| 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 | 19.0 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess whether the clinical efficacy of RPC1063 is superior to interferon (IFN) β-1a (Avonex®) in reducing the rate of clinical relapses in patients with RMS.
|
|
| E.2.2 | Secondary objectives of the trial |
• To assess the effect of RPC1063 on the proportion of patients with new/enlarging T2 lesions at Month 12
• To evaluate whether the efficacy of RPC1063 is superior to IFN β-1a in delaying the accumulation of disability, as assessed by the Multiple Sclerosis Functional Composite (MSFC) and visual function as measured by the low-contrast letter acuity test (LCLA)
• To evaluate whether the efficacy of RPC1063 is superior to IFN β-1a in delaying The accumulation of disability, as assessed by the Expanded Disability Status Scale (EDSS)
• To assess the effect of RPC1063 on brain atrophy over 12 months
• To evaluate the effect of RPC1063 on patient-reported quality of life as assessed by the Multiple Sclerosis Quality of Life-54 (MSQOL-54)
• To assess the safety and tolerability of RPC1063 in patients with RMS |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. MS, as diagnosed by the revised 2010 McDonald criteria
2. Exhibiting a relapsing clinical course consistent with RMS and history of brain MRI lesions consistent with MS
3. Ages 18-55 years, inclusive
4. EDSS score between 0 and 5.0 at baseline
5. Meet one of the following disease activity criteria:
o At least 1 documented relapse within the last 12 months prior to screening
OR
o At least 1 documented relapse occurred within the last 24 months prior to screening and documented evidence of at least 1 GdE lesion on brain MRI within the last 12 months prior to randomization
6. No history of relapse with onset from 30 days prior to screening until randomization; during this period, patients must have been clinically stable, without systemic corticosteroid treatment or adrenocorticotrophic hormone (ACTH)
7. Ability to provide written informed consent and to be compliant with the schedule of protocol assessments
8. Patients of reproduction potential (males and females) must practice an acceptable method of birth control (acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, vasectomy, or double-barrier method [condom or diaphragm with spermicide]) during study participation and for 30 days after their last dose of treatment of study medication or true sexual abstinence (periodic abstinence [calendar, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
9. Patients must have documentation of positive Varicella zoster virus (VZV) IgG antibody status or complete VZV vaccination at least 30 days prior to randomization |
|
| E.4 | Principal exclusion criteria |
1. Primary progressive MS at screening
2. Disease duration of more than 15 years in patients with an EDSS ≤2.0
3. Contraindications to MRI or Gadolinium contrast, such as known allergy to Gadolinium contrast dyes, renal insufficiency, claustrophobia, body size incompatible with the scanner, pacemaker, cochlear implants, intracranial vascular clips
4. Incompatibility with beta IFN use (e.g. intolerable side effects)
5. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (β-hCG) measured during screening
6. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the patient at risk by participating in the study in the opinion of treating investigator
7. Specific cardiac conditions are excluded, including history or presence of:
i. Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, Class III/IV heart failure, sick sinus syndrome, or severe untreated sleep apnea
ii. Prolonged QTcF interval (QTcF >450 msec males, >470 msec females), or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome, concurrent therapy with QT-prolonging drugs)
iii. Patients with other pre-existing stable cardiac conditions who have not been cleared for the study by an appropriate cardiac evaluation by a cardiologist
iv. Other clinically significant conduction abnormalities or any other significant cardiac condition that could jeopardize a patient’s health or put them at significant safety risk during the course of the study in the opinion of treating investigator
8. Resting heart rate less than 55 bpm at Screening
9. Diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c >9% , or diabetic patients with significant co-morbid conditions such as retinopathy or nephropathy
10. History of uveitis
11. Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal infection of nail beds, minor upper respiratory tract infections [URTI] and minor skin infections]) or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or oral antibiotics within 14 days prior to screening
12. History or known presence of recurrent or chronic infection; recurring urinary tract infections could be allowed
13. History of cancer, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved)
14. Suicide attempts in the past or current signs of major depression
15. History of alcohol or drug abuse within 1 year prior to randomization
16. History of or currently active primary or secondary immunodeficiency
17. Prior use of any investigational agent within 6 months prior to enrollment
18. Receipt of a live vaccine within 4 weeks prior to randomization
19. Non-lymphocyte-depleting disease-modifying MS agents must be discontinued from signing of informed consent
20. Previous treatment with lymphocyte-depleting therapies
21. Treatment with other immunosuppressant agents such as azathioprine, cyclosporine, methotrexate, or mycophenolate within 6 months prior to randomization
22. Systemic corticosteroid therapy or ACTH use within 30 days prior to screening
23. Prior treatment with lymphocyte trafficking blockers
24. Treatment with intravenous immune globulin (IVIg) or plasmapheresis within 3 months prior to randomization
25. Treatment with other disease modifying therapies within 3 months prior to randomization
26. Intolerance of or contraindication to oral or IV corticosteroids
27. Use of therapies that are not allowed based on CYP3A4 metabolism within 4 weeks prior to randomization
28. Treatment with medications with a known impact on the cardiac conduction system are excluded
29. Positive rapid plasma reagin
30. Serum creatinine >1.4 mg/dL for women or >1.6 mg/dL for men
31. Liver function impairment or persisting elevations of aspartate aminotransferase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) >1.5 times the upper limit of normal (ULN), or direct bilirubin >1.5 times the ULN
32. Hemoglobin <8.5 g/dL
33. Clinically significant findings on brain MRI scan consistent with conditions other than MS
34. ECG showing any clinically significant abnormality (e.g., acute ischemia, significant heart conduction abnormality (e.g., left bundle branch block)
35. FEV1 or FVC <70% of predicted values at screening)
36.Presence of >20 gadolinium-enhancing lesions on baseline brain MRI scan
Please refer to the protocol for the remaining Exclusion Criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Annual relapse rate (ARR) during the treatment period |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please see Section E.5.1 above |
|
| E.5.2 | Secondary end point(s) |
• The number of new or enlarging hyperintense T2-weighted brain MRI lesions over 12 months
• The number of GdE brain MRI lesions at Month 12
• Time to onset of disability progression as defined by a sustained worsening in EDSS of 1.0 points or more, confirmed after 3 months and after 6 months
• Proportion of patients who are GdE lesion-free at Month 12
• Proportion of patients who are new or enlarging T2 lesion-free at Month12
• The percent change in normalized brain volume (atrophy) on brain MRI scans from Baseline to Month 12
• Change in MSFC score from Baseline to Month 12 (including the Low-Contrast Letter Acuity Test [LCLA] measurement of visual function as a component)
• Change in MSQOL-54 score from Baseline to Month 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see Section E.5.2 above |
|
| 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 | Yes |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| 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 |
| Austria |
| Belarus |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| Croatia |
| Czech Republic |
| Estonia |
| Georgia |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Moldova, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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