| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RELAPSING MULTIPLE SCLEROSIS |
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| E.1.1.1 | Medical condition in easily understood language |
| RELAPSING MULTIPLE SCLEROSIS |
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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 | 17.1 |
| 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 |
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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 |
Part A
To demonstrate the superior clinical efficacy of RPC1063 compared to placebo by showing a reduction in the cumulative number of total gadolinium enhancing (GdE) lesions from Week 12 to Week 24 in patients with relapsing multiple sclerosis (RMS).
Part B
To assess whether the clinical efficacy of RPC1063 is superior to interferon (IFN) β-1a (Avonex®) in reducing the rate of clinical relapses at the end of Month 24 in patients with RMS.
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| E.2.2 | Secondary objectives of the trial |
Part A
-assess the proportion of patients who are free of GdE lesions at Week 24
-assess the effect of RPC1063 on the cumulative number of new/enlarging T2 lesions from W12 to W24
-compare the clinical efficacy of RPC1063 to placebo in pts with RMS by reduction in ARR & proportion of relapse free pts at W24
-assess the safety, tolerability, PK and PD of RPC1063 in pts with RMS
Part B
-assess the effect of RPC1063 on the proportion of patients with new/enlarging T2 lesions at M24
-evaluate whether the efficacy of RPC1063 is superior to IFN β-1a in delaying the accumulation of disability, measured by MSFC and by the LCLA.
-evaluate whether the efficacy of RPC1063 is superior to IFN β-1a in delaying the accumulation of disability, as assessed by the EDSS
-assess the effect of RPC1063 on brain atrophy over 24m
-evaluate the effect of RPC1063 on patient-reported quality of life as assessed by the MSQOL-54
-assess the safety & tolerability of RPC1063 in pts with RMS
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Per Protocol dated 31 July 2013.
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:
a.At least 1 documented relapse within the last 12 months prior to screening
OR
b.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 study entry
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| E.4 | Principal exclusion criteria |
Per Protocol dated 31 July 2013.
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) (Part B only)
Exclusions Related to General Health:
5.Pregnancy, lactation, or a positive serum beta human chorionic gonadotrophin (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.Clinically relevant cardiovascular conditions, outlined below:
Part A: Clinically relevent cardiovascular conditions including history or presence of ischemic heart disease, myocardial infarction, congestive heart failure, stroke, transient ischemic attack, sick sinus syndrome, recurrent syncope, second degree or higher AV block, prolonged QTcF interval (QTcF > 450 msec males, > 470 msec females) or relevent risk factors for QT prolongation (e.g., hypokalemia, hypomagnesemia), severe untreated sleep apnea
Part B: 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
Part A and B: 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 the treating investigator.
8.Resting heart rate less than 55 bpm at screening
9.History of diabetes mellitus
Part A: Any history of Type 1 or Type 2 diabetes mellitus
Part B: Diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c > 7%, 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 URTI and minor skin conditions]) 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 (e.g., hepatitis A, B, or C, human immunodeficiency virus (HIV), syphilis, TB); 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
Exclusions Related to Medications:
17.Prior use of any investigational agent within 6 months prior to enrollment
18.Receipt of a live vaccine within 4 weeks prior to screening
19.Non-lymphocyte-depleting disease-modifying MS agents (e.g., glatiramer acetate, interferons) must be discontinued from signing of informed consent
20.Previous treatment with lymphocyte-depleting therapies (e.g., alemtuzumab, anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation)
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 (e.g., natalizumab, fingolimod, other S1PR agonists).
24.Treatment with intravenous immune globulin (IVIg), plasmapheresis, within 3 months prior to randomization
(Please refer to Page 60 of the protocol for the remaining criteria) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Part A: Total number of GdE lesions, assessed on brain MRIs from Week 12 to Week 24
Part B: ARR at the end of Month 24
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please see section E.5.1 above |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
Part A:
Key Secondary Endpoints (rank ordered):
• The number of GdE lesions at Week 24
• Total number of new or enlarging hyperintense T2-weighted brain MRI lesions from Week 12 to Week 24
•ARR at the end of Week 24
Part B:
Key Secondary Endpoints (rank ordered):
•The number of new or enlarging hyperintense T2-weighted brain MRI lesions at Month 24
•Change in MSFC score and visual function as measured by the LCLA
•Time to onset of sustained disability progression as defined by a sustained worsening in EDSS of 1.0 points or more, confirmed after 12 weeks
•Time to onset of sustained disability progression as defined by a sustained worsening in EDSS of 1.0 points or more, confirmed after 24 weeks
•The change in brain atrophy on brain MRI scans from baseline to 24 months
•Change in MSQOL-54 score at 24 months
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see section E.5.2 above |
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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 | 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) | Yes |
| 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 |
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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 | 6 |
| 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 | 101 |
| 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 |
| Belarus |
| Belgium |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| Croatia |
| Czech Republic |
| Georgia |
| Greece |
| Hungary |
| Italy |
| Moldova, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Ukraine |
| 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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| 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 | 5 |
| 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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