| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing-remitting Multiple Sclerosis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
|
| 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 |
| The primary objective of this study is to evaluate the safety and efficacy of ONO-4641 in patients with relapsing-remitting multiple sclerosis (RRMS) when given over a 26-week treatment period. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients will be eligible to participate in this study if they meet all of the following criteria:
1. Male and female patients aged 18 to 55 years (inclusive) at screening (Visit 1)
2. Patients who have a definite diagnosis of relapsing remitting MS according to the 2005 revised McDonald criteria (Appendix 19.2); AND who meet at least one of the following criteria:
a. At least 2 documented relapses within previous 2 years prior to screening; OR
b. At least 1 documented relapse within the year prior to screening; OR
c. At least 1 Gd-enhanced lesion detected on locally-read MRI within 3 months prior to randomization (Visit 2);
3. Patients with a stable neurological condition who have no evidence of relapse for at least 1 month prior to screening and during the screening period and at baseline (Visit 1 and reconfirm at Visit 2);
4. Expanded Disability Status Scale (EDSS) score between 0 and 5.5 at Visits 1 and 2 (Appendix 19.3);
5. For females:
a. Female patients must prevent pregnancy or otherwise be unable to conceive as follows:
i) Surgically sterilized (e.g., hysterectomy or tubal ligation) at least 6 months prior to screening; OR
ii) Postmenopausal (defined as no menstrual bleeding for at least 1 year prior to screening and a serum follicle-stimulating hormone (FSH) level of > 40 IU/L); OR
iii) Patients of childbearing potential who agree to use an acceptable form of birth control (i.e. double barrier method; diaphragm plus condom, intrauterine device plus condom, hormonal contraception plus condom, spermicidal gel plus condom, or abstinence) from 1 month prior to the first dose until 2 months after the last dose;
b. Must not be lactating or breastfeeding within 3 months prior to screening and during the study participation;
c. Negative serum human chorionic gonadotropin (hCG) assay at screening and baseline, and negative urine hCG assay at baseline;
6. For males:
a. Surgically sterilized or agree to the use of a double-barrier method (as described above in 5.a.iii) when engaging in sexual intercourse for the period from 2 weeks before initiation of study drug administration until 2 months after the last dose;
b. Agree to refrain from sperm donation from the initiation of study drug administration until 2 months after the last dose;
7. Positive antibody enyzyme-linked immunosorbent assay (ELISA) for varicella zoster virus (chicken pox);
8. Able and willing to provide signed, written, Informed Consent; |
|
| E.4 | Principal exclusion criteria |
Patients will not be eligible to participate in this study if any of the following criteria apply:
1. MS course other than RRMS;
2. Patients who experienced their first MS symptom more than 12 years before the screening visit;
3. Patients who have 10 or more Gd-enhanced lesions on locally-read MRI obtained during either Visits 1 or 2;
4. Diagnosis of neuromyelitis optica (NMO);
5. History of significant cardiac, hepatic, pulmonary, gastrointestinal or renal disease, immune deficiency, or any other medical conditions that would, in the investigator’s opinion, preclude therapy with ONO-4641;
6. Diagnosis of diabetes mellitus (type I or type II);
7. History of severe respiratory disease, pulmonary fibrosis or asthma requiring chronic therapy (resolved childhood asthma is permitted);
8. History of malignancy (including basal cell carcinoma);
9. History of idiopathic CD4+ T-cell lymphopenia;
10. History of clinically significant chronic disease of the immune system (other than MS);
11. History of bone marrow transplant or total lymphoid irradiation;
12. History of macular edema or macular dystrophy;
13. Active systemic bacterial, viral or fungal infections, or positive for hepatitis B (HBsAg) antigen, hepatitis C (HCV) antibody or human immunodeficiency virus (HIV-1 and HIV-2) antibody at screening;
14. Inability to undergo Gd-enhanced MRI scans;
15. Prior treatment with:
a. Alemtuzumab, rituximab, cladribine, cyclophosphamide or mitoxantrone at any time;
b. Immunosuppressive medications (including, but not limited to, azathioprine, methotrexate, mycophenolate mofetil) within 6 months prior to randomization (Visit 1 and reconfirm at Visit 2);
c. Immunoglobulins or monoclonal antibodies (including natalizumab) within 6 months prior to randomization (Visit 1 and reconfirm at Visit 2);
d. Interferon beta or glatiramer acetate within 3 months prior to randomization (Visit 1 and reconfirm at Visit 2);
e. Systemic or inhaled corticosteroids or adrenocorticotropic hormones (ACTH) within 1 month prior to screening;
f. Plasmapheresis therapy within 1 month prior to screening;
g. CYP3A4 inhibitors/inducers (except for rifampin) within 1 week prior to screening;
h. Rifampin within 1 month prior to screening;
i. Live vaccine within 1 month prior to randomization.
16. Any of the following abnormal laboratory values:
a. WBC < 3,500 cell/μL at screening;
b. Lymphocyte count < 800 cell/μL at screening;
c. ALT or aspartate aminotransferase (AST) > 2 × ULN at screening;
d. Creatinine >1.5 mg/dL or EGFR is ≤30 mL/min/1.73 m2
17. Any of the following cardiovascular conditions:
a. History of symptomatic bradycardia, sick sinus syndrome, sino-atrial block, second (Mobitz type II) or third degree AV block, sustained VT, atrial fibrillation;
b. History of myocardial infarction within 6 months at screening;
c. Current unstable angina pectoris, history of angina pectoris due to coronary spasm, Raynaud’s syndrome (secondary Raynaud’s), or cardiac arrest;
d. Resting heart rate < 55 beat/min based on ECG at screening or history of any cardiac conditions that might increase the risk of a significant reduction in heart rate;
e. QTc interval > 450 msec on 12-lead ECG at screening;
f. Arrhythmia requiring current treatment;
g. Hypertension uncontrolled by medication;
18. Forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) < 75% of the predicted values at screening;
19. Positive on the substance abuse screen conducted at screening; (not if based on medication prescribed by a physician (e.g. opioids for chronic pain))
20. History of substance abuse or dependence (except nicotine or caffeine) within 6 months as judged by the Investigator at screening;
21. History of alcohol abuse or dependence within 6 months as judged by the Investigator at screening;
22. Received any investigational drug or participated in any clinical trials involving exposure to experimental medications within 6 months (except S1P receptor agonists including ONO-4641 within 3 months) prior to randomization;
23. In the opinion of the Investigator, a patient who may not be able to cooperate fully with the study staff, may have difficulty in some study requirements, or is otherwise not qualified for the study;
24. Patients who may not have the ability to provide a valid, signed written informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the cumulative number of T1 weighted gadolinium (Gd)-enhanced lesions obtained with MRI at Weeks 10, 14, 18, 22 and 26. Patients who complete the treatment period or who discontinued during the treatment period and do not proceed to the extension study will enter the 4-week Follow-up Period. |
|
| 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 | Yes |
| 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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