Efficacy and Safety Study of Ozanimod in Relapsing Multiple Sclerosis (RADIANCE)

• ClinicalTrials.gov Identifier: NCT02047734
• Recruitment Status: Completed
• First Posted: January 28, 2014
• Results First Posted: February 11, 2021
• Last Update Posted: February 11, 2021
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Relapsing Multiple Sclerosis
• Interventions: Drug: Ozanimod; Drug: Ozanimod placebo; Drug: Interferon beta-1a; Drug: Interferon beta-1a placebo
• Enrollment: 1320

Participant Flow

Recruitment Details

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.

Pre-assignment Details

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).

Arm/Group Title	Interferon Beta-1a (IFN β-1a)	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Period Title: Overall Study
Started	443	443	434
Received Treatment	441 [1]	439 [2]	433
Completed [3]	376	374	388
Not Completed	67	69	46
Reason Not Completed
Adverse Event	18	13	13
Lack of Efficacy	4	5	1
Protocol Violation	3	1	1
Lost to Follow-up	1	4	0
Death	0	1	0
Withdrawal by Subject	30	31	19
Physician Decision	7	6	5
Miscellaneous	2	4	6
Did Not Receive Study Drug	2	4	1
[1] One participant received ozanimod 0.5 mg in error; [2] One participant received ozanimod 1.0 mg in error; [3] Completed study drug

Baseline Characteristics

Arm/Group Title		Interferon Beta-1a (IFN β-1a)	Ozanimod 0.5 mg	Ozanimod 1 mg	Total
Arm/Group Description		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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.	Total of all reporting groups
Overall Number of Baseline Participants		441	439	433	1313
Baseline Analysis Population Description		Intent-to-treat (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.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
		35.1 (9.07)	35.4 (8.82)	36.0 (8.89)	35.5 (8.93)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	Female	304 68.9%	287 65.4%	291 67.2%	882 67.2%
	Male	137 31.1%	152 34.6%	142 32.8%	431 32.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	Hispanic or Latino	5 1.1%	6 1.4%	10 2.3%	21 1.6%
	Not Hispanic or Latino	436 98.9%	433 98.6%	423 97.7%	1292 98.4%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	White	432 98.0%	431 98.2%	428 98.8%	1291 98.3%
	Black	7 1.6%	6 1.4%	5 1.2%	18 1.4%
	Asian	1 0.2%	0 0.0%	0 0.0%	1 0.1%
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Other	1 0.2%	2 0.5%	0 0.0%	3 0.2%
Region; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	North America	16 3.6%	16 3.6%	16 3.7%	48 3.7%
	Western Europe	40 9.1%	40 9.1%	36 8.3%	116 8.8%
	Eastern Europe	379 85.9%	378 86.1%	374 86.4%	1131 86.1%
	Southern Africa	6 1.4%	5 1.1%	7 1.6%	18 1.4%
Country of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	Belarus	40 9.1%	38 8.7%	37 8.5%	115 8.8%
	Belgium	4 0.9%	4 0.9%	4 0.9%	12 0.9%
	Bosnia And Herzegovina	3 0.7%	3 0.7%	2 0.5%	8 0.6%
	Bulgaria	11 2.5%	12 2.7%	11 2.5%	34 2.6%
	Canada	1 0.2%	1 0.2%	0 0.0%	2 0.2%
	Croatia	16 3.6%	15 3.4%	14 3.2%	45 3.4%
	Georgia	12 2.7%	11 2.5%	13 3.0%	36 2.7%
	Greece	3 0.7%	4 0.9%	2 0.5%	9 0.7%
	Hungary	7 1.6%	9 2.1%	6 1.4%	22 1.7%
	Italy	8 1.8%	9 2.1%	7 1.6%	24 1.8%
	Poland	125 28.3%	124 28.2%	124 28.6%	373 28.4%
	Republic of Moldova	2 0.5%	4 0.9%	3 0.7%	9 0.7%
	Romania	9 2.0%	9 2.1%	10 2.3%	28 2.1%
	Russian Federation	41 9.3%	40 9.1%	40 9.2%	121 9.2%
	Serbia	34 7.7%	34 7.7%	34 7.9%	102 7.8%
	Slovakia	2 0.5%	1 0.2%	2 0.5%	5 0.4%
	South Africa	6 1.4%	5 1.1%	7 1.6%	18 1.4%
	Spain	19 4.3%	17 3.9%	19 4.4%	55 4.2%
	Ukraine	77 17.5%	78 17.8%	78 18.0%	233 17.7%
	United Kingdom	6 1.4%	6 1.4%	4 0.9%	16 1.2%
	United States	15 3.4%	15 3.4%	16 3.7%	46 3.5%
Type of Multiple Sclerosis; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	Relapsing-remitting multiple sclerosis	432 98.0%	432 98.4%	425 98.2%	1289 98.2%
	Progressive-relapsing multiple sclerosis	8 1.8%	7 1.6%	8 1.8%	23 1.8%
	Secondary progressive multiple sclerosis	1 0.2%	0 0.0%	0 0.0%	1 0.1%
Age at MS Symptom Onset; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
		28.9 (8.60)	29.3 (8.41)	29.2 (8.67)	29.1 (8.56)
Age at MS Diagnosis; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
		31.6 (8.82)	32.0 (8.59)	32.1 (8.95)	31.9 (8.78)
Time Since MS Symptom Onset; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
		6.36 (6.065)	6.23 (5.547)	6.92 (6.201)	6.50 (5.947)
Expanded Disability Status Scale (EDSS) Score [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
		2.49 (1.158)	2.48 (1.166)	2.55 (1.145)	2.51 (1.156)
		[1] Measure Description: The EDSS is a scale for quantifying disability in MS. Eight functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, and other functions) are scored on a scale from 0 (no disability) to 5 or 6 (more severe disability). Ambulation is also scored. Based on scores in the 8 functional systems plus gait, an overall score ranging from 0 (normal) to 10 (death due to MS) in 0.5 unit increments is assigned. Participants with EDSS scores of 0.0 to 4.5 are fully ambulatory; patients with EDSS scores of 5.0 to 9.5 have impaired ambulation.
EDSS Category [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	441 participants	439 participants	433 participants	1313 participants
	EDSS ≤ 3.5	375 85.0%	374 85.2%	371 85.7%	1120 85.3%
	EDSS > 3.5	66 15.0%	65 14.8%	62 14.3%	193 14.7%
		[1] Measure Description: The EDSS is a scale for quantifying disability in MS. Eight functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, and other functions) are scored on a scale of 0 (no disability) to 5 or 6 (more severe disability). Ambulation is also scored. Based on scores in these 8 functional systems and gait, an overall score ranging from 0 (normal) to 10 (death due to MS) in 0.5 unit increments is assigned. Participants with EDSS scores of 0.0 to 4.5 are fully ambulatory; patients with EDSS scores of 5.0 to 9.5 have impaired ambulation.
Number of Gadolinium-enhancing (GdE) Lesions [1] [2]; Mean (Standard Deviation); Unit of measure: Lesions
	Number Analyzed	440 participants	439 participants	433 participants	1312 participants
		1.8 (3.54)	1.8 (3.62)	1.6 (3.78)	1.7 (3.65)
		[1] Measure Description: A lesion appearing on magnetic resonance imagery (MRI), following injection of the chemical compound gadolinium, that reveals a breakdown in the blood-brain barrier. This breakdown of the blood-brain barrier indicates either a newly active lesion or the re-activation of an old one.; [2] Measure Analysis Population Description: Participants with available MRI data
Number of T2 Lesions [1] [2]; Mean (Standard Deviation); Unit of measure: Lesions
	Number Analyzed	440 participants	439 participants	432 participants	1311 participants
		48.7 (32.62)	48.7 (36.27)	47.9 (32.37)	48.4 (33.78)
		[1] Measure Description: A T2-weighted MRI scan shows the number of old and new lesions in a specific part of the brain or spinal cord.; [2] Measure Analysis Population Description: Participants with available MRI data
Normalized Brain Volume [1] [2]; Mean (Standard Deviation); Unit of measure: Cm³
	Number Analyzed	439 participants	437 participants	432 participants	1308 participants
		1449.581 (77.156)	1452.852 (71.978)	1441.949 (79.228)	1448.153 (76.250)
		[1] Measure Description: Measured using MRI; [2] Measure Analysis Population Description: Participants with available data

Outcome Measures

1. Primary Outcome

Title	Adjusted Annualized Relapse Rate (ARR) at the End of Month 24
Description	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.
Time Frame	At the end of month 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	441	439	433
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: relapses/year
	0.276; (0.234 to 0.324)	0.218; (0.183 to 0.259)	0.172; (0.142 to 0.208)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.025 level.
	Method	Poisson regression model
	Comments	Adjusted for region, age, and Baseline number of GdE lesions, and Included the natural log transformation of time on study as an offset term.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.623
	Confidence Interval	(2-Sided) 95%; 0.506 to 0.768
	Estimation Comments	Rate Ratio = Ozanimod / IFN β-1a

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0167
	Comments	To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.025 level.
	Method	Poisson Regression Model
	Comments	Adjusted for region, age, and Baseline number of GdE lesions, and Included the natural log transformation of time on study as an offset term.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.791
	Confidence Interval	(2-Sided) 95%; 0.652 to 0.958
	Estimation Comments	Rate Ratio = Ozanimod / IFN β-1a

2. Secondary Outcome

Title	Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging (MRI) Lesions Per Scan Over 24 Months
Description	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.
Time Frame	24 month treatment period; MRI scans were performed at Months 12 and 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	336	329	327
Least Squares Mean (95% Confidence Interval); Unit of Measure: lesions/scan
	3.183; (2.640 to 3.838)	2.092; (1.741 to 2.514)	1.835; (1.523 to 2.211)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Negative Binomial Regression Model
	Comments	Adjusted for region, age, and Baseline GdE lesions, and included the natural log transformation of available number of MRI scans as an offset term.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.576
	Confidence Interval	(2-Sided) 95%; 0.465 to 0.714
	Estimation Comments	Rate Ratio = Ozanimod / IFN β-1a

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Negative binomial regression model
	Comments	Adjusted for region, age, and Baseline GdE lesions and included the natural log transformation of available number of MRI scans as an offset term.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.657
	Confidence Interval	(2-Sided) 95%; 0.531 to 0.813
	Estimation Comments	Rate Ratio = Ozanimod / IFN β-1a

3. Secondary Outcome

Title	Adjusted Mean Number of Gadolinium Enhancing Brain Lesions at Month 24
Description	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).
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	336	329	327
Least Squares Mean (95% Confidence Interval); Unit of Measure: lesions
	0.373; (0.256 to 0.543)	0.197; (0.131 to 0.296)	0.176; (0.116 to 0.266)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0006
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Negative Binomial Regression Model
	Comments	Adjusted for region, age, and Baseline GdE lesions with the natural log transformation of available MRI scans at Month 24 as an offset term.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.471
	Confidence Interval	(2-Sided) 95%; 0.306 to 0.725
	Estimation Comments	Rate ratio = Ozanimod / IFN β-1a

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0030
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Negative binomial regression model,
	Comments	Adjusted for region, age, and Baseline GdE lesions with the natural log transformation of available MRI scans at Month 24 as an offset term.
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.528
	Confidence Interval	(2-Sided) 95%; 0.346 to 0.805
	Estimation Comments	Rate ratio = Ozanimod / IFN β-1a

4. Secondary Outcome

Title	Time to Onset of Disability Progression Confirmed After 3 Months
Description	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.
Time Frame	From first dose to the end of the 24-month treatment period

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	441	439	433
Median (95% Confidence Interval); Unit of Measure: days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not estimable as there were insufficient disability events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8224
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Cox proportional hazards model
	Comments	Adjusted for region (Eastern Europe vs Rest of World) age at Baseline, and Baseline EDSS score
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.045
	Confidence Interval	(2-Sided) 95%; 0.711 to 1.537
	Estimation Comments	Hazard ratio (Ozanimod / IFN β-1a) based on Cox proportional hazard model with factors for treatment group, adjusted for region, age at Baseline, and Baseline EDSS score.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2849
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Cox proportional hazards model
	Comments	Adjusted for region (Eastern Europe vs Rest of World), age at Baseline, and Baseline EDSS score
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.798
	Confidence Interval	(2-Sided) 95%; 0.528 to 1.206
	Estimation Comments	Hazard ratio (Ozanimod / IFN β-1a) based on Cox proportional hazard model with factors for treatment group, adjusted for region, age at Baseline, and Baseline EDSS score.

5. Secondary Outcome

Title	Time to Onset of Disability Progression Confirmed After 6 Months
Description	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.
Time Frame	From first dose to the end of the 24-month treatment period

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	441	439	433
Median (95% Confidence Interval); Unit of Measure: days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not estimable as there were insufficient disability events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1353
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Cox proportional hazard model
	Comments	Adjusted for region (Eastern Europe vs Rest of World), age at Baseline, and Baseline EDSS score
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.435
	Confidence Interval	(2-Sided) 95%; 0.893 to 2.305
	Estimation Comments	Hazard ratio (Ozanimod / IFN β-1a) based on Cox proportional hazard model with factors for treatment group, adjusted for region, age at Baseline, and Baseline EDSS score.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7154
	Comments	To control for type 1 error, the key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
	Method	Cox proportional hazard model
	Comments	Adjusted for region (Eastern Europe vs Rest of World), age at Baseline, and Baseline EDSS score
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.098
	Confidence Interval	(2-Sided) 95%; 0.664 to 1.815
	Estimation Comments	Hazard ratio (Ozanimod / IFN β-1a) based on Cox proportional hazard model with factors for treatment group, adjusted for region, age at Baseline, and Baseline EDSS score.

6. Secondary Outcome

Title	Percentage of Participants Who Were Gadolinium Enhancing (GdE) Lesion-Free at Month 24
Description	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.
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	441	439	433
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	56.2; (51.6 to 60.9)	63.3; (58.8 to 67.8)	65.6; (61.1 to 70.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0047
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by region (Eastern Europe vs Rest of the World) and Baseline EDSS category
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	9.4
	Confidence Interval	(2-Sided) 95%; 2.9 to 15.8
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0320
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by region (Eastern Europe vs Rest of the World) and Baseline EDSS category
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	7.1
	Confidence Interval	(2-Sided) 95%; 0.6 to 13.6
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24
Description	MRI images were assessed and scored by an independent MRI analysis center with no knowledge of treatment assignment or outcomes.
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	441	439	433
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	18.4; (14.8 to 22.0)	23.5; (19.5 to 27.4)	23.8; (19.8 to 27.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0466
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Based on the Cochran-Mantel-Haenszel test stratified by region (Eastern Europe vs. rest of the world) and Baseline EDSS category
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	5.4
	Confidence Interval	(2-Sided) 95%; 0.0 to 10.8
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0581
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Based on the Cochran-Mantel-Haenszel test stratified by region (Eastern Europe vs. rest of the world) and Baseline EDSS category
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 10.5
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Percent Change From Baseline in Normalized Brain Volume to Month 24
Description	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.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	397	398	390
Mean (Standard Deviation); Unit of Measure: percent change
	-0.937 (0.944)	-0.707 (0.746)	-0.707 (0.878)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Based on the analysis of covariance model, adjusted for region (Eastern Europe vs. rest of the world), Baseline EDSS category, and brain volume at Baseline
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	0.244
	Confidence Interval	(2-Sided) 95%; 0.125 to 0.363
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs. rest of the world), Baseline EDSS category, and brain volume at Baseline.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	Based on the analysis of covariance model, adjusted for region (Eastern Europe vs. rest of the world), Baseline EDSS category, and brain volume at Baseline.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	0.224
	Confidence Interval	(2-Sided) 95%; 0.106 to 0.342
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs. rest of the world), Baseline EDSS category, and brain volume at Baseline.

9. Secondary Outcome

Title	Change From Baseline to Month 24 in Multiple Sclerosis Functional Composite (MSFC) Score Including the Low-Contrast Letter Acuity (LCLA) Test
Description	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.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

The ITT population with available MSFC Z-scores

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	437	435	428
Mean (Standard Deviation); Unit of Measure: Z-score
	-0.052 (0.601)	0.036 (0.440)	-0.010 (0.622)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2480
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Based on the analysis of covariance model, adjusted for region, Baseline EDSS category, and Baseline MSFC Z-score
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	0.043
	Confidence Interval	(2-Sided) 95%; -0.030 to 0.116
	Estimation Comments	Difference in means are based on the analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), Baseline EDSS category, and the Baseline MSFC Z-score.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0123
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Based on the analysis of covariance model, adjusted for region, Baseline EDSS category, and Baseline MSFC Z-score
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	0.093
	Confidence Interval	(2-Sided) 95%; 0.020 to 0.165
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), Baseline EDSS category, and the Baseline MSFC Z-score.

10. Secondary Outcome

Title	Mean Change From Baseline in Multiple Sclerosis Quality of Life (MSQOL)-54 Physical Health Composite Summary and Mental Health Composite Summary Scores
Description	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.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	441	439	433
Mean (Standard Deviation); Unit of Measure: units on a scale
Physical Health Composite Summary	-1.526 (12.319)	0.609 (12.315)	0.209 (12.321)
Mental Health Composite Summary	-1.831 (16.422)	-1.182 (14.379)	-1.517 (15.544)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	Analysis of Physical Health Composite Summary Score
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0988
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Based on the analysis of covariance model, adjusted for region, Baseline EDSS category, and Baseline summary score
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	1.345
	Confidence Interval	(2-Sided) 95%; -0.252 to 2.943
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), Baseline EDSS category, and Baseline summary score.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	Analysis of Physical Health Composite Summary Score
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0228
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Based on the analysis of covariance model, adjusted for region, Baseline EDSS category, and Baseline summary score.
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	1.849
	Confidence Interval	(2-Sided) 95%; 0.258 to 3.440
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), Baseline EDSS category, and Baseline summary score.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	Analysis of Mental Health Composite Summary Score
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6997
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Based on the analysis of covariance model, adjusted for region, Baseline EDSS category, and Baseline summary score
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	0.380
	Confidence Interval	(2-Sided) 95%; -1.553 to 2.313
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), Baseline EDSS category, and Baseline summary score.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	Analysis of Mental Health Composite Summary Score
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5501
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Based on the analysis of covariance model, adjusted for region, Baseline EDSS category, and the Baseline summary score
Method of Estimation	Estimation Parameter	Difference in means
	Estimated Value	0.587
	Confidence Interval	(2-Sided) 95%; -1.339 to 2.513
	Estimation Comments	Difference in means based on the analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), Baseline EDSS category, and Baseline summary score.

11. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	440	439	434
Measure Type: Count of Participants; Unit of Measure: Participants
Any TEAE	365 83.0%	326 74.3%	324 74.7%
Any Moderate or Severe TEAE	235 53.4%	169 38.5%	170 39.2%
Any Severe TEAE	19 4.3%	19 4.3%	15 3.5%
Any Related TEAE	30 6.8%	12 2.7%	19 4.4%
Any Serious TEAE	28 6.4%	31 7.1%	28 6.5%
Any Related Serious TEAE	0 0.0%	1 0.2%	1 0.2%
Any TEAE Leading to discontinuation of Study Drug	18 4.1%	14 3.2%	13 3.0%
Any TEAE Leading to Study Withdrawal	20 4.5%	13 3.0%	13 3.0%
Any Death on Study	0 0.0%	1 0.2%	0 0.0%

12. Post-Hoc Outcome

Title	Percent Change From Baseline in Normalized Brain Volume to Month 24 Based on Rank ANCOVA
Description	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.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description:	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
Overall Number of Participants Analyzed	279	274	271
Median (Full Range); Unit of Measure: percent change
	-0.940; (-5.33 to 1.44)	-0.710; (-5.21 to 1.36)	-0.690; (-5.65 to 0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 1 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Rank ANCOVA
	Comments	Adjusted for region and Baseline EDSS category, with the dependent variable as the residual of the rank of brain volume at Baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Interferon Beta-1a, Ozanimod 0.5 mg
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Rank ANCOVA
	Comments	Adjusted for region and Baseline EDSS category, with the dependent variable as the residual of the rank of brain volume at Baseline

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	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.
Arm/Group Title	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
Arm/Group Description	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.	Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.	Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.
All-Cause Mortality
	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Serious Adverse Events
	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	28/440 (6.36%)	31/439 (7.06%)	28/434 (6.45%)
Cardiac disorders
Acute Myocardial Infarction † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Atrial Fibrillation † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Sinus Tachycardia † 1	0/440 (0.00%)	2/439 (0.46%)	0/434 (0.00%)
Supraventricular Tachycardia † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Endocrine disorders
Goitre † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Eye disorders
Keratoconus † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Gastrointestinal disorders
Abdominal Pain † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Abdominal Wall Haematoma † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Large Intestine Polyp † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Umbilical Hernia † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
General disorders
Cyst † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Drowning † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Fatigue † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Pyrexia † 1	1/440 (0.23%)	0/439 (0.00%)	1/434 (0.23%)
Hepatobiliary disorders
Cholecystitis Chronic † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Cholelithiasis † 1	1/440 (0.23%)	1/439 (0.23%)	0/434 (0.00%)
Hyperplastic Cholecystopathy † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Infections and infestations
Acute Hepatitis B † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Appendicitis † 1	2/440 (0.45%)	1/439 (0.23%)	2/434 (0.46%)
Chronic Sinusitis † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Diverticulitis † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Gastroenteritis † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Pneumonia † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Pyelonephritis Acute † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Tonsillitis † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Injury, poisoning and procedural complications
Ankle Fracture † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Carbon Monoxide Poisoning † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Clavicle Fracture † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Comminuted Fracture † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Concussion † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Craniocerebral Injury † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Intentional Overdose † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Jaw Fracture † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Joint Injury † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Ligament Sprain † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Lower Limb Fracture † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Lumbar Vertebral Fracture † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Traumatic Fracture † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Investigations
Hepatic Enzyme Increased † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Musculoskeletal and connective tissue disorders
Back Pain † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Intervertebral Disc Disorder † 1	1/440 (0.23%)	0/439 (0.00%)	1/434 (0.23%)
Intervertebral Disc Protrusion † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Osteitis † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Pseudarthrosis † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Chronic Lymphocytic Leukaemia † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Invasive Breast Carcinoma † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Keratoacanthoma † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Malignant Melanoma In Situ † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Medulloblastoma † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Ovarian Fibroma † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Nervous system disorders
Acoustic Neuritis † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Autonomic Nervous System Imbalance † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Central Nervous System Lesion † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Cerebral Haemorrhage † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Cerebral Infarction † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Cervical Radiculopathy † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Epilepsy † 1	1/440 (0.23%)	1/439 (0.23%)	1/434 (0.23%)
Generalised Tonic-Clonic Seizure † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Guillain-Barre Syndrome † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Headache † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Lumbar Radiculopathy † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Multiple Sclerosis Relapse † 1	1/440 (0.23%)	1/439 (0.23%)	0/434 (0.00%)
Neuralgia † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Sciatica † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Seizure † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Speech Disorder † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Syncope † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Pregnancy, puerperium and perinatal conditions
Foetal Growth Restriction † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Placental Polyp † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Vanishing Twin Syndrome † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Psychiatric disorders
Suicide Attempt † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Renal and urinary disorders
Calculus Urinary † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Chronic Kidney Disease † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Renal Colic † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Urethral Stenosis † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Reproductive system and breast disorders
Breast Cyst † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Cervical Polyp † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Dysfunctional Uterine Bleeding † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Endometriosis † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Metrorrhagia † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Ovarian Cyst † 1	0/440 (0.00%)	0/439 (0.00%)	2/434 (0.46%)
Uterine Polyp † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism † 1	0/440 (0.00%)	0/439 (0.00%)	1/434 (0.23%)
Skin and subcutaneous tissue disorders
Skin Ulcer † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Urticaria † 1	0/440 (0.00%)	1/439 (0.23%)	0/434 (0.00%)
Vascular disorders
Hypertension † 1	1/440 (0.23%)	0/439 (0.00%)	0/434 (0.00%)
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Interferon Beta-1a	Ozanimod 0.5 mg	Ozanimod 1 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	275/440 (62.50%)	185/439 (42.14%)	199/434 (45.85%)
General disorders
Influenza Like Illness † 1	215/440 (48.86%)	26/439 (5.92%)	27/434 (6.22%)
Pyrexia † 1	27/440 (6.14%)	12/439 (2.73%)	10/434 (2.30%)
Infections and infestations
Nasopharyngitis † 1	48/440 (10.91%)	59/439 (13.44%)	68/434 (15.67%)
Pharyngitis † 1	15/440 (3.41%)	24/439 (5.47%)	17/434 (3.92%)
Upper Respiratory Tract Infection † 1	37/440 (8.41%)	36/439 (8.20%)	34/434 (7.83%)
Urinary Tract Infection † 1	17/440 (3.86%)	22/439 (5.01%)	19/434 (4.38%)
Investigations
Alanine Aminotransferase Increased † 1	20/440 (4.55%)	29/439 (6.61%)	26/434 (5.99%)
Gamma-Glutamyltransferase Increased † 1	9/440 (2.05%)	16/439 (3.64%)	25/434 (5.76%)
Nervous system disorders
Headache † 1	53/440 (12.05%)	55/439 (12.53%)	44/434 (10.14%)
Vascular disorders
Hypertension † 1	14/440 (3.18%)	20/439 (4.56%)	24/434 (5.53%)
Orthostatic Hypotension † 1	27/440 (6.14%)	27/439 (6.15%)	30/434 (6.91%)
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb
• Phone: Please email:
• EMail: Clinical.Trials@bms.com

Publications of Results:

Cree B, et al. The RADIANCE and SUNBEAM phase 3 studies of ozanimod in relapsing multiple sclerosis: study design and baseline characteristics. Presented at the 69th Annual American Academy of Neurology Meeting, April 22-28, 2017, Boston, MA. Abstract No. P6-344

Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1021-1033. doi: 10.1016/S1474-4422(19)30238-8. Epub 2019 Sep 3.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02047734
• Other Study ID Numbers: RPC01-201-PartB; 2012-002714-40 ( EudraCT Number )
• First Submitted: January 26, 2014
• First Posted: January 28, 2014
• Results First Submitted: January 25, 2021
• Results First Posted: February 11, 2021
• Last Update Posted: February 11, 2021