OPTIMUM: Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis

• Sponsor: Actelion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02425644
• Collaborator: (none)
• Enrollment: 1,133
• Locations: 162
• Arms: 2
• Actual Duration (Months): 47.4
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

International clinical trial to compare ponesimod and teriflunomide in relapsing multiple sclerosis

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: ponesimod; Drug: teriflunomide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1133 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multicenter, Randomized, Double-blind, Parallel-group, Active-controlled, Superiority Study to Compare the Efficacy and Safety of Ponesimod to Teriflunomide in Subjects With Relapsing Multiple Sclerosis
• Actual Study Start Date: Jun 4, 2015
• Actual Primary Completion Date: May 16, 2019
• Actual Study Completion Date: May 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ponesimod Subjects to receive 20 mg ponesimod	Drug: ponesimod; film-coated tablet with 20 mg ponesimod, administered orally once daily in the morning; Other Names: ACT-128800
Active Comparator: Teriflunomide Subjects to receive 14 mg teriflunomide	Drug: teriflunomide; film-coated tablet with 14 mg teriflunomide, administered orally once daily in the morning

Outcome Measures

Primary Outcome Measures

1. Annualized Confirmed Relapse Rate [From randomization to end of study (Week 108)]

   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 indicates overall functional impairment assessing Visual,Brain Stem,Pyramidal,Cerebellar,Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS in conjunction with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10(death due to MS).

Secondary Outcome Measures

1. Change From Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) Score to Week 108 [Baseline to Week 108]

   The FSIQ-RMS is a 20-item Patient Reported Outcomes (PRO) measure to evaluate fatigue-related symptoms and the impacts of those symptoms on the lives of people. The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing fatigue-related symptoms daily with a recall period of 24 hours measured on an 11-point numeric rating scale; the (normalized) symptom domain score ranges from 0 to 100 with a higher score indicating greater fatigue. This domain was completed on 7 consecutive days. A negative change from baseline indicates an improvement in fatigue symptoms.

2. Cumulative Number of Combined Unique Active Lesions (CUAL) Per Year From Baseline to Week 108 [Baseline to Week 108]

   CUALs was calculated as sum of new Gadolinium-enhanced (Gd+) T1 lesions plus new or enlarging T2 lesions (without double-counting of lesions) from baseline based on the Magnetic resonance imaging (MRI) scans up to Week 108. Average number of lesions per year were reported.

3. 12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS [Baseline to Week 60 and 108 Weeks]

   A 12-week CDA was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score greater than or equal to (>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS).

4. 24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS [Baseline to 60 Weeks and 108 Weeks]

   A 24-week CDA was defined as an increase of at least 1.5 in EDSS for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score >= 5.5, which was confirmed after 24 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. The EDSS is an ordinal scale ranging from 0 (normal neurological exam) to 10 (death to MS).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Male and female subjects aged 18 to 55 years with established diagnosis of MS McDonald 2010 with relapsing course from onset (i.e., RRMS and SPMS with superimposed relapses).

Subjects must have active disease evidenced by one or more MS attacks with onset within the period of 12 to 1 months prior to randomization, or by two or more MS attacks with onset within the 24 to 1 months prior to randomization, or with one or more gadolinium-enhancing (Gd+) lesion(s) of the brain on an MRI performed within 6 months prior to randomization.

Enrolled subjects must be ambulatory (EDSS score of up to 5.5 inclusive) and may be treatment-naïve or previously treated with MS disease modifying therapy.

Exclusion Criteria:

Subjects with significant medical conditions or therapies for such conditions (e.g., cardiovascular, pulmonary, immunological, hepatic,ophthalmological conditions) or lactating or pregnant women are not eligible to enter the study.

Subjects with contraindications to MRI or with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study are not eligible to enter the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigator Site 8045	Carlsbad	California	United States	92011
2	Investigator Site 8311	Pomona	California	United States	91767
3	Investigator Site 8036	Denver	Colorado	United States	80209
4	Investigator Site 8065	Ormond Beach	Florida	United States	32174
5	Investigator Site 8018	Tampa	Florida	United States	33612
6	Investigator Site 8013	Indianapolis	Indiana	United States	46256
7	Investigator Site 8040	Raleigh	North Carolina	United States	27607
8	Investigator Site 8006	Columbus	Ohio	United States	43214
9	Investigator Site 8015	Franklin	Tennessee	United States	37064
10	Investigator Site 8042	Orem	Utah	United States	84058
11	Investigator Site 3605	Grodno		Belarus	230017
12	Investigator Site 3603	Minsk		Belarus	220026
13	Investigator Site 3602	Minsk		Belarus	220114
14	Investigator Site 3606	Vitebsk		Belarus	210023
15	Investigator Site 3604	Vitebsk		Belarus	210037
16	Investigator Site 9104	Sarajevo		Bosnia and Herzegovina	71000
17	Investigator Site 2709	Plovdiv		Bulgaria	4002
18	Investigator Site 2711	Sofia		Bulgaria	1113
19	Investigator Site 2702	Sofia		Bulgaria	1309
20	Investigator Site 2707	Sofia		Bulgaria	1407
21	Investigator Site 2701	Sofia		Bulgaria	1431
22	Investigator Site 2708	Sofia		Bulgaria	1431
23	Investigator Site 2703	Sofia		Bulgaria	1606
24	Investigator Site 8102	Edmonton	Alberta	Canada	T6G 1Z1
25	Investigator Site 8120	Victoria	British Columbia	Canada	V8R 1J8
26	Investigator Site 8101	Ottawa	Ontario	Canada	K1H 8L6
27	Investigator Site 8113	Greenfield Park	Quebec	Canada	J4V 2J2
28	Investigator Site 2506	Osijek		Croatia	31000
29	Investigator Site 2502	Zagreb		Croatia	10000
30	Investigator Site 2508	Zagreb		Croatia	10000
31	Investigator Site 2509	Zagreb		Croatia	10000
32	Investigator Site 3009	Brno		Czechia	625 00
33	Investigator Site 3003	Brno		Czechia	656 91
34	Investigator Site 3010	Hradec Králové		Czechia	500 05
35	Investigator Site 3006	Jihlava		Czechia	586 33
36	Investigator Site 3002	Ostrava-Poruba		Czechia	708 52
37	Investigator Site 3007	Pardubice		Czechia	532 03
38	Investigator Site 3001	Praha 2		Czechia	128 08
39	Investigator Site 3008	Praha 5		Czechia	150 06
40	Investigator Site 3004	Teplice		Czechia	415 29
41	Investigator Site 2212	Tampere		Finland	33100
42	Investigator Site 2202	Turku		Finland	20520
43	Investigator Site 1713	Bordeaux Cedex		France	33076
44	Investigator Site 1703	Clermont Ferrand Cedex 1		France	63003
45	Investigator Site 1715	Nantes Cedex 1		France	44093
46	Investigator Site 1706	Nice Cedex 1		France	06002
47	Investigator Site 1705	Strasbourg Cedex		France	67091
48	Investigator Site 3905	Tbilisi		Georgia	0112
49	Investigator Site 3904	Tbilisi		Georgia	0160
50	Investigator Site 3903	Tbilisi		Georgia	0179
51	Investigator Site 3906	Tbilisi		Georgia	0179
52	Investigator Site 3902	Tbilisi		Georgia	0194
53	Investigator Site 1113	Dresden		Germany	01307
54	Investigator Site 1107	Erfurt		Germany	99089
55	Investigator Site 1109	Leipzig		Germany	04107
56	Investigator Site 1104	Mainz		Germany	55131
57	Investigator Site 1102	Ulm		Germany	89081
58	Investigator Site 1303	Athens		Greece	11521
59	Investigator Site 1301	Athens		Greece	11525
60	Investigator Site 1307	Athens		Greece	15125
61	Investigator Site 2903	Budapest		Hungary	1145
62	Investigator Site 2905	Budapest		Hungary	1204
63	Investigator Site 2910	Esztergom		Hungary	2500
64	Investigator Site 2902	Gyor		Hungary	9023
65	Investigator Site 2909	Kistarcsa		Hungary	2143
66	Investigator Site 4005	Ashkelon		Israel	7830604
67	Investigator Site 4004	Haifa		Israel	3109601
68	Investigator Site 4006	Jerusalem		Israel	9112001
69	Investigator Site 4010	Zfat		Israel	13100
70	Investigator Site 1403	Cefalu		Italy	90015
71	Investigator Site 1409	Genova		Italy	16132
72	Investigator Site 1413	L'Aquila		Italy	67100
73	Investigator Site 1405	Roma		Italy	00189
74	Investigator Site 3401	Riga		Latvia	1015
75	Investigator Site 3402	Riga		Latvia	LV-1002
76	Investigator Site 3403	Riga		Latvia	LV-1038
77	Investigator Site 3502	Kaunas		Lithuania	50161
78	Investigator Site 3503	Klaipeda		Lithuania	92288
79	Investigator Site 3504	Siauliai		Lithuania	76231
80	Investigator Site 7410	Chihuahua		Mexico	31203
81	Investigator Site 7409	Monterrey		Mexico	64710
82	Investigator Site 3219	Bialystok		Poland	15-270
83	Investigator Site 3215	Bydgoszcz		Poland	85-795
84	Investigator Site 3208	Gdansk		Poland	80-803
85	Investigator Site 3217	Katowice		Poland	40-595
86	Investigator Site 3203	Katowice		Poland	40-752
87	Investigator Site 3205	Konstancin-Jeziorna		Poland	05-510
88	Investigator Site 3216	Ksawerow		Poland	95-054
89	Investigator Site 3220	Lublin		Poland	20-015
90	Investigator Site 3202	Poznan		Poland	60-355
91	Investigator Site 3214	Poznan		Poland	60-848
92	Investigator Site 3207	Poznan		Poland	61-853
93	Investigator Site 3213	Wroclaw		Poland	51-685
94	Investigator Site 1602	Amadora		Portugal	2720 276
95	Investigator Site 1605	Braga		Portugal	4710-243
96	Investigator Site 1603	Coimbra		Portugal	3000-075
97	Investigator Site 1604	Porto		Portugal	4099-001
98	Investigator Site 2807	Bucuresti		Romania	010825
99	Investigator Site 2811	Bucuresti		Romania	022903
100	Investigator Site 2804	Bucuresti		Romania	050098
101	Investigator Site 2802	Timisoara		Romania	300723
102	Investigator Site 3821	Barnaul	Altai Krai	Russian Federation	656024
103	Investigator Site 3818	Belgorod		Russian Federation	308007
104	Investigator Site 3837	Bryansk		Russian Federation	241033
105	Investigator Site 3836	Ekaterinburg		Russian Federation	620102
106	Investigator Site 3811	Kazan		Russian Federation	420029
107	Investigator Site 3822	Kemerovo		Russian Federation	650066
108	Investigator Site 3814	Krasnoyarsk		Russian Federation	660037
109	Investigator Site 3823	Kursk		Russian Federation	305007
110	Investigator Site 3831	Moscow		Russian Federation	119049
111	Investigator Site 3803	Moscow		Russian Federation	127015
112	Investigator Site 3840	Moscow		Russian Federation	127015
113	Investigator Site 3810	Moscow		Russian Federation	129128
114	Investigator Site 3802	Nizhniy Novgorod		Russian Federation	603155
115	Investigator Site 3834	Nizhny Novgorod		Russian Federation	603076
116	Investigator Site 3835	Novgorod		Russian Federation	173008
117	Investigator Site 3829	Novosibirsk		Russian Federation	630007
118	Investigator Site 3839	Perm		Russian Federation	614990
119	Investigator Site 3812	Pyatigorsk		Russian Federation	357538
120	Investigator Site 3813	Saint Petersburg		Russian Federation	197110
121	Investigator Site 3805	Samara		Russian Federation	443095
122	Investigator Site 3825	Smolensk		Russian Federation	214019
123	Investigator Site 3808	St. Petersburg		Russian Federation	194354
124	Investigator Site 3833	St. Petersburg		Russian Federation	197022
125	Investigator Site 3807	St. Petersburg		Russian Federation	197376
126	Investigator Site 3815	St. Petersburg		Russian Federation	197706
127	Investigator Site 3801	Tomsk		Russian Federation	634050
128	Investigator Site 3819	Tver		Russian Federation	170026
129	Investigator Site 3842	Yaroslavl		Russian Federation	150030
130	Investigator Site 2601	Belgrade		Serbia	11000
131	Investigator Site 2606	Belgrade		Serbia	11000
132	Investigator Site 2607	Belgrade		Serbia	11080
133	Investigator Site 2603	Kragujevac		Serbia	34000
134	Investigator Site 2602	Nis		Serbia	18000
135	Investigator Site 1509	Barcelona		Spain	08003
136	Investigator Site 1505	Barcelona		Spain	08035
137	Investigator Site 1504	Barcelona		Spain	08036
138	Investigator Site 1502	Madrid		Spain	28006
139	Investigator Site 1501	Malaga		Spain	29010
140	Investigator Site 1506	Sevilla		Spain	41009
141	Investigator Site 2103	Goteborg		Sweden	413 45
142	Investigator Site 2110	Stockholm		Sweden	141 86
143	Investigator Site 2101	Stockholm		Sweden	171 76
144	Investigator Site 9004	Trabzon		Turkey	61080
145	Investigator Site 3714	Chernihiv		Ukraine	14001
146	Investigator Site 3701	Chernihiv		Ukraine	14029
147	Investigator Site 3713	Ivano-Frankivsk		Ukraine	76008
148	Investigator Site 3711	Ivano-Frankivsk		Ukraine	76018
149	Investigator Site 3723	Kharkiv		Ukraine	61103
150	Investigator Site 3724	Kharkiv		Ukraine	61176
151	Investigator Site 3716	Kyiv		Ukraine	03115
152	Investigator Site 3715	Lviv		Ukraine	79000
153	Investigator Site 3721	Lviv		Ukraine	79010
154	Investigator Site 3703	Odessa		Ukraine	65009
155	Investigator Site 3717	Poltava		Ukraine	36011
156	Investigator Site 3730	Ternopil		Ukraine	46027
157	Investigator Site 3718	Vinnytsia		Ukraine	21005
158	Investigator Site 3722	Zaporizhia		Ukraine	69000
159	Investigator Site 3725	Zhytomyr		Ukraine	10008
160	Investigator Site 2015	Glasgow		United Kingdom	G51 4TF
161	Investigator Site 2021	Lancashire		United Kingdom	PR2 9HT
162	Investigator Site 2003	Salford		United Kingdom	M6 8HD

Sponsors and Collaborators

• Actelion

Investigators

• Study Director: Tatiana Scherz, MD, PhD, Actelion

Study Documents (Full-Text)

• Study Protocol - Dec 5, 2018
• Statistical Analysis Plan - Jun 20, 2019

More Information

Additional Information:

• Multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study to compare the efficacy and safety of ponesimod to teriflunomide in subjects with relapsing multiple sclerosis

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02425644
• Other Study ID Numbers: AC-058B301; 2012-000540-10
• First Posted: Apr 24, 2015
• Last Update Posted: Jan 26, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Actelion: relapsing multiple sclerosis
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Teriflunomide; Ponesimod

Study Results

Participant Flow

Pre-assignment Detail	As planned, Placebo was not a separate arm as this was included for double dummy design study part (up to Day 14).

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
Period Title: Overall Study
STARTED	567	566
Treated	565	566
COMPLETED	490	495
NOT COMPLETED	77	71

Baseline Characteristics

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg	Total
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.	Total of all reporting groups
Overall Participants	567	566	1133
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.7 (8.74)	36.8 (8.74)	36.7 (8.74)
Sex: Female, Male (Count of Participants)
Female	363 64%	372 65.7%	735 64.9%
Male	204 36%	194 34.3%	398 35.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.2%	1 0.1%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 0.5%	2 0.4%	5 0.4%
White	551 97.2%	553 97.7%	1104 97.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	13 2.3%	10 1.8%	23 2%
Region of Enrollment (Count of Participants)
BELARUS	21 3.7%	24 4.2%	45 4%
BULGARIA	18 3.2%	27 4.8%	45 4%
CANADA	10 1.8%	7 1.2%	17 1.5%
CROATIA	14 2.5%	20 3.5%	34 3%
CZECH REPUBLIC	55 9.7%	46 8.1%	101 8.9%
FINLAND	4 0.7%	3 0.5%	7 0.6%
FRANCE	8 1.4%	8 1.4%	16 1.4%
GEORGIA	24 4.2%	17 3%	41 3.6%
GERMANY	9 1.6%	7 1.2%	16 1.4%
GREECE	9 1.6%	6 1.1%	15 1.3%
HUNGARY	7 1.2%	12 2.1%	19 1.7%
ISRAEL	4 0.7%	9 1.6%	13 1.1%
ITALY	7 1.2%	7 1.2%	14 1.2%
LATVIA	11 1.9%	4 0.7%	15 1.3%
LITHUANIA	3 0.5%	8 1.4%	11 1%
MEXICO	7 1.2%	10 1.8%	17 1.5%
POLAND	80 14.1%	71 12.5%	151 13.3%
PORTUGAL	10 1.8%	10 1.8%	20 1.8%
ROMANIA	10 1.8%	5 0.9%	15 1.3%
RUSSIAN FEDERATION	116 20.5%	111 19.6%	227 20%
SPAIN	34 6%	39 6.9%	73 6.4%
SWEDEN	8 1.4%	6 1.1%	14 1.2%
TURKEY	2 0.4%	0 0%	2 0.2%
UKRAINE	57 10.1%	66 11.7%	123 10.9%
UNITED KINGDOM	2 0.4%	5 0.9%	7 0.6%
UNITED STATES	22 3.9%	17 3%	39 3.4%
Serbia	14 2.5%	19 3.4%	33 2.9%
Bosnia	1 0.2%	2 0.4%	3 0.3%

Outcome Measures

1. Primary 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 indicates overall functional impairment assessing Visual,Brain Stem,Pyramidal,Cerebellar,Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS in conjunction with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10(death due to MS).
Time Frame	From randomization to end of study (Week 108)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all participants randomized in the study.

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
Measure Participants	567	566
Mean (99% Confidence Interval) [relapses per year]	0.202	0.290

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 20 mg, Teriflunomide 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.695
	Confidence Interval	(2-Sided) 99%; 0.536 to 0.902
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) Score to Week 108
Description	The FSIQ-RMS is a 20-item Patient Reported Outcomes (PRO) measure to evaluate fatigue-related symptoms and the impacts of those symptoms on the lives of people. The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing fatigue-related symptoms daily with a recall period of 24 hours measured on an 11-point numeric rating scale; the (normalized) symptom domain score ranges from 0 to 100 with a higher score indicating greater fatigue. This domain was completed on 7 consecutive days. A negative change from baseline indicates an improvement in fatigue symptoms.
Time Frame	Baseline to Week 108

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized in the study. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure with available baseline and at least one post-baseline assessment.

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
Measure Participants	449	458
Least Squares Mean (95% Confidence Interval) [score on scale]	-0.01	3.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 20 mg, Teriflunomide 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.57
	Confidence Interval	(2-Sided) 95%; -5.83 to -1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Cumulative Number of Combined Unique Active Lesions (CUAL) Per Year From Baseline to Week 108
Description	CUALs was calculated as sum of new Gadolinium-enhanced (Gd+) T1 lesions plus new or enlarging T2 lesions (without double-counting of lesions) from baseline based on the Magnetic resonance imaging (MRI) scans up to Week 108. Average number of lesions per year were reported.
Time Frame	Baseline to Week 108

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized in the study. Here 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
Measure Participants	539	536
Mean (95% Confidence Interval) [lesions per year]	1.405	3.164

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 20 mg, Teriflunomide 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.444
	Confidence Interval	(2-Sided) 95%; 0.364 to 0.542
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS
Description	A 12-week CDA was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score greater than or equal to (>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS).
Time Frame	Baseline to Week 60 and 108 Weeks

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized in this study.

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
Measure Participants	567	566
60 Weeks- from Kaplan Meier estimates	7.6 1.3%	8.3 1.5%
108 Weeks- from Kaplan Meier estimates	10.8 1.9%	13.2 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 20 mg, Teriflunomide 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2939
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS
Description	A 24-week CDA was defined as an increase of at least 1.5 in EDSS for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score >= 5.5, which was confirmed after 24 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. The EDSS is an ordinal scale ranging from 0 (normal neurological exam) to 10 (death to MS).
Time Frame	Baseline to 60 Weeks and 108 Weeks

Outcome Measure Data

Analysis Population Description

FAS included all participants randomized in this study.

Arm/Group Title	Ponesimod 20 mg	Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108	Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
Measure Participants	567	566
60 Weeks- from Kaplan Meier estimates	6.3 1.1%	6.9 1.2%
108 Weeks- from Kaplan Meier estimates	8.7 1.5%	10.5 1.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod 20 mg, Teriflunomide 14 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3720
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 111 Weeks (From treatment start [Day 1] to end of treatment [Week 108] plus 15 days)
Adverse Event Reporting Description	Safety analysis set included all participants who received at least one dose of study treatment.
Arm/Group Title	Ponesimod 20 mg		Teriflunomide 14 mg
Arm/Group Description	Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108		Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo.
All Cause Mortality
	Ponesimod 20 mg		Teriflunomide 14 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/565 (0%)		2/566 (0.4%)
Serious Adverse Events
	Ponesimod 20 mg		Teriflunomide 14 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/565 (8.7%)		46/566 (8.1%)
Blood and lymphatic system disorders
Lymphadenitis	0/565 (0%)		1/566 (0.2%)
Thrombocytopenia	1/565 (0.2%)		0/566 (0%)
Cardiac disorders
Atrial Fibrillation	0/565 (0%)		1/566 (0.2%)
Coronary Artery Insufficiency	0/565 (0%)		1/566 (0.2%)
Gastrointestinal disorders
Abdominal Pain	3/565 (0.5%)		0/566 (0%)
Bowel Movement Irregularity	0/565 (0%)		1/566 (0.2%)
Constipation	1/565 (0.2%)		0/566 (0%)
Duodenal Ulcer Haemorrhage	0/565 (0%)		1/566 (0.2%)
Duodenitis	0/565 (0%)		1/566 (0.2%)
Dyspepsia	0/565 (0%)		1/566 (0.2%)
Gastritis	0/565 (0%)		1/566 (0.2%)
Haemorrhoidal Haemorrhage	1/565 (0.2%)		0/566 (0%)
Intestinal Haemorrhage	1/565 (0.2%)		0/566 (0%)
Pancreatitis Acute	1/565 (0.2%)		0/566 (0%)
Hepatobiliary disorders
Biliary Colic	0/565 (0%)		1/566 (0.2%)
Cholecystitis Acute	0/565 (0%)		1/566 (0.2%)
Cholecystitis Chronic	0/565 (0%)		1/566 (0.2%)
Cholelithiasis	1/565 (0.2%)		3/566 (0.5%)
Drug-Induced Liver Injury	1/565 (0.2%)		0/566 (0%)
Hepatitis	0/565 (0%)		1/566 (0.2%)
Hepatitis Toxic	0/565 (0%)		1/566 (0.2%)
Infections and infestations
Abdominal Infection	1/565 (0.2%)		0/566 (0%)
Appendicitis	3/565 (0.5%)		0/566 (0%)
Bronchitis	0/565 (0%)		1/566 (0.2%)
Herpes Zoster	1/565 (0.2%)		0/566 (0%)
Lymph Node Abscess	0/565 (0%)		1/566 (0.2%)
Meningitis	0/565 (0%)		1/566 (0.2%)
Meningitis Enteroviral	0/565 (0%)		1/566 (0.2%)
Pilonidal Cyst	1/565 (0.2%)		0/566 (0%)
Salpingitis	0/565 (0%)		1/566 (0.2%)
Urinary Tract Infection	1/565 (0.2%)		0/566 (0%)
Vestibular Neuronitis	0/565 (0%)		1/566 (0.2%)
Injury, poisoning and procedural complications
Concussion	0/565 (0%)		2/566 (0.4%)
Fall	0/565 (0%)		1/566 (0.2%)
Femur Fracture	0/565 (0%)		1/566 (0.2%)
Fibula Fracture	0/565 (0%)		1/566 (0.2%)
Jaw Fracture	1/565 (0.2%)		0/566 (0%)
Ligament Injury	1/565 (0.2%)		0/566 (0%)
Meniscus Injury	0/565 (0%)		1/566 (0.2%)
Multiple Injuries	1/565 (0.2%)		0/566 (0%)
Post Procedural Haematoma	1/565 (0.2%)		0/566 (0%)
Soft Tissue Injury	0/565 (0%)		1/566 (0.2%)
Toxicity to Various Agents	0/565 (0%)		1/566 (0.2%)
Investigations
Alanine Aminotransferase Increased	0/565 (0%)		2/566 (0.4%)
Aspartate Aminotransferase Increased	0/565 (0%)		1/566 (0.2%)
Hepatic Enzyme Increased	1/565 (0.2%)		0/566 (0%)
Transaminases Increased	0/565 (0%)		1/566 (0.2%)
Weight Decreased	1/565 (0.2%)		0/566 (0%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	0/565 (0%)		1/566 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/565 (0%)		1/566 (0.2%)
Intervertebral Disc Protrusion	1/565 (0.2%)		1/566 (0.2%)
Myofascial Pain Syndrome	0/565 (0%)		1/566 (0.2%)
Osteoarthritis	1/565 (0.2%)		0/566 (0%)
Rheumatoid Arthritis	1/565 (0.2%)		0/566 (0%)
Spinal Pain	0/565 (0%)		1/566 (0.2%)
Synovitis	0/565 (0%)		1/566 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	1/565 (0.2%)		0/566 (0%)
Eyelid Haemangioma	1/565 (0.2%)		0/566 (0%)
Invasive Ductal Breast Carcinoma	0/565 (0%)		1/566 (0.2%)
Malignant Melanoma	1/565 (0.2%)		0/566 (0%)
Pituitary Tumour Benign	1/565 (0.2%)		0/566 (0%)
Squamous Cell Carcinoma of the Cervix	1/565 (0.2%)		0/566 (0%)
Uterine Leiomyoma	1/565 (0.2%)		2/566 (0.4%)
Nervous system disorders
Clonic Convulsion	1/565 (0.2%)		0/566 (0%)
Epilepsy	1/565 (0.2%)		0/566 (0%)
Headache	1/565 (0.2%)		0/566 (0%)
Ischaemic Stroke	0/565 (0%)		1/566 (0.2%)
Loss of Consciousness	0/565 (0%)		1/566 (0.2%)
Lumbar Radiculopathy	2/565 (0.4%)		1/566 (0.2%)
Multiple Sclerosis	0/565 (0%)		1/566 (0.2%)
Multiple Sclerosis Relapse	1/565 (0.2%)		1/566 (0.2%)
Partial Seizures with Secondary Generalisation	1/565 (0.2%)		0/566 (0%)
Restless Legs Syndrome	1/565 (0.2%)		0/566 (0%)
Syncope	1/565 (0.2%)		0/566 (0%)
Trigeminal Neuralgia	0/565 (0%)		1/566 (0.2%)
Psychiatric disorders
Conversion Disorder	0/565 (0%)		1/566 (0.2%)
Depression	0/565 (0%)		1/566 (0.2%)
Panic Attack	1/565 (0.2%)		0/566 (0%)
Renal and urinary disorders
Nephrolithiasis	1/565 (0.2%)		0/566 (0%)
Proteinuria	1/565 (0.2%)		0/566 (0%)
Renal Colic	1/565 (0.2%)		0/566 (0%)
Tubulointerstitial Nephritis	1/565 (0.2%)		0/566 (0%)
Ureterolithiasis	0/565 (0%)		1/566 (0.2%)
Reproductive system and breast disorders
Breast Cyst	0/565 (0%)		1/566 (0.2%)
Endometrial Hyperplasia	1/565 (0.2%)		1/566 (0.2%)
Endometriosis	1/565 (0.2%)		1/566 (0.2%)
Menorrhagia	1/565 (0.2%)		0/566 (0%)
Metrorrhagia	0/565 (0%)		2/566 (0.4%)
Ovarian Cyst	0/565 (0%)		1/566 (0.2%)
Pelvic Adhesions	0/565 (0%)		1/566 (0.2%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/565 (0.2%)		0/566 (0%)
Bronchospasm	1/565 (0.2%)		0/566 (0%)
Hyperventilation	0/565 (0%)		1/566 (0.2%)
Surgical and medical procedures
Abortion Induced	2/565 (0.4%)		0/566 (0%)
Haemorrhoid Operation	1/565 (0.2%)		0/566 (0%)
Hysterectomy	1/565 (0.2%)		0/566 (0%)
Ligament Operation	1/565 (0.2%)		0/566 (0%)
Uterine Dilation and Curettage	0/565 (0%)		1/566 (0.2%)
Vascular disorders
Deep Vein Thrombosis	1/565 (0.2%)		0/566 (0%)
Hypertensive Crisis	1/565 (0.2%)		1/566 (0.2%)
Raynaud's Phenomenon	0/565 (0%)		1/566 (0.2%)
Thrombophlebitis Superficial	1/565 (0.2%)		0/566 (0%)
Other (Not Including Serious) Adverse Events
	Ponesimod 20 mg		Teriflunomide 14 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	434/565 (76.8%)		422/566 (74.6%)
Blood and lymphatic system disorders
Neutropenia	6/565 (1.1%)		13/566 (2.3%)
Ear and labyrinth disorders
Vertigo	13/565 (2.3%)		7/566 (1.2%)
Gastrointestinal disorders
Abdominal Pain	9/565 (1.6%)		18/566 (3.2%)
Abdominal Pain Upper	19/565 (3.4%)		24/566 (4.2%)
Constipation	16/565 (2.8%)		21/566 (3.7%)
Diarrhoea	20/565 (3.5%)		44/566 (7.8%)
Dyspepsia	13/565 (2.3%)		13/566 (2.3%)
Nausea	43/565 (7.6%)		47/566 (8.3%)
Vomiting	11/565 (1.9%)		18/566 (3.2%)
General disorders
Asthenia	11/565 (1.9%)		18/566 (3.2%)
Fatigue	34/565 (6%)		37/566 (6.5%)
Pyrexia	12/565 (2.1%)		7/566 (1.2%)
Infections and infestations
Bronchitis	26/565 (4.6%)		24/566 (4.2%)
Gastroenteritis	12/565 (2.1%)		18/566 (3.2%)
Influenza	24/565 (4.2%)		23/566 (4.1%)
Nasopharyngitis	109/565 (19.3%)		95/566 (16.8%)
Oral Herpes	17/565 (3%)		21/566 (3.7%)
Pharyngitis	14/565 (2.5%)		14/566 (2.5%)
Respiratory Tract Infection	17/565 (3%)		16/566 (2.8%)
Respiratory Tract Infection Viral	18/565 (3.2%)		10/566 (1.8%)
Rhinitis	12/565 (2.1%)		17/566 (3%)
Sinusitis	8/565 (1.4%)		16/566 (2.8%)
Tonsillitis	8/565 (1.4%)		14/566 (2.5%)
Upper Respiratory Tract Infection	60/565 (10.6%)		59/566 (10.4%)
Urinary Tract Infection	31/565 (5.5%)		29/566 (5.1%)
Investigations
Alanine Aminotransferase Increased	110/565 (19.5%)		51/566 (9%)
Aspartate Aminotransferase Increased	36/565 (6.4%)		19/566 (3.4%)
C-Reactive Protein Increased	12/565 (2.1%)		7/566 (1.2%)
Hepatic Enzyme Increased	13/565 (2.3%)		8/566 (1.4%)
Weight Decreased	6/565 (1.1%)		14/566 (2.5%)
Metabolism and nutrition disorders
Hypercholesterolaemia	13/565 (2.3%)		3/566 (0.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	17/565 (3%)		15/566 (2.7%)
Back Pain	33/565 (5.8%)		38/566 (6.7%)
Pain in Extremity	20/565 (3.5%)		17/566 (3%)
Nervous system disorders
Dizziness	28/565 (5%)		15/566 (2.7%)
Headache	64/565 (11.3%)		72/566 (12.7%)
Hypoaesthesia	14/565 (2.5%)		14/566 (2.5%)
Paraesthesia	17/565 (3%)		28/566 (4.9%)
Somnolence	18/565 (3.2%)		9/566 (1.6%)
Psychiatric disorders
Anxiety	18/565 (3.2%)		16/566 (2.8%)
Depression	21/565 (3.7%)		28/566 (4.9%)
Insomnia	11/565 (1.9%)		16/566 (2.8%)
Respiratory, thoracic and mediastinal disorders
Cough	20/565 (3.5%)		14/566 (2.5%)
Dyspnoea	30/565 (5.3%)		7/566 (1.2%)
Skin and subcutaneous tissue disorders
Alopecia	18/565 (3.2%)		72/566 (12.7%)
Rash	8/565 (1.4%)		14/566 (2.5%)
Vascular disorders
Hypertension	45/565 (8%)		44/566 (7.8%)

Limitations/Caveats

Low probability of this study to provide robust evaluation of ponesimod effect on disability accumulation compared to active comparator; study was not powered for this secondary endpoint. Impact of accelerated elimination procedure during safety follow-up: Accelerated elimination procedure for teriflunomide with cholestyramine/activated charcoal was frequently associated with benign, transient elevation in liver enzymes. Confounding effect of this procedure on assessing liver test was included.

More Information

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.