Clinical Study to Evaluate the Efficacy, Safety, and Tolerability of ACT-128800 in Patients With Relapsing-remitting Multiple Sclerosis

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01006265
• Collaborator: (none)
• Enrollment: 464
• Locations: 115
• Arms: 4
• Actual Duration (Months): 21
• Patients Per Site: 4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will assess the efficacy, safety, and tolerability of ACT-128800 in patients with relapsing-remitting multiple sclerosis.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: ACT-128800 Dose 1; Drug: Placebo; Drug: ACT-128800 Dose 2; Drug: ACT-128800 Dose 3	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 464 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-finding Study to Evaluate the Efficacy, Safety, and Tolerability of Three Doses of ACT-128800, an Oral S1P1 Receptor Agonist, Administered for Twenty-four Weeks in Patients With Relapsing-remitting Multiple Sclerosis
• Actual Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ACT-128800 Dose 1 ACT-128800 Dose 1	Drug: ACT-128800 Dose 1; ACT-128800 (Dose 1) administered orally once daily
Experimental: ACT-128800 Dose 2 ACT-128800 Dose 2	Drug: ACT-128800 Dose 2; ACT-128800 (Dose 2) administered orally once daily
Experimental: ACT-128800 Dose 3 ACT-128800 Dose 3	Drug: ACT-128800 Dose 3; ACT-128800 (Dose 3) administered orally once daily
Placebo Comparator: Placebo Matching placebo	Drug: Placebo; Matching placebo administered orally once daily

Outcome Measures

Primary Outcome Measures

1. Cumulative Number of New T1 Gadolinium-Enhancing (Gd+) Lesions on Magnetic Resonance Imaging (MRI) Scan From Week 12 to Week 24 [From Week 12 to 24]

   Cumulative Number of new T1 gadolinium-enhancing (Gd+) lesions per year on magnetic resonance imaging (MRI) scan from Week 12 to Week 24 were reported. Negative binomial (NB) regression analysis on Per protocol analysis set and imputation was applied for the missing data. Here, MS signifies multiple sclerosis.

Secondary Outcome Measures

1. Annualized Confirmed Relapse Rate [Up to 24 weeks]

   Relapse: occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple Sclerosis (MS), not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicating overall functional impairment assessing Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS with information concerning gait and use of assistance. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10(death due to MS)

2. Number of Participants With First Confirmed Relapse as Assessed by Kaplan-Meier Estimate From Baseline to Week 24 [Baseline to Week 24]

   Relapse: occurrence of acute episode of one or more new symptoms or worsened symptoms of MS, not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicating overall functional impairment assessing Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS with information concerning gait and use of assistance. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10(death due to MS). Kaplan-Meier estimate used for Outcome Measure analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult males and females

• Diagnosis of RRMS as defined by the revised (2005) McDonald Diagnostic Criteria for Multiple Sclerosis (MS).

• Signed inform consent prior to initiation of any study-mandated procedure.

Exclusion Criteria:

• A diagnosis of MS categorized as primary progressive or secondary progressive or progressive relapsing.

• Patients currently treated for an autoimmune disorder other than MS.

• Contraindications for MRI.

• Ongoing bacterial, viral, or fungal infection.

• History or presence of malignancy.

Additional inclusion and exclusion criteria apply with respect to medical conditions and concomitant treatments which could affect patients' risk from participating in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Investigative Site 3132	Scottsdale	Arizona	United States	85259
2	Clinical Investigative Site 3100	Tucson	Arizona	United States	85741
3	Clinical Investigative Site 3115	Sacramento	California	United States	95817
4	Clinical Investigative Site 3117	Stanford	California	United States	94305
5	Clinical Invesigative Site 3116	Sarasota	Florida	United States	34233
6	Clinical Investigative Site 3101	Indianapolis	Indiana	United States	46202
7	Clinical Investigative Site 3105	Kansas City	Kansas	United States	66160
8	Clinical Investigative Site 3107	Lenexa	Kansas	United States	66214
9	Clinical Investigative Site 3118	Baltimore	Maryland	United States	21201
10	Clinical Investigative Site 3133	Worcester	Massachusetts	United States	01605
11	Clinical Investigator 3136	Saint Louis	Missouri	United States	63100
12	Clinical Investigative Site # 3135	Newark	New Jersey	United States	07103
13	Clinical Investigative Site 3129	Latham	New York	United States	12110
14	Clinical Investigative Site # 3128	New York	New York	United States	10032
15	Clinical Investigative Site 3127	Schenectady	New York	United States	12308
16	Clinical Investigative Site 3120	Stony Brook	New York	United States	11794
17	Clinical Investigative Site 3119	Raleigh	North Carolina	United States	27607
18	Clinical Investigator 3126	Akron	Ohio	United States	44320
19	Clinical Investigative Site 3113	Cincinnati	Ohio	United States	45219
20	Clinical Investigative Site 3130	Columbus	Ohio	United States	43221
21	Clinical Investigator 3104	Portland	Oregon	United States	97225
22	Clinical Investigative Site 3125	Philadelphia	Pennsylvania	United States	19107
23	Clinical Investigative Site 3112	Burlington	Vermont	United States	05401
24	Clinical Investigative Site 3111	Richmond	Virginia	United States	23298
25	Clinical Investigative Site 3102	Kirkland	Washington	United States	98034
26	Clinical Investigative Site # 1001	Fitzroy		Australia	3065
27	Clinical Investigative Site 1000	Westmead		Australia	2145
28	Clinical Investigative Site 1102	Amstetten		Austria	3300
29	Clinical Investigative Site 1100	St Polten		Austria	3100
30	Clinical Investigative Site 1101	Vienna		Austria	1090
31	Clinical Investigative Site 1201	La Louviere		Belgium	7100
32	Clinical Investigative Site # 1205	Liege		Belgium	4000
33	Clinical Investigative Site 1204	Ottignies		Belgium	1340
34	Clinical Investigative Site 1203	Sijsele-Damme		Belgium	8340
35	Clinical Investigative Site 1302	Sofia		Bulgaria	1309
36	Clinical Investigative Site 1301	Sofia		Bulgaria	1431
37	Clinical Investigative Site 1303	Varna		Bulgaria	9010
38	Clinical Investigative Site 1304	Varna		Bulgaria	9010
39	Clinical Investigative Site 1401	Burbaby	British Columbia	Canada	V5G 2X6
40	Clinical Investigative Site # 1401	Burnaby		Canada	V5G 2X6
41	Clinical Investigative Site 1400	Ottawa		Canada	K1H 8L6
42	Clinical Investigative Site 1502	Brno		Czechia	656 91
43	Clinical Investigative Site 1506	Jihlava		Czechia	586 33
44	Clinical Investigative Site 1504	Olomouc		Czechia	775 20
45	Clinical Investigative Site 1501	Ostrava-Poruba		Czechia	70852
46	Clinical Investigative Site 1500	Praha		Czechia	128 08
47	Clinical Investigative Site 1503	Teplice		Czechia
48	Clinical Investigative Site 1600	Helsinki		Finland	00100
49	Clinical Investigative Site 1601	Hyvinkaa		Finland	05800
50	Clinical Investigative Site 1603	Tampere		Finland	33520
51	Clinical Investigative Site 1602	Turku		Finland	20100
52	Clinical Investigative Site 1701	Montpellier Cedex		France	34295
53	Clinical Investigative Site # 1806	Bayreuth		Germany	95445
54	Clinical Investigative 1807	Berlin		Germany	10117
55	Clinical Investigative Site 1803	Berlin		Germany	13347
56	Clinical Investigative site 1800	Dusseldorf		Germany	40225
57	Clinical Investigative Site 1802	Essen		Germany	45147
58	Clinical Investigative Site 1805	Homburg/Saar		Germany	66421
59	Clinical Investigative Site 1804	Ulm		Germany	89081
60	Clinical Investigative Site 1905	Budapest		Hungary	1134
61	Clinical Investigative Site # 1904	Budapest		Hungary	H-1115
62	Clinical Investigative Site 1908	Budapest		Hungary	H-1145
63	Clinical Investigative Site 1902	Gyor		Hungary	11-9024
64	Clinical Investigative Site 1900	Petofi		Hungary	2500
65	Clinical Investigative Site 1901	Szentpeteri-Kapu		Hungary	3526
66	Clinical Investigative Site 2000	Ashkelon		Israel	78278
67	Clinical Investigative Site 2003	Tel-Aviv		Israel	64239
68	Clinical Investigative Site 2001	Tel-Hashomer		Israel	52621
69	Clinical Investigative Site 2002	Zerifin		Israel	70300
70	Clinical Investigative Site 2101	Gallarte		Italy	21013
71	Clinical Investigative Site 2104	Genova		Italy	16132
72	Clinical Investigative Site # 2106	Milan		Italy	20132
73	Clinical Investigative Site 2102	Padova		Italy	35128
74	Clinical Investigative Site 2103	Roma		Italy	00189
75	Clinical Investigative Site 2105	Siena		Italy	53100
76	Clinical Investigative Site 2203	Breda		Netherlands	4818
77	Clinical Investigative Site 2202	Nijmegen		Netherlands	6533
78	Clinical Investigative Site 2201	Sittard-Geleen		Netherlands	6162
79	Clinical Investigative Site 2305	Katowice		Poland	47-752
80	Clinical Investigative Site 2303	Poznan		Poland	60-355
81	Clinical Investigative Site 2304	Warsaw		Poland	02-957
82	Clinical Investigative Site 2302	Wroclaw		Poland	50-044
83	Clinical Investigative Site 2400	Bucuresti		Romania	022903
84	Clinical Investigative Site 2401	Cluj-Napoca		Romania	428063
85	Clinical Investigative Site 2402	Timisoara		Romania	300736
86	Clinical Investigative Site # 3202	Moscow		Russian Federation	127018
87	Clinical Investigative Site # 3203	Nizhniy Novgorod		Russian Federation	603155
88	Clinical Investigative Site # 3206	Pyatigorsk		Russian Federation	357538
89	Clinical Investigative Site # 3201	Samara		Russian Federation	443095
90	Clinical Investigative Site 3209	Saratov		Russian Federation	410030
91	Clinical Investigative Site # 3204	St. Petersburg		Russian Federation	194354
92	Clinical Investigative Site 3201	St. Petersburg		Russian Federation	197022
93	Clinical Investigative Site 3200	St. Petersburg		Russian Federation	197376
94	Clinical Investigative Site 3208	Ufa		Russian Federation	450005
95	Clinical Investigative Site 2501	Belgrade		Serbia	11000
96	Clinical Investigative Site 2503	Kragujevac		Serbia	34000
97	Clinical Investigative Site 2502	Nis		Serbia	18000
98	Clinical Investigative Site 2706	Barcelona		Spain	08035
99	Clinical Investigative Site 2702	Madrid		Spain	28040
100	Clinical Investigative Site 2705	Madrid		Spain	28222
101	Clinical Investigative Site 2701	Malaga		Spain	29010
102	Clinical Investigative Site 2700	Sevilla		Spain	41009
103	Clinical Investigative Site 2704	Valencia		Spain	46009
104	Clinical Investigative Site 2802	Goteburg		Sweden	41345
105	Clinical Investigative Site 2800	Stockholm		Sweden	17176
106	Clinical Investigative Site 2801	Umed		Sweden	90185
107	Clinical Investigative Site 2901	Lugano		Switzerland	CH-6900
108	Clinical Investigative Site 2900	St Gallen		Switzerland	CH-9007
109	Clinical Investigative Site 3302	Chernihiv		Ukraine	14029
110	Clinical Investigative Site 3303	Dnipropetrovsk		Ukraine	49044
111	Clinical Investigative Site 3300	Kyiv		Ukraine	03110
112	Clinical Investigative Site 3304	Odesa		Ukraine	65000
113	Clinical Investigative Site 3003	Bristol		United Kingdom	BS16 1LE
114	Clinical Investigative Site 3004	Devon		United Kingdom	PL6 SBX
115	Clinical Investigative Site 3002	London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• Actelion

Investigators

• Study Director: Actelion Pharmaceuticals, Actelion

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A dose-finding study to evaluate the efficacy, safety, and tolerability of three doses of ACT-128800, an oral S1P1 receptor agonist, administered for twenty-four weeks in patients with relapsing-remitting multiple sclerosis

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01006265
• Other Study ID Numbers: AC-058B201
• First Posted: Nov 1, 2009
• Last Update Posted: Feb 7, 2022
• Last Verified: Feb 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Ponesimod

Study Results

Participant Flow

Arm/Group Title	Ponesimod 40 mg	Ponesimod 20 mg	Ponesimod 10 mg	Placebo
Arm/Group Description	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 milligram (mg) ponesimod on Days 1 to 7 followed by first up-titration dose of 20 mg ponesimod on Days 8 to 14 and lastly received 40 mg ponesimod as second up-titration dose on Day 15 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 mg ponesimod on Days 1 to 7 followed by 20 mg ponesimod on Day 8 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with a dose of 10 mg ponesimod on Day 1 to Week 24.	Participants received the ponesimod matching placebo tablets once daily for up to Week 24 as per up-titration schedule.
Period Title: Overall Study
STARTED	119	116	108	121
Treated	119	114	108	121
COMPLETED	113	107	99	116
NOT COMPLETED	6	9	9	5

Baseline Characteristics

Arm/Group Title	Ponesimod 40 mg	Ponesimod 20 mg	Ponesimod 10 mg	Placebo	Total
Arm/Group Description	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 milligram (mg) ponesimod on Days 1 to 7 followed by first up-titration dose of 20 mg ponesimod on Days 8 to 14 and lastly received 40 mg ponesimod as second up-titration dose on Day 15 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 mg ponesimod on Days 1 to 7 followed by 20 mg ponesimod on Day 8 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with a dose of 10 mg ponesimod on Day 1 to Week 24.	Participants received the ponesimod matching placebo tablets once daily for up to Week 24 as per up-titration schedule.	Total of all reporting groups
Overall Participants	119	116	108	121	464
Age (years) [Mean (Standard Deviation) ]
Age ( years )	36.5 (8.52)	35.3 (8.52)	36.9 (9.24)	36.6 (8.58)	36.3 (8.7)
Sex: Female, Male (Count of Participants)
Female	79 66.4%	78 67.2%	71 65.7%	85 70.2%	313 67.5%
Male	40 33.6%	38 32.8%	37 34.3%	36 29.8%	151 32.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.7%	0 0%	0 0%	0 0%	2 0.4%
Not Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	117 98.3%	116 100%	108 100%	121 100%	462 99.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 0.8%	1 0.2%
Asian	1 0.8%	0 0%	1 0.9%	0 0%	2 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 1.7%	2 1.7%	2 1.9%	6 5%	12 2.6%
White	114 95.8%	114 98.3%	105 97.2%	114 94.2%	447 96.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1.7%	0 0%	0 0%	0 0%	2 0.4%
Region of Enrollment (Count of Participants)
Australia	0 0%	1 0.9%	0 0%	0 0%	1 0.2%
Austria	2 1.7%	2 1.7%	2 1.9%	3 2.5%	9 1.9%
Belgium	2 1.7%	0 0%	0 0%	0 0%	2 0.4%
Bulgaria	5 4.2%	4 3.4%	5 4.6%	5 4.1%	19 4.1%
Canada	3 2.5%	3 2.6%	4 3.7%	3 2.5%	13 2.8%
Finland	6 5%	4 3.4%	4 3.7%	6 5%	20 4.3%
Czech Republic	14 11.8%	14 12.1%	12 11.1%	12 9.9%	52 11.2%
France	1 0.8%	1 0.9%	1 0.9%	1 0.8%	4 0.9%
Germany	1 0.8%	2 1.7%	1 0.9%	2 1.7%	6 1.3%
Hungary	7 5.9%	7 6%	2 1.9%	3 2.5%	19 4.1%
Israel	3 2.5%	2 1.7%	1 0.9%	3 2.5%	9 1.9%
Italy	8 6.7%	7 6%	6 5.6%	7 5.8%	28 6%
Netherlands	1 0.8%	1 0.9%	2 1.9%	2 1.7%	6 1.3%
Poland	7 5.9%	8 6.9%	10 9.3%	12 9.9%	37 8%
Romania	1 0.8%	2 1.7%	3 2.8%	3 2.5%	9 1.9%
Russia	9 7.6%	9 7.8%	8 7.4%	7 5.8%	33 7.1%
Spain	4 3.4%	2 1.7%	3 2.8%	4 3.3%	13 2.8%
Serbia	10 8.4%	10 8.6%	11 10.2%	11 9.1%	42 9.1%
Sweden	5 4.2%	6 5.2%	4 3.7%	6 5%	21 4.5%
Switzerland	0 0%	2 1.7%	2 1.9%	1 0.8%	5 1.1%
United Kingdom	5 4.2%	5 4.3%	4 3.7%	4 3.3%	18 3.9%
Ukraine	5 4.2%	6 5.2%	5 4.6%	7 5.8%	23 5%
United States	20 16.8%	18 15.5%	18 16.7%	19 15.7%	75 16.2%

Outcome Measures

1. Primary Outcome

Title	Cumulative Number of New T1 Gadolinium-Enhancing (Gd+) Lesions on Magnetic Resonance Imaging (MRI) Scan From Week 12 to Week 24
Description	Cumulative Number of new T1 gadolinium-enhancing (Gd+) lesions per year on magnetic resonance imaging (MRI) scan from Week 12 to Week 24 were reported. Negative binomial (NB) regression analysis on Per protocol analysis set and imputation was applied for the missing data. Here, MS signifies multiple sclerosis.
Time Frame	From Week 12 to 24

Outcome Measure Data

Analysis Population Description

Per protocol analysis set included participants of mITT set (randomized participants who received at least one dose of study drug, and had at least one valid post-baseline MRI) who met the criteria for evaluable participants for the analysis of MRI data (participants with Relapsing-remitting multiple sclerosis (RRMS) received study drug until 168 days, two post-baseline MRIs b/w Week 12-24, no forbidden treatment for MS).

Arm/Group Title	Ponesimod 40 mg	Ponesimod 20 mg	Ponesimod 10 mg	Placebo
Arm/Group Description	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 milligram (mg) ponesimod on Days 1 to 7 followed by first up-titration dose of 20 mg ponesimod on Days 8 to 14 and lastly received 40 mg ponesimod as second up-titration dose on Day 15 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 mg ponesimod on Days 1 to 7 followed by 20 mg ponesimod on Day 8 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with a dose of 10 mg ponesimod on Day 1 to Week 24.	Participants received the ponesimod matching placebo tablets once daily for up to Week 24 as per up-titration schedule.
Measure Participants	93	98	88	110
Mean (Standard Deviation) [Lesions]	1.4 (3.24)	1.1 (1.96)	3.5 (7.27)	6.2 (13.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 40 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (rate ratio)
	Estimated Value	0.226
	Confidence Interval	(2-Sided) 95%; 0.133 to 0.384
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 20 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (rate ratio)
	Estimated Value	0.170
	Confidence Interval	(2-Sided) 95%; 0.100 to 0.289
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 10 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0318
	Comments
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (rate ratio)
	Estimated Value	0.566
	Confidence Interval	(2-Sided) 95%; 0.337 to 0.952
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Annualized Confirmed Relapse Rate
Description	Relapse: occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple Sclerosis (MS), not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicating overall functional impairment assessing Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS with information concerning gait and use of assistance. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10(death due to MS)
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

All treated analysis set included all randomized participants who received at least one dose of study drug.

Arm/Group Title	Ponesimod 40 mg	Ponesimod 20 mg	Ponesimod 10 mg	Placebo
Arm/Group Description	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 milligram (mg) ponesimod on Days 1 to 7 followed by first up-titration dose of 20 mg ponesimod on Days 8 to 14 and lastly received 40 mg ponesimod as second up-titration dose on Day 15 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 mg ponesimod on Days 1 to 7 followed by 20 mg ponesimod on Day 8 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with a dose of 10 mg ponesimod on Day 1 to Week 24.	Participants received the ponesimod matching placebo tablets once daily for up to Week 24 as per up-titration schedule.
Measure Participants	119	114	108	121
Mean (Standard Deviation) [Relapse per year]	0.224 (0.7834)	0.396 (1.0169)	0.297 (0.7987)	0.601 (1.6626)

3. Secondary Outcome

Title	Number of Participants With First Confirmed Relapse as Assessed by Kaplan-Meier Estimate From Baseline to Week 24
Description	Relapse: occurrence of acute episode of one or more new symptoms or worsened symptoms of MS, not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicating overall functional impairment assessing Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS with information concerning gait and use of assistance. EDSS is ordinal clinical scale ranges 0 (normal neurological examination) to 10(death due to MS). Kaplan-Meier estimate used for Outcome Measure analysis.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All treated analysis set included all randomized participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) included all participants who were evaluated for this outcome measure.

Arm/Group Title	Ponesimod 40 mg	Ponesimod 20 mg	Ponesimod 10 mg	Placebo
Arm/Group Description	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 milligram (mg) ponesimod on Days 1 to 7 followed by first up-titration dose of 20 mg ponesimod on Days 8 to 14 and lastly received 40 mg ponesimod as second up-titration dose on Day 15 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 mg ponesimod on Days 1 to 7 followed by 20 mg ponesimod on Day 8 to Week 24.	Participants received ponesimod capsules once daily as per up-titration schedule with a dose of 10 mg ponesimod on Day 1 to Week 24.	Participants received the ponesimod matching placebo tablets once daily for up to Week 24 as per up-titration schedule.
Measure Participants	66	71	60	65
Count of Participants [Participants]	10 8.4%	17 14.7%	14 13%	25 20.7%

Adverse Events

Time Frame	Up to 29 weeks (AEs for Treatment duration (24 weeks) and follow up (5 Weeks) on Day 7 and Day 30 after last dose)
Adverse Event Reporting Description	All Treated Analysis set included all randomized participants who received at least one dose of study drug.
Arm/Group Title	Ponesimod 40 mg		Ponesimod 20 mg		Ponesimod 10 mg		Placebo
Arm/Group Description	Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 milligram (mg) ponesimod on Days 1 to 7 followed by first up-titration dose of 20 mg ponesimod on Days 8 to 14 and lastly received 40 mg ponesimod as second up-titration dose on Day 15 to Week 24.		Participants received ponesimod capsules once daily as per up-titration schedule with an initial dose of 10 mg ponesimod on Days 1 to 7 followed by 20 mg ponesimod on Day 8 to Week 24.		Participants received ponesimod capsules once daily as per up-titration schedule with a dose of 10 mg ponesimod on Day 1 to Week 24.		Participants received the ponesimod matching placebo tablets once daily for up to Week 24 as per up-titration schedule.
All Cause Mortality
	Ponesimod 40 mg		Ponesimod 20 mg		Ponesimod 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/119 (0%)		0/114 (0%)		0/108 (0%)		0/121 (0%)
Serious Adverse Events
	Ponesimod 40 mg		Ponesimod 20 mg		Ponesimod 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/119 (2.5%)		7/114 (6.1%)		7/108 (6.5%)		5/121 (4.1%)
Cardiac disorders
Atrioventricular Block Second Degree	0/119 (0%)		1/114 (0.9%)		2/108 (1.9%)		0/121 (0%)
Coronary Artery Disease	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Ear and labyrinth disorders
Vertigo	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Eye disorders
Macular Oedema	0/119 (0%)		2/114 (1.8%)		0/108 (0%)		0/121 (0%)
Papilloedema	0/119 (0%)		1/114 (0.9%)		0/108 (0%)		0/121 (0%)
Gastrointestinal disorders
Abdominal Pain Upper	0/119 (0%)		1/114 (0.9%)		0/108 (0%)		0/121 (0%)
General disorders
Pyrexia	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Immune system disorders
Anaphylactoid Reaction	0/119 (0%)		0/114 (0%)		0/108 (0%)		1/121 (0.8%)
Infections and infestations
Appendicitis	1/119 (0.8%)		1/114 (0.9%)		0/108 (0%)		0/121 (0%)
Cellulitis	1/119 (0.8%)		0/114 (0%)		0/108 (0%)		0/121 (0%)
Measles	0/119 (0%)		0/114 (0%)		0/108 (0%)		1/121 (0.8%)
Urinary Tract Infection Bacterial	0/119 (0%)		0/114 (0%)		0/108 (0%)		1/121 (0.8%)
Investigations
Alanine Aminotransferase Increased	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Aspartate Aminotransferase Increased	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Electrocardiogram QT Prolonged	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Nuclear Magnetic Resonance Imaging Abnormal	0/119 (0%)		1/114 (0.9%)		0/108 (0%)		0/121 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Cervix Carcinoma	0/119 (0%)		0/114 (0%)		0/108 (0%)		1/121 (0.8%)
Nervous system disorders
Somnolence	0/119 (0%)		0/114 (0%)		1/108 (0.9%)		0/121 (0%)
Reproductive system and breast disorders
Postmenopausal Haemorrhage	0/119 (0%)		0/114 (0%)		0/108 (0%)		1/121 (0.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/119 (0.8%)		0/114 (0%)		0/108 (0%)		0/121 (0%)
Pleural Effusion	1/119 (0.8%)		0/114 (0%)		0/108 (0%)		0/121 (0%)
Surgical and medical procedures
Appendicectomy	0/119 (0%)		1/114 (0.9%)		0/108 (0%)		0/121 (0%)
Other (Not Including Serious) Adverse Events
	Ponesimod 40 mg		Ponesimod 20 mg		Ponesimod 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/119 (69.7%)		73/114 (64%)		69/108 (63.9%)		77/121 (63.6%)
Blood and lymphatic system disorders
Lymphopenia	1/119 (0.8%)		3/114 (2.6%)		1/108 (0.9%)		0/121 (0%)
Cardiac disorders
Bradycardia	2/119 (1.7%)		5/114 (4.4%)		0/108 (0%)		0/121 (0%)
Palpitations	2/119 (1.7%)		1/114 (0.9%)		3/108 (2.8%)		3/121 (2.5%)
Ear and labyrinth disorders
Ear Pain	0/119 (0%)		1/114 (0.9%)		1/108 (0.9%)		3/121 (2.5%)
Eye disorders
Eye Pain	0/119 (0%)		0/114 (0%)		3/108 (2.8%)		2/121 (1.7%)
Gastrointestinal disorders
Abdominal Pain	1/119 (0.8%)		0/114 (0%)		0/108 (0%)		3/121 (2.5%)
Abdominal Pain Upper	3/119 (2.5%)		1/114 (0.9%)		1/108 (0.9%)		1/121 (0.8%)
Diarrhoea	3/119 (2.5%)		3/114 (2.6%)		3/108 (2.8%)		8/121 (6.6%)
Dry Mouth	0/119 (0%)		3/114 (2.6%)		0/108 (0%)		1/121 (0.8%)
Dyspepsia	1/119 (0.8%)		3/114 (2.6%)		0/108 (0%)		2/121 (1.7%)
Nausea	4/119 (3.4%)		3/114 (2.6%)		2/108 (1.9%)		6/121 (5%)
Vomiting	2/119 (1.7%)		1/114 (0.9%)		3/108 (2.8%)		0/121 (0%)
General disorders
Asthenia	3/119 (2.5%)		1/114 (0.9%)		1/108 (0.9%)		4/121 (3.3%)
Chest Discomfort	4/119 (3.4%)		5/114 (4.4%)		0/108 (0%)		3/121 (2.5%)
Disease Progression	11/119 (9.2%)		9/114 (7.9%)		10/108 (9.3%)		6/121 (5%)
Fatigue	6/119 (5%)		9/114 (7.9%)		7/108 (6.5%)		7/121 (5.8%)
Oedema Peripheral	13/119 (10.9%)		3/114 (2.6%)		2/108 (1.9%)		2/121 (1.7%)
Pain	0/119 (0%)		0/114 (0%)		0/108 (0%)		3/121 (2.5%)
Infections and infestations
Bronchitis	5/119 (4.2%)		4/114 (3.5%)		4/108 (3.7%)		3/121 (2.5%)
Gastroenteritis	1/119 (0.8%)		3/114 (2.6%)		5/108 (4.6%)		4/121 (3.3%)
Influenza	5/119 (4.2%)		3/114 (2.6%)		3/108 (2.8%)		2/121 (1.7%)
Nasopharyngitis	13/119 (10.9%)		12/114 (10.5%)		16/108 (14.8%)		17/121 (14%)
Oral Herpes	2/119 (1.7%)		0/114 (0%)		2/108 (1.9%)		6/121 (5%)
Rhinitis	0/119 (0%)		4/114 (3.5%)		3/108 (2.8%)		1/121 (0.8%)
Sinusitis	6/119 (5%)		5/114 (4.4%)		4/108 (3.7%)		5/121 (4.1%)
Upper Respiratory Tract Infection	11/119 (9.2%)		9/114 (7.9%)		4/108 (3.7%)		11/121 (9.1%)
Urinary Tract Infection	3/119 (2.5%)		1/114 (0.9%)		2/108 (1.9%)		6/121 (5%)
Injury, poisoning and procedural complications
Contusion	1/119 (0.8%)		1/114 (0.9%)		3/108 (2.8%)		0/121 (0%)
Muscle Strain	0/119 (0%)		1/114 (0.9%)		3/108 (2.8%)		0/121 (0%)
Investigations
Alanine Aminotransferase Increased	7/119 (5.9%)		7/114 (6.1%)		4/108 (3.7%)		1/121 (0.8%)
Blood Cholesterol Increased	2/119 (1.7%)		3/114 (2.6%)		3/108 (2.8%)		1/121 (0.8%)
Forced Expiratory Volume Decreased	3/119 (2.5%)		2/114 (1.8%)		2/108 (1.9%)		0/121 (0%)
Hepatic Enzyme Increased	1/119 (0.8%)		0/114 (0%)		3/108 (2.8%)		0/121 (0%)
Pulmonary Function Test Decreased	5/119 (4.2%)		0/114 (0%)		2/108 (1.9%)		0/121 (0%)
Metabolism and nutrition disorders
Hypercholesterolaemia	3/119 (2.5%)		3/114 (2.6%)		2/108 (1.9%)		2/121 (1.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/119 (0.8%)		1/114 (0.9%)		2/108 (1.9%)		7/121 (5.8%)
Back Pain	6/119 (5%)		5/114 (4.4%)		2/108 (1.9%)		6/121 (5%)
Joint Swelling	1/119 (0.8%)		4/114 (3.5%)		0/108 (0%)		0/121 (0%)
Muscle Spasms	3/119 (2.5%)		0/114 (0%)		1/108 (0.9%)		5/121 (4.1%)
Musculoskeletal Chest Pain	3/119 (2.5%)		1/114 (0.9%)		1/108 (0.9%)		1/121 (0.8%)
Musculoskeletal Pain	1/119 (0.8%)		0/114 (0%)		3/108 (2.8%)		3/121 (2.5%)
Myalgia	1/119 (0.8%)		2/114 (1.8%)		1/108 (0.9%)		5/121 (4.1%)
Pain in Extremity	2/119 (1.7%)		3/114 (2.6%)		0/108 (0%)		1/121 (0.8%)
Nervous system disorders
Dizziness	11/119 (9.2%)		7/114 (6.1%)		8/108 (7.4%)		3/121 (2.5%)
Headache	15/119 (12.6%)		16/114 (14%)		15/108 (13.9%)		18/121 (14.9%)
Hypoaesthesia	3/119 (2.5%)		2/114 (1.8%)		2/108 (1.9%)		2/121 (1.7%)
Migraine	5/119 (4.2%)		3/114 (2.6%)		1/108 (0.9%)		0/121 (0%)
Paraesthesia	1/119 (0.8%)		2/114 (1.8%)		3/108 (2.8%)		1/121 (0.8%)
Psychiatric disorders
Affect Lability	0/119 (0%)		0/114 (0%)		0/108 (0%)		3/121 (2.5%)
Anxiety	4/119 (3.4%)		3/114 (2.6%)		5/108 (4.6%)		0/121 (0%)
Depression	4/119 (3.4%)		3/114 (2.6%)		1/108 (0.9%)		1/121 (0.8%)
Insomnia	2/119 (1.7%)		4/114 (3.5%)		4/108 (3.7%)		1/121 (0.8%)
Respiratory, thoracic and mediastinal disorders
Cough	8/119 (6.7%)		3/114 (2.6%)		1/108 (0.9%)		2/121 (1.7%)
Dyspnoea	16/119 (13.4%)		7/114 (6.1%)		5/108 (4.6%)		4/121 (3.3%)
Oropharyngeal Pain	5/119 (4.2%)		2/114 (1.8%)		4/108 (3.7%)		4/121 (3.3%)

Limitations/Caveats

No limitation was identified for this study.

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Certain Agreements

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

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.