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

Summary
EudraCT number	2012-002714-40
Trial protocol	IT BE ES HU BG GR GB SK HR
Global end of trial date	13 Apr 2017

Results information
Results version number	v1(current)
This version publication date	24 May 2018
First version publication date	24 May 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

RPC01-201-PartA

ISRCTN number

US NCT number

NCT01628393

WHO universal trial number (UTN)

Sponsor organisation name

Celgene International Sarle II

Sponsor organisation address

Rue des Moulins 4, Couvet, Switzerland,

Public contact

Clinical Trial Disclosure, Celgene Corporation, 01 8882601599, ClinicalTrialDisclosure@Celgene.com

Scientific contact

James Sheffield, Celgene Corporation, 01 619-371-1506, JSheffield@Celgene.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 May 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Apr 2017

Was the trial ended prematurely?

Main objective of the trial

Part A: To demonstrate the superior clinical efficacy of RPC1063 compared to placebo by showing a reduction in the cumulative number of total gadolinium enhancing (GdE) lesions from Week 12 to Week 24 in patients with relapsing multiple sclerosis (RMS). Part B: To assess whether the clinical efficacy of RPC1063 is superior to IFN-1a (Avonex®) in reducing the rate of clinical relapses at the end of Month 24 in patients with RMS.

Protection of trial subjects

Patient Confidentiality, Personal Data Protection. This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Sep 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Georgia: 41

Country: Number of subjects enrolled

Greece: 13

Country: Number of subjects enrolled

Hungary: 24

Country: Number of subjects enrolled

Italy: 27

Country: Number of subjects enrolled

Poland: 507

Country: Number of subjects enrolled

Romania: 34

Country: Number of subjects enrolled

Russian Federation: 140

Country: Number of subjects enrolled

Serbia: 140

Country: Number of subjects enrolled

Spain: 61

Country: Number of subjects enrolled

Ukraine: 261

Country: Number of subjects enrolled

United States: 59

Country: Number of subjects enrolled

Bulgaria: 38

Country: Number of subjects enrolled

Belarus: 116

Country: Number of subjects enrolled

Bosnia and Herzegovina: 8

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Croatia: 45

Country: Number of subjects enrolled

Moldova, Republic of: 9

Country: Number of subjects enrolled

Slovakia: 5

Country: Number of subjects enrolled

South Africa: 18

Country: Number of subjects enrolled

United Kingdom: 16

Worldwide total number of subjects

1578

EEA total number of subjects

784

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1578

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Part A of the study was conducted at 55 study centers in 13 countries including the United States, Europe and Russia and consisted of a 24-week placebo-controlled period and an optional 96-week extension period. Part B was performed at 150 sites in North America, Europe, and South Africa with a overall treatment period of 24 months.

Screening details

Part A subjects were randomly assigned to one of two daily doses of ozanimod 0.5 mg or 1 mg or placebo for 24 weeks. Those who completed 24 weeks could enter an extension phase and continue ozanimod 0.5 mg or 1 mg daily; Part B subjects were randomly assigned to one of two daily doses of ozanimod 0.5 mg or 1 mg or weekly Interferon injection.

Period 1 title

Overall Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

A “dual assessor” approach was used to evaluate efficacy and safety to prevent potential unblinding as result of observed efficacy, adverse events, (AEs) or laboratory changes. A patients treatment group assignment blind was not to be broken until the end of the study unless medical treatment of that patient depened upon knowing whether the patient was receiving active drug.

Are arms mutually exclusive

Yes

Placebo (Part A Core)

Arm description

Participants received placebo capsules (identical in appearance to ozanimod) by mouth (PO) daily during the 24-week placebo-controlled phase. Participants were given the option to enter into a blinded extension phase and were re-randomized to receive ozanimod 0.5 mg or 1mg capsules PO daily for an additional 96 weeks of treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo capsules (identical in appearance to ozanimod) PO daily for 24 weeks

Ozanimod 0.5 mg (Part A Core)

Arm description

Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 0.5 mg capsules PO daily for an additional 96 weeks of treatment.

Arm type

Experimental

Investigational medicinal product name

Ozanimod

Investigational medicinal product code

Other name

RPC1063

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 0.5 mg capsules PO daily for 24 weeks

Ozanimod 1 mg (Part A Core)

Arm description

Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. These participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.

Arm type

Experimental

Investigational medicinal product name

Ozanimod

Investigational medicinal product code

Other name

RPC1063

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 1 mg capsules PO daily for 24 weeks.

Interferon Beta-1a (IFN β-1a) (Part B)

Arm description

Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

Arm type

Active comparator

Investigational medicinal product name

Interferon Beta - 1a

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

IFN β-1a 30 µg intramuscular (IM) injection weekly for two years.

Ozanimod 0.5 mg (Part B)

Arm description

Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Arm type

Experimental

Investigational medicinal product name

Ozanimod

Investigational medicinal product code

Other name

RPC1063

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 0.5 mg capsules PO daily for two years

Ozanimod 1 mg (Part B)

Arm description

Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months

Arm type

Experimental

Investigational medicinal product name

Ozanimod

Investigational medicinal product code

Other name

RPC1063

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 1 mg capsules PO daily for two years.

Number of subjects in period 1	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Started	88	87	83	443	443	434
Received Treatment	88	87	83	441	439	433
Completed	85	85	82	376	374	388
Not completed	3	2	1	67	69	46
Randomized; no study drug received	-	-	-	2	4	1
Adverse event, serious fatal	-	-	-	-	1	-
Consent withdrawn by subject	2	1	1	30	31	19
Physician decision	-	-	-	7	6	5
Adverse event, non-fatal	-	-	-	18	13	13
Miscellaneous	-	-	-	2	4	6
Lost to follow-up	1	-	-	1	4	-
Protocol deviation	-	1	-	3	1	1
Lack of efficacy	-	-	-	4	5	1

Period 2 title

Part A: Blinded Active Extension Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

During the blinded extension phase of Part A, the sponsor and Clinical Research Organization (CRO) were blinded until the Week 24 primary endpoint was reached by all patients and the data through Week 24 was finalized, after which the sponsor and CRO were unblinded to the treatment assignment. Investigators and patients remained blinded throughout the extension phase.

Are arms mutually exclusive

Yes

Placebo-Ozanimod 0.5 mg (Part A Extension)

Arm description

Participants initially randomized to placebo capsules PO daily during the 24-week placebo controlled treatment phase were re-randomized to receive ozanimod 0.5 mg capsules during the optional blinded extension period for an additional 96 weeks of treatment.

Arm type

Experimental

Investigational medicinal product name

RPC1063

Investigational medicinal product code

Other name

Ozanimod

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 0.5 mg capsules PO daily during the 96-week extension phase.

Ozanimod 0.5 mg - 0.5 mg (Part A Extension)

Arm description

Arm type

Experimental

Investigational medicinal product name

RPC1063

Investigational medicinal product code

Other name

Ozanimod

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 0.5 mg capsules PO daily during the 96-week extension phase.

Placebo-Ozanimod 1 mg (Part A Extension)

Arm description

Participants initially randomized to placebo capsules PO daily during the 24-week placebo controlled treatment phase were re-randomized to receive ozanimod 1 mg capsules during the optional blinded extension period for an additional 96 weeks of treatment.

Arm type

Experimental

Investigational medicinal product name

RPC1063

Investigational medicinal product code

Other name

Ozanimod

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 1 mg capsules PO daily during the 96-week extension phase.

Ozanimod 1 mg - 1mg (Part A Extension)

Arm description

Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase. Participants were given the option to enter into a blinded extension phase and continued to receive ozanimod 1 mg capsules PO daily for an additional 96 weeks of treatment.

Arm type

Experimental

Investigational medicinal product name

RPC1063

Investigational medicinal product code

Other name

Ozanimod

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ozanimod 1 mg capsules PO daily during the 96-week extension phase.

Number of subjects in period 2 ^[1]	Placebo-Ozanimod 0.5 mg (Part A Extension)	Ozanimod 0.5 mg - 0.5 mg (Part A Extension)	Placebo-Ozanimod 1 mg (Part A Extension)	Ozanimod 1 mg - 1mg (Part A Extension)
Started	41	85	42	81
Completed	37	75	36	75
Not completed	4	10	6	6
Physician decision	1	3	-	2
Consent withdrawn by subject	-	6	2	2
Adverse event, non-fatal	2	1	2	-
Protocol deviation	1	-	-	-
Lack of efficacy	-	-	2	2

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects were given the option to participate in the blinded active extension phase and some subjects chose not to participate.

Baseline characteristics

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Reporting group title

Placebo (Part A Core)

Reporting group description

Reporting group title

Ozanimod 0.5 mg (Part A Core)

Reporting group description

Reporting group title

Ozanimod 1 mg (Part A Core)

Reporting group description

Reporting group title

Interferon Beta-1a (IFN β-1a) (Part B)

Reporting 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 24 months.

Reporting group title

Ozanimod 0.5 mg (Part B)

Reporting group description

Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Reporting group title

Ozanimod 1 mg (Part B)

Reporting group description

Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months

Reporting group values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)	Total
Number of subjects	88	87	83	443	443	434	1578
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	88	87	83	443	443	434	1578
From 65-84 years	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	39.0 ± 8.67	38.1 ± 9.17	38.4 ± 40.0	35.1 ± 9.1	35.5 ± 8.82	36.0 ± 8.88	-
Sex: Female, Male
Units: Subjects
Female	62	60	59	305	289	292	1067
Male	26	27	24	138	154	142	511
Race/Ethnicity, Customized
Units: Subjects
White\|	87	84	83	432	431	428	1545
Black\|	1	2	0	7	6	5	21
Asian\|	0	1	0	1	0	0	2
Other	0	0	0	3	6	1	10
Region, Category
Units: Subjects
North America	4	4	4	16	16	16	60
Western Europe	6	4	3	40	40	36	129
Eastern Europe	78	79	76	379	378	374	1364
South Africa	0	0	0	6	5	7	18
Missing	0	0	0	2	4	1	7
Age at Multiple Sclerosis Diagnosis
Units: Years
arithmetic mean (standard deviation)	33.9 ± 8.30	34.8 ± 10.01	34.4 ± 9.51	31.6 ± 8.82	32.0 ± 8.5	32.1 ± 8.95	-
Years Since Multiple Sclerosis Diagnosis
Units: Years
arithmetic mean (standard deviation)	4.6 ± 5.12	2.8 ± 4.98	3.6 ± 4.43	3.63 ± 4.613	3.50 ± 4.207	3.97 ± 5.171	-
Expanded Disability Status Scale (EDSS) Score at Baseline
The EDSS is a scale for assessing disability in 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, ambulation and other functions). Based on scores in these 8 functional systems, an overall score ranging from 0 (normal) to 10 (death due to MS) was 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.
Units: units on a scale
arithmetic mean (standard deviation)	2.85 ± 1.273	2.94 ± 1.287	2.86 ± 1.213	2.49 ± 1.158	2.48 ± 1.166	2.55 ± 1.145	-
Years Since MS Symptom Onset
Units: Years
arithmetic mean (standard deviation)	8.1 ± 6.97	6.0 ± 6.41	6.2 ± 5.79	6.36 ± 6.065	6.23 ± 5.547	6.92 ± 6.201	-
Number of Relapses Within the Last 12 months Prior to Screening
Units: Relapses
arithmetic mean (standard deviation)	1.3 ± 0.64	1.5 ± 1.18	1.3 ± 0.73	1.3 ± 0.58	1.4 ± 0.64	1.3 ± 0.60	-
Number of Gadolinium Enhancing (GdE) Lesions at Baseline
Units: Lesions
arithmetic mean (standard deviation)	1.4 ± 3.36	0.9 ± 1.42	1.3 ± 2.75	1.8 ± 3.54	1.8 ± 3.62	1.6 ± 3.78	-

Subject analysis set title

Placebo (Part A Core)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received placebo capsules (identical in appearance to RPC1063) by mouth (PO) daily during the 24-week placebo-controlled phase.

Subject analysis set title

Ozanimod 0.5 mg (Part A Core)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase

Subject analysis set title

Ozanimod 1 mg (Part A Core)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase.

Subject analysis set title

Interferon Beta-1a (IFN β-1a) (Part B)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

Subject analysis set title

Ozanimod 0.5 mg (Part B)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Subject analysis set title

Ozanimod 1 mg (Part B)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 1 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Subject analysis sets values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects	88	87	83	441	439	433
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	88	87	83	441	439	433
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	39.0 ± 8.67	38.1 ± 9.17	38.4 ± 40.0	35.1 ± 9.07	35.4 ± 8.82	36.0 ± 8.89
Sex: Female, Male
Units: Subjects
Female	62	60	59	304	287	291
Male	26	27	27	137	151	142
Race/Ethnicity, Customized
Units: Subjects
White\|	87	84	83	432	431	428
Black\|	1	2	0	7	6	5
Asian\|	0	1	0	1	0	0
Other	0	0	0	1	2	0
Region, Category
Units: Subjects
North America	4	4	4	16	16	16
Western Europe	6	4	3	40	40	36
Eastern Europe	78	79	76	379	378	374
South Africa	0	0	0	6	5	7
Missing	0	0	0	0	0	0
Age at Multiple Sclerosis Diagnosis
Units: Years
arithmetic mean (standard deviation)	33.9 ± 8.30	34.8 ± 10.01	34.4 ± 9.51	31.6 ± 8.82	32.0 ± 8.5	32.1 ± 8.95
Years Since Multiple Sclerosis Diagnosis
Units: Years
arithmetic mean (standard deviation)	4.6 ± 5.12	2.8 ± 4.98	3.6 ± 4.43	3.63 ± 4.613	3.50 ± 4.207	3.97 ± 5.171
Expanded Disability Status Scale (EDSS) Score at Baseline
The EDSS is a scale for assessing disability in 8 functional systems (visual, brain stem, pyramidal, cerebellar, sensory, bowel & bladder, cerebral, ambulation and other functions). Based on scores in these 8 functional systems, an overall score ranging from 0 (normal) to 10 (death due to MS) was 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.
Units: units on a scale
arithmetic mean (standard deviation)	2.85 ± 1.273	2.94 ± 1.287	2.86 ± 1.213	2.49 ± 1.158	2.48 ± 1.166	2.55 ± 1.145
Years Since MS Symptom Onset
Units: Years
arithmetic mean (standard deviation)	8.1 ± 6.97	6.0 ± 6.41	6.2 ± 5.79	6.36 ± 6.065	6.23 ± 5.547	6.92 ± 6.201
Number of Relapses Within the Last 12 months Prior to Screening
Units: Relapses
arithmetic mean (standard deviation)	1.3 ± 0.64	1.5 ± 1.18	1.3 ± 0.73	1.3 ± 0.58	1.4 ± 0.64	1.3 ± 0.60
Number of Gadolinium Enhancing (GdE) Lesions at Baseline
Units: Lesions
arithmetic mean (standard deviation)	1.4 ± 3.36	0.9 ± 1.42	1.3 ± 2.75	1.8 ± 3.54	1.8 ± 3.62	1.6 ± 3.78

End points

Top of page

Reporting group title

Placebo (Part A Core)

Reporting group description

Reporting group title

Ozanimod 0.5 mg (Part A Core)

Reporting group description

Reporting group title

Ozanimod 1 mg (Part A Core)

Reporting group description

Reporting group title

Interferon Beta-1a (IFN β-1a) (Part B)

Reporting 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 24 months.

Reporting group title

Ozanimod 0.5 mg (Part B)

Reporting group description

Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Reporting group title

Ozanimod 1 mg (Part B)

Reporting group description

Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months

Reporting group title

Placebo-Ozanimod 0.5 mg (Part A Extension)

Reporting group description

Reporting group title

Ozanimod 0.5 mg - 0.5 mg (Part A Extension)

Reporting group description

Reporting group title

Placebo-Ozanimod 1 mg (Part A Extension)

Reporting group description

Reporting group title

Ozanimod 1 mg - 1mg (Part A Extension)

Reporting group description

Subject analysis set title

Placebo (Part A Core)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received placebo capsules (identical in appearance to RPC1063) by mouth (PO) daily during the 24-week placebo-controlled phase.

Subject analysis set title

Ozanimod 0.5 mg (Part A Core)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 0.5 mg capsules PO daily during the 24-week placebo-controlled treatment phase

Subject analysis set title

Ozanimod 1 mg (Part A Core)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 1 mg capsules PO daily during the 24-week placebo-controlled treatment phase.

Subject analysis set title

Interferon Beta-1a (IFN β-1a) (Part B)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received IFN β-1a 30 µg intramuscular (IM) injection weekly and matching placebo capsules (identical in physical appearance to ozanimod) orally daily 24 months.

Subject analysis set title

Ozanimod 0.5 mg (Part B)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 0.5 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Subject analysis set title

Ozanimod 1 mg (Part B)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received ozanimod 1 mg capsules PO daily and an intramuscular placebo injection (identical in appearance to interferon) weekly for 24 months.

Primary: Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24

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End point title

Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24 ^[1]

End point description

The number of gadolinium-enhancing lesions per MRI scan was measured as the total number of Gd-enhancing lesions that occurred from Week 12 to Week 24. Missing GdE data values were imputed using the last valid non-missing, post-baseline observation which was carried forward if the participant was only missing 1 or 2 consecutive post-baseline scans. If there were no post-baseline values to be carried forward or if the participant was missing more than 2 consecutive scans then the mean number of lesions from participants in the same treatment group at the same visit was used as the imputed value. The ITT population is defined as all randomized participants who received at least 1 dose of study drug; participants analyzed according to the treatment they were randomized to receive and not according to what they actually received, if different. Includes participants with non-missing MRI results and included to the analysis population.

End point type

Primary

End point timeframe

From Week 12 to Week 24

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24 statistical analysis was performed in the study for Part A only.

End point values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)
Number of subjects analysed	88	87	83
Units: Brain Lesions
arithmetic mean (standard deviation)	11.1 ± 29.86	1.5 ± 3.68	1.5 ± 3.44

Statistical Analysis 1

Comparison groups

Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.0001 ^[3]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[2] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.
[3] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.04944 level of significance.

Statistical Analysis 2

Comparison groups

Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001 ^[5]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[4] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline
[5] - To account for multiple comparisons, each of the 2 treatment comparisons was tested at the alpha = 0.04944 level of significance

Primary: Part B: Adjusted Annualized Relapse Rate (ARR) at the End of Month 24

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End point title

Part B: Adjusted Annualized Relapse Rate (ARR) at the End of Month 24

End point description

The relapse rate was based on confirmed relapses. Relapses that met the clinical criteria for a relapse and were accompanied by objective neurological worsening (based upon EDSS evaluated by a blinded EDSS evaluator) were confirmed by a treating investigator. A relapse was defined as new or recurrent neurological symptoms preceded by a relatively stable or improving neurological state of at least 30 days (less than 30 days following the onset of a protocol-defined relapse was considered part of the same relapse). Symptoms must have persisted for >24 hours and should not be attributable to confounding clinical factors. The relapse rate (per person) was calculated as the number of relapses for an individual patient divided by the number of days that patient participated in the study, and multiplied by 365.25. The adjusted ARR was performed using a Poisson regression model. The ITT population included all randomized participants who received at least 1 dose of study drug.

End point type

Primary

End point timeframe

At the end of month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	441	439	433
Units: Relapses/Year
least squares mean (confidence interval 95%)	0.276 (0.234 to 0.324)	0.218 (0.183 to 0.259)	0.172 (0.142 to 0.208)

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.0001 ^[7]

Method

Poisson regression model

Parameter type

Rate Ratio

Point estimate

0.623

Confidence interval

level

95%

sides

2-sided

lower limit

0.506

upper limit

0.768

Notes
[6] - To account for multiple comparisons, each of the 2 treatment (0.5 mg and 1 mg ozanimod vs IFN) comparisons was tested at the alpha = 0.025 level.
[7] - Adjusted for region, age at baseline and the baseline number of gadolinium-enhancing (GdE) lesions, and included the natural log transformation of time on study as an offset term.

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.0167 ^[9]

Method

Poisson Regression Model

Parameter type

Rate Ratio

Point estimate

0.791

Confidence interval

level

95%

sides

2-sided

lower limit

0.652

upper limit

0.958

Notes
[8] - To account for multiple comparisons, each of the 2 treatment (0.5 mg and 1 mg ozanimod vs IFN) comparisons was tested at the alpha = 0.025 level.
[9] - Adjusted for region, age at baseline and the baseline number of gadolinium-enhancing (GdE) lesions, and included the natural log transformation of time on study as an offset term.

Secondary: Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24

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End point title

Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24 ^[10]

End point description

The number of Gd-enhancing lesions per MRI scan was measured as the total number of Gd-enhancing lesions that occurred at Week 24. The ITT population is defined as all randomized participants who received at least 1 dose of study drug. Missing GdE data values were imputed using the mean number of lesions from participants in the same treatment group at the same visit.

End point type

Secondary

End point timeframe

At Week 24

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24 statistical analysis was performed in the study for Part A only

End point values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)
Number of subjects analysed	88	87	83
Units: Lesions
arithmetic mean (standard deviation)	3.2 ± 9.80	0.3 ± 0.86	0.2 ± 0.59

Statistical Analysis 1

Comparison groups

Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[11] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.

Statistical Analysis 2

Comparison groups

Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[12]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[12] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.

Secondary: Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24

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End point title

Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24 ^[13]

End point description

The number of new or enlarging hyperintense T2-weighted brain MRI lesions was based on the cumulative number of new or enlarging T2 lesions since baseline from Week 12 to Week 24. The ITT population is defined as all randomized participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Week 12 to Week 24

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24 statistical analysis was performed in the study for Part A only.

End point values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)
Number of subjects analysed	88	87	83
Units: Brain Lesions
arithmetic mean (standard deviation)	9.0 ± 20.87	1.4 ± 3.21	0.8 ± 1.86

Statistical Analysis 1

Comparison groups

Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[14]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[14] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.

Statistical Analysis 2

Comparison groups

Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[15]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[15] - Comparison between the active and placebo arms is based on a stratified Wilcoxon-Mann-Whitney test, stratified by presence of GdE lesions at baseline.

Secondary: Part A: Adjusted Annualized Relapse Rate (ARR) at Week 24

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End point title

Part A: Adjusted Annualized Relapse Rate (ARR) at Week 24 ^[16]

End point description

The relapse rate was based on confirmed relapses. Relapses that met the clinical criteria for a relapse and were accompanied by objective neurological worsening (based upon EDSS evaluated by an independent, blinded EDSS evaluator) were confirmed by the treating investigator. A relapse was defined as new or recurrent neurological symptoms preceded by a relatively stable or improving neurological state of at least 30 days (less than 30 days following the onset of a protocol-defined relapse was considered part of the same relapse). Symptoms must have persisted for >24 hours and should not be attributable to confounding clinical factors. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

At the End of Week 24

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part A: The Adjusted Annualized Relapse Rate (ARR) at Week 24 statistical analysis was performed in the study for Part A only.

End point values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)
Number of subjects analysed	88	87	83
Units: Relapses/Year
least squares mean (confidence interval 95%)	0.50 (0.22 to 1.15)	0.35 (0.15 to 0.82)	0.24 (0.09 to 0.61)

Statistical Analysis 1

Comparison groups

Placebo (Part A Core) v Ozanimod 1 mg (Part A Core)

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0531 ^[17]

Method

Poisson regression model

Parameter type

Rate Ratio

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

1.01

Notes
[17] - Adjusted for region, the number of relapses within 24 months prior to the study, and the presence of GdE lesions as baseline.

Statistical Analysis 2

Comparison groups

Placebo (Part A Core) v Ozanimod 0.5 mg (Part A Core)

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2714 ^[18]

Method

Poisson regression model

Parameter type

Rate Ratio

Point estimate

0.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

1.34

Notes
[18] - Adjusted for region, the number of relapses within 24 months prior to the study, and the presence of GdE lesions as baseline.

Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Treatment Phase

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End point title

Part A: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Treatment Phase ^[19]

End point description

A TEAE was defined as any event with an onset date on or after first dose date, or any ongoing event on the first dose date that worsened in severity after first dose date to the time that the participant concluded or was terminated in the study. AEs included, but were not limited to a worsening or change in nature, severity, or frequency of conditions present at the start of the study, patient deterioration due to primary illness, intercurrent illness and drug interaction. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose results in death, was life threatening, required inpatient hospitalization or prolongation of existing inpatient hospitalization, was a congenital abnormality or birth defect, or resulted in significant disability/incapacity. Adverse events were classified by severity (mild, moderate and severe).

End point type

Secondary

End point timeframe

Day 1 of first dose of study drug to the time that the participant concluded or was terminated in the study. The maximum duration of exposure in the ozanimod 0.5 mg arm was 189 days and 190 days in the ozanimod 1 mg arm.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses were performed for the TEAE during the placebo-controlled period in 201 Part A.

End point values	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1 mg (Part A Core)
Number of subjects analysed	88	87	83
Units: Participants
Any TEAE	52	57	47
Any Moderate or Severe TEAE	23	23	13
Any Severe TEAE	1	2	1
Any Possible, Probable or Related TEAE	11	19	15
Any Related TEAE	1	1	0
Any Serious TEAE\|	0	3	0
Any Related Serious TEAE	0	0	0
Any TEAE Leading to Discontinuation of Drug	0	0	0
Any Death Related to RPC1063	0	0	0

No statistical analyses for this end point

Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events During the Placebo Controlled and Blinded Extension Phase

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End point title

Part A: Number of Participants With Treatment Emergent Adverse Events During the Placebo Controlled and Blinded Extension Phase

End point description

A TEAE was defined as any adverse event with a start date on or after the date of first dose of study drug up through the first dose of study drug in the open-label extension for those who continued into the open-label extension. AEs included, but were not limited to a worsening or change in nature, severity, or frequency of conditions present at the tart of the study, patient deterioration due to primary illness, intercurrent illness and drug interaction. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose results in death, was life threatening, required inpatient hospitalization or prolongation of existing inpatient hospitalization, was a congenital abnormality or birth defect, or resulted in significant disability/incapacity. Adverse events were classified by severity (mild, moderate and severe).

End point type

Secondary

End point timeframe

Day 1 of first dose of study drug to the time that the participant concluded or was terminated in the study; maximum duration of exposure for PBO-Ozanimod 0.5 mg was 30.82 months, 37.04 months for Ozanimod 0.5 mg-0.5mg, 33.21 months for PBO-Ozanimod 1mg.

End point values	Placebo-Ozanimod 0.5 mg (Part A Extension)	Ozanimod 0.5 mg - 0.5 mg (Part A Extension)	Placebo-Ozanimod 1 mg (Part A Extension)	Ozanimod 1 mg - 1mg (Part A Extension)
Number of subjects analysed	41	85	42	81
Units: Participants
Any TEAE	26	73	32	61
Any Moderate or Severe TEAE	17	42	18	35
Any Severe TEAE	2	4	1	2
Any Possible, Probable or Related TEAE	11	30	12	26
Any Related TEAE	2	3	1	3
Any Serious TEAE\|	2	10	3	6
Any Related Serious TEAE	0	0	0	0
Any TEAE Leading to Discontinuation of Ozanimod	2	1	1	0
Any Death Related to Ozanimod	0	0	0	0

No statistical analyses for this end point

Secondary: Part B: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging Lesions Per Scan Over 24 Months

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End point title

Part B: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging Lesions Per Scan Over 24 Months

End point description

The adjusted mean number of new or enlarging hyperintense T2-weighted brain MRI lesions was based on the cumulative number of new or enlarging T2 lesions since baseline over 24 months. Adjusted mean (95% CI) over 24 months was calculated as the model-based adjusted mean (95% CI) per scan multiplied by the mean number of available MRI scans over 24 months. The ITT population included all randomized participants who received at least 1 dose of study drug. Includes participants with non-missing MRI results.

End point type

Secondary

End point timeframe

24 month treatment period; MRI scans performed at baseline, at month 12 and 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	336	329	327
Units: Lesions/Scan
least squares mean (confidence interval 95%)	3.183 (2.640 to 3.838)	2.092 (1.741 to 2.514)	1.835 (1.523 to 2.211)

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

< 0.0001 ^[21]

Method

Negative Binomial Regression Model

Parameter type

Rate Ratio

Point estimate

0.576

Confidence interval

level

95%

sides

2-sided

lower limit

0.465

upper limit

0.714

Notes
[20] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level
[21] - Adjusted for region, age at baseline, and baseline GdE lesions; included the natural log transformation of available MRI scans as an offset term.

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

< 0.0001 ^[23]

Method

Negative binomial regression model

Parameter type

Rate Ratio

Point estimate

0.657

Confidence interval

level

95%

sides

2-sided

lower limit

0.531

upper limit

0.813

Notes
[22] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level
[23] - Adjusted for region, age at baseline, and baseline GdE lesions; included the natural log transformation of available MRI scans as an offset term.

Secondary: Part B: Adjusted Mean Number of Gadolinium Enhancing Brain Lesions per Scan at Month 24

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End point title

Part B: Adjusted Mean Number of Gadolinium Enhancing Brain Lesions per Scan at Month 24

End point description

The number of GdE T1-lesions per MRI scan was measured as the total number of Gd- enhancing T1-lesions on the 24-month MRI scan. The ITT population consisted of all randomized participants who received at least 1 dose of study medication. Includes participants with non-missing MRI results.

End point type

Secondary

End point timeframe

Month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	336	329	237
Units: Lesions
least squares mean (confidence interval 95%)	0.373 (0.256 to 0.543)	0.197 (0.131 to 0.296)	0.176 (0.116 to 0.266)

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

< 0.0006 ^[25]

Method

Negative Binomial Regression Model

Parameter type

Rate Ratio

Point estimate

0.471

Confidence interval

level

95%

sides

2-sided

lower limit

0.306

upper limit

0.725

Notes
[24] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
[25] - Adjusted for region, age at baseline, and baseline GdE lesions. Included the natural log transformation of the number available MRI scans at 24 month was used as an offset term.

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

665

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

< 0.003 ^[27]

Method

Negative binomial regression model

Parameter type

Rate Ratio

Point estimate

0.528

Confidence interval

level

95%

sides

2-sided

lower limit

0.346

upper limit

0.805

Notes
[26] - To control for type 1 error, the 3 key secondary endpoints were tested in order in a sequential, closed hierarchical testing procedure. Each comparison was tested at the alpha = 0.05 level.
[27] - Adjusted for region, age at baseline, and baseline GdE lesions. Included the natural log transformation of the number available MRI scans at 24 month was used as an offset term.

Secondary: Part B: Time to Onset of Disability Progression Confirmed After 3 Months

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End point title

Part B: Time to Onset of Disability Progression Confirmed After 3 Months

End point description

The Expanded Disability Status Scale (EDSS) is an ordinal scale in half-point increments that quantifies disability progression in MS patients over time. It assesses seven functional (neurologic) systems and ambulation scores that are combined to determine the EDSS score ranging from 1 (normal) to 10 (death due to MS) with higher scores indicating greater disability. The 7 Functional System (FS) scales are: pyramidal, cerebellar, brainstem, sensory, bowel or bladder, visual, and cerebral. Disability progression was defined by a sustained worsening (increase) in EDSS of 1.0 points or more from baseline, confirmed after 3 months. Participants were censored if follow-up ended before a sustained progression occurred, whether due to the patient completing study, withdrawing from the study, or due to the cutoff of data collection for the analysis. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

For the duration of the entire treatment period; 24 months

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	441 ^[28]	439 ^[29]	433 ^[30]
Units: days
median (confidence interval 95%)	99999 (-99999 to 99999)	99999 (-99999 to 99999)	99999 (-99999 to 99999)

Notes
[28] - 99999 = data was not estimable as there were insufficient disability events at 3 months
[29] - 99999 = data was not estimable as there were insufficient disability events at 3 months
[30] - 99999 = data was not estimable as there were insufficient disability events at 3 months

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.8224 ^[32]

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

1.045

Confidence interval

level

95%

sides

2-sided

lower limit

0.711

upper limit

1.537

Notes
[31] - Cox proportional hazard model with factors for treatment group
[32] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.2849 ^[34]

Method

Cox proportional hazard model

Parameter type

Hazard ratio (HR)

Point estimate

0.798

Confidence interval

level

95%

sides

2-sided

lower limit

0.528

upper limit

1.206

Notes
[33] - Cox proportional hazard model with factors for treatment group.
[34] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.

Secondary: Part B: Time to Onset of Disability Progression Confirmed After 6 months

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End point title

Part B: Time to Onset of Disability Progression Confirmed After 6 months

End point description

The Expanded Disability Status Scale (EDSS) is an ordinal scale in half-point increments that quantifies disability progression in MS patients over time. It assesses seven functional (neurologic) systems and ambulation scores that are combined to determine the EDSS score ranging from 1 (normal) to 10 (death due to MS) with higher scores indicating greater disability. The 7 Functional System (FS) scales are: pyramidal, cerebellar, brainstem, sensory, bowel or bladder, visual, and cerebral. Disability progression was defined by a sustained worsening (increase) in EDSS of 1.0 points or more from baseline, confirmed after 6 months. Participants were censored if follow-up ended before a sustained progression occurred, whether due to the patient completing study, withdrawing from the study, or due to the cutoff of data collection for the analysis. The ITT population consisted of all randomized participants who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

For the duration of the entire treatment period; 24 months

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	441 ^[35]	439 ^[36]	433 ^[37]
Units: days
median (confidence interval 95%)	99999 (-99999 to 99999)	99999 (-99999 to 99999)	99999 (-99999 to 99999)

Notes
[35] - 99999 = Not Estimable as there were insufficient disability events at 6 months
[36] - 99999 = Not Estimable as there were insufficient disability events at 6 months
[37] - 99999 = Not Estimable as there were insufficient disability events at 6 months

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.1353 ^[39]

Method

Cox proportional hazard model

Parameter type

Hazard ratio (HR)

Point estimate

1.435

Confidence interval

level

95%

sides

2-sided

lower limit

0.893

upper limit

2.305

Notes
[38] - Cox proportional hazard model with factors for treatment group.
[39] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.7154 ^[41]

Method

Cox proportional hazard model

Parameter type

Hazard ratio (HR)

Point estimate

1.098

Confidence interval

level

95%

sides

2-sided

lower limit

0.664

upper limit

1.815

Notes
[40] - Cox proportional hazard model with factors for treatment group.
[41] - Adjusted for region (Eastern Europe vs Rest of World) age at baseline, and baseline EDSS score.

Secondary: Part B: Percentage of Participants Who Were Gadolinium Enhancing Lesion-Free at Month 24

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End point title

Part B: Percentage of Participants Who Were Gadolinium Enhancing Lesion-Free at Month 24

End point description

Participants were considered lesion free at Month 24 if they did not show evidence of GdE lesions at the month 24 MRI scan. The ITT population included all randomized participants who received at least 1 dose of study drug; analysis included non-responder imputation that being as not lesion-free.

End point type

Secondary

End point timeframe

Month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	441	439	433
Units: Percentage of Participants
number (confidence interval 95%)	56.2 (51.6 to 60.9)	63.3 (58.8 to 67.8)	65.6 (61.1 to 70.1)

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0047 ^[42]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Percentage

Point estimate

9.4

Confidence interval

level

95%

sides

2-sided

lower limit

2.9

upper limit

15.8

Notes
[42] - Stratified by region (Eastern Europe vs Rest of the World) and EDSS category per Interactive Voice Response System (IVRS).

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.032 ^[43]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Percentage

Point estimate

7.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

13.6

Notes
[43] - Stratified by region (Eastern Europe vs Rest of the World) and EDSS category per Interactive Voice Response System (IVRS).

Secondary: Part B: Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24

Top of page

End point title

Part B: Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24

End point description

Participants were considered T2 lesion free at Month 24 if they did not show evidence of a relapse in T2 lesions at month 24. The ITT population consisted of all randomized participants who received at least 1 dose of study medication; participants who were missing the Month 24 MRI data were considered non-responders, ie, as not being lesion-free.

End point type

Secondary

End point timeframe

Month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	441	439	433
Units: Percentage of Participants
number (confidence interval 95%)	18.4 (14.8 to 22.0)	23.5 (19.5 to 27.4)	23.8 (19.8 to 27.8)

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0466 ^[44]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Percentage

Point estimate

5.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

10.8

Notes
[44] - Based on the Cochran-Mantel-Haenszel test stratified by region (Eastern Europe vs. rest of the world) and EDSS category per IVRS.

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0581 ^[45]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Percentage

Point estimate

5.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

10.5

Notes
[45] - Based on the Cochran-Mantel-Haenszel test stratified by region (Eastern Europe vs. rest of the world) and EDSS category per IVRS.

Secondary: Part B: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 24

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End point title

Part B: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 24

End point description

Atrophy or loss in brain volume was measured by MRI scan from baseline to month 24. Observed values for the ITT Population; included all randomized participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Baseline and Month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	439	437	432
Units: Percent Change in Brain Volume Loss
median (full range (min-max))
Baseline	1455.662 (1208.191 to 1667.703)	1452.878 (1171.858 to 1663.032)	1445.978 (1190.494 to 1660.718)
Percent Change from Baseline to Month 24	-0.940 (-5.33 to 1.44)	-0.710 (-5.21 to 1.36)	-0.690 (-5.65 to 0.85)

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

871

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[46]

Method

Rank Ancova

Confidence interval

Notes
[46] - Based on the analysis of covariance model, adjusted for region, and EDSS category per IVRS, with the dependent variable as the residual of the rank of brain volume at Baseline (Month 12 brain volume for Percent Change from Month 12 to Month 24).

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

876

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[47]

Method

Rank Ancova

Confidence interval

Notes
[47] - Based on the analysis of covariance model, adjusted for region, and EDSS category per IVRS, with the dependent variable as the residual of the rank of brain volume at Baseline (Month 12 brain volume for Percent Change from Month 12 to Month 24).

Secondary: Part B: Change in Multiple Sclerosis Functional Composite (MSFC) Score from Baseline to Month 24 (including the Low-Contrast Letter Acuity test [LCLA] Measurement of Visual Function as a Component)

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End point title

Part B: Change in Multiple Sclerosis Functional Composite (MSFC) Score from Baseline to Month 24 (including the Low-Contrast Letter Acuity test [LCLA] Measurement of Visual Function as a Component)

End point description

The MSFC-LCLA is a battery of tests including 4 scales: • The Timed 25-Foot Walk is an ambulation measure of walking 25 feet with time taken recorded in seconds • The 9-Hole Peg Test is a quantitative measure of upper extremity (arm and hand) function • The Symbol Digit Modalities Test is a measure of executive cognitive function that assesses processing speed, flexibility, and calculation ability • LCLA used a standardized set of charts to assess low contrast visual acuity Z-scores were calculated for the MSFC for each component and averaged to create an overall composite Z -score. 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 score of +1 indicates that, on average, an individual scored 1 standard deviation better than the reference population and a score of -1 indicates that an individual scored 1 SD worse than the reference population.

End point type

Secondary

End point timeframe

Baseline to Month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	437	435	428
Units: units on a scale
arithmetic mean (standard deviation)	-0.052 ± 0.601	0.036 ± 0.440	-0.010 ± 0.622

Statistical Analysis 1

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

865

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.248 ^[48]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.116

Notes
[48] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS and baseline MSFC Z-score

Statistical Analysis 2

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0123 ^[49]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

0.093

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.165

Notes
[49] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and baseline MSFC Z-score

Secondary: Part B: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 24

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End point title

Part B: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 24

End point 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 generates 12 subscales along with two summary scores, and two additional single-item measures. The subscales are: physical function, role limitations-physical, role limitations-emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, and sexual function. The summary scores are the physical health composite summary and the mental health composite summary. The change for the summary scores for the physical health and mental health composite, plus statistical analysis are reported. Each domain has a range from 0 to 100 where higher means better. The ITT population consisted of all randomized participants who received at least 1 dose of study drug. Missing data were imputed using a mixed effects regression model.

End point type

Secondary

End point timeframe

Baseline to Month 24

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	441	439	433
Units: units on a scale
arithmetic mean (standard deviation)
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 description

Analysis of Physical Health Composite Summary Month 24

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0988 ^[50]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.345

Confidence interval

level

95%

sides

2-sided

lower limit

-0.252

upper limit

2.943

Notes
[50] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.

Statistical Analysis 2

Statistical analysis description

Analysis of Physical Health Composite Summary Month 24

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0228 ^[51]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.849

Confidence interval

level

95%

sides

2-sided

lower limit

0.258

upper limit

3.44

Notes
[51] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.

Statistical Analysis 3

Statistical analysis description

Analysis of Mental Health Composite Summary Month 24

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 1 mg (Part B)

Number of subjects included in analysis

874

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6997 ^[52]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-1.553

upper limit

2.313

Notes
[52] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.

Statistical Analysis 4

Statistical analysis description

Analysis of Mental Health Composite Summary Month 24

Comparison groups

Interferon Beta-1a (IFN β-1a) (Part B) v Ozanimod 0.5 mg (Part B)

Number of subjects included in analysis

880

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5501 ^[53]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.587

Confidence interval

level

95%

sides

2-sided

lower limit

-1.339

upper limit

2.513

Notes
[53] - Based on the analysis of covariance model, adjusted for region, EDSS category per IVRS, and the baseline summary score of interest.

Secondary: Part B: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During Part B

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End point title

Part B: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During Part B

End point description

An AE is any untoward medical occurrence that does not necessarily have a causal relationship with the investigational product (IP). An AE can be any unfavorable or unintended sign, including an abnormal laboratory finding, symptom or disease temporally associated with the use of an IP whether or not considered related to the IP. A TEAE = an AE with a start date on or after the date of first dose of IP to the time that the participant concluded or was terminated in the study. A serious AE (SAE) is any untoward medical occurrence or effect that results in death, is life- threatening, requires hospitalization or prolongation of existing inpatient hospitalization. The investigator assessed the severity of AEs as mild, moderate, or severe. Safety Population consisted of all participants who received at least 1 dose of randomized study medication.

End point type

Secondary

End point timeframe

Day 1 of first dose of study drug to the time that the participant concluded or was terminated in the study; the overall maximum study duration of exposure to IFN = 24.46 months, 25.05 months for ozanimod 0.5 mg and 25.05 months for ozanimod 1 mg.

End point values	Interferon Beta-1a (IFN β-1a) (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1 mg (Part B)
Number of subjects analysed	440	439	434
Units: Participants
number (not applicable)
Any TEAE	365	326	324
Any Moderate or Severe TEAE	235	169	170
Any Severe TEAE	19	19	15
Any Suspected TEAE	113	104	115
Any Related TEAE	30	12	19
Any Serious TEAE	28	31	28
Any Suspected Serious TEAE	3	4	4
Any Related Serious TEAE	0	1	1
Any TEAE Leading to Stopping of Study Drug	18	14	13
Any TEAE Leading to Study Withdrawal	20	13	13
Any Death	0	1	1
Any Death on Study	0	1	0

No statistical analyses for this end point

Post-hoc: Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period

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End point title

Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period

End point description

Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period.

End point type

Post-hoc

End point timeframe

From Week 24 to Week 120

End point values	Placebo-Ozanimod 0.5 mg (Part A Extension)	Ozanimod 0.5 mg - 0.5 mg (Part A Extension)	Placebo-Ozanimod 1 mg (Part A Extension)	Ozanimod 1 mg - 1mg (Part A Extension)
Number of subjects analysed	41 ^[54]	85 ^[55]	42 ^[56]	81 ^[57]
Units: Lesions
geometric mean (standard error)
Week 24	4.5 ± 13.02	0.4 ± 1.28	1.9 ± 5.93	0.2 ± 0.60
Week 72	0.4 ± 1.95	0.4 ± 1.60	0.1 ± 0.28	0.2 ± 0.56
Week 120	0.1 ± 0.46	0.4 ± 1.49	0.1 ± 0.37	0.2 ± 0.51

Notes
[54] - Week 72 = 38 Week 120 N = 37
[55] - Week 72 N = 76 Week 120 N = 72
[56] - Week 72 N = 37 Week 120 N = 36
[57] - Week 72 N = 79 Week 120 N = 74

No statistical analyses for this end point

Post-hoc: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions In the Blinded Extension Period

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End point title

The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions In the Blinded Extension Period

End point description

The number of new or enlarging hyperintense T2-weighted brain MRI lesions was based on the cumulative number of new or enlarging T2 lesions on MRI

End point type

Post-hoc

End point timeframe

From Week 0 to Week 24 of Part A of the 201A Core Period and Year 1 and 2 of the Extension Period

End point values	Placebo-Ozanimod 0.5 mg (Part A Extension)	Ozanimod 0.5 mg - 0.5 mg (Part A Extension)	Placebo-Ozanimod 1 mg (Part A Extension)	Ozanimod 1 mg - 1mg (Part A Extension)
Number of subjects analysed	41 ^[58]	85 ^[59]	42 ^[60]	81 ^[61]
Units: lesions
geometric mean (standard error)
ROC01-201A Core (Weeks 0 to 24)	10.8 ± 3.58	1.4 ± 0.35	7.3 ± 3.07	0.9 ± 0.21
Year 1 In Extension Study	4.3 ± 1.99	2.8 ± 0.72	1.5 ± 0.39	1.9 ± 0.84
Year 2 In Extension Study	3.2 ± 1.31	2.3 ± 0.61	1.9 ± 0.48	0.7 ± 0.16

Notes
[58] - Year 1 N = 38 Year 2 N = 37
[59] - Year 1 N = 76 Year 2 N = 71
[60] - Year 1 N = 37 Year 2 N = 36
[61] - Year 1 N = 79 Year 2 N = 74

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From Day 1 of study drug to the date that the participant concluded or was terminated in the study. AEs are reported for Part A placebo-controlled and extension periods followed by Part B for 2 years.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Placebo (Part A Core)

Reporting group description

Participants received placebo capsules (identical in appearance to ozanimod) PO daily during the placebo-controlled phase (Weeks 0-24).

Reporting group title

Ozanimod 0.5 mg (Part A Core)

Reporting group description

Participants received ozanimod 0.5 mg capsules PO daily during the placebo-controlled phase (Weeks 0 to 24).

Reporting group title

Ozanimod 1.0 mg (Part A Core)

Reporting group description

Participants received ozanimod 1 mg capsules PO daily during the placebo-controlled phase (Weeks 0 to 24).

Reporting group title

Ozanimod 0.5 mg (Part A Extension)

Reporting group description

Participants received ozanimod 0.5 mg capsules PO daily during the blinded extension phase (Weeks 25 to 96).

Reporting group title

Ozanimod 1.0 mg (Part A Extension)

Reporting group description

Participants received ozanimod 1 mg capsules PO daily during the blinded extension phase (Weeks 25 to 96).

Reporting group title

Interferon ß-1a 30 µg (Part B)

Reporting 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.

Reporting group title

Ozanimod 0.5 mg (Part B)

Reporting group description

Participants received ozanimod 0.5 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.

Reporting group title

Ozanimod 1.0 mg (Part B)

Reporting group description

Participants received ozanimod 1 mg oral capsules daily and an intramuscular placebo injection (identical in appearance to Interferon) weekly for 24 months.

Serious adverse events	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1.0 mg (Part A Core)	Ozanimod 0.5 mg (Part A Extension)	Ozanimod 1.0 mg (Part A Extension)	Interferon ß-1a 30 µg (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1.0 mg (Part B)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 88 (0.00%)	3 / 87 (3.45%)	0 / 83 (0.00%)	10 / 126 (7.94%)	9 / 123 (7.32%)	28 / 440 (6.36%)	31 / 439 (7.06%)	28 / 434 (6.45%)
number of deaths (all causes)	0	0	0	0	0	0	1	1
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Lymphocytic Leukaemia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive Breast Carcinoma
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Keratoacanthoma
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant Melanoma In Situ
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Medulloblastoma
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Fibroma
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Foetal Growth Restriction
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Placental Polyp
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vanishing Twin Syndrome
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Cyst
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drowning
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Fatigue
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Breast Cyst
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Polyp
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysfunctional Uterine Bleeding
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Menometrorrhagia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cyst
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Cervical Squamous Metaplasia
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Haemorrhage
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Polyp
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somatoform Disorder
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide Attempt
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Hepatic Enzyme Increased
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carbon Monoxide Poisoning
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Comminuted Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral Injury
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intentional Overdose
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaw Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint Injury
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ligament Sprain
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower Limb Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar Vertebral Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic Fracture
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute Myocardial Infarction
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus Tachycardia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	2 / 439 (0.46%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular Tachycardia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Acoustic Neuritis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autonomic Nervous System Imbalance
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cauda Equina Syndrome
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central Nervous System Lesion
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral Haemorrhage
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral Infarction
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Radiculopathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	1 / 439 (0.23%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Generalised Tonic-Clonic Seizure
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre Syndrome
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial Aneurysm
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar Radiculopathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple Sclerosis Relapse
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Optic Neuritis
subjects affected / exposed	0 / 88 (0.00%)	1 / 87 (1.15%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Speech Disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Keratoconus
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Wall Haematoma
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Irritable Bowel Syndrome
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large Intestine Polyp
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical Hernia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis Chronic
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperplastic Cholecystopathy
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin Ulcer
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stasis Dermatitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus Urinary
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Kidney Disease
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Renal Colic
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urethral Stenosis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Disorder
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudarthrosis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid Arthritis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	1 / 123 (0.81%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Acute Hepatitis B
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	2 / 440 (0.45%)	1 / 439 (0.23%)	2 / 434 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Sinusitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	1 / 439 (0.23%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis Infectious
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	1 / 126 (0.79%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis Acute
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	1 / 440 (0.23%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	0 / 440 (0.00%)	0 / 439 (0.00%)	1 / 434 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo (Part A Core)	Ozanimod 0.5 mg (Part A Core)	Ozanimod 1.0 mg (Part A Core)	Ozanimod 0.5 mg (Part A Extension)	Ozanimod 1.0 mg (Part A Extension)	Interferon ß-1a 30 µg (Part B)	Ozanimod 0.5 mg (Part B)	Ozanimod 1.0 mg (Part B)
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 88 (27.27%)	24 / 87 (27.59%)	10 / 83 (12.05%)	52 / 126 (41.27%)	43 / 123 (34.96%)	275 / 440 (62.50%)	185 / 439 (42.14%)	199 / 434 (45.85%)
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 88 (0.00%)	3 / 87 (3.45%)	4 / 83 (4.82%)	10 / 126 (7.94%)	12 / 123 (9.76%)	20 / 440 (4.55%)	29 / 439 (6.61%)	26 / 434 (5.99%)
occurrences all number	0	4	4	17	17	28	37	35
Gamma-Glutamyltransferase Increased
subjects affected / exposed	0 / 88 (0.00%)	2 / 87 (2.30%)	5 / 83 (6.02%)	11 / 126 (8.73%)	8 / 123 (6.50%)	9 / 440 (2.05%)	16 / 439 (3.64%)	25 / 434 (5.76%)
occurrences all number	0	2	5	16	10	10	20	28
Vascular disorders
Hypertension
subjects affected / exposed	1 / 88 (1.14%)	1 / 87 (1.15%)	2 / 83 (2.41%)	8 / 126 (6.35%)	2 / 123 (1.63%)	14 / 440 (3.18%)	20 / 439 (4.56%)	24 / 434 (5.53%)
occurrences all number	1	1	2	8	2	14	21	24
Orthostatic Hypotension
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	27 / 440 (6.14%)	27 / 439 (6.15%)	30 / 434 (6.91%)
occurrences all number	0	0	0	0	0	30	29	33
Nervous system disorders
Headache
subjects affected / exposed	8 / 88 (9.09%)	5 / 87 (5.75%)	3 / 83 (3.61%)	7 / 126 (5.56%)	9 / 123 (7.32%)	53 / 440 (12.05%)	55 / 439 (12.53%)	44 / 434 (10.14%)
occurrences all number	9	11	4	14	38	138	134	187
General disorders and administration site conditions
Influenza Like Illness
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	215 / 440 (48.86%)	26 / 439 (5.92%)	27 / 434 (6.22%)
occurrences all number	0	0	0	0	0	485	38	41
Pyrexia
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	27 / 440 (6.14%)	12 / 439 (2.73%)	10 / 434 (2.30%)
occurrences all number	0	0	0	0	0	279	12	11
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	9 / 88 (10.23%)	5 / 87 (5.75%)	2 / 83 (2.41%)	5 / 126 (3.97%)	7 / 123 (5.69%)	0 / 440 (0.00%)	0 / 439 (0.00%)	0 / 434 (0.00%)
occurrences all number	9	5	2	5	12	0	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	12 / 88 (13.64%)	11 / 87 (12.64%)	5 / 83 (6.02%)	17 / 126 (13.49%)	17 / 123 (13.82%)	48 / 440 (10.91%)	59 / 439 (13.44%)	68 / 434 (15.67%)
occurrences all number	15	11	6	37	28	77	101	100
Pharyngitis
subjects affected / exposed	0 / 88 (0.00%)	0 / 87 (0.00%)	0 / 83 (0.00%)	0 / 126 (0.00%)	0 / 123 (0.00%)	15 / 440 (3.41%)	24 / 439 (5.47%)	17 / 434 (3.92%)
occurrences all number	0	0	0	0	0	16	30	23
Upper Respiratory Tract Infection
subjects affected / exposed	3 / 88 (3.41%)	4 / 87 (4.60%)	3 / 83 (3.61%)	20 / 126 (15.87%)	11 / 123 (8.94%)	37 / 440 (8.41%)	36 / 439 (8.20%)	34 / 434 (7.83%)
occurrences all number	3	5	4	25	15	47	47	42
Urinary Tract Infection
subjects affected / exposed	2 / 88 (2.27%)	6 / 87 (6.90%)	2 / 83 (2.41%)	7 / 126 (5.56%)	4 / 123 (3.25%)	17 / 440 (3.86%)	22 / 439 (5.01%)	19 / 434 (4.38%)
occurrences all number	3	6	2	11	4	21	30	25

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Were there any global substantial amendments to the protocol? Yes

14 Sep 2012

1. Modification of the primary objective in Part A from cumulative number of new GdE lesions to cumulative total number of GdE lesions. 2. Addition of a secondary objective in Part A to assess proportion of patients who are free of GdE lesions at Week 24. 3. Modification to treatment duration in Part B to 24 months for all patients. 4. Modification to inclusion/exclusion criteria to remove the exclusion of diagnosis with secondary progressive MS, and to require that patients must discontinue nonlymphocyte-depleting disease-modifying MS agents from signing of the informed consent until randomization. 5. Corresponding changes to study endpoints to accommodate modifications to study objectives in Part A. 6. Change in PK sampling schedule. 7. Addition of QuantiFERON Gold test as alternative to purified protein derivative test for TB screening. 8. Clarification of timing of procedures for Part A patients who elect to enter the blinded extension period after the Week 24 visit. 9. Clarification of unblinding procedure and timing of treatment for relapse. 10. Clarifications to the inclusion/exclusion criteria, study design, study procedures (throughout), Schedule of Assessment and corresponding footnotes, handling missed doses, matching placebo for IFN β-1, allowed/prohibited medications, clinical laboratory procedures, and notifications. Many of the remaining changes were related to consistency within the protocol, addition of clinical laboratory and corresponding contact details, project biostatistician personnel change, correction of typographical errors in the protocol and formatting throughout.

31 Jul 2013

1. Addition of exploratory endpoint to Part B: “the number of GdE brain MRI lesions at 24 months”. 2. Duration of the blinded extension of Part A was increased to at least 48 weeks for all patients (with total duration of Part A of at least 72 weeks, 24 weeks placebo-controlled period and at least 48 weeks blinded extension). 3. Clarifications that for patients continuing to the blinded extension, MRI scans would be performed annually after the Week 24 visit (at approximately Week 72) and/or at the End of-Study Visit. 4. Increase in sample size in Part B to 1200 patients (400 per arm) and modification of sample size justification accordingly. 5. Addition of section on “Considerations for Patients with Comorbid Conditions”. 6. Modification to withdrawal criteria and discontinuation of study medication. 7. Modifications to inclusion/exclusion criteria: Inclusion criterion no. 8 – clarification of sexual abstinence, Inclusion criterion no. 9 – clarification regarding proof of immunization for varicella zoster virus, Exclusion criterion no. 7 – specification of excluded cardiac conditions, Exclusion criterion no. 9 – specification of diabetes mellitus history, Addition of exclusion criterion no. 25 on excluded disease modifying therapies, Removal of exclusion criterion regarding B12 deficiency. 8. Modification to statistical methods including Clarification when the interim analysis of Part A would be done, and clarification of the Part B primary analysis per request of FDA. 9. Clarification that dermatological (skin) examination would be done by the investigator, not the dermatologist. 10. Other changes included clarifications to inclusion/exclusion criteria, study design, study procedures (throughout), Schedule of Assessment and corresponding footnotes, number of participating sites in Part A and B, study drug accountability, allowed and prohibited medications, and procedures in case of pregnancy.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/26879276

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24

Primary: Part A: The Total Number of Gadolinium-Enhancing Lesions Assessed on Brain Magnetic Resonance Imaging (MRI) from Week 12 to Week 24

Primary: Part B: Adjusted Annualized Relapse Rate (ARR) at the End of Month 24

Primary: Part B: Adjusted Annualized Relapse Rate (ARR) at the End of Month 24

Secondary: Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24

Secondary: Part A: The Number of Gadolinium-Enhancing Lesions on Brain MRI Scan at Week 24

Secondary: Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24

Secondary: Part A: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions from Week 12 to Week 24

Secondary: Part A: Adjusted Annualized Relapse Rate (ARR) at Week 24

Secondary: Part A: Adjusted Annualized Relapse Rate (ARR) at Week 24

Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Treatment Phase

Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Placebo-Controlled Treatment Phase

Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events During the Placebo Controlled and Blinded Extension Phase

Secondary: Part A: Number of Participants With Treatment Emergent Adverse Events During the Placebo Controlled and Blinded Extension Phase

Secondary: Part B: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging Lesions Per Scan Over 24 Months

Secondary: Part B: Adjusted Mean Number of New or Enlarging Hyperintense T2-Weighted Brain Magnetic Resonance Imaging Lesions Per Scan Over 24 Months

Secondary: Part B: Adjusted Mean Number of Gadolinium Enhancing Brain Lesions per Scan at Month 24

Secondary: Part B: Adjusted Mean Number of Gadolinium Enhancing Brain Lesions per Scan at Month 24

Secondary: Part B: Time to Onset of Disability Progression Confirmed After 3 Months

Secondary: Part B: Time to Onset of Disability Progression Confirmed After 3 Months

Secondary: Part B: Time to Onset of Disability Progression Confirmed After 6 months

Secondary: Part B: Time to Onset of Disability Progression Confirmed After 6 months

Secondary: Part B: Percentage of Participants Who Were Gadolinium Enhancing Lesion-Free at Month 24

Secondary: Part B: Percentage of Participants Who Were Gadolinium Enhancing Lesion-Free at Month 24

Secondary: Part B: Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24

Secondary: Part B: Percentage of Participants Who Were New or Enlarging T2 Lesion-Free at Month 24

Secondary: Part B: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 24

Secondary: Part B: Percent Change in Normalized Brain Volume (Atrophy) on Brain MRI Scans from Baseline to Month 24

Secondary: Part B: Change in Multiple Sclerosis Functional Composite (MSFC) Score from Baseline to Month 24 (including the Low-Contrast Letter Acuity test [LCLA] Measurement of Visual Function as a Component)

Secondary: Part B: Change in Multiple Sclerosis Functional Composite (MSFC) Score from Baseline to Month 24 (including the Low-Contrast Letter Acuity test [LCLA] Measurement of Visual Function as a Component)

Secondary: Part B: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 24

Secondary: Part B: Mean Change in Multiple Sclerosis Quality of Life (MSQOL)-54 Score from Baseline to Month 24

Secondary: Part B: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During Part B

Secondary: Part B: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During Part B

Post-hoc: Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period

Post-hoc: Summary of Gadolinium-Enhancing Lesion Counts by Visit in the Extension Period

Post-hoc: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions In the Blinded Extension Period

Post-hoc: The Total Number of New or Enlarging Hyperintense T2-Weighted Brain MRI Lesions In the Blinded Extension Period

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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