POINT: Clinical Study to Compare the Efficacy and Safety of Ponesimod to Placebo in Subjects With Active Relapsing Multiple Sclerosis Who Are Treated With Dimethyl Fumarate (Tecfidera®)

• Sponsor: Actelion (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02907177
• Collaborator: (none)
• Enrollment: 136
• Locations: 119
• Arms: 2
• Actual Duration (Months): 35.9
• Patients Per Site: 1.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This clinical study compares the efficacy, safety, and tolerability of therapy with ponesimod vs placebo in subjects with active RMS who are treated with DMF (Tecfidera®).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Ponesimod; Other: Placebo	Phase 3

Detailed Description

The study will assess the efficacy, safety, and tolerability of add-on therapy with ponesimod 20 mg vs placebo in adult participants with active relapsing multiple sclerosis (RMS) who are treated with dimethyl fumarate (DMF). Approximately 600 participants who have been receiving DMF for at least 6 months will be randomized in a 1:1 ratio to ponesimod 20 mg or placebo. The study consists of the following study periods: Pre-randomization period; Treatment period; Post-treatment observation period. The study includes one ponesimod treatment arm at the maintenance dose of 20 mg o.d. corresponding to the optimal dose when used as monotherapy based on the Phase 2 dose-finding trial and its ongoing extension. The study includes a placebo comparator arm, but all patients will remain on DMF background therapy throughout the study. Moreover, participants who experience a confirmed relapse or an event of 24-week confirmed disability accumulation (DMF) while on study drug will have the option to switch to an alternative treatment. The treatment period has a variable duration from a minimum of 60 weeks (for the last subject randomized) to a maximum of 156 weeks for the first subjects randomized in the trial and includes a gradual up-titration of ponesimod from a 2 mg starting dose to a 20 mg maintenance dose over a period of 14 days. The total duration of the study will be approximately up to 167 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 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, add-on, Superiority Study to Compare the Efficacy and Safety of Ponesimod to Placebo in Subjects With Active Relapsing Multiple Sclerosis Who Are Treated With Dimethyl Fumarate (Tecfidera®)
• Actual Study Start Date: Mar 30, 2017
• Actual Primary Completion Date: Mar 26, 2020
• Actual Study Completion Date: Mar 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ponesimod Ponesimod	Drug: Ponesimod; One tablet of ponesimod 20 mg administered orally once daily in the morning from Day 15 to EOT. To reduce the first-dose effect of ponesimod, an uptitration scheme will be implemented from Day 1 to Day 14 (with dose strength increasing from 2 mg to 20 mg).
Placebo Comparator: Placebo Placebo	Other: Placebo; One tablet of matching placebo administered orally once daily in the morning

Outcome Measures

Primary Outcome Measures

1. Annualized Confirmed Relapse Rate (ARR) [Through study completion, an average of 68 weeks]

   Relapse: occurrence of acute episode of one or more new 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. Percentage of Participants With 12-Week Confirmed Disability Accumulation (CDA) as Assessed by Kaplan Meier Estimate at Week 96 [Week 96]

   Percentage of participants with 12-week CDA as assessed by Kaplan Meier estimate at week 96 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).

2. Percentage of Participants Experiencing a Confirmed Relapse as Assessed by Kaplan Meier Estimate at Week 96 [Week 96]

   Percentage of participants experiencing a confirmed relapse as assessed by Kaplan Meier estimate at week 96 was reported. The time to first confirmed relapse (in days) is defined as [Date of first confirmed relapse minus Date of randomization plus 1] in days. Relapse: Occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple sclerosis (MS), not related with fever/infection and lasting 24 hours after 30 days stable period.

3. Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability [Up to 147 Weeks]

   An AE is any untoward medical event that occurs in a participants administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

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

• Women of childbearing potential must have a negative pregnancy test and use reliable methods of contraception

• Presenting with a diagnosis of MS as defined by the revised (2010) McDonald Diagnostic Criteria for MS with relapsing course from onset (i.e., relapsing-remitting multiple sclerosis (RRMS), or secondary progressive multiple sclerosis (SPMS) with superimposed relapses).

• Ongoing treatment with DMF for at least 6 months prior to screening

• Active disease after at least 3 months of DMF treatment

• Ambulatory and with an EDSS score between 0 and 6.0 (inclusive).

Exclusion Criteria:

• Lactating or pregnant women and women intending to become pregnant during the study.

• Presenting with a diagnosis of MS with progressive course from onset (i.e., primary progressive MS or progressive relapsing MS).

• Evidence of a relapse of MS with onset within 30 days prior to baseline EDSS assessment.

• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Dpt of Neurology	Birmingham	Alabama	United States	35233
2	Neuro-Pain Medical Center	Fresno	California	United States	93710
3	SC3 Research - Pasadena	Pasadena	California	United States	91105
4	Care Access Research - Santa Clarita	Santa Clarita	California	United States	91321
5	Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center	Torrance	California	United States	90502
6	University of Colorado Hospital	Aurora	Colorado	United States	80045
7	Mountain View Clinical Research, Inc	Denver	Colorado	United States	80209
8	Associated Neurologists	Danbury	Connecticut	United States	06810
9	Bradenton Research Center	Bradenton	Florida	United States	34205
10	Neurology Associates - MS Center of Greater Orlando	Maitland	Florida	United States	32751
11	Neurology Assoc of Ormond Beach - CNS Trials	Ormond Beach	Florida	United States	32174
12	Suncoast Neuroscience Associates, Inc	Saint Petersburg	Florida	United States	33713
13	The MS Center of Vero Beach	Vero Beach	Florida	United States	32960
14	Fort Wayne Neurological Center - North Office	Fort Wayne	Indiana	United States	46825
15	University of Kansas Med Center	Kansas City	Kansas	United States	66160
16	MidAmerica Neuroscience Research Foundation/Rowe Neurology	Lenexa	Kansas	United States	66214
17	Henry Ford Health System - Neurology	Detroit	Michigan	United States	48202
18	Univ of New Mexico - Health Sciences Center	Albuquerque	New Mexico	United States	87131
19	NYU Langone Medical Center - MS Comprehensive Care Center	New York	New York	United States	10016
20	Riverhills Healthcare, Inc.	Cincinnati	Ohio	United States	45212
21	OhioHealth Research Institute	Columbus	Ohio	United States	43214
22	Neurology and Neuromuscular Center	Oklahoma City	Oklahoma	United States	73102
23	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
24	Thomas Jefferson University Hospital - Dpt Neurology MS Center	Philadelphia	Pennsylvania	United States	19107
25	Advanced Neuroscience Institute	Franklin	Tennessee	United States	37064
26	Neurology Center of San Antonio	San Antonio	Texas	United States	78258
27	Austin Health - Neuro-Immunology Clinical Research, Education and Support Service	Heidelberg	Victoria	Australia	3084
28	MS Ambulanz Maida	Wien		Austria	1010
29	Medizinische Universität Wien, Universitätsklinik für Neurologie	Wien		Austria	1090
30	Hospital universitair Brussels_neurology department	Brussels		Belgium	1090
31	Hospital - Universitair Gent __Neurology Department	Gent		Belgium	9000
32	Hospital - Revalidatie & MS Centrum Overpelt_Neurology Department	Overpelt		Belgium	3900
33	"Multiprofile Hospital for Active Treatment of Neurology and Psychiatry - Sveti Naum" EAD - Neurology Clinic for Movement Disorders	Sofia		Bulgaria	1113
34	"University Multiprofile Hospital for Active Treatment - Alexandrovska" EAD, Neurology Clinic	Sofia		Bulgaria	1431
35	University Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski" EAD, Neurology Clinic	Sofia		Bulgaria	1431
36	University of Alberta	Edmonton		Canada	T6G 1Z1
37	Fakultní nemocnice u sv. Anny Brno, RS Centrum	Brno		Czechia	656 91
38	Fakultní nemocnice Hradec Králové, Neurologická klinika	Hradec Králové		Czechia	500 05
39	Nemocnice Jihlava, Neurologické oddělení	Jihlava		Czechia	586 33
40	Pardubicka krajska nemocnice, MS Centrum	Pardubice		Czechia	532 03
41	Krajská zdravotní a.s. - Nemonice Teplice o.z., RS Centrum	Teplice		Czechia	415 29
42	Aalborg Universitetshospital, Skleroseklinikken Neurologisk afdelning	Aalborg		Denmark	9000
43	Glostrup Hospital, Neurologisk afdelning	Glostrup		Denmark	2600
44	Hôpital Avicenne, Service de Neurologie	Bobigny		France	93000
45	Hosp Gabriel Montpied, Dept Neurology	Clermont Ferrand		France	63003
46	Centre Hospitalier Sud Francilien - Service de Neurologie	Corbeil-Essonnes		France	91100
47	CHU de Dijon - Hôpital François Miterrand, Service de Neurologie	Dijon		France	21079
48	CHRU de Lille - Hôpital Roger Salengro, Service de Neurologie	Lille		France	59037
49	Hopital Gui de Chauliac - CHU Montpellier	Montpellier		France	34295
50	Hôpital Central - CHU Nancy, Département Neurologie	Nancy		France	54035
51	Hôpital Universitaire Carémeau, Service de Neurologie	Nimes		France	30029
52	CHI POISSY-Saint Germay en Laye_Service de Neurologie et Réeducation	Poissy		France	78303
53	Hosp Pontchaillou, Dept Cardiology	Rennes		France	35033
54	Hosp Charles Nicolle Dept Neurology	Rouen		France	76000
55	Zentrum für klinische Forschung Dr. med. Irma Schöll	Bad Homburg		Germany	61348
56	Neurologische Klinik und Poliklinik - Universitätsklinikum Carl Gustav Carus, Zentrum für klinische Neurowissenschaften	Dresden		Germany	01307
57	Helios Klinikum Erfurt	Erfurt		Germany	99089
58	Universitätsklinikum Giessen Klinik und Poliklinik für Neurologie	Giessen		Germany	35385
59	Universitätsmedizin Greifswald - Körperschaft des öffentlichen Rechts - Klinik und Poliklinik für Neurologie	Greifswald		Germany	17475
60	Medizinische Hochschule Hannover, Neurologie	Hannover		Germany	30625
61	AFL Arzneimittelforschung Leipzig GmbH	Leipzig		Germany	04107
62	Universitätsklinikum Münster, Klinik für Allgemeine Neurologie	Münster		Germany	48149
63	Medizinzentrum Siegerland Weidenau	Siegen		Germany	57076
64	NeuroPoint GmbH, Gesellschaft für vorbeugende Gesundheitspflege	Ulm		Germany	89073
65	Gemeinschaftspraxis Dr. med. Joachim Springub / Wolfgang Schwarz, Studienzentrum Nord-West (Study Center)	Westerstede		Germany	26655
66	Naval Hospital of Athens - Neurology Dpt	Athens		Greece	11521
67	401 Military Hospital of Athens - Neurology Dept	Athens		Greece	11525
68	Aeginition Hospital - Neurology Department	Athens		Greece	11528
69	Medical Center of Athens - Neurology Dpt	Marousi		Greece	15125
70	General Hospital of Thessaloniki	Thessaloniki		Greece	57010
71	Uzsoki utcai Kórház, Neurológiai Osztály	Budapest		Hungary	1145
72	Valeomed EGÉSZSÉGÜGYI KÖZPONT	Esztergom		Hungary	2500
73	Pest Megyei Flór Ferenc Kórház, Neurológia és Stroke ambulancia	Kistarcsa		Hungary	2143
74	Fondazione Istituto San Raffaele , Unità Operativa di Neurologia	Cefalù		Italy	90015
75	Università degli Studi di Firenze - Azienda Ospedaliero Universitaria Careggi - CTO - SOD Neurologia 2	Firenze		Italy	50139
76	AOU San Martino di Genova, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI)	Genova		Italy	16132
77	Istituto Neurologico Carlo Besta, UOC Neurologia 4, Neuroimmunologia e Malattie Neuromuscolari, Centro Sclerosi Multipla	Milano		Italy	20133
78	Azienda Ospedaliera Universitaria (AOU) "Federico II" - Centro Regionale Per la Sclerosi Multipla c/o Clinica Neurologica II - Dipartimento di Scienze	Napoli		Italy	80131
79	AOU Università degli Studi della Campania L. Vanvitelli - I° Policlinico - DAI di Medicina Interna e Specialistica CS, Centro Sclerosi Multipla	Napoli		Italy	80138
80	Azienda Ospedaliero Universitaria San Luigi Gonzaga - Centro Sclerosi Multipla CRESM	Orbassano		Italy	10043
81	IRCCS NEUROMED - Istituto Neurologico Mediterraneo - Unità Operativa di Neurologia I	Pozzilli		Italy	86077
82	Azienda Ospedaliera S. Andrea di Roma - Unità Operativa Complessa di Neurologia	Roma		Italy	00189
83	Azienda Ospedaliera Universitaria Senese - Dipartimento di Scienze Neurologiche e neurosensoriali - UOSA Neurologia Sperimentale	Siena		Italy	53100
84	Unidad de Investigacion en Salud de Chihuahua SC, Médica Sur, Unidad de Neurociencias	Tlalpan	DF	Mexico	14050
85	Desarrollo Ético en Investigación Clínica S.C .	Guadalajara	Jalisco	Mexico	44500
86	Axis Heilsa S. de R.L. de C.V. (Althian)	Nuevo Leon	Monterrey	Mexico	64060
87	Unidad de Investigación de Salud en Chihuahua	Chihuahua		Mexico	31203
88	Uniwersytecki Szpital Kliniczny w Bialymstoku, Klinika Neurologii i Oddziat Udarowy	Bialystok		Poland	15-276
89	B&B Robert Bonek, Pawel Bochniak S.C	Bydgoszcz		Poland	85-795
90	COPERNICUS - Podmiot Leczniczy Sp. z o.o.	Gdansk		Poland	80-803
91	Centrum Terapii SM	Katowice		Poland	40-571
92	Neuro-Medic Janusz Zbrojkiewicz Poradnia Weilospecjalistyczna	Katowice		Poland	40-752
93	Centrum Kompleksowej Rehabilitacji	Konstancin-Jeziorna		Poland	05-510
94	Centrum Opieki Zdrowotnej Orkan - Med.	Ksawerów		Poland	95-054
95	Instytut Psychiatrii i Neurologii, II Klinika Neurologiczna	Warszawa		Poland	02-957
96	WroMedica, J. Bielicka A. Strzałkowska SC	Wroclaw		Poland	51-685
97	Centro Hospitalar de Lisboa Central	Lisboa		Portugal	1169-050
98	Hospital de Santa Maria - Neurology Department	Lisboa		Portugal	1649-035
99	Centro Hospitalar de São João, E.P.E. - Hospital de São João - Neurology Department	Porto		Portugal	4200-319
100	State Budgetary Healthcare Institution Regional Clinical Hospital No 3	Chelyabinsk		Russian Federation	454021
101	Center of Professional Therapy, LLC	Krasnodar		Russian Federation	350051
102	Moscow State Budgetary Healthcare Institution Filatov City Clinical Hospital No.15 of Moscow Health Department	Moscow		Russian Federation	111539
103	Neuro-Clinic, LLC	Moscow		Russian Federation	117186
104	Moscow State Budgetary Healthcare Institution Pirogov City Clinical Hospital No. 1 of Moscow Health Department	Moscow		Russian Federation	119049
105	Moscow State Budgetary Healthcare Institution City Clinical Hospital No. 24 of Moscow Health Department	Moscow		Russian Federation	127015
106	Hospital Santa Creu I Sant Pau - Neurology Dpt	Barcelona		Spain	08041
107	Hosp Virgen de la Arrixaca, Neurology	El Palmar		Spain	30120
108	Hosp Gregorio Marañón, Neurology	Madrid		Spain	28007
109	Hospital Clinico San Carlos, Neurology	Madrid		Spain	28040
110	Hospital Santa Caterina - Neurology Department	Salt		Spain	17190
111	Complejo Hospitalario Universitario de Santiago de Compostela (CHUS) - Neurology Department 2	Santiago de Compostela		Spain	15703
112	Hospital Universitario Virgen Macarena - Neurofisiology Department	Sevilla		Spain	41009
113	Centro de Neurologia Avanzada, Neurology	Sevilla		Spain	41013
114	Univeritätsspital Basel Neurologie, Neurologische Klinik und Poliklinik	Basel		Switzerland	4031
115	Ospedale Regionale di Lugano - Civico e Italiano, Neurologia, Lugano	Lugano		Switzerland	6903
116	Queen Square MS Centre / NMR research Unit UCL Institute of Neurology	London		United Kingdom	WC1N 3BG
117	Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital	Oxford		United Kingdom	OX3 9DU
118	Royal Hallamshire Hospital	Sheffield		United Kingdom	S10 2JF
119	University Hospitals of North Midlands NHS Trust	Stoke-on-Trent		United Kingdom	ST4 6QG

Sponsors and Collaborators

• Actelion

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Dec 21, 2017
• Statistical Analysis Plan - Jun 16, 2020

More Information

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT02907177
• Other Study ID Numbers: AC-058B302
• First Posted: Sep 20, 2016
• Last Update Posted: May 18, 2021
• Last Verified: Apr 1, 2021

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

Study Results

Participant Flow

Pre-assignment Detail	Total 136 participants were randomized,68 in both arms (ponesimod 20mg plus DMF [dimethyl fumarate] & placebo plus DMF). Of 136 participants,107 (50 in ponesimod 20mg plus DMF; 57 in placebo plus DMF) completed study till early termination.This study was discontinued due to sponsor's decision.

Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)	Placebo Plus Dimethyl Fumarate (DMF)
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.
Period Title: Overall Study
STARTED	68	68
Treated	67	68
Randomized Analysis Set	68	68
COMPLETED	0	0
NOT COMPLETED	68	68

Baseline Characteristics

Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)	Placebo Plus Dimethyl Fumarate (DMF)	Total
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Total of all reporting groups
Overall Participants	68	68	136
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	68 100%	68 100%	136 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.8 (9.1)	38.1 (9.1)	37.9 (9.07)
Sex: Female, Male (Count of Participants)
Female	43 63.2%	46 67.6%	89 65.4%
Male	25 36.8%	22 32.4%	47 34.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 5.9%	2 2.9%	6 4.4%
Not Hispanic or Latino	61 89.7%	61 89.7%	122 89.7%
Unknown or Not Reported	3 4.4%	5 7.4%	8 5.9%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	1 1.5%	1 0.7%
Black or African American	3 4.4%	1 1.5%	4 2.9%
Other	0 0%	2 2.9%	2 1.5%
Unknown or Not Reported	1 1.5%	1 1.5%	2 1.5%
White	64 94.1%	63 92.6%	127 93.4%
Region of Enrollment (Count of Participants)
AUSTRIA	5 7.4%	7 10.3%	12 8.8%
BELGIUM	2 2.9%	0 0%	2 1.5%
BULGARIA	2 2.9%	2 2.9%	4 2.9%
CANADA	0 0%	1 1.5%	1 0.7%
CZECH REPUBLIC	16 23.5%	17 25%	33 24.3%
FRANCE	4 5.9%	6 8.8%	10 7.4%
GERMANY	4 5.9%	6 8.8%	10 7.4%
GREECE	4 5.9%	6 8.8%	10 7.4%
HUNGARY	1 1.5%	0 0%	1 0.7%
ITALY	5 7.4%	4 5.9%	9 6.6%
MEXICO	1 1.5%	0 0%	1 0.7%
POLAND	4 5.9%	5 7.4%	9 6.6%
PORTUGAL	1 1.5%	0 0%	1 0.7%
RUSSIAN FEDERATION	4 5.9%	2 2.9%	6 4.4%
SPAIN	2 2.9%	3 4.4%	5 3.7%
UNITED KINGDOM	5 7.4%	4 5.9%	9 6.6%
UNITED STATES	8 11.8%	5 7.4%	13 9.6%

Outcome Measures

1. Primary Outcome

Title	Annualized Confirmed Relapse Rate (ARR)
Description	Relapse: occurrence of acute episode of one or more new 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	Through study completion, an average of 68 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who were treated with at least one dose of study treatment and had at least one post baseline efficacy assessment. Participants were analyzed according to randomized treatment.

Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)	Placebo Plus Dimethyl Fumarate (DMF)
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.
Measure Participants	66	67
Mean (95% Confidence Interval) [Relapses per year]	0.237	0.187

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ponesimod Plus Dimethyl Fumarate (DMF), Placebo Plus Dimethyl Fumarate (DMF)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5252
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Treatment effect (rate ratio)
	Estimated Value	1.270
	Confidence Interval	(2-Sided) 95%; 0.608 to 2.654
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio is ponesimod 20 mg / DMF versus placebo /DMF

2. Secondary Outcome

Title	Percentage of Participants With 12-Week Confirmed Disability Accumulation (CDA) as Assessed by Kaplan Meier Estimate at Week 96
Description	Percentage of participants with 12-week CDA as assessed by Kaplan Meier estimate at week 96 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	Week 96

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who were treated with at least one dose of study treatment and had at least one post baseline efficacy assessment. Participants were analyzed according to randomized treatment.

Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)	Placebo Plus Dimethyl Fumarate (DMF)
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.
Measure Participants	66	67
Number (95% Confidence Interval) [Percentage of participants with a CDA.]	18.7 27.5%	11.9 17.5%

3. Secondary Outcome

Title	Percentage of Participants Experiencing a Confirmed Relapse as Assessed by Kaplan Meier Estimate at Week 96
Description	Percentage of participants experiencing a confirmed relapse as assessed by Kaplan Meier estimate at week 96 was reported. The time to first confirmed relapse (in days) is defined as [Date of first confirmed relapse minus Date of randomization plus 1] in days. Relapse: Occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple sclerosis (MS), not related with fever/infection and lasting 24 hours after 30 days stable period.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who were treated with at least one dose of study treatment and had at least one post baseline efficacy assessment. Participants were analyzed according to randomized treatment.

Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)	Placebo Plus Dimethyl Fumarate (DMF)
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.
Measure Participants	66	67
Number (95% Confidence Interval) [Percentage of Participants]	33.6 49.4%	25.7 37.8%

4. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability
Description	An AE is any untoward medical event that occurs in a participants administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time Frame	Up to 147 Weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF) includes all participants who received at least one dose of study treatment.

Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)	Placebo Plus Dimethyl Fumarate (DMF)
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.	Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.
Measure Participants	67	68
Count of Participants [Participants]	48 70.6%	53 77.9%

Adverse Events

Time Frame	Up to End of treatment + 15 days (maximum up to 147 Weeks)
Adverse Event Reporting Description	Treatment-Emergent Adverse Events (TEAEs) included deaths, Serious Adverse Events (SAEs), Adverse Events (AEs) leading to premature treatment discontinuation, and Adverse Events of Special Interest (AESIs) were summarized. Safety Analysis Set (SAF) includes all participants who received at least one dose of study treatment.
Arm/Group Title	Ponesimod Plus Dimethyl Fumarate (DMF)		Placebo Plus Dimethyl Fumarate (DMF)
Arm/Group Description	Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.		Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy.
All Cause Mortality
	Ponesimod Plus Dimethyl Fumarate (DMF)		Placebo Plus Dimethyl Fumarate (DMF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0%)		1/68 (1.5%)
Serious Adverse Events
	Ponesimod Plus Dimethyl Fumarate (DMF)		Placebo Plus Dimethyl Fumarate (DMF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/67 (9%)		7/68 (10.3%)
Cardiac disorders
Right Ventricular Failure	0/67 (0%)		1/68 (1.5%)
Infections and infestations
Gastroenteritis Bacterial	1/67 (1.5%)		0/68 (0%)
Influenza	0/67 (0%)		1/68 (1.5%)
Pneumonia Influenzal	0/67 (0%)		1/68 (1.5%)
Pneumonia Pseudomonal	0/67 (0%)		1/68 (1.5%)
Injury, poisoning and procedural complications
Multiple Injuries	1/67 (1.5%)		0/68 (0%)
Procedural Nausea	1/67 (1.5%)		0/68 (0%)
Road Traffic Accident	1/67 (1.5%)		0/68 (0%)
Tendon Rupture	0/67 (0%)		1/68 (1.5%)
Musculoskeletal and connective tissue disorders
Exostosis	0/67 (0%)		1/68 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Testicle Adenoma	1/67 (1.5%)		0/68 (0%)
Nervous system disorders
Epilepsy	0/67 (0%)		1/68 (1.5%)
Multiple Sclerosis Relapse	0/67 (0%)		1/68 (1.5%)
Seizure	1/67 (1.5%)		0/68 (0%)
Status Epilepticus	1/67 (1.5%)		0/68 (0%)
Psychiatric disorders
Depression	0/67 (0%)		1/68 (1.5%)
Suicide Attempt	0/67 (0%)		1/68 (1.5%)
Renal and urinary disorders
Urinary Retention	1/67 (1.5%)		0/68 (0%)
Other (Not Including Serious) Adverse Events
	Ponesimod Plus Dimethyl Fumarate (DMF)		Placebo Plus Dimethyl Fumarate (DMF)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/67 (67.2%)		41/68 (60.3%)
Blood and lymphatic system disorders
Lymphadenopathy	0/67 (0%)		2/68 (2.9%)
Lymphopenia	2/67 (3%)		0/68 (0%)
Cardiac disorders
Palpitations	2/67 (3%)		1/68 (1.5%)
Ear and labyrinth disorders
Ear Pain	2/67 (3%)		0/68 (0%)
Vertigo	2/67 (3%)		2/68 (2.9%)
Eye disorders
Diplopia	2/67 (3%)		0/68 (0%)
Dry Eye	2/67 (3%)		1/68 (1.5%)
Eye Pain	2/67 (3%)		1/68 (1.5%)
Gastrointestinal disorders
Abdominal Discomfort	0/67 (0%)		2/68 (2.9%)
Diarrhoea	2/67 (3%)		1/68 (1.5%)
Dysphagia	3/67 (4.5%)		0/68 (0%)
Nausea	3/67 (4.5%)		1/68 (1.5%)
General disorders
Asthenia	3/67 (4.5%)		1/68 (1.5%)
Fatigue	4/67 (6%)		4/68 (5.9%)
Influenza Like Illness	1/67 (1.5%)		2/68 (2.9%)
Non-Cardiac Chest Pain	3/67 (4.5%)		1/68 (1.5%)
Pyrexia	2/67 (3%)		2/68 (2.9%)
Immune system disorders
Seasonal Allergy	0/67 (0%)		2/68 (2.9%)
Infections and infestations
Bronchitis	5/67 (7.5%)		3/68 (4.4%)
Conjunctivitis	2/67 (3%)		0/68 (0%)
Folliculitis	2/67 (3%)		0/68 (0%)
Gastroenteritis	1/67 (1.5%)		2/68 (2.9%)
Gastroenteritis Viral	0/67 (0%)		2/68 (2.9%)
Herpes Zoster	0/67 (0%)		2/68 (2.9%)
Influenza	1/67 (1.5%)		2/68 (2.9%)
Nasopharyngitis	6/67 (9%)		13/68 (19.1%)
Oral Herpes	3/67 (4.5%)		1/68 (1.5%)
Otitis Externa	2/67 (3%)		0/68 (0%)
Rhinitis	2/67 (3%)		1/68 (1.5%)
Tinea Versicolour	2/67 (3%)		1/68 (1.5%)
Upper Respiratory Tract Infection	3/67 (4.5%)		7/68 (10.3%)
Urinary Tract Infection	4/67 (6%)		5/68 (7.4%)
Viral Infection	1/67 (1.5%)		3/68 (4.4%)
Injury, poisoning and procedural complications
Contusion	1/67 (1.5%)		2/68 (2.9%)
Fall	4/67 (6%)		1/68 (1.5%)
Foot Fracture	0/67 (0%)		2/68 (2.9%)
Investigations
Alanine Aminotransferase Increased	3/67 (4.5%)		1/68 (1.5%)
Aspartate Aminotransferase Increased	2/67 (3%)		1/68 (1.5%)
Hepatic Enzyme Increased	3/67 (4.5%)		1/68 (1.5%)
Metabolism and nutrition disorders
Decreased Appetite	2/67 (3%)		0/68 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/67 (6%)		7/68 (10.3%)
Back Pain	2/67 (3%)		6/68 (8.8%)
Joint Swelling	1/67 (1.5%)		2/68 (2.9%)
Muscle Spasms	2/67 (3%)		3/68 (4.4%)
Pain in Extremity	4/67 (6%)		4/68 (5.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of Skin	2/67 (3%)		0/68 (0%)
Melanocytic Naevus	3/67 (4.5%)		0/68 (0%)
Uterine Leiomyoma	2/67 (3%)		0/68 (0%)
Nervous system disorders
Dizziness	7/67 (10.4%)		1/68 (1.5%)
Headache	6/67 (9%)		6/68 (8.8%)
Hypoaesthesia	0/67 (0%)		3/68 (4.4%)
Migraine	2/67 (3%)		1/68 (1.5%)
Paraesthesia	0/67 (0%)		6/68 (8.8%)
Psychiatric disorders
Insomnia	2/67 (3%)		1/68 (1.5%)
Reproductive system and breast disorders
Dysmenorrhoea	0/67 (0%)		2/68 (2.9%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/67 (0%)		2/68 (2.9%)
Cough	3/67 (4.5%)		3/68 (4.4%)
Dyspnoea	2/67 (3%)		2/68 (2.9%)
Dyspnoea Exertional	3/67 (4.5%)		0/68 (0%)
Obstructive Airways Disorder	3/67 (4.5%)		0/68 (0%)
Skin and subcutaneous tissue disorders
Alopecia	2/67 (3%)		2/68 (2.9%)
Pruritus Generalised	2/67 (3%)		0/68 (0%)
Rash Macular	2/67 (3%)		0/68 (0%)
Skin Burning Sensation	0/67 (0%)		2/68 (2.9%)
Vascular disorders
Hypertension	2/67 (3%)		2/68 (2.9%)

Limitations/Caveats

Due to slow recruitment rate the study was considered futile by the Independent Data Monitoring Committee and the sponsor agreed to prematurely terminate the study. Due to this premature termination of study, the insufficient sample size did not allow to detect the differences for the main efficacy endpoints. The safety profile of ponesimod as add-on to DMF therapy could not be fully characterized due to limited data.

More Information

Certain Agreements

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

Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights. Neither the institution nor the investigator should permit publication during such a review period.