Efficacy and Safety Study of Ozanimod in Relapsing Multiple Sclerosis

Study Overview
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Brief Summary
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This study is a two-part trial consisting of Part A (see NCT01628393) and Part B, presented within this record. The primary objective of Part B is to assess whether the clinical efficacy of ozanimod (RPC1063) is superior to interferon beta-1a (IFN β-1a; Avonex®) in reducing the rate of clinical relapses at the end of Month 24 in patients with relapsing multiple sclerosis (RMS).

Detailed Description
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This clinical trial (RPC01-201; RADIANCE) consisted of 2 parts, each reported separately on ClinicalTrials.gov: Part A (NCT01628393) and Part B (this record). Part A was a phase 2 study in which two doses of ozanimod were administered daily for 24 weeks with an efficacy and safety comparison to a placebo control and is reported separately as ClinicalTrials.gov record NCT01628393. Part B, reported herein, was a phase 3 study in which two doses of ozanimod were administered daily for a 24 month period compared to an active control, interferon β-1a. Participants were allowed to enroll in the open-label extension study RPC01-3001 (NCT02576717) or complete the study with a safety follow-up visit 28 days after their last dose of study treatment.

Official Title
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A Phase 2/3, Multi-center, Randomized, Double-blind, Placebo-controlled (Part A) and Double-blind, Double-dummy, Active-controlled (Part B), Parallel Group Study to Evaluate the Efficacy and Safety of RPC1063 Administered Orally to Relapsing Multiple Sclerosis Patients

Conditions
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Relapsing Multiple Sclerosis

Intervention / Treatment
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* Drug: Ozanimod
* Drug: Ozanimod placebo
* Drug: Interferon beta-1a
* Drug: Interferon beta-1a placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multiple sclerosis as diagnosed by the revised 2010 McDonald criteria Expanded Disability Status Scale (EDSS) score between 0 and 5.0 at baseline Exclusion Criteria: Primary progressive multiple sclerosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ozanimod 0.5 mg<br>Ozanimod 0.5 mg oral capsules daily and a weekly intramuscular placebo injection (identical in appearance to Interferon) for 24 months. | Drug: Ozanimod<br>* Oral capsule, daily for 24 months<br>* Other names: Zeposia®;Drug: Interferon beta-1a placebo<br>* Intramuscular injection, weekly for 24 months<br>|
| Experimental: Ozanimod1 mg<br>Ozanimod 1 mg oral capsules daily and a weekly intramuscular placebo injection (identical in appearance to Interferon) for 24 months. | Drug: Ozanimod<br>* Oral capsule, daily for 24 months<br>* Other names: Zeposia®;Drug: Interferon beta-1a placebo<br>* Intramuscular injection, weekly for 24 months<br>|
| Active Comparator: Interferon β-1a<br>interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months. | Drug: Ozanimod placebo<br>* Oral capsule, daily for 24 months<br>Drug: Interferon beta-1a<br>* Intramuscular injection, 30 µg, weekly for 24 months<br>* Other names: Avonex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Annualized Relapse Rate (ARR) at the End of Month 24 | A relapse was defined as new or worsening neurological symptoms attributable to MS and preceded by a relatively stable or improving neurological state for at least 30 days. Symptoms must have persisted for > 24 hours and not be attributable to confounding clinical factors. Relapses were confirmed when accompanied by objective neurological worsening based on examination by the blinded evaluator, consistent with an increase of ≥ 0.5 on the overall EDSS score relative to the most recent EDSS assessment, or 2 points on one of the functional system scale scores, or 1 point on ≥ two functional system scale scores. Relapse rate was calculated as the total number of confirmed relapses divided by the total number of days in the study * 365.25. ARR was based on a Poisson regression model, adjusted for region (Eastern Europe vs Rest of the World), age, and the Baseline number of gadolinium-enhancing lesions, and included the natural log transformation of time on study as an offset term. | At the end of month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging (MRI) Lesions Per Scan Over 24 Months | The adjusted mean number of new or enlarging hyperintense T2-weighted brain MRI lesions per scan was based on the cumulative number of new or enlarging T2 lesions since Baseline over 24 months. MRI images were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes. The adjusted mean per scan over 24 months was based based on a negative binomial regression model using observed data, adjusted for region (Eastern Europe vs. Rest of the World), age at Baseline, and Baseline number of GdE lesions. The natural log transformation of the number of available MRI scans over 24 months is used as an offset term. | 24 month treatment period; MRI scans were performed at Months 12 and 24 | 
| Adjusted Mean Number of Gadolinium Enhancing Brain Lesions at Month 24 | MRI images were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes. The number of gadolinium-enhancing (GdE) lesions at 24 months was analyzed based on observed data using a negative binomial regression model adjusted for region (Eastern Europe vs Rest of World), Baseline age, and Baseline number of GdE lesions, with natural log transformation of number of available MRI scans over 24 months as an offset term (1 scan for per participant). | Month 24 | 
| Time to Onset of Disability Progression Confirmed After 3 Months | EDSS is used to quantify disability and disability progression over time in MS. Based on a neurological examination, 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, and other functions) are scored from 0 (no disability) to 5 or 6 (more severe disability). Ambulation is assessed based on distance the patient is able to walk, whether assistance is required or restrictions are present. The EDSS score ranges from 0 (normal) to 10 (death due to MS) in 0.5 unit increments. Disability progression is defined by a sustained worsening in EDSS score of 1.0 point or more confirmed after 3 months. Time to onset of disability progression was calculated from the date of first dose to the date of the first visit at which the 1.0 point increase in EDSS was met using Kaplan-Meier methods. Participants without a sustained disease progression event were censored on the date of their last assessment or last dose of study drug, whichever was later. | From first dose to the end of the 24-month treatment period | 
| Time to Onset of Disability Progression Confirmed After 6 Months | EDSS is used to quantify disability and disability progression over time in MS. Based on a neurological examination, 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, and other functions) are scored from 0 (no disability) to 5 or 6 (more severe disability). Ambulation is assessed based on distance the patient is able to walk, whether assistance is required or restrictions are present. The EDSS score ranges from 0 (normal) to 10 (death due to MS) in 0.5 unit increments. Disability progression is defined by a sustained worsening in EDSS score of 1.0 point or more confirmed after 3 months. Time to onset of disability progression was calculated from the date of first dose to the date of the first visit at which the 1.0 point increase in EDSS was met using Kaplan-Meier methods. Participants without a sustained disease progression event were censored on the date of their last assessment or last dose of study drug, whichever was later. | From first dose to the end of the 24-month treatment period | 
| Percentage of Participants Who Were Gadolinium Enhancing (GdE) Lesion-Free at Month 24 | Participants were considered lesion free at Month 24 if they did not show evidence of GdE lesions at the Month 24 MRI scan. MRI images were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes. | Month 24 | 
| Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24 | MRI images were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes. | Month 24 | 
| Percent Change From Baseline in Normalized Brain Volume to Month 24 | Brain volume (a measure of brain atrophy) was measured by brain MRI scans that were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes. | Baseline and Month 24 | 
| Change From Baseline to Month 24 in Multiple Sclerosis Functional Composite (MSFC) Score Including the Low-Contrast Letter Acuity (LCLA) Test | The MSFC-LCLA is a battery including the following 4 individual scales: Timed 25-Foot Walk is an ambulation measure of walking 25 feet with time taken recorded in seconds 9-Hole Peg Test (9HPT) is a quantitative measure of upper extremity (arm and hand) function Symbol Digit Modalities Test (SDMT) is a measure of executive cognitive function that assesses processing speed, flexibility, and calculation ability Low-Contrast Letter Acuity Test (LCLA) used a standardized set of charts to assess low contrast visual acuity, charts are scored according to the number of letters that are identified correctly Z-scores were calculated for for each component and averaged to create an overall composite score, using the study population as the reference population. A Z-score represents the number of standard deviations a patient's test result is higher (Z > 0) or lower (Z < 0) than the average test result (Z = 0) of the reference population. A positive change indicates improvement. | Baseline to Month 24 | 
| Mean Change From Baseline in Multiple Sclerosis Quality of Life (MSQOL)-54 Physical Health Composite Summary and Mental Health Composite Summary Scores | The MSQOL-54 is a multidimensional health-related QOL measure that combines both generic and MS-specific items into a single instrument. The instrument includes 12 subscales, two summary scores, and two single-item measures. The two summary scores - physical health and mental health - are derived from a weighted combination of scale scores. The physical health composite score includes Physical function, Health perceptions, Energy/fatigue, Role limitations - physical, Pain, Sexual function, Social function, and Health distress. The mental health composite score includes Health distress, Overall quality of life, Emotional well-being, Role limitations - emotional, and Cognitive function. Each composite summary score has a range from 0 to 100 where higher scores indicate better quality of life. A positive change from Baseline indicates improvement. | Baseline to Month 24 | 
| Number of Participants With Treatment Emergent Adverse Events | An adverse event (AE) is any untoward medical occurrence that does not necessarily have a causal relationship with the investigational product (IP), including an abnormal laboratory finding, symptom or disease temporally associated with the use of an IP whether or not considered related to the IP. Serious AEs were events that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, were congenital abnormalities/birth defects, or important medical events which may have required medical intervention to prevent one of the above outcomes. The investigator assessed the severity of AEs as mild, moderate, or severe and the relationship of each AE to treatment as unrelated, unlikely, possible, probable, or related based on timing and other known factors such as clinical state, environment, or other therapies. | From the first dose of study drug up to the first dose of the open-label extension study RPC01-3001, or up to 28 days after last dose for participants who did not continue into the open-label extension study; median duration of treatment was 24 months. |