Multiple Sclerosis
Conditions
Keywords
relapsing multiple sclerosis
Brief summary
International clinical trial to compare ponesimod and teriflunomide in relapsing multiple sclerosis
Interventions
DRUGponesimod
film-coated tablet with 20 mg ponesimod, administered orally once daily in the morning
DRUGteriflunomide
film-coated tablet with 14 mg teriflunomide, administered orally once daily in the morning
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Male and female subjects aged 18 to 55 years with established diagnosis of MS McDonald 2010 with relapsing course from onset (i.e., RRMS and SPMS with superimposed relapses). Subjects must have active disease evidenced by one or more MS attacks with onset within the period of 12 to 1 months prior to randomization, or by two or more MS attacks with onset within the 24 to 1 months prior to randomization, or with one or more gadolinium-enhancing (Gd+) lesion(s) of the brain on an MRI performed within 6 months prior to randomization. Enrolled subjects must be ambulatory (EDSS score of up to 5.5 inclusive) and may be treatment-naïve or previously treated with MS disease modifying therapy.
Exclusion criteria
Subjects with significant medical conditions or therapies for such conditions (e.g., cardiovascular, pulmonary, immunological, hepatic,ophthalmological conditions) or lactating or pregnant women are not eligible to enter the study. Subjects with contraindications to MRI or with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study are not eligible to enter the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Confirmed Relapse Rate | From randomization to end of study (Week 108) | Relapse: occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple sclerosis (MS), not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicates overall functional impairment assessing Visual,Brain Stem,Pyramidal,Cerebellar,Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS in conjunction with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10(death due to MS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) Score to Week 108 | Baseline to Week 108 | The FSIQ-RMS is a 20-item Patient Reported Outcomes (PRO) measure to evaluate fatigue-related symptoms and the impacts of those symptoms on the lives of people. The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing fatigue-related symptoms daily with a recall period of 24 hours measured on an 11-point numeric rating scale; the (normalized) symptom domain score ranges from 0 to 100 with a higher score indicating greater fatigue. This domain was completed on 7 consecutive days. A negative change from baseline indicates an improvement in fatigue symptoms. |
| Cumulative Number of Combined Unique Active Lesions (CUAL) Per Year From Baseline to Week 108 | Baseline to Week 108 | CUALs was calculated as sum of new Gadolinium-enhanced (Gd+) T1 lesions plus new or enlarging T2 lesions (without double-counting of lesions) from baseline based on the Magnetic resonance imaging (MRI) scans up to Week 108. Average number of lesions per year were reported. |
| 12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | Baseline to Week 60 and 108 Weeks | A 12-week CDA was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score greater than or equal to (\>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). |
| 24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | Baseline to 60 Weeks and 108 Weeks | A 24-week CDA was defined as an increase of at least 1.5 in EDSS for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score \>= 5.5, which was confirmed after 24 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. The EDSS is an ordinal scale ranging from 0 (normal neurological exam) to 10 (death to MS). |
Countries
Belarus, Bosnia and Herzegovina, Bulgaria, Canada, Croatia, Czechia, Finland, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, Mexico, Poland, Portugal, Romania, Russia, Serbia, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
As planned, Placebo was not a separate arm as this was included for double dummy design study part (up to Day 14).
Participants by arm
| Arm | Count |
|---|---|
| Ponesimod 20 mg Participants were up-titrated during Days 1 to 14 from 2 to 10 mg of ponesimod once daily (one ponesimod tablet and one matching placebo capsule per day). From Day 15 to Week 108 participants received ponesimod 20 mg once daily up to Week 108 | 567 |
| Teriflunomide 14 mg Participants received teriflunomide 14 mg capsule once daily from Day 1 up to Week 108. During Days 1 to 14 (mock uptitration period), participants received in addition one tablet of matching placebo. | 566 |
| Total | 1,133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 3 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Lack of Efficacy | 3 | 10 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Other | 18 | 17 |
| Overall Study | Withdrawal by Subject | 41 | 36 |
Baseline characteristics
| Characteristic | Ponesimod 20 mg | Teriflunomide 14 mg | Total |
|---|---|---|---|
| Age, Continuous | 36.7 years STANDARD_DEVIATION 8.74 | 36.8 years STANDARD_DEVIATION 8.74 | 36.7 years STANDARD_DEVIATION 8.74 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 10 Participants | 23 Participants |
| Race (NIH/OMB) White | 551 Participants | 553 Participants | 1104 Participants |
| Region of Enrollment BELARUS | 21 Participants | 24 Participants | 45 Participants |
| Region of Enrollment Bosnia | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment BULGARIA | 18 Participants | 27 Participants | 45 Participants |
| Region of Enrollment CANADA | 10 Participants | 7 Participants | 17 Participants |
| Region of Enrollment CROATIA | 14 Participants | 20 Participants | 34 Participants |
| Region of Enrollment CZECH REPUBLIC | 55 Participants | 46 Participants | 101 Participants |
| Region of Enrollment FINLAND | 4 Participants | 3 Participants | 7 Participants |
| Region of Enrollment FRANCE | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment GEORGIA | 24 Participants | 17 Participants | 41 Participants |
| Region of Enrollment GERMANY | 9 Participants | 7 Participants | 16 Participants |
| Region of Enrollment GREECE | 9 Participants | 6 Participants | 15 Participants |
| Region of Enrollment HUNGARY | 7 Participants | 12 Participants | 19 Participants |
| Region of Enrollment ISRAEL | 4 Participants | 9 Participants | 13 Participants |
| Region of Enrollment ITALY | 7 Participants | 7 Participants | 14 Participants |
| Region of Enrollment LATVIA | 11 Participants | 4 Participants | 15 Participants |
| Region of Enrollment LITHUANIA | 3 Participants | 8 Participants | 11 Participants |
| Region of Enrollment MEXICO | 7 Participants | 10 Participants | 17 Participants |
| Region of Enrollment POLAND | 80 Participants | 71 Participants | 151 Participants |
| Region of Enrollment PORTUGAL | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment ROMANIA | 10 Participants | 5 Participants | 15 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 116 Participants | 111 Participants | 227 Participants |
| Region of Enrollment Serbia | 14 Participants | 19 Participants | 33 Participants |
| Region of Enrollment SPAIN | 34 Participants | 39 Participants | 73 Participants |
| Region of Enrollment SWEDEN | 8 Participants | 6 Participants | 14 Participants |
| Region of Enrollment TURKEY | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment UKRAINE | 57 Participants | 66 Participants | 123 Participants |
| Region of Enrollment UNITED KINGDOM | 2 Participants | 5 Participants | 7 Participants |
| Region of Enrollment UNITED STATES | 22 Participants | 17 Participants | 39 Participants |
| Sex: Female, Male Female | 363 Participants | 372 Participants | 735 Participants |
| Sex: Female, Male Male | 204 Participants | 194 Participants | 398 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 565 | 2 / 566 |
| other Total, other adverse events | 434 / 565 | 422 / 566 |
| serious Total, serious adverse events | 49 / 565 | 46 / 566 |
Outcome results
Primary
Annualized Confirmed Relapse Rate
Relapse: occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple sclerosis (MS), not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicates overall functional impairment assessing Visual,Brain Stem,Pyramidal,Cerebellar,Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS in conjunction with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10(death due to MS).
Time frame: From randomization to end of study (Week 108)
Population: Full analysis set (FAS) included all participants randomized in the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ponesimod 20 mg | Annualized Confirmed Relapse Rate | 0.202 relapses per year |
| Teriflunomide 14 mg | Annualized Confirmed Relapse Rate | 0.290 relapses per year |
p-value: 0.000399% CI: [0.536, 0.902]Negative binomial regression model
Secondary
12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS
A 12-week CDA was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score greater than or equal to (\>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS).
Time frame: Baseline to Week 60 and 108 Weeks
Population: FAS included all participants randomized in this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ponesimod 20 mg | 12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 60 Weeks- from Kaplan Meier estimates | 7.6 Percentage of Participants |
| Ponesimod 20 mg | 12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 108 Weeks- from Kaplan Meier estimates | 10.8 Percentage of Participants |
| Teriflunomide 14 mg | 12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 60 Weeks- from Kaplan Meier estimates | 8.3 Percentage of Participants |
| Teriflunomide 14 mg | 12-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 108 Weeks- from Kaplan Meier estimates | 13.2 Percentage of Participants |
p-value: 0.293995% CI: [0.58, 1.18]Log Rank
Secondary
24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS
A 24-week CDA was defined as an increase of at least 1.5 in EDSS for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score \>= 5.5, which was confirmed after 24 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. The EDSS is an ordinal scale ranging from 0 (normal neurological exam) to 10 (death to MS).
Time frame: Baseline to 60 Weeks and 108 Weeks
Population: FAS included all participants randomized in this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ponesimod 20 mg | 24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 60 Weeks- from Kaplan Meier estimates | 6.3 Percentage of Participants |
| Ponesimod 20 mg | 24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 108 Weeks- from Kaplan Meier estimates | 8.7 Percentage of Participants |
| Teriflunomide 14 mg | 24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 60 Weeks- from Kaplan Meier estimates | 6.9 Percentage of Participants |
| Teriflunomide 14 mg | 24-Week Confirmed Disability Accumulation (CDA) Assessed From Baseline to EOS | 108 Weeks- from Kaplan Meier estimates | 10.5 Percentage of Participants |
p-value: 0.37295% CI: [0.57, 1.24]Log Rank
Secondary
Change From Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) Score to Week 108
The FSIQ-RMS is a 20-item Patient Reported Outcomes (PRO) measure to evaluate fatigue-related symptoms and the impacts of those symptoms on the lives of people. The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven items assessing fatigue-related symptoms daily with a recall period of 24 hours measured on an 11-point numeric rating scale; the (normalized) symptom domain score ranges from 0 to 100 with a higher score indicating greater fatigue. This domain was completed on 7 consecutive days. A negative change from baseline indicates an improvement in fatigue symptoms.
Time frame: Baseline to Week 108
Population: FAS included all participants randomized in the study. Here 'N' (number of participants analyzed) included all participants who were evaluable for this outcome measure with available baseline and at least one post-baseline assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ponesimod 20 mg | Change From Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) Score to Week 108 | -0.01 score on scale |
| Teriflunomide 14 mg | Change From Baseline in Fatigue-related Symptoms as Measured by the Symptoms Domain of the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) Score to Week 108 | 3.56 score on scale |
p-value: 0.001995% CI: [-5.83, -1.32]Mixed Models Analysis
Secondary
Cumulative Number of Combined Unique Active Lesions (CUAL) Per Year From Baseline to Week 108
CUALs was calculated as sum of new Gadolinium-enhanced (Gd+) T1 lesions plus new or enlarging T2 lesions (without double-counting of lesions) from baseline based on the Magnetic resonance imaging (MRI) scans up to Week 108. Average number of lesions per year were reported.
Time frame: Baseline to Week 108
Population: FAS included all participants randomized in the study. Here 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ponesimod 20 mg | Cumulative Number of Combined Unique Active Lesions (CUAL) Per Year From Baseline to Week 108 | 1.405 lesions per year |
| Teriflunomide 14 mg | Cumulative Number of Combined Unique Active Lesions (CUAL) Per Year From Baseline to Week 108 | 3.164 lesions per year |
p-value: <0.000195% CI: [0.364, 0.542]Negative binomial regression model