| 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 |
| Multiple sclerosis is the result of damage to myelin a protective sheath surrounding nerve fibres of the central nervous system. This interferes with messages between the brain and rest of the body. |
|
| 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 | 14.0 |
| 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 |
| The objective of the study is to evaluate the safety and efficacy of ONO-4641 at potentially therapeutic doses in patients with RRMS 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;
5. duration of the study, male and female subjects of childbearing potential (ie, nonsterilized, premenopausal females) who are sexually active must use adequate contraception from 1 month prior to the first dose until 2 months after the last dose of study medication. An acceptable method of contraception is defined as one that has no failure rate or a <1% failure rate. It is recommended to combine a hormonal method (PEARL index < 1) with a barrier method.
The following contraception methods are especially reliable according to the guidelines of the German Association of Gynaecology and Obstetrics:
• Oral contraceptive pill with estrogen and gestagen (no micro pill)
• Vaginal ring (i.e.. NuvaRing®)
• Contraception plaster (i.e. EVRA®)
• Estrogen-free ovulation inhibitor (i.e. Cerazette®)
• Intradermal contraception sticks with progesteron (i.e. Implanon®)
• Injection of gestagen every 3 months
• Contraceptive coil with Progesteron (i.e. Minera®)
Contraception with double barrier method (condom, contraceptive sponge, diaphragm, or vaginal ring with spermicidal gel or foam) Male subjects and women of child bearing potential will be provided with information on acceptable methods of contraception as part of the subject informed consent process, and will be advised of the requirements for avoidance of pregnancy from 1 month prior to the first dose until 2 months after the last dose of study medication. Subjects will receive continued guidance with respect to the avoidance of pregnancy as part of the study procedures. In addition to a negative serum hCG pregnancy test throughout the study period including screening, subjects also must have a negative urine hCG pregnancy test on the day of the first dose of study medication, prior to receiving any dose of study drug.
6. Positive antibody enyzyme-linked immunosorbent assay (ELISA) for varicella zoster virus (chicken pox);
7. 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 documented 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 (e.g. coronary heart disease, myocarditis, cardiomyopathy, heart failure NYHA IIIV), 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 estimated glomerular fitration rate (EGFR)
≤30 mL/min/1.73 m2 at screening.
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.g. any delay in the cardiac stimulus conduction on ECG);
e. QTcB 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 for the substance abuse screen conducted at screening (not if 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 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.
25. Any medical condition that poses a significant risk of predisposing a patient to induction of cardiac arrhythmias (e.g. status post catheter ablation, hyperkalemia [defined as 2 consecutive measures of K+ above 6.0 mEq/L])
26. History of syncope
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be the cumulative number of T1-weighted Gd-enhanced lesions obtained with MRI at Visits 5 to 9 (Weeks 10, 14, 18, 22 and 26).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Weeks 10, 14, 18, 22 and 26 |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints include:
- the total number of T1-weighted Gd-enhanced lesions obtained with MRI at 4-week intervals for 26 weeks,
- the cumulative volume of Gd-enhanced lesions,
- the total number of new or enlarging T2 lesions,
- change in T2 lesion volume,
- change in brain volume,
- the proportion of patients with Gd-enhanced lesions,
- the number of patients remaining free of relapse,
- annualized relapse rate,
- the time to the first relapse,
- and the change from baseline in EDSS scores. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 10, 14, 18, 22 and 26 |
|
| 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 | No |
| 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) | 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.8.2.4 | 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 | 11 |
| 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 | 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 |
| Canada |
| Japan |
| Russian Federation |
| Ukraine |
| 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
|
|
| 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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