| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsing remitting multiple sclerosis
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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 | 16.1 |
| 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 |
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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 |
The primary objective of this trial is to demonstrate the effect of ONO 4641 versus interferon (IFN) β 1a (Avonex) 30 µg on the proportion of subjects, with relapsing-remitting multiple sclerosis (RRMS), who remain qualifying relapse–free during their participation in the trial when the last evaluable subject completes 1 year.
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| E.2.2 | Secondary objectives of the trial |
"To demonstrate the effect of ONO 4641 versus:
-IFN-β-1a (Avonex) 30 µg on qualifying ARR in subjects with RRMS treated over 2 years
-IFN β 1a (30 µg) on the number of new or enlarging T2 lesions over 1 and 2 years
-IFN β 1a (30 µg) on disability progression over 2 years and disability improvement over 2 years
Other Secondary Objectives are to demonstrate the effect of ONO 4641 on:
-additional clinical relapse outcomes (e.g., proportion relapse-free at 2 years) and MRI parameters (e.g., brain atrophy) in subjects with RRMS
-disease-activity-free (DAF) status in subjects with RRMS
-Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) as measures of cognitive function in subjects with RRMS
To demonstrate the safety and tolerability of treatment with ONO 4641 in RRMS subjects"
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
"For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
A. Signed Informed Consent
1. Written informed consent obtained prior to the initiation of any protocol-required procedures.
B. Target Population
2. Diagnosis of MS as defined by McDonald criteria of 2010
3. Onset of MS symptoms within 12 years
4. At least 1 documented relapse during the previous year OR at least 2 documented relapses during the previous 2 years prior to Randomization 5. EDSS (Expanded Disability Status Score) of 0 to 5.5, inclusive
6. Clinically stable, with no relapse within 30 days prior to Randomization
C. Age and Reproductive Status
7. Male or female subjects 18 to 55 years of age
8. Women of childbearing potential (WOCBP) must use 2 adequate forms of contraception to avoid pregnancy throughout the trial (such as a double barrier method) and for up to 8 weeks after the last dose of IMP in such a manner that the risk of pregnancy is minimized
NOTE: WOCBP includes any female who has experienced menarche and who has not undergone successful sterilization (such as hysterectomy, bilateral tubal ligation, bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months, or women on hormone replacement therapy with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL). Women using oral, implanted, or injectable contraceptive hormones or using mechanical products (such as an intrauterine device, diaphragm, condoms, etc) to prevent pregnancy; or practicing abstinence; or where the partner is sterile (such as with a vasectomy), must be considered to be of childbearing potential.
9. WOCBP must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at the time of Screening AND a negative urine (dipstick) pregnancy test at the time of Randomization
10. Women must not be breastfeeding
11. Males must be surgically sterilized or agree to the use of a double-barrier method for the duration of the trial and must agree to refrain from sperm donation for the duration of the trial "
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| E.4 | Principal exclusion criteria |
"A. Medical History and Concurrent Diseases
1. Neuromyelitis optica, clinically isolated syndrome, primary or secondary progressive multiple sclerosis
2. Chronic disease of the immune system other than MS or a known immunodeficiency syndrome
3. Malignancy
4. Macular edema or uveitis
5. Corneal herpes
6. Inability to undergo slit lamp and OCT assessments
7. Inability to complete an MRI or contraindications for MRI
8. History of sudden cardiac arrest
9. Ischemic cardiac disease including myocardial infarction, stable angina pectoris, unstable angina pectoris
10. Congestive heart failure New York Heart Association Class III or Class IV
11. Uncontrolled hypertension
12. Severe untreated sleep apnea
13. Cerebrovascular disease in the 6 months prior to Randomization
14. Symptomatic bradycardia or recurrent syncope
15. Mobitz Type II second degree or high-grade AV block
16. Sinoatrial heart block or sick sinus syndrome
17. Resting HR of < 50 bpm on Screening ECG
18. Higher risk of symptomatic bradycardia or heart block due to coexisting medical condition or certain concomitant medications
19. Concurrent therapy with drugs that slow the HR or AV conduction
20. Family history of long QT syndrome or sudden death
21. Subjects receiving Class Ia or Class III anti-arrhythmic drugs
22. Other arrhythmias such as ventricular tachycardia or atrial fibrillation requiring treatment
23. Uncontrolled diabetes mellitus (Type I or Type II)
24. Active or latent viral, fungal or other infections, including hepatitis B virus, hepatitis C virus, or known history of human immunodeficiency virus (HIV)-1 or HIV-2
25. Active or chronic bacterial infection, including untreated tuberculosis, or history of untreated borreliosis (Lyme disease)
26. Alcohol or drug abuse in the 12 months prior to Randomization
27. Subject has been vaccinated with live, attenuated vaccines within 2 months prior to Randomization
28. Renal condition that would preclude the administration of Gd
29. Respiratory disease, such as pulmonary fibrosis, or asthma requiring chronic daily therapy (exception: resolved childhood asthma)
30. Abnormal chest X-ray suggestive of active pulmonary disease
31. Abnormal Pulmonary Function Tests: forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) < 75% or DLCO < 60%
32. Any other unstable medical conditions (such as congenital heart disease, acute or chronic liver diseases, etc.)
33. Current uncontrolled or untreated major depressive disorder, and/or at imminent risk of self harm or harm to others
34. Known hypersensitivity to the trial treatment(s)
B. Physical and Laboratory Test Findings
35. Any other abnormal ECG finding, laboratory test result, or vital sign result
36. Resting HR < 50 bpm based on ECG at Screening, or history of any cardiac conditions that might increase the risk of a significant reduction in HR
37. Fridericia-corrected QT interval > 450 msec for male subjects and > 470 msec for female subjects on 12-lead ECG
38. Left bundle branch block
39. Right bundle branch block with fascicular block (left or right) or any ECG with RBBB and first degree AV block (PR interval > 240 msec) or RBBB with a QRS duration > 140 msec
40. Intraventricular conduction defect with a QRS duration > 140 msec
Laboratory exclusions:
41. ALT or AST > 2 x ULN at Screening
42. Serum creatinine > 1.5 mg/dL at Screening
43. Total bilirubin > 1.5 x ULN (except for Gilbert’s disease) at Screening
44. Lymphocyte count < 800 cells/µL at Screening
45. WBC < 3,500 cells/µL at Screening
46. Hemoglobin ≤ 9 g/dL at Screening
47. Platelets < 100,000/mm3 at Screening
48. Hemoglobin A1C > 7.5% at Screening
C. Allergies
49. History of allergic reaction to IFN-β-1a (Avonex).
D. Prohibited Medications and Therapies
50. Systemic corticosteroids or adrenocorticotropic hormone within 1 month prior to Randomization
51. Immunoglobulins or plasmapheresis within 3 months prior to Randomization
52. Cyclophosphamide, cladribine, or mitoxantrone at any time
53. Immunosuppressive medications such as azathioprine, methotrexate, cyclophosphamide, cladribine, or mitoxantrone at any time
54. Any previous therapy with alemtuzumab, ocrelizumab, ofatumumab, rituximab, belimumab, natalizumab, total body irradiation, or bone marrow transplantation
55. Any investigational drug or placebo within 12 weeks prior to Randomization OR > 5 half lives prior to Randomization, whichever is longer
56. Previous experimental procedures for the treatment of MS, such as treatment for chronic cerebrospinal venous insufficiency, or T-cell / T-cell receptor activation
57. Any prior exposure to ONO 4641
58. Prior therapy with fingolimod, or any treatment (either approved or investigational) for MS (excluding corticosteroids, plasmapheresis, immunoglobulins as described above) other than a β-interferon, glatiramer acetate, BG-12, or teriflunomide "
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| E.5 End points |
| E.5.1 | Primary end point(s) |
"Proportion of subjects free of qualifying relapse over at least 1 year (48 weeks).
Relapses confirmed by the Adjudication Committee to meet the definition of qualifying relapse will contribute to the analysis for the primary endpoint."
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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) |
"• The qualifying Annual Relapse Rate over 2 years
• Number of new or enlarging hyperintense lesions on T2 weighted MRI over 1 and 2 years
• Time to 3-month confirmed disability progression over 2 years
• Time to 3-month confirmed disability improvement over 2 years
• Time to 6-month confirmed disability progression and improvement over 2 years
• Change from Baseline on the MSFC Z-score at 2 years
• Proportion of subjects relapse-free over 2 years
• Number and volume of new or persisting T1 Gd-enhancing lesions
• T2 lesion volume
• Number of combined unique active MRI lesions
• Proportion of subjects with no new T1 Gd-enhancing lesions
• Proportion of subjects with no new or enlarging T2 lesions
• Number of new T1 hypointense lesions
• Percent change in brain volume
• Proportion of T1 Gd-enhancing lesions evolving into new persistent black holes
• Proportion of subjects DAF (Disease Activity Free) (DAF status is defined as a subject having no qualifying relapse, no 3-month sustained change in EDSS, or no active lesions as assessed by MRI [new T1 Gd-enhancing lesions, or new/enlarging T2 lesions])
• Change from Baseline in SDMT and PASAT scores
• Safety and tolerability of ONO 4641
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 | 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) | 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 130 |
| 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 |
| Belgium |
| Bulgaria |
| Canada |
| Denmark |
| France |
| Italy |
| Japan |
| Austria |
| Croatia |
| Portugal |
| Romania |
| Slovakia |
| Sweden |
| Bosnia and Herzegovina |
| Argentina |
| Belarus |
| Brazil |
| Chile |
| Colombia |
| Czech Republic |
| Egypt |
| Estonia |
| Finland |
| Georgia |
| Germany |
| Hungary |
| Jordan |
| Latvia |
| Lebanon |
| Lithuania |
| Morocco |
| Spain |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| Serbia |
| Tunisia |
| Turkey |
| Ukraine |
| United Arab Emirates |
| 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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For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock.
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 23 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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