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Clinical Trial Results:
Multicenter, non-comparative extension to study AC-058B301, to investigate the long-term safety, tolerability, and control of disease of ponesimod 20 mg in subjects with relapsing multiple sclerosis

Summary
EudraCT number	2016-004719-10
Trial protocol	ES SE PL CZ BG LV HU LT PT HR GB FI GR RO
Global end of trial date	15 Jan 2024

Results information
Results version number	v1(current)
This version publication date	30 Jan 2025
First version publication date	30 Jan 2025
Other versions

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

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Trial information

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Sponsor protocol code

AC-058B303

ISRCTN number

US NCT number

NCT03232073

WHO universal trial number (UTN)

Sponsor organisation name

Actelion Pharmaceuticals Ltd

Sponsor organisation address

Gewerbestrasse 16, Allschwil, Switzerland, 4123

Public contact

Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

14 Mar 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Jan 2024

Was the trial ended prematurely?

Main objective of the trial

The main objective of trial is to describe the long-term (LT) safety and tolerability of ponesimod 20 milligrams (mg) in subjects with relapsing multiple sclerosis (RMS), to describe the effects of reinitiation of ponesimod treatment after interruption in subjects with RMS, to describe the long-term (LT) disease control in subjects with RMS receiving ponesimod 20 mg, and to describe the effect of a switch from teriflunomide to ponesimod 20 mg on disease control in subjects with RMS.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices (GCP) and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jul 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

United States: 23

Country: Number of subjects enrolled

Bulgaria: 32

Country: Number of subjects enrolled

Croatia: 29

Country: Number of subjects enrolled

Czechia: 83

Country: Number of subjects enrolled

Finland: 4

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

Greece: 11

Country: Number of subjects enrolled

Hungary: 15

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Latvia: 6

Country: Number of subjects enrolled

Lithuania: 8

Country: Number of subjects enrolled

Poland: 122

Country: Number of subjects enrolled

Portugal: 15

Country: Number of subjects enrolled

Romania: 13

Country: Number of subjects enrolled

Spain: 56

Country: Number of subjects enrolled

Sweden: 9

Country: Number of subjects enrolled

Türkiye: 1

Country: Number of subjects enrolled

Bosnia and Herzegovina: 2

Country: Number of subjects enrolled

Ukraine: 100

Country: Number of subjects enrolled

Belarus: 38

Country: Number of subjects enrolled

Canada: 13

Country: Number of subjects enrolled

Georgia: 30

Country: Number of subjects enrolled

Israel: 9

Country: Number of subjects enrolled

Mexico: 11

Country: Number of subjects enrolled

Russian Federation: 191

Country: Number of subjects enrolled

Serbia: 28

Worldwide total number of subjects

877

EEA total number of subjects

427

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

877

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Total of 877 subjects entered this extension study from the core study (NCT02425644) and all received at least one dose of ponesimod 20 milligrams (mg) treatment.

Screening details

Efficacy data: reporting extension set (ES) in combined analysis period (all data from randomisation in core study till extension end of study [EOS] for those who entered ES). Safety data: reporting ES in extension analysis period (all data collected on/after date of 1st intake of ponesimod till last treatment date in extension study+15 days).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ponesimod 20 mg (Core and Extension Study)

Arm description

Subjects with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (2012-000540-10), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Subjects received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a subject's country. Subjects located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.

Arm type

Experimental

Investigational medicinal product name

Ponesimod

Investigational medicinal product code

Other name

JNJ-67896153, ACT-128800

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received ponesimod 20 mg treatment.

Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)

Arm description

Subjects with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (2012-000540-10), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Subjects received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a subject's country. Subjects located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.

Arm type

Experimental

Investigational medicinal product name

Ponesimod

Investigational medicinal product code

Other name

JNJ-67896153, ACT-128800

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received ponesimod 20 mg treatment.

Number of subjects in period 1	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Started	439	438
Completed	352	371
Not completed	87	67
Adverse event, serious fatal	1	-
Physician decision	9	2
Consent withdrawn by subject	54	39
Adverse event, non-fatal	7	12
Lost to follow-up	6	6
Lack of efficacy	10	8

Baseline characteristics

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Reporting group title

Ponesimod 20 mg (Core and Extension Study)

Reporting group description

Reporting group title

Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)

Reporting group description

Reporting group values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Total
Number of subjects	439	438
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	36.5 ( 8.75 )	37.2 ( 8.75 )	-
Gender categorical
Units: Subjects
Male	153	148	301
Female	286	290	576
Age Categorical
Units: Subjects
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	439	438	877
From 65 to 84 years	0	0	0
85 years and over	0	0	0

End points

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Reporting group title

Ponesimod 20 mg (Core and Extension Study)

Reporting group description

Reporting group title

Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)

Reporting group description

Primary: Time From Core Study Randomisation to First Confirmed Relapse

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End point title

Time From Core Study Randomisation to First Confirmed Relapse ^[1]

End point description

Time to first confirmed relapse: date of first confirmed relapse (core or extension study) minus date of randomisation in core study+1 day. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, that lasted at least 24 hours,in absence of fever/infection. Confirmed relapse: when patient's symptoms worsen by increase in EDSS or FS scores, consistent to previous clinically stable assessments. Specific criteria for confirmed relapse: increase of 0.5 points on EDSS;(unless EDSS=0, then increase of 1.0-point); increase of 1.0 point in at least two FS scores; or 2.0-point increase in one FS score (excluding bladder/bowel/cerebral).Rating individual FS scores is used to rate EDSS (ordinal clinical rating scale ranging:0[normal]-10[death due to MS]) along with observations/ information concerning gait and use of assistance. Extension set was used. Here, '99999' refers to data not estimable due to low number of events.

End point type

Primary

End point timeframe

From randomisation in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subjects and could be up to 98.5 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: weeks
median (inter-quartile range (Q1-Q3))	402.71 (82.29 to 99999)	99999 (53.57 to 99999)

No statistical analyses for this end point

Primary: Annualized Confirmed Relapse Rate (ARR)

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End point title

Annualized Confirmed Relapse Rate (ARR)

End point description

ARR: number of confirmed relapses per patient-year. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours,in absence of fever or infection. Confirmed relapse: when patient's symptoms worsen by increase in Expanded Disability Status Scale (EDSS) or Functional Systems (FS) scores, consistent to previous clinically stable assessments. Specific criteria for confirmed relapse: increase of 0.5 points on EDSS;(unless EDSS=0, then increase of 1.0-point); increase of 1.0 point in at least two FS scores; or 2.0-point increase in one FS score (excluding bladder/bowel/cerebral).Rating individual FS scores is used to rate EDSS (ordinal clinical rating scale ranging:0[normal]-10[death due to MS]) along with observations/ information concerning gait and use of assistance. Extension set: all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

From randomisation in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: relapses per year
arithmetic mean (confidence interval 95%)	0.143 (0.123 to 0.167)	0.184 (0.158 to 0.213)

Statistical Analysis 1

Statistical analysis description

The Analysis type is Exploratory.

Comparison groups

Ponesimod 20 mg (Core and Extension Study) v Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)

Number of subjects included in analysis

877

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Treatment effect (rate ratio)

Point estimate

0.779

Confidence interval

level

95%

sides

2-sided

lower limit

0.629

upper limit

0.965

Primary: Time to First 12-week Confirmed Disability Accumulation (CDA)

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End point title

Time to First 12-week Confirmed Disability Accumulation (CDA) ^[2]

End point description

Time to first 12-week CDA is defined as start date of the first 12-week CDA minus date of randomisation in the core study+1 day. A 12-week CDA is defined as a 12-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 12-weeks. CDA is defined as: (a) Sustained increase of at least 1.5 in EDSS for subjects with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for subjects with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for subjects with a core baseline EDSS score >=5.5, confirmed after 12 weeks. EDSS is an ordinal clinical rating scale ranged 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomisation in the core study for each endpoint and subject individually. Extension set was used. Here, '99999' refers to data not estimable due to low number of events.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: weeks
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)	99999 (254.86 to 99999)

No statistical analyses for this end point

Primary: Time to First 24-week Confirmed Disability Accumulation (CDA)

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End point title

Time to First 24-week Confirmed Disability Accumulation (CDA) ^[3]

End point description

Time to first 24-week CDA is defined as start date of the first 24-week CDA minus date of randomisation in the core study+1 day. A 24-week CDA is defined as a 24-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 24-weeks. CDA is defined as: (a) Sustained increase of at least 1.5 in EDSS for subjects with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for subjects with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for subjects with a core baseline EDSS score >=5.5, confirmed after 24 weeks. EDSS is an ordinal clinical rating scale ranged 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomisation in the core study for each endpoint and subject individually. Extension set was used. Here, '99999' refers to data not estimable due to low number of events.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: weeks
median (inter-quartile range (Q1-Q3))	99999 (99999 to 99999)	99999 (313.29 to 99999)

No statistical analyses for this end point

Primary: Percentage of Subjects with Absence of Relapses

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End point title

Percentage of Subjects with Absence of Relapses ^[4]

End point description

Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours, in absence of fever or infection. Confirmed relapse is identified when a patient's symptoms worsen as indicated by an increase in their EDSS or FS scores, consistent with previous clinically stable assessments. Specific criteria for a confirmed relapse include: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS). Extension set: all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: Percentage of Subjects
number (not applicable)	56.7	51.6

No statistical analyses for this end point

Primary: Change from Baseline in Expanded Disability Status Scale (EDSS)

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End point title

Change from Baseline in Expanded Disability Status Scale (EDSS) ^[5]

End point description

EDSS is ordinal clinical rating scale based on standard neurological examination for assessing neurological disability and impairment in MS. Seven FS scores were rated on a scale ranged from 0 to 5 or 6 to assess visual, brain, stem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral functions while ambulation was scored on scale ranged from 0 to 12 to assess walking distance and assistance. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS) in 0.5 unit increments that represented higher levels of disability. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each endpoint and each subject individually. Extension set was used. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	346	364
Units: Score on a scale
arithmetic mean (standard deviation)	0.16 ( 1.008 )	0.34 ( 1.105 )

No statistical analyses for this end point

Primary: Percentage of Subjects With No Evidence of Disease (NEDA-3) Status Until Extension End of Study

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End point title

Percentage of Subjects With No Evidence of Disease (NEDA-3) Status Until Extension End of Study ^[6]

End point description

NEDA-3 up to extension EOS is defined by the absence of confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, and 12-week CDA. If at least one of the criteria was not fulfilled or the subject discontinued treatment prematurely, the subject was not considered to have achieved NEDA-3. Confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS). Core baseline for efficacy is the last non-missing value recorded before or on randomisation in core study for each outcome measure and each subject individually. Extension set was used. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	436
Units: Percentage of Subjects
number (not applicable)	17.5	7.5

No statistical analyses for this end point

Primary: Percent Change from Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)

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End point title

Percent Change from Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI) ^[7]

End point description

Percent change from baseline in brain volume (PCBV) measured by MRI were reported. Normalized Brain Volume at core baseline was measured in cubic centimeter (cm^3). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each outcome measure and each subject individually. In this endpoint, results were presented for extension end of treatment visit. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each subject and could be up to 94.8 months

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	196	193
Units: Percent Change
arithmetic mean (standard deviation)	-2.52 ( 2.179 )	-2.72 ( 2.024 )

No statistical analyses for this end point

Primary: Percentage of Subjects With No Evidence of Disease (NEDA-4) Status Until Extension End of Study

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End point title

Percentage of Subjects With No Evidence of Disease (NEDA-4) Status Until Extension End of Study ^[8]

End point description

NEDA-4 up to EOS is defined by absence of confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, 12-week CDA until EOS, and absence of annual brain volume decrease >=0.4% from core baseline up to extension EOS. If at least one of the criteria was not fulfilled or the subject discontinued treatment prematurely, the subject was not considered to have achieved NEDA-4. Confirmed relapse: when patient's symptoms worsen by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS (ordinal clinical rating scale ranging 0:normal-10:death due to MS) along with observations, information concerning gait and use of assistance. Core baseline for efficacy: last non-missing value recorded before or on randomisation in core study for each outcome measure and subject individually. Extension set was used. Here, 'N' is number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	437	435
Units: Percentage of Subjects
number (not applicable)	5.2	2.3

No statistical analyses for this end point

Primary: Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI

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End point title

Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI ^[9]

End point description

CUALs was calculated as sum of new T1 Gd+ lesions and new or enlarging T2 lesions (without double-counting of lesions) from baseline up to extension EOS based on the Magnetic resonance imaging (MRI). Average number of lesions per-patient year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each outcome measure and each subject individually. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	438	435
Units: CUAL per patient-year
arithmetic mean (confidence interval 95%)	1.352 (1.153 to 1.586)	1.954 (1.667 to 2.291)

No statistical analyses for this end point

Primary: Number of Gadolinium-enhancing (Gd+) T1 lesions Measured by MRI

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End point title

Number of Gadolinium-enhancing (Gd+) T1 lesions Measured by MRI ^[10]

End point description

Number of Gd+ T1 lesions measured by MRI were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each endpoint and each subject individually. In this endpoint, results were presented for extension end of treatment visit based on a negative-binomial regression model. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each subject and could be up to 94.8 months

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	350	347
Units: Gd+ T1 lesions
arithmetic mean (confidence interval 95%)	0.211 (0.131 to 0.341)	0.395 (0.250 to 0.622)

No statistical analyses for this end point

Primary: Cumulative Number of New or Enlarging T2 Lesions Measured by MRI

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End point title

Cumulative Number of New or Enlarging T2 Lesions Measured by MRI ^[11]

End point description

Cumulative number of new or enlarging T2 lesions measured by MRI were reported. Average number of lesions per year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each outcome measure and each subject individually. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each subject and could be up to 98.5 months

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	438	435
Units: Lesions per year
arithmetic mean (confidence interval 95%)	1.352 (1.152 to 1.586)	1.951 (1.664 to 2.287)

No statistical analyses for this end point

Primary: Change from Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)

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End point title

Change from Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions) ^[12]

End point description

Change from baseline in volume of MRI lesions (T2 lesions, T1 hypointense lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each outcome measure and each subject individually. In this endpoint, results were presented for extension end of treatment visit. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint. Here, 'n' (number analysed) is defined as subjects analysed at specified categories.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each subject and could be up to 94.8 months

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	347	348
Units: cubic millimetres (mm^3)
arithmetic mean (standard deviation)
T2 Lesions (n=347, 348)	-435.7 ( 2822.71 )	91.5 ( 3647.08 )
T1 Hypointense Lesions (n=346, 345)	165.6 ( 1427.30 )	309.4 ( 1712.36 )

No statistical analyses for this end point

Primary: Number of Subjects with Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions)

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End point title

Number of Subjects with Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) ^[13]

End point description

Number of subjects with absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each outcome measure and each subject individually. In this endpoint, results were presented for extension end of treatment visit. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint. Here, 'n' (number analysed) is defined as subjects analysed at specified categories.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each subject and could be up to 94.8 months

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	435
Units: Subjects
Gd+ T1 lesions (n= 439, 435)	293	236
T2 lesions (n= 438, 435)	152	101

No statistical analyses for this end point

Primary: Number of Subjects with Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities

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End point title

Number of Subjects with Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities ^[14]

End point description

Number of subjects with treatment-emergent new morphological ECG abnormalities were reported. Treatment-emergent new morphological ECG abnormalities are defined as those ECG abnormalities occurring from start of treatment up to treatment end date + 15 days. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each subject and could be up to 71.8 months + 15 days

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: Subjects	153	140

No statistical analyses for this end point

Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs)

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End point title

Number of Subjects with Treatment-emergent Adverse Events (TEAEs) ^[15]

End point description

Number of subjects with TEAEs were reported. An AE is any untoward medical event that occurs in a subjects being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to end of treatment date + 15 days. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: Subjects	411	410

No statistical analyses for this end point

Primary: Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)

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End point title

Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs) ^[16]

End point description

Percentage of Gd+ lesions at baseline evolving to PBHs were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomisation in the core study for each outcome measure and each subject individually. In this endpoint, results were presented for extension end of treatment visit. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each subjects and could be up to 94.8 months

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	350	346
Units: Percentage of lesions
number (not applicable)	22.3	25.1

No statistical analyses for this end point

Primary: Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate

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End point title

Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate ^[17]

End point description

Actual values of 12-lead ECG measurements: heart rate were reported. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	361	361
Units: Beats per minute (bpm)
arithmetic mean (standard deviation)	67.4 ( 9.64 )	67.6 ( 9.33 )

No statistical analyses for this end point

Primary: Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF

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End point title

Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF ^[18]

End point description

Actual values of 12-lead ECG measurements up to end of study: PR, QRS, QT, QTcB, QTcF were reported. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	361	361
Units: millisecond (ms)
arithmetic mean (standard deviation)
PR Interval	150.0 ( 20.41 )	153.3 ( 20.27 )
QRS Duration	92.1 ( 9.22 )	93.3 ( 10.63 )
QT Interval	392.5 ( 27.26 )	391.0 ( 25.67 )
QTcB Interval	414.8 ( 19.20 )	413.8 ( 19.66 )
QTcF Interval	406.9 ( 17.78 )	405.7 ( 17.78 )

No statistical analyses for this end point

Primary: Change from Baseline in Heart Rate (HR) up to End of Study Treatment

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End point title

Change from Baseline in Heart Rate (HR) up to End of Study Treatment ^[19]

End point description

Change from baseline in heart rate (HR) were reported. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	361	361
Units: beats per minute (bpm)
arithmetic mean (standard deviation)	-1.7 ( 10.00 )	-1.5 ( 9.17 )

No statistical analyses for this end point

Primary: Change from Baseline in PR, QRS, QT, QTcB, QTcF up to End of Study Treatment

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End point title

Change from Baseline in PR, QRS, QT, QTcB, QTcF up to End of Study Treatment ^[20]

End point description

Change from baseline in PR, QRS, QT, QTcB, QTcF were reported. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	361	361
Units: millisecond (ms)
arithmetic mean (standard deviation)
PR Interval	0.5 ( 14.09 )	2.0 ( 14.37 )
QRS Duration	-0.4 ( 6.79 )	2.9 ( 6.88 )
QT Interval	7.8 ( 25.68 )	8.9 ( 21.66 )
QTcB Interval	2.9 ( 16.75 )	5.2 ( 17.07 )
QTcF Interval	4.6 ( 15.28 )	6.5 ( 14.18 )

No statistical analyses for this end point

Primary: Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values

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End point title

Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values ^[21]

End point description

Absolute values in FEV1 and FVC were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Results are presented for extension end of treatment visit. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	315	327
Units: Percent predicted FEV1 and FVC
arithmetic mean (standard deviation)
FEV1	3.01 ( 0.768 )	3.08 ( 0.797 )
FVC	-3.96 ( 0.965 )	4.04 ( 1.031 )

No statistical analyses for this end point

Primary: Percent Change in FEV1 and FVC From Baseline (%)

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End point title

Percent Change in FEV1 and FVC From Baseline (%) ^[22]

End point description

Percent Change in FEV1 and FVC From Baseline (%) were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Results are presented for extension end of treatment visit. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	315	327
Units: Percent change
arithmetic mean (standard deviation)
FEV1	-7.96 ( 13.356 )	-6.75 ( 12.323 )
FVC	-5.09 ( 11.793 )	-3.93 ( 12.141 )

No statistical analyses for this end point

Primary: Number of Subjects With Treatment-emergent Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment-emergent Serious Adverse Events (SAEs) ^[23]

End point description

Number of subjects with treatment-emergent SAEs were reported. A SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a subject, or was an important medical event. Treatment-emergent SAEs are defined as SAEs occurring from start of treatment up to treatment end date + 15 days. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: Subjects	56	57

No statistical analyses for this end point

Primary: Number of Subjects with Treatment-emergent Adverse Events of Special Interest (AESIs)

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End point title

Number of Subjects with Treatment-emergent Adverse Events of Special Interest (AESIs) ^[24]

End point description

Number of subjects with treatment-emergent AESIs were reported. AESIs included bradyarrhythmia occurred post-first dose, macular edema, bronchoconstriction, severe liver injury, serious opportunistic infections including progressive multifocal leukoencephalopathy (PML), skin cancer, non-skin malignancy, convulsions, unexpected neurological or psychiatric symptoms/signs (posterior reversible encephalopathy syndrome [PRES], acute disseminated encephalomyelitis [ADEM], and atypical MS relapses). Treatment-emergent AESIs are defined as AESIs occurring from start of treatment up to treatment end date + 15 days. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

Notes
[24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: Subjects
Bradyarrhythmia occurring post-first dose	11	13
Severe liver injury	5	5
Bronchoconstriction	31	25
Macular edema	4	6
Serious opportunistic infections including PML	2	1
Skin cancer	4	3
Non-skin malignancy	4	3
Unexpected neurological/psychiatric symptom/sign	1	2
Convulsions	2	3

No statistical analyses for this end point

Primary: Number of Subjects with Adverse Events Leading to Premature Discontinuation of Study Treatment

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End point title

Number of Subjects with Adverse Events Leading to Premature Discontinuation of Study Treatment ^[25]

End point description

Number of subjects with AE leading to premature discontinuation of study treatment were reported. An AE is any untoward medical event that occurs in a subjects being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod.

End point type

Primary

End point timeframe

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	439	438
Units: Subjects	34	41

No statistical analyses for this end point

Primary: Number of Subjects with Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC

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End point title

Number of Subjects with Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC ^[26]

End point description

Number of subjects with treatment-emergent decrease from baseline >20% and >30% in FEV1 or FVC were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study). Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Notes
[26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	424	423
Units: Subjects
FEV1: >20 %	80	82
FEV1: >30 %	18	21
FVC: >20 %	54	60
FVC: >30 %	19	15

No statistical analyses for this end point

Primary: Number of Subjects with Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC from Baseline

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End point title

Number of Subjects with Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC from Baseline ^[27]

End point description

Number of subjects with treatment-emergent decrease of >20% points in percent predicted FEV1 and FVC from baseline were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study). Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	423	423
Units: Subjects
FEV1: >20 %	70	68
FVC: >20 %	59	57

No statistical analyses for this end point

Primary: Number of Subjects with a Decrease of >=200 mL or >=12% in FEV1 or FVC from baseline to EOT

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End point title

Number of Subjects with a Decrease of >=200 mL or >=12% in FEV1 or FVC from baseline to EOT ^[28]

End point description

Number of subjects with a decrease of >=200 mL or >=12% in FEV1 or FVC from baseline to EOT were planned to be reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. This endpoint is not relevant as a substantial proportion of patients continued onto post-treatment disease-modifying therapy (DMT), hence it cannot provide an assessment of reversibility.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	0 ^[29]	0 ^[30]
Units: Participants

Notes
[29] - The reason has been already provided above in endpoint description.
[30] - The reason has been already provided above in endpoint description.

No statistical analyses for this end point

Primary: Change in FEV1 and FVC (% predicted) from baseline to End of Treatment (EOT)

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End point title

Change in FEV1 and FVC (% predicted) from baseline to End of Treatment (EOT) ^[31]

End point description

Change in FEV1 and FVC (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	315	327
Units: Percentage predicted change
arithmetic mean (standard deviation)
FEV1	-7.14 ( 13.315 )	-5.43 ( 11.839 )
FVC	-4.70 ( 13.129 )	-3.19 ( 13.081 )

No statistical analyses for this end point

Primary: Change in FEV1 and FVC (% predicted) from baseline to End of Study (EOS)

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End point title

Change in FEV1 and FVC (% predicted) from baseline to End of Study (EOS) ^[32]

End point description

Change in FEV1 and FVC (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Extension set included all subjects who signed informed consent to enter extension study and received one dose of ponesimod. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study in the extension study. The actual time varied for each subject and could be up to 73.2 months

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	288	299
Units: Percentage predicted change
arithmetic mean (standard deviation)
FEV1	-5.95 ( 12.854 )	-4.08 ( 14.365 )
FVC	-4.48 ( 13.727 )	-1.98 ( 15.747 )

No statistical analyses for this end point

Primary: Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline

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End point title

Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline ^[33]

End point description

Absolute change in lung diffusion capacity as assessed by DL[CO] from baseline were reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. The DLCO sub-study extension set includes all subjects in the extension set who have consented to participate in the DLCO sub-study during the extension study. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study in the extension study. The actual time varied for each subject and could be up to 73.2 months

Notes
[33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	65	53
Units: Millimoles/minute/kilopascal
arithmetic mean (standard deviation)	0.7 ( 3.44 )	0.1 ( 4.17 )

No statistical analyses for this end point

Primary: Change in DL[CO] (% predicted) from Baseline to EOT

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End point title

Change in DL[CO] (% predicted) from Baseline to EOT ^[34]

End point description

Change in DL[CO] (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. The DLCO sub-study extension set includes all subjects in the extension set who have consented to participate in the DLCO sub-study during the extension study. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each subject and could be up to 71.8 months

Notes
[34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	50	41
Units: Percentage predicted DL[CO]
arithmetic mean (standard deviation)	5.7 ( 32.20 )	-9.4 ( 7.82 )

No statistical analyses for this end point

Primary: Change in DL[CO] (% predicted) from Baseline to EOS

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End point title

Change in DL[CO] (% predicted) from Baseline to EOS ^[35]

End point description

Change in DL[CO] (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. The DLCO sub-study extension set includes all subjects in the extension set who have consented to participate in the DLCO sub-study during the extension study. Here, 'N' (number of subjects analysed) signifies number of subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

From extension study baseline up to the end of study in the extension study. The actual time varied for each subject and could be up to 73.2 months

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only statistical analysis were planned for this endpoint. No inferential statistics were planned.

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	39	35
Units: Percentage predicted DL[CO]
arithmetic mean (standard deviation)	9.3 ( 39.38 )	2.2 ( 49.50 )

No statistical analyses for this end point

Other pre-specified: Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate

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End point title

Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate

End point description

Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: heart rate were reported. Population analysis included numbers of subjects based on sub-set of extension set who had a re-initiation. Here, 'n' (number analyzed) is defined as subjects analysed at specified timepoints.

End point type

Other pre-specified

End point timeframe

Extension analysis period: Predose, 1, 2, 3, 4 hours post dose on Day 1 of re-initiation (re-initiation could occur on any day during the treatment period when drug was interrupted for at least 3 consecutive days [up to 71.8 months])

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	30	40
Units: beats per minute (bpm)
arithmetic mean (standard deviation)
Predose (n=30, 40)	68.1 ( 8.73 )	71.0 ( 9.21 )
1 hour Post-dose (n=24, 34)	66.5 ( 10.53 )	69.0 ( 10.13 )
2 hours Post-dose (n=24, 31)	64.3 ( 9.91 )	65.1 ( 8.68 )
3 hours Post-dose (n=24, 31)	64.6 ( 9.33 )	67.8 ( 10.71 )
4 hours Post-dose (n=24, 31)	66.0 ( 9.73 )	67.6 ( 10.01 )

No statistical analyses for this end point

Other pre-specified: Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF

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End point title

Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF

End point description

Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: PR, QRS, QT, QTcB, QTcF were reported. Population analysis included numbers of subjects based on sub-set of extension set who had a re-initiation. Here, 'n' (number analyzed) is defined as subjects analysed at specified timepoints.

End point type

Other pre-specified

End point timeframe

End point values	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Number of subjects analysed	30	40
Units: millisecond (ms)
arithmetic mean (standard deviation)
PR Interval: Predose (n=30, 40)	152.8 ( 17.66 )	149.8 ( 19.13 )
PR Interval: 1 hour Post-dose (n=24, 34)	150.5 ( 17.25 )	152.6 ( 22.66 )
PR Interval: 2 hours Post-dose (n=24, 31)	150.1 ( 16.60 )	153.6 ( 23.51 )
PR Interval: 3 hours Post-dose (n=24, 31)	152.3 ( 17.73 )	154.5 ( 21.91 )
PR Interval: 4 hours Post-dose (n=24, 31)	150.7 ( 17.82 )	151.8 ( 19.68 )
QRS Duration: Predose (n=30, 40)	94.6 ( 11.06 )	91.5 ( 7.03 )
QRS Duration: 1 hour Post-dose (n=24, 34)	95.2 ( 11.42 )	93.2 ( 8.72 )
QRS Duration: 2 hours Post-dose (n=24, 31)	93.9 ( 11.71 )	92.7 ( 7.57 )
QRS Duration: 3 hours Post-dose (n=24, 31)	94.5 ( 11.60 )	94.5 ( 7.80 )
QRS Duration: 4 hours Post-dose (n=24, 31)	94.7 ( 10.48 )	92.5 ( 7.35 )
QT Interval: Predose (n=30, 40)	391.5 ( 24.80 )	378.8 ( 23.61 )
QT Interval: 1 hour Post-dose (n=24, 34)	396.7 ( 28.76 )	380.9 ( 21.78 )
QT Interval: 2 hours Post-dose (n=24, 31)	402.0 ( 29.00 )	386.0 ( 19.62 )
QT Interval: 3 hours Post-dose (n=24, 31)	400.2 ( 27.78 )	386.9 ( 21.38 )
QT Interval: 4 hours Post-dose (n=24, 31)	400.0 ( 27.49 )	383.9 ( 23.14 )
QTcB: Predose (n=30, 40)	416.2 ( 19.05 )	411.4 ( 20.85 )
QTcB Interval: 1 hour Post-dose (n=24, 34)	416.0 ( 24.11 )	407.6 ( 22.96 )
QTcB Interval: 2 hours Post-dose (n=24, 31)	414.8 ( 22.83 )	401.7 ( 20.88 )
QTcB Interval: 3 hours Post-dose (n=24, 31)	414.2 ( 23.30 )	410.1 ( 22.33 )
QTcB Interval: 4 hours Post-dose (n=24, 31)	418.0 ( 20.30 )	406.6 ( 22.33 )
QTcF: Predose (n=30, 40)	407.4 ( 17.09 )	400.0 ( 18.69 )
QTcF Interval: 1 hour Post-dose (n=24, 34)	409.2 ( 20.58 )	398.1 ( 18.22 )
QTcF Interval: 2 hours Post-dose (n=24, 31)	410.1 ( 20.41 )	396.2 ( 16.61 )
QTcF Interval: 3 hours Post-dose (n=24, 31)	409.0 ( 20.97 )	402.0 ( 16.82 )
QTcF Interval: 4 hours Post-dose (n=24, 31)	411.5 ( 18.36 )	398.5 ( 18.27 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious and Other AEs:From treatment start in extension study to EOT+15 days in extension study. Actual time varied till 71.8 months+15 days; All-cause mortality:From extension study baseline to EOS in extension study. Actual time varied till 73.2 months

Adverse event reporting additional description

The extension set included all subjects who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Ponesimod 20 mg (Core and Extension Study)

Reporting group description

Reporting group title

Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)

Reporting group description

Serious adverse events	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Total subjects affected by serious adverse events
subjects affected / exposed	56 / 439 (12.76%)	57 / 438 (13.01%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive Ductal Breast Carcinoma
subjects affected / exposed	1 / 439 (0.23%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal Cell Carcinoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast Cancer
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive Breast Carcinoma
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine Leiomyoma
subjects affected / exposed	1 / 439 (0.23%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melanocytic Naevus
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant Melanoma
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Papillary Renal Cell Carcinoma
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Iliac Artery Embolism
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous Thrombosis Limb
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Peripheral Artery Thrombosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicose Vein
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Abdominoplasty
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion Induced
subjects affected / exposed	2 / 439 (0.46%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical Conisation
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uvulopalatopharyngoplasty
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine Dilation and Curettage
subjects affected / exposed	1 / 439 (0.23%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Botulinum Toxin Injection
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hysterosalpingo-Oophorectomy
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal Hernia Repair
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Internal Fixation of Fracture
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mastectomy
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteotomy
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Operation
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Unintended Pregnancy
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abortion Spontaneous
subjects affected / exposed	1 / 439 (0.23%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Papillitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine with Aura
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine Polyp
subjects affected / exposed	2 / 439 (0.46%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian Cyst
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Heavy Menstrual Bleeding
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical Dysplasia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis Chronic
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nasal Septum Deviation
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental Disorder Due to A General Medical Condition
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mood Disorder Due to A General Medical Condition
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic Disorder
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device Dislocation
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Tendon Rupture
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia Fracture
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist Fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper Limb Fracture
subjects affected / exposed	0 / 439 (0.00%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to Various Agents
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle Fracture
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip Fracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated Incisional Hernia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament Injury
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament Sprain
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus Injury
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative Wound Complication
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon Injury
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus Node Dysfunction
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute Myocardial Infarction
subjects affected / exposed	0 / 439 (0.00%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Hemianopia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Amnesia
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple Sclerosis Relapse
subjects affected / exposed	1 / 439 (0.23%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Partial Seizures with Secondary Generalisation
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sacral Radiculopathy
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Transient Ischaemic Attack
subjects affected / exposed	1 / 439 (0.23%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uhthoff's Phenomenon
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo CNS Origin
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo Positional
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Vision Blurred
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Macular Oedema
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Chronic Gastritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal Ulcer Haemorrhage
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Functional Gastrointestinal Disorder
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal Hernia
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Umbilical Hernia
subjects affected / exposed	0 / 439 (0.00%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal Obstruction
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal Fissure
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic Cytolysis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis Chronic
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 439 (0.00%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Tubulointerstitial Nephritis
subjects affected / exposed	2 / 439 (0.46%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus Urinary
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal Colic
subjects affected / exposed	2 / 439 (0.46%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral Disc Disorder
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint Ankylosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint Contracture
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Pain
subjects affected / exposed	0 / 439 (0.00%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal Instability
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriatic Arthropathy
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular Weakness
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Large Intestine Infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis Viral
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periodontitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Covid-19 Pneumonia
subjects affected / exposed	1 / 439 (0.23%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	3 / 439 (0.68%)	3 / 438 (0.68%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Complicated Appendicitis
subjects affected / exposed	2 / 439 (0.46%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Covid-19
subjects affected / exposed	2 / 439 (0.46%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes Zoster
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis Acute
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis E
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	1 / 439 (0.23%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suspected Covid-19
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal Abscess
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory Syncytial Virus Infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis Chronic
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia Urinary Tract Infection
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Furuncle
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 439 (0.00%)	1 / 438 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal Infection
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 439 (0.00%)	2 / 438 (0.46%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	1 / 439 (0.23%)	0 / 438 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)
Total subjects affected by non serious adverse events
subjects affected / exposed	339 / 439 (77.22%)	328 / 438 (74.89%)
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	73 / 439 (16.63%)	98 / 438 (22.37%)
occurrences all number	120	183
Aspartate Aminotransferase Increased
subjects affected / exposed	17 / 439 (3.87%)	26 / 438 (5.94%)
occurrences all number	24	34
Lymphocyte Count Decreased
subjects affected / exposed	30 / 439 (6.83%)	30 / 438 (6.85%)
occurrences all number	41	43
Vascular disorders
Hypertension
subjects affected / exposed	37 / 439 (8.43%)	44 / 438 (10.05%)
occurrences all number	40	48
Nervous system disorders
Dizziness
subjects affected / exposed	22 / 439 (5.01%)	17 / 438 (3.88%)
occurrences all number	25	21
Headache
subjects affected / exposed	57 / 439 (12.98%)	64 / 438 (14.61%)
occurrences all number	70	96
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	18 / 439 (4.10%)	23 / 438 (5.25%)
occurrences all number	25	28
Lymphopenia
subjects affected / exposed	66 / 439 (15.03%)	64 / 438 (14.61%)
occurrences all number	86	82
General disorders and administration site conditions
Fatigue
subjects affected / exposed	24 / 439 (5.47%)	30 / 438 (6.85%)
occurrences all number	27	37
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	22 / 439 (5.01%)	15 / 438 (3.42%)
occurrences all number	26	18
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	45 / 439 (10.25%)	30 / 438 (6.85%)
occurrences all number	59	36
Arthralgia
subjects affected / exposed	31 / 439 (7.06%)	38 / 438 (8.68%)
occurrences all number	37	44
Infections and infestations
Covid-19
subjects affected / exposed	115 / 439 (26.20%)	108 / 438 (24.66%)
occurrences all number	133	126
Urinary Tract Infection
subjects affected / exposed	36 / 439 (8.20%)	33 / 438 (7.53%)
occurrences all number	51	43
Upper Respiratory Tract Infection
subjects affected / exposed	47 / 439 (10.71%)	51 / 438 (11.64%)
occurrences all number	70	73
Respiratory Tract Infection
subjects affected / exposed	23 / 439 (5.24%)	15 / 438 (3.42%)
occurrences all number	25	20
Nasopharyngitis
subjects affected / exposed	82 / 439 (18.68%)	74 / 438 (16.89%)
occurrences all number	140	126

More information

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Were there any global substantial amendments to the protocol? Yes

28 Feb 2018

The main reason for this amendment was to modify the pulmonary treatment discontinuation criteria based on changes in pulmonary function variables during the study treatment.

14 May 2020

The main reasons for this amendment were: (a) To allow the analysis of biomarkers in the serum sample taken at Visit 1 (Enrollment); (b) To amend the guidance for re-initiation of study treatment in the event of study treatment interruption in order to allow patients without the identified cardiovascular risk factors to re-initiate study drug at home; (c) The efficacy assessor role is no longer defined as “independent” and, depending on site setting, can now be assumed by the primary investigator / treating neurologist; (d) To provide guidance regarding conduct of the study during the coronavirus disease (COVID)-19 (coronavirus) pandemic.

19 Oct 2020

The main reasons for this amendment were: (a) To inform study sites that the Independent Data Monitoring Committee (IDMC) will be disbanded after the clinical database closure of the last ponesimod double-blind study, in line with the disbandment date agreed per the IDMC Charter; (b) To provide further guidance on study conduct if/when ponesimod becomes commercially available during the study and patients are switched from study treatment to commercially available ponesimod; (c) To align the safety reporting procedures with Janssen Safety processes and standards following the integration of Actelion Safety into Janssen Safety.

20 Jul 2021

The main reasons for this amendment were: (a) To introduce vaccination sub-study for a sub-set of subjects to investigate the immune response induced by the Janssen COVID-19 vaccine (Ad26.COV2.S); (b) Inclusion of additional serum samples for all subjects at all scheduled visits for immunogenicity evaluations; for example, to measure anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibody levels induced by vaccination with any COVID-19 vaccination or after recovery from COVID 19; (c) Addition of clarifications regarding conduct of the study during the COVID-19 pandemic and the administration of non-live and live vaccinations; (d) To make updates with regard to teriflunomide testing per the Aubagio prescribing information.

Were there any global interruptions to the trial? No

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

Due to limited availability of COVID-19 vaccine-naïve MS patients, the COVID-19 vaccination sub-study was cancelled and removed from the protocol after implementation of amendment 5.

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Clinical trials

Clinical Trial Results: Multicenter, non-comparative extension to study AC-058B301, to investigate the long-term safety, tolerability, and control of disease of ponesimod 20 mg in subjects with relapsing multiple sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time From Core Study Randomisation to First Confirmed Relapse

Primary: Time From Core Study Randomisation to First Confirmed Relapse

Primary: Annualized Confirmed Relapse Rate (ARR)

Primary: Annualized Confirmed Relapse Rate (ARR)

Primary: Time to First 12-week Confirmed Disability Accumulation (CDA)

Primary: Time to First 12-week Confirmed Disability Accumulation (CDA)

Primary: Time to First 24-week Confirmed Disability Accumulation (CDA)

Primary: Time to First 24-week Confirmed Disability Accumulation (CDA)

Primary: Percentage of Subjects with Absence of Relapses

Primary: Percentage of Subjects with Absence of Relapses

Primary: Change from Baseline in Expanded Disability Status Scale (EDSS)

Primary: Change from Baseline in Expanded Disability Status Scale (EDSS)

Primary: Percentage of Subjects With No Evidence of Disease (NEDA-3) Status Until Extension End of Study

Primary: Percentage of Subjects With No Evidence of Disease (NEDA-3) Status Until Extension End of Study

Primary: Percent Change from Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)

Primary: Percent Change from Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)

Primary: Percentage of Subjects With No Evidence of Disease (NEDA-4) Status Until Extension End of Study

Primary: Percentage of Subjects With No Evidence of Disease (NEDA-4) Status Until Extension End of Study

Primary: Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI

Primary: Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI

Primary: Number of Gadolinium-enhancing (Gd+) T1 lesions Measured by MRI

Primary: Number of Gadolinium-enhancing (Gd+) T1 lesions Measured by MRI

Primary: Cumulative Number of New or Enlarging T2 Lesions Measured by MRI

Primary: Cumulative Number of New or Enlarging T2 Lesions Measured by MRI

Primary: Change from Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)

Primary: Change from Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)

Primary: Number of Subjects with Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions)

Primary: Number of Subjects with Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions)

Primary: Number of Subjects with Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities

Primary: Number of Subjects with Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities

Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs)

Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs)

Primary: Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)

Primary: Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)

Primary: Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate

Primary: Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate

Primary: Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF

Primary: Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF

Primary: Change from Baseline in Heart Rate (HR) up to End of Study Treatment

Primary: Change from Baseline in Heart Rate (HR) up to End of Study Treatment

Primary: Change from Baseline in PR, QRS, QT, QTcB, QTcF up to End of Study Treatment

Primary: Change from Baseline in PR, QRS, QT, QTcB, QTcF up to End of Study Treatment

Primary: Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values

Primary: Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values

Primary: Percent Change in FEV1 and FVC From Baseline (%)

Primary: Percent Change in FEV1 and FVC From Baseline (%)

Primary: Number of Subjects With Treatment-emergent Serious Adverse Events (SAEs)

Primary: Number of Subjects With Treatment-emergent Serious Adverse Events (SAEs)

Primary: Number of Subjects with Treatment-emergent Adverse Events of Special Interest (AESIs)

Primary: Number of Subjects with Treatment-emergent Adverse Events of Special Interest (AESIs)

Primary: Number of Subjects with Adverse Events Leading to Premature Discontinuation of Study Treatment

Primary: Number of Subjects with Adverse Events Leading to Premature Discontinuation of Study Treatment

Primary: Number of Subjects with Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC

Primary: Number of Subjects with Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC

Primary: Number of Subjects with Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC from Baseline

Primary: Number of Subjects with Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC from Baseline

Primary: Number of Subjects with a Decrease of >=200 mL or >=12% in FEV1 or FVC from baseline to EOT

Primary: Number of Subjects with a Decrease of >=200 mL or >=12% in FEV1 or FVC from baseline to EOT

Primary: Change in FEV1 and FVC (% predicted) from baseline to End of Treatment (EOT)

Primary: Change in FEV1 and FVC (% predicted) from baseline to End of Treatment (EOT)

Primary: Change in FEV1 and FVC (% predicted) from baseline to End of Study (EOS)

Primary: Change in FEV1 and FVC (% predicted) from baseline to End of Study (EOS)

Primary: Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline

Primary: Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline

Primary: Change in DL[CO] (% predicted) from Baseline to EOT

Primary: Change in DL[CO] (% predicted) from Baseline to EOT

Primary: Change in DL[CO] (% predicted) from Baseline to EOS

Primary: Change in DL[CO] (% predicted) from Baseline to EOS

Other pre-specified: Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate

Other pre-specified: Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate

Clinical Trial Results:
Multicenter, non-comparative extension to study AC-058B301, to investigate the long-term safety, tolerability, and control of disease of ponesimod 20 mg in subjects with relapsing multiple sclerosis