Trial Outcomes & Findings for Efficacy and Safety Study of Ozanimod in Relapsing Multiple Sclerosis (NCT NCT02047734)

NCT ID: NCT02047734

Last Updated: 2021-02-11

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1320 participants

Primary outcome timeframe

At the end of month 24

Results posted on

2021-02-11

Participant Flow

The study was conducted at 147 academic medical centers and clinical practices in 21 countries in North America, Europe, and South Africa. Between December 2013 and March 2015, 1695 participants were screened, of which 375 did not meet inclusion criteria. One thousand, three hundred and twenty participants with relapsing multiple sclerosis (MS) were enrolled and randomly assigned to a treatment group.

Participants were randomized in a 1:1:1 ratio to one of three treatment groups. Randomization was stratified by Baseline Expanded Disability Status Scale (EDSS) score (≤ 3.5, \> 3.5) and by country. Participants who completed the 24-month study were eligible to enroll in a long-term, open-label extension study (RPC01-3001; NCT02576717).

Participant milestones

Participant milestones
Measure	Interferon Beta-1a (IFN β-1a) Participants received 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.	Ozanimod 0.5 mg Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Study STARTED	443	443	434
Overall Study Received Treatment	441	439	433
Overall Study COMPLETED	376	374	388
Overall Study NOT COMPLETED	67	69	46

Reasons for withdrawal

Reasons for withdrawal
Measure	Interferon Beta-1a (IFN β-1a) Participants received 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.	Ozanimod 0.5 mg Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Study Adverse Event	18	13	13
Overall Study Lack of Efficacy	4	5	1
Overall Study Protocol Violation	3	1	1
Overall Study Lost to Follow-up	1	4	0
Overall Study Death	0	1	0
Overall Study Withdrawal by Subject	30	31	19
Overall Study Physician Decision	7	6	5
Overall Study Miscellaneous	2	4	6
Overall Study Did Not Receive Study Drug	2	4	1

Baseline Characteristics

Participants with available MRI data

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Interferon Beta-1a (IFN β-1a) n=441 Participants Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.	Total n=1313 Participants Total of all reporting groups
Age, Continuous	35.1 years STANDARD_DEVIATION 9.07 • n=441 Participants	35.4 years STANDARD_DEVIATION 8.82 • n=439 Participants	36.0 years STANDARD_DEVIATION 8.89 • n=433 Participants	35.5 years STANDARD_DEVIATION 8.93 • n=1313 Participants
Sex: Female, Male Female	304 Participants n=441 Participants	287 Participants n=439 Participants	291 Participants n=433 Participants	882 Participants n=1313 Participants
Sex: Female, Male Male	137 Participants n=441 Participants	152 Participants n=439 Participants	142 Participants n=433 Participants	431 Participants n=1313 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=441 Participants	6 Participants n=439 Participants	10 Participants n=433 Participants	21 Participants n=1313 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	436 Participants n=441 Participants	433 Participants n=439 Participants	423 Participants n=433 Participants	1292 Participants n=1313 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=441 Participants	0 Participants n=439 Participants	0 Participants n=433 Participants	0 Participants n=1313 Participants
Race/Ethnicity, Customized White	432 Participants n=441 Participants	431 Participants n=439 Participants	428 Participants n=433 Participants	1291 Participants n=1313 Participants
Race/Ethnicity, Customized Black	7 Participants n=441 Participants	6 Participants n=439 Participants	5 Participants n=433 Participants	18 Participants n=1313 Participants
Race/Ethnicity, Customized Asian	1 Participants n=441 Participants	0 Participants n=439 Participants	0 Participants n=433 Participants	1 Participants n=1313 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=441 Participants	0 Participants n=439 Participants	0 Participants n=433 Participants	0 Participants n=1313 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=441 Participants	0 Participants n=439 Participants	0 Participants n=433 Participants	0 Participants n=1313 Participants
Race/Ethnicity, Customized Other	1 Participants n=441 Participants	2 Participants n=439 Participants	0 Participants n=433 Participants	3 Participants n=1313 Participants
Region North America	16 Participants n=441 Participants	16 Participants n=439 Participants	16 Participants n=433 Participants	48 Participants n=1313 Participants
Region Western Europe	40 Participants n=441 Participants	40 Participants n=439 Participants	36 Participants n=433 Participants	116 Participants n=1313 Participants
Region Eastern Europe	379 Participants n=441 Participants	378 Participants n=439 Participants	374 Participants n=433 Participants	1131 Participants n=1313 Participants
Region Southern Africa	6 Participants n=441 Participants	5 Participants n=439 Participants	7 Participants n=433 Participants	18 Participants n=1313 Participants
Country of Enrollment Belarus	40 Participants n=441 Participants	38 Participants n=439 Participants	37 Participants n=433 Participants	115 Participants n=1313 Participants
Country of Enrollment Belgium	4 Participants n=441 Participants	4 Participants n=439 Participants	4 Participants n=433 Participants	12 Participants n=1313 Participants
Country of Enrollment Bosnia And Herzegovina	3 Participants n=441 Participants	3 Participants n=439 Participants	2 Participants n=433 Participants	8 Participants n=1313 Participants
Country of Enrollment Bulgaria	11 Participants n=441 Participants	12 Participants n=439 Participants	11 Participants n=433 Participants	34 Participants n=1313 Participants
Country of Enrollment Canada	1 Participants n=441 Participants	1 Participants n=439 Participants	0 Participants n=433 Participants	2 Participants n=1313 Participants
Country of Enrollment Croatia	16 Participants n=441 Participants	15 Participants n=439 Participants	14 Participants n=433 Participants	45 Participants n=1313 Participants
Country of Enrollment Georgia	12 Participants n=441 Participants	11 Participants n=439 Participants	13 Participants n=433 Participants	36 Participants n=1313 Participants
Country of Enrollment Greece	3 Participants n=441 Participants	4 Participants n=439 Participants	2 Participants n=433 Participants	9 Participants n=1313 Participants
Country of Enrollment Hungary	7 Participants n=441 Participants	9 Participants n=439 Participants	6 Participants n=433 Participants	22 Participants n=1313 Participants
Country of Enrollment Italy	8 Participants n=441 Participants	9 Participants n=439 Participants	7 Participants n=433 Participants	24 Participants n=1313 Participants
Country of Enrollment Poland	125 Participants n=441 Participants	124 Participants n=439 Participants	124 Participants n=433 Participants	373 Participants n=1313 Participants
Country of Enrollment Republic of Moldova	2 Participants n=441 Participants	4 Participants n=439 Participants	3 Participants n=433 Participants	9 Participants n=1313 Participants
Country of Enrollment Romania	9 Participants n=441 Participants	9 Participants n=439 Participants	10 Participants n=433 Participants	28 Participants n=1313 Participants
Country of Enrollment Russian Federation	41 Participants n=441 Participants	40 Participants n=439 Participants	40 Participants n=433 Participants	121 Participants n=1313 Participants
Country of Enrollment Serbia	34 Participants n=441 Participants	34 Participants n=439 Participants	34 Participants n=433 Participants	102 Participants n=1313 Participants
Country of Enrollment Slovakia	2 Participants n=441 Participants	1 Participants n=439 Participants	2 Participants n=433 Participants	5 Participants n=1313 Participants
Country of Enrollment South Africa	6 Participants n=441 Participants	5 Participants n=439 Participants	7 Participants n=433 Participants	18 Participants n=1313 Participants
Country of Enrollment Spain	19 Participants n=441 Participants	17 Participants n=439 Participants	19 Participants n=433 Participants	55 Participants n=1313 Participants
Country of Enrollment Ukraine	77 Participants n=441 Participants	78 Participants n=439 Participants	78 Participants n=433 Participants	233 Participants n=1313 Participants
Country of Enrollment United Kingdom	6 Participants n=441 Participants	6 Participants n=439 Participants	4 Participants n=433 Participants	16 Participants n=1313 Participants
Country of Enrollment United States	15 Participants n=441 Participants	15 Participants n=439 Participants	16 Participants n=433 Participants	46 Participants n=1313 Participants
Type of Multiple Sclerosis Relapsing-remitting multiple sclerosis	432 Participants n=441 Participants	432 Participants n=439 Participants	425 Participants n=433 Participants	1289 Participants n=1313 Participants
Type of Multiple Sclerosis Progressive-relapsing multiple sclerosis	8 Participants n=441 Participants	7 Participants n=439 Participants	8 Participants n=433 Participants	23 Participants n=1313 Participants
Type of Multiple Sclerosis Secondary progressive multiple sclerosis	1 Participants n=441 Participants	0 Participants n=439 Participants	0 Participants n=433 Participants	1 Participants n=1313 Participants
Age at MS Symptom Onset	28.9 years STANDARD_DEVIATION 8.60 • n=441 Participants	29.3 years STANDARD_DEVIATION 8.41 • n=439 Participants	29.2 years STANDARD_DEVIATION 8.67 • n=433 Participants	29.1 years STANDARD_DEVIATION 8.56 • n=1313 Participants
Age at MS Diagnosis	31.6 years STANDARD_DEVIATION 8.82 • n=441 Participants	32.0 years STANDARD_DEVIATION 8.59 • n=439 Participants	32.1 years STANDARD_DEVIATION 8.95 • n=433 Participants	31.9 years STANDARD_DEVIATION 8.78 • n=1313 Participants
Time Since MS Symptom Onset	6.36 years STANDARD_DEVIATION 6.065 • n=441 Participants	6.23 years STANDARD_DEVIATION 5.547 • n=439 Participants	6.92 years STANDARD_DEVIATION 6.201 • n=433 Participants	6.50 years STANDARD_DEVIATION 5.947 • n=1313 Participants
Expanded Disability Status Scale (EDSS) Score	2.49 units on a scale STANDARD_DEVIATION 1.158 • n=441 Participants	2.48 units on a scale STANDARD_DEVIATION 1.166 • n=439 Participants	2.55 units on a scale STANDARD_DEVIATION 1.145 • n=433 Participants	2.51 units on a scale STANDARD_DEVIATION 1.156 • n=1313 Participants
EDSS Category EDSS ≤ 3.5	375 Participants n=441 Participants	374 Participants n=439 Participants	371 Participants n=433 Participants	1120 Participants n=1313 Participants
EDSS Category EDSS > 3.5	66 Participants n=441 Participants	65 Participants n=439 Participants	62 Participants n=433 Participants	193 Participants n=1313 Participants
Number of Gadolinium-enhancing (GdE) Lesions	1.8 lesions STANDARD_DEVIATION 3.54 • n=440 Participants • Participants with available MRI data	1.8 lesions STANDARD_DEVIATION 3.62 • n=439 Participants • Participants with available MRI data	1.6 lesions STANDARD_DEVIATION 3.78 • n=433 Participants • Participants with available MRI data	1.7 lesions STANDARD_DEVIATION 3.65 • n=1312 Participants • Participants with available MRI data
Number of T2 Lesions	48.7 lesions STANDARD_DEVIATION 32.62 • n=440 Participants • Participants with available MRI data	48.7 lesions STANDARD_DEVIATION 36.27 • n=439 Participants • Participants with available MRI data	47.9 lesions STANDARD_DEVIATION 32.37 • n=432 Participants • Participants with available MRI data	48.4 lesions STANDARD_DEVIATION 33.78 • n=1311 Participants • Participants with available MRI data
Normalized Brain Volume	1449.581 cm³ STANDARD_DEVIATION 77.156 • n=439 Participants • Participants with available data	1452.852 cm³ STANDARD_DEVIATION 71.978 • n=437 Participants • Participants with available data	1441.949 cm³ STANDARD_DEVIATION 79.228 • n=432 Participants • Participants with available data	1448.153 cm³ STANDARD_DEVIATION 76.250 • n=1308 Participants • Participants with available data

PRIMARY outcome

Timeframe: At the end of month 24

Population: The ITT population included all randomized participants who received at least 1 dose of study drug; participants were analyzed according to the treatment they were randomized to receive and not according to what they actually received, if different.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=441 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Adjusted Annualized Relapse Rate (ARR) at the End of Month 24	0.276 relapses/year Interval 0.234 to 0.324	0.218 relapses/year Interval 0.183 to 0.259	0.172 relapses/year Interval 0.142 to 0.208

SECONDARY outcome

Timeframe: 24 month treatment period; MRI scans were performed at Months 12 and 24

Population: ITT Population included all randomized participants who received at least 1 dose of study drug. Includes participants with non-missing MRI results.

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=336 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=329 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=327 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging (MRI) Lesions Per Scan Over 24 Months	3.183 lesions/scan Interval 2.64 to 3.838	2.092 lesions/scan Interval 1.741 to 2.514	1.835 lesions/scan Interval 1.523 to 2.211

SECONDARY outcome

Timeframe: Month 24

Population: The ITT population consisted of all randomized participants who received at least 1 dose of study medication. Includes participants with non-missing GdE MRI results 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).

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=336 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=329 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=327 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Adjusted Mean Number of Gadolinium Enhancing Brain Lesions at Month 24	0.373 lesions Interval 0.256 to 0.543	0.197 lesions Interval 0.131 to 0.296	0.176 lesions Interval 0.116 to 0.266

SECONDARY outcome

Timeframe: From first dose to the end of the 24-month treatment period

Population: The ITT population consisted of all randomized participants who received at least 1 dose of study medication.

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=441 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Time to Onset of Disability Progression Confirmed After 3 Months	NA days Not estimable as there were insufficient disability events	NA days Not estimable as there were insufficient disability events	NA days Not estimable as there were insufficient disability events

SECONDARY outcome

Timeframe: From first dose to the end of the 24-month treatment period

Population: The ITT population consisted of all randomized participants who received at least 1 dose of study medication.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=441 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Time to Onset of Disability Progression Confirmed After 6 Months	NA days Not estimable as there were insufficient disability events	NA days Not estimable as there were insufficient disability events	NA days Not estimable as there were insufficient disability events

SECONDARY outcome

Timeframe: Month 24

Population: ITT population included all randomized participants who received at least 1 dose of study drug; participants with missing data at Month 24 were considered non-responders.

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=441 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Percentage of Participants Who Were Gadolinium Enhancing (GdE) Lesion-Free at Month 24	56.2 percentage of participants Interval 51.6 to 60.9	63.3 percentage of participants Interval 58.8 to 67.8	65.6 percentage of participants Interval 61.1 to 70.1

SECONDARY outcome

Timeframe: Month 24

Population: The ITT population consisted of all randomized participants who received at least 1 dose of study medication; Participants with missing data at Month 24 were considered non-responders.

MRI images were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=441 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24	18.4 percentage of participants Interval 14.8 to 22.0	23.5 percentage of participants Interval 19.5 to 27.4	23.8 percentage of participants Interval 19.8 to 27.8

SECONDARY outcome

Timeframe: Baseline and Month 24

Population: ITT Population; last observation carried forward was used for participants with missing data at Month 24 (only post-baseline MRI scans were carried forward)

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=397 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=398 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=390 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Percent Change From Baseline in Normalized Brain Volume to Month 24	-0.937 percent change Standard Deviation 0.944	-0.707 percent change Standard Deviation 0.746	-0.707 percent change Standard Deviation 0.878

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: The ITT population with available MSFC Z-scores

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=437 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=435 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=428 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Change From Baseline to Month 24 in Multiple Sclerosis Functional Composite (MSFC) Score Including the Low-Contrast Letter Acuity (LCLA) Test	-0.052 Z-score Standard Deviation 0.601	0.036 Z-score Standard Deviation 0.440	-0.010 Z-score Standard Deviation 0.622

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: The ITT population consisted of all randomized participants who received at least 1 dose of study medication. Missing data were imputed using a mixed-effects regression model.

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=441 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=433 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Mean Change From Baseline in Multiple Sclerosis Quality of Life (MSQOL)-54 Physical Health Composite Summary and Mental Health Composite Summary Scores Physical Health Composite Summary	-1.526 units on a scale Standard Deviation 12.319	0.609 units on a scale Standard Deviation 12.315	0.209 units on a scale Standard Deviation 12.321
Mean Change From Baseline in Multiple Sclerosis Quality of Life (MSQOL)-54 Physical Health Composite Summary and Mental Health Composite Summary Scores Mental Health Composite Summary	-1.831 units on a scale Standard Deviation 16.422	-1.182 units on a scale Standard Deviation 14.379	-1.517 units on a scale Standard Deviation 15.544

SECONDARY outcome

Timeframe: 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.

Population: Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.

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.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=440 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=434 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Number of Participants With Treatment Emergent Adverse Events Any TEAE	365 Participants	326 Participants	324 Participants
Number of Participants With Treatment Emergent Adverse Events Any Moderate or Severe TEAE	235 Participants	169 Participants	170 Participants
Number of Participants With Treatment Emergent Adverse Events Any Severe TEAE	19 Participants	19 Participants	15 Participants
Number of Participants With Treatment Emergent Adverse Events Any Related TEAE	30 Participants	12 Participants	19 Participants
Number of Participants With Treatment Emergent Adverse Events Any Serious TEAE	28 Participants	31 Participants	28 Participants
Number of Participants With Treatment Emergent Adverse Events Any Related Serious TEAE	0 Participants	1 Participants	1 Participants
Number of Participants With Treatment Emergent Adverse Events Any TEAE Leading to discontinuation of Study Drug	18 Participants	14 Participants	13 Participants
Number of Participants With Treatment Emergent Adverse Events Any TEAE Leading to Study Withdrawal	20 Participants	13 Participants	13 Participants
Number of Participants With Treatment Emergent Adverse Events Any Death on Study	0 Participants	1 Participants	0 Participants

POST_HOC outcome

Timeframe: Baseline and Month 24

Population: ITT Population; participants with available data at Baseline and Month 24

Brain volume (a measure of brain atrophy) was measured by brain MRI scans that were read at a centralized MRI reading facility by a blinded reader. Due to the non-normal distribution of the data for brain volume loss, the analyses for percent change from Baseline in normalized brain volume was repeated using rank-analysis of covariance (ANCOVA) and observed values.

Outcome measures

Outcome measures
Measure	Interferon Beta-1a n=279 Participants Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=274 Participants Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=271 Participants Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Percent Change From Baseline in Normalized Brain Volume to Month 24 Based on Rank ANCOVA	-0.940 percent change Interval -5.33 to 1.44	-0.710 percent change Interval -5.21 to 1.36	-0.690 percent change Interval -5.65 to 0.85

Adverse Events

Interferon Beta-1a

Serious events: 28 serious events

Other events: 275 other events

Deaths: 0 deaths

Ozanimod 0.5 mg

Serious events: 31 serious events

Other events: 185 other events

Deaths: 1 deaths

Ozanimod 1 mg

Serious events: 28 serious events

Other events: 199 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Interferon Beta-1a n=440 participants at risk Participants received IFN β-1a 30 µg intramuscular injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily for 24 months.	Ozanimod 0.5 mg n=439 participants at risk Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Ozanimod 1 mg n=434 participants at risk Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
General disorders Influenza Like Illness	48.9% 215/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	5.9% 26/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	6.2% 27/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
General disorders Pyrexia	6.1% 27/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	2.7% 12/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	2.3% 10/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Infections and infestations Nasopharyngitis	10.9% 48/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	13.4% 59/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	15.7% 68/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Infections and infestations Pharyngitis	3.4% 15/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	5.5% 24/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	3.9% 17/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Infections and infestations Upper Respiratory Tract Infection	8.4% 37/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	8.2% 36/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	7.8% 34/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Infections and infestations Urinary Tract Infection	3.9% 17/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	5.0% 22/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	4.4% 19/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Investigations Alanine Aminotransferase Increased	4.5% 20/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	6.6% 29/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	6.0% 26/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Investigations Gamma-Glutamyltransferase Increased	2.0% 9/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	3.6% 16/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	5.8% 25/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Nervous system disorders Headache	12.0% 53/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	12.5% 55/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	10.1% 44/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Vascular disorders Hypertension	3.2% 14/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	4.6% 20/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	5.5% 24/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.
Vascular disorders Orthostatic Hypotension	6.1% 27/440 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	6.2% 27/439 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.	6.9% 30/434 • From first dose of study drug to 28 days following the last dose of study drug; median duration of treatment was 24 months in each treatment group. The Safety Population included all participants who received at least 1 dose of study drug, analyzed according to the highest dose of ozanimod treatment actually received, not according to the treatment they were randomized to receive, if different.

Additional Information

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Bristol-Myers Squibb

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Results disclosure agreements

Principal investigator is a sponsor employee Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than one (1) year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene sixty (60) days prior to submission. Investigator must delete confidential information before submission.
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