| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing-Remitting Multiple Sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| 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 evaluate the efficacy of orelabrutinib on the cumulative number of new gadolinium-enhancing (Gd+) T1 magnetic resonance (MRI) brain lesions versus placebo over 12 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of orelabrutinib on clinical symptoms and imaging measures.
- To evaluate the safety and tolerability of orelabrutinib.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For the Core Part:
Age:
1. 18 to 55 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics:
2. Diagnosed with Relapsing Remitting Multiple Sclerosis (RRMS) in accordance with 2017 Revised McDonald criteria.
3. Neurologically stable for ≥ 30 days prior to both Screening and Baseline.
4. One or more documented relapses within the 2 years before Screening with either:
a. one relapse which occurred within the last year prior to randomization, OR
b. the presence of at least 1 Gd+ T1 lesion on MRI within 6 months prior to randomization.
5. An EDSS step of 0 to 5.5 at Screening and Baseline (Day 1)
a. Patients with an EDSS step ≤ 2 at Screening and Baseline (Day 1) are only eligible for participation if their disease duration (time since onset of symptoms) is no more than 10 years.
6. Women of childbearing potential must agree to use a supplementary barrier method together with a highly effective method of contraception (according to ICH guidance M3[R2]) for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of investigational medicinal product (IMP).
Informed Consent:
7. Signed and dated informed consent (patient must be able to understand the informed consent) indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrollment and will comply with the requirements of the protocol
8. Patients must be contactable by email or telephone throughout the study.
For the OLE Part:
1. Written informed consent must be obtained before any assessment is performed.
2. Patient currently participating in the Core Part who has completed the end of treatment visit (the Week 24 visit) and will be benefit from continued treatment per investigator's assessment.
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|
| E.4 | Principal exclusion criteria |
For the Core Part:
Medical Conditions:
1. Progressive MS
2. Disease duration > 10 years in patients with an EDSS ≤ 2.0
3. Immunologic disorder other than MS
4. Other neurological disorders that may mimic MS
5. Progressive multifocal leukoencephalopathy (PML)
6. Significant infection
7. Active TB
8. Gilbert's disease, chronic liver disease or pre-existing or potential risk factors for hepatic dysfunction
9. Hemophilia OR serious bleeding OR coagulopathy
10. Splenectomy
11. Significant active medical condition in the Investigator’s opinion and in agreement with the Medical Monitor
12. Attempted suicide
13. Major depression
14. History of cancer
15. Breastfeeding/lactating or pregnant women
16. Any abnormality on Screening electrocardiogram (ECG); or clinically significant prolonged QTc interval, or QTc interval >470 ms in women and >450 ms in men at screening
17. Any other clinically significant abnormality per Investigator opinion
Prior/Concomitant Therapy:
18. Glucocorticoids, or ACTH within 4 weeks prior to randomization
19. Beta-interferons or glatiramer acetate within 4 weeks prior to randomization
20. Dimethyl fumarate, diroximel fumarate, or other fumaric acid esters within 4 weeks prior to randomization
21. Teriflunomide and leflunomide within 4 weeks if an accelerated elimination procedure AEP is performed or 14 weeks without the completion of an Accelerated Elimination Procedure (AEP) prior to randomization
22. Natalizumab within 3 months prior to randomization
23. Use of S1P agents within 12 weeks prior to randomization
24. IV immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization.
25. Daclizumab, BTK inhibitors, mitoxantrone, or lymphocyte-depleting therapies
26. Cyclophosphamidewithin 36 months (3 years) prior to randoization and azathioprine within 6 months prior to randomization.
27.Tacrolimus, cyclosporin, methotrexate, and mycophenolate mofetil
within 3 months prior to randomization.
28 Dalfampridine (Ampyra®) or fampridine can be included only if they have been on a stable dose for 3 months prior to randomization
29. Medical marijuana
30. On anticoagulation, or antiplatelet therapy, or NSAIDs used regularly
31. Strong to moderate inducers of CYP3A or strong to moderate inhibitors of CYP3A
Prior/Concurrent Clinical Study Experience:
32. Participation in any investigational drug study within 6 months or 5 half-lives of the investigational drug, whichever is longest, prior to Screening
Diagnostic Assessments:
33. Any of the following:
a. History of or positive for HIV at Screening
b. History of or positive for HCV antibody at Screening
c. Positive for hepatitis B surface antigen (HBsAg) and/or positive for hepatitis B core antibody (HBcAb) at Screening
34. GFR < 30 mL/min/1.73 m2
35. ALT, AST, or total bilirubin >ULN of laboratory reference range; amylase, or lipase >2×ULN OR total bilirubin >1.5×ULN or any other clinically significant laboratory abnormality; or any pre- existing liver diseases, including but not limited to viral hepatitis, alcoholic hepatitis and steatosis, nonalcoholic steatohepatitis, cirrhosis,
autoimmune hepatitis
36. Neutrophil count < 1,500 / mm3, platelet count < 75,000 / mm3, absolute lymphocyte count < 1,000 / mm3, or a white blood cell count < 3,500 / mm3
37. INR≥ 1.5 or APTT≥ 1.5 x ULN
38. B cell CD19 count below the lower limit of normal range
Other Exclusions:
39. Any allergy, contraindication, or inability to tolerate orelabrutinib
40. Inability to comply with MRI scanning
41. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
42. Regular alcohol consumption
For the OLE Part:
1. Permanent discontinuation from the Core Part due to:
- An adverse event or serious adverse event or laboratory abnormality.
- Conditions leading to permanent study drug discontinuation.
2. Patient who has new abnormality appeared in the Core Part,
including:
- Chronic disease of the immune system other than MS which may require immunosuppressive treatment.
- Severe active infection or active chronic infection.
- Any medical unstable condition that may interfere with the patient's ability to cooperate and comply with the study procedures, as assessed by the investigator.
3. As determined by the Investigator, any significant change in the patient's medical history that would preclude administration of orelabrutinib, including:
- History of any significant cardiac, endocrine, hematological, hepatic, immunologic, metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurological (other than MS), and/orother major disease (e.g., malignancy) that would preclude administration of orelabrutinib.
- Clinically significant laboratory abnormalities from the most recently available test in the Core Part that would preclude administration of orelabrutinib. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Cumulative number of new G+ T1 brain lesions at Week 12 (based on T1-weighted MRI scans at Weeks 4, 8, 12) compared to placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
for the Core Part:
Evaluate the efficacy of each orelabrutinib group compared to placebo group
1. Cumulative number of new Gd+ T1 lesions at Weeks 16, 20, and 24.
2. Cumulative number of total Gd+ T1 lesions at Weeks 12, 16, 20, and 24.
3. Cumulative number of new or enlarging T2 lesions at Weeks 12, 16,20, and 24
4. Annualized relapse rate (ARR), based on protocol-defined qualified relapses, at Weeks 12 and 24.
5. Proportion of patients who remain qualified relapse-free at Weeks 12 and 24.
6. Change from baseline in EDSS at Weeks 12 and 24.
7. Change from baseline in the volume of Gd+ T1 lesions at Weeks 12 and 24.
8. Change from baseline in the volume of T2 lesions at Weeks 12 and 24.
Efficacy Endpoints for the OLE Part:
Evaluate the efficacy of long-term treatment with orelabrutinib.
9. Relapse outcomes: annualized relapse rate (ARR) and proportion of patients who relapse, at Weeks 48, 72, 96 and 120.
10. Magnetic resonance imaging (MRI) outcomes, at Weeks 48, 96 and
120:
- Cumulative number of new Gd+ T1 lesions.
- Total number of Gd+ T1 lesions.
- Total number of new or enlarging T2 lesions.
11. Change in EDSS step, at Weeks 48, 72, 96 and 120.
12. Sustained disability progression defined as an increase in EDSS of .
1.0 sustained for 24 weeks in patients with a baseline EDSS . 5.5 or .
0.5 sustained for 24 weeks in patients with a baseline EDSS of > 5.5.
Safety Endpoints
13. Safety as assessed by the nature, severity, and incidence of adverse events (AEs) (graded according to National Cancer Institute-common
Terminology Criteria for AEs, NCI-CTCAE version 5.0); vital signs;
electrocardiograms (ECGs); and clinical laboratory safety parameters.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Weeks 16, 20 and 24.
2.-3. Weeks 12, 16, 20 and 24.
4.-8. Weeks 12 and 24.
9. Weeks 48, 72, 96 and 120.
10. Weeks 48, 96 and 120.
11. Weeks 48, 72, 96 and 120.
12. Week 24.
13.Week 24 |
|
| 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 | Yes |
| 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 |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Ukraine |
| China |
| United States |
| Poland |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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