheresis within 12 weeks prior to randomization
27. Treatment with rituximab and/or ocrelizumab
28. Treatment with any other B cell depleting therapy, BTK inhibitors (including evobrutinib), mitoxantrone, or lymphocyte-depleting therapies (e.g., alemtuzumab, antiCD4, cladribine, cyclophosphamide, total body irradiation, bone marrow transplantation).
29. Concomitant treatment with medications commonly used for symptom management of MS
30. Treatment with medical marijuana for MS symptoms, unless it is consistent with local guidelines and local regulations
31. On anticoagulation, or antiplatelet therapy other than daily aspirin for cardioprotection. Use of fish oil supplements within 4 weeks prior to randomization.
32. Participants currently receiving potent inducers of cytochrome P450 3A (CYP3A) medications or herbal supplements known to be potent (strong to moderate) inhibitors of CYP3A or drugs mainly metabolized by CYP3A with a narrow therapeutic index
33. Participation in any investigational drug study within 6 months or 5 half-lives of the investigational drug, whichever is longest, prior to Screening
34. Any of the following:
a. History of or positive for human immunodeficiency virus
b. History of or positive for hepatitis C virus (HCV)
c. Positive for hepatitis B surface antigen (HBsAg)
35. Estimated glomerular filtration rate by the 4-variable Modification of Diet in Renal Disease equation of < 60 mL/min/1.73 m2 or any renal condition that would preclude the administration of gadolinium
36. ALT, AST, amylase, or lipase > 2 × upper limit of normal (ULN) of laboratory reference range, total bilirubin > 1.5 × ULN
37. Significant cytopenia
38. Any allergy, contraindication, or inability to tolerate Avonex or evobrutinib or any of their excipients.
39. Inability to comply with MRI scanning
40. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
41. Regular alcohol consumption within 6 months prior to the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ARR based on qualified relapses at Week 96 in participants with RMS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
a. Time to first occurrence of 12-week confirmed Expanded Disability Status Scale (EDSS) progression over 96 weeks
b.Time to first occurrence of 24-week confirmed EDSS progression over 96 weeks
c.Change from Baseline (CFB) in Patient Reported Outcomes Measurement Information System [PROMIS] PF score at 96 weeks
d.CFB in PROMIS Fatigue score at 96 weeks
e.Total number of T1 Gd+ lesions based on assessments at Week 24, Week 48, and Week 96.
f. Total number of new or enlarging T2 lesions based on assessments at Week 24, Week 48, and Week 96
g.Safety as assessed by the nature, severity, and occurrence of adverse events (AEs) and adverse events of special interest (AESIs); vital signs; electrocardiograms (ECGs); absolute concentrations and change from Baseline in immunoglobulin (Ig) levels; and clinical laboratory safety parameters up to Week 108
h. OLE period:
•Efficacy and HRQoL endpoints at Weeks 48, 96, and 144
oARR, based on protocol-defined qualified relapses
oChange from Baseline in PROMIS PF score
oChange from Baseline in PROMIS fatigue score
oChange from Baseline in Medical Outcomes Study 36 Item Short Form Health Survey (SF-36v2)
•Efficacy and HRQoL endpoints over 144 weeks
oTime to first occurrence of 12-week confirmed EDSS progression over 144 weeks
oTime to first occurrence of 24-week confirmed EDSS progression over 144 weeks
oTime to first occurrence of 12-week confirmed PF deterioration compared to Baseline over 144 weeks
•Efficacy endpoints at Weeks 24, 48, 96, and 144
oTotal number of new or enlarging T2 lesions
oTotal number of T1 Gd+ lesions
•Safety as assessed by the nature, severity, and occurrence of AEs and AESIs; vital signs; ECGs; absolute concentrations and change from Baseline in Ig levels; clinical laboratory safety parameters up to Week 144 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a. 12 week over 96 weeks
b. 24-week over 96 weeks
c, d: 96 weeks
e, f: Week 24, Week 48, and Week 96.
g. Week 108
h. OLE period timepoints described in E.5.2 |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 87 |
| 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 | No |
| 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 |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| Croatia |
| Czech Republic |
| Estonia |
| France |
| Georgia |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| Montenegro |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
A participant has completed the study if he/she has completed all study parts, including the
Treatment Period and the last visit (Safety Follow-up Visit).
The end of the study is defined as the date of the last visit of the last participant. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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