Multiple Sclerosis
Conditions
Brief summary
This clinical study compares the efficacy, safety, and tolerability of therapy with ponesimod vs placebo in subjects with active RMS who are treated with DMF (Tecfidera®).
Detailed description
The study will assess the efficacy, safety, and tolerability of add-on therapy with ponesimod 20 mg vs placebo in adult participants with active relapsing multiple sclerosis (RMS) who are treated with dimethyl fumarate (DMF). Approximately 600 participants who have been receiving DMF for at least 6 months will be randomized in a 1:1 ratio to ponesimod 20 mg or placebo. The study consists of the following study periods: Pre-randomization period; Treatment period; Post-treatment observation period. The study includes one ponesimod treatment arm at the maintenance dose of 20 mg o.d. corresponding to the optimal dose when used as monotherapy based on the Phase 2 dose-finding trial and its ongoing extension. The study includes a placebo comparator arm, but all patients will remain on DMF background therapy throughout the study. Moreover, participants who experience a confirmed relapse or an event of 24-week confirmed disability accumulation (DMF) while on study drug will have the option to switch to an alternative treatment. The treatment period has a variable duration from a minimum of 60 weeks (for the last subject randomized) to a maximum of 156 weeks for the first subjects randomized in the trial and includes a gradual up-titration of ponesimod from a 2 mg starting dose to a 20 mg maintenance dose over a period of 14 days. The total duration of the study will be approximately up to 167 weeks.
Interventions
DRUGPonesimod
One tablet of ponesimod 20 mg administered orally once daily in the morning from Day 15 to EOT. To reduce the first-dose effect of ponesimod, an uptitration scheme will be implemented from Day 1 to Day 14 (with dose strength increasing from 2 mg to 20 mg).
OTHERPlacebo
One tablet of matching placebo 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
* Signed informed consent prior to initiation of any study-mandated procedure. * Women of childbearing potential must have a negative pregnancy test and use reliable methods of contraception * Presenting with a diagnosis of MS as defined by the revised (2010) McDonald Diagnostic Criteria for MS with relapsing course from onset (i.e., relapsing-remitting multiple sclerosis (RRMS), or secondary progressive multiple sclerosis (SPMS) with superimposed relapses). * Ongoing treatment with DMF for at least 6 months prior to screening * Active disease after at least 3 months of DMF treatment * Ambulatory and with an EDSS score between 0 and 6.0 (inclusive).
Exclusion criteria
* Lactating or pregnant women and women intending to become pregnant during the study. * Presenting with a diagnosis of MS with progressive course from onset (i.e., primary progressive MS or progressive relapsing MS). * Evidence of a relapse of MS with onset within 30 days prior to baseline EDSS assessment. * Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Confirmed Relapse Rate (ARR) | Through study completion, an average of 68 weeks | Relapse: occurrence of acute episode of one or more new or worsened symptoms of Multiple sclerosis (MS), not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicates overall functional impairment assessing Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS in conjunction with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10(death due to MS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 12-Week Confirmed Disability Accumulation (CDA) as Assessed by Kaplan Meier Estimate at Week 96 | Week 96 | Percentage of participants with 12-week CDA as assessed by Kaplan Meier estimate at week 96 was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score greater than or equal to (\>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). |
| Percentage of Participants Experiencing a Confirmed Relapse as Assessed by Kaplan Meier Estimate at Week 96 | Week 96 | Percentage of participants experiencing a confirmed relapse as assessed by Kaplan Meier estimate at week 96 was reported. The time to first confirmed relapse (in days) is defined as \[Date of first confirmed relapse minus Date of randomization plus 1\] in days. Relapse: Occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple sclerosis (MS), not related with fever/infection and lasting 24 hours after 30 days stable period. |
| Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability | Up to 147 Weeks | An AE is any untoward medical event that occurs in a participants administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, Italy, Mexico, Poland, Portugal, Russia, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Total 136 participants were randomized,68 in both arms (ponesimod 20mg plus DMF \[dimethyl fumarate\] & placebo plus DMF). Of 136 participants,107 (50 in ponesimod 20mg plus DMF; 57 in placebo plus DMF) completed study till early termination.This study was discontinued due to sponsor's decision.
Participants by arm
| Arm | Count |
|---|---|
| Ponesimod Plus Dimethyl Fumarate (DMF) Participants were up-titrated during Days 1 to 14 with 2 to 10 mg of ponesimod once daily and maintenance dose of 20 mg ponesimod tablets once daily from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy. | 68 |
| Placebo Plus Dimethyl Fumarate (DMF) Participants received matching placebo once daily during Days 1 to 14 and maintenance dose from Day 15 to end of treatment. In addition, participants also continued receiving DMF capsules, orally, as background therapy. | 68 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Sponsor's Decision | 50 | 57 |
| Overall Study | Withdrawal by Subject | 15 | 7 |
Baseline characteristics
| Characteristic | Ponesimod Plus Dimethyl Fumarate (DMF) | Total | Placebo Plus Dimethyl Fumarate (DMF) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants | 136 Participants | 68 Participants |
| Age, Continuous | 37.8 years STANDARD_DEVIATION 9.1 | 37.9 years STANDARD_DEVIATION 9.07 | 38.1 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 122 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 64 Participants | 127 Participants | 63 Participants |
| Region of Enrollment AUSTRIA | 5 Participants | 12 Participants | 7 Participants |
| Region of Enrollment BELGIUM | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment BULGARIA | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment CANADA | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment CZECH REPUBLIC | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment FRANCE | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment GERMANY | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment GREECE | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment HUNGARY | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment ITALY | 5 Participants | 9 Participants | 4 Participants |
| Region of Enrollment MEXICO | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment POLAND | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment PORTUGAL | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 4 Participants | 6 Participants | 2 Participants |
| Region of Enrollment SPAIN | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment UNITED KINGDOM | 5 Participants | 9 Participants | 4 Participants |
| Region of Enrollment UNITED STATES | 8 Participants | 13 Participants | 5 Participants |
| Sex: Female, Male Female | 43 Participants | 89 Participants | 46 Participants |
| Sex: Female, Male Male | 25 Participants | 47 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 67 | 1 / 68 |
| other Total, other adverse events | 45 / 67 | 41 / 68 |
| serious Total, serious adverse events | 6 / 67 | 7 / 68 |
Outcome results
Primary
Annualized Confirmed Relapse Rate (ARR)
Relapse: occurrence of acute episode of one or more new or worsened symptoms of Multiple sclerosis (MS), not associated with fever/infection and lasting 24 hours after stable 30 days period. Confirmed relapse: increase from baseline at least 0.5 point Expanded Disability Status Scale (EDSS) score or increase of one point in one, two or three Functional Systems (FS), excluding bowel/bladder and cerebral/mental FS. EDSS and FS scores are based on neurological examination for assessing its impairment in MS. Among eight FS, seven are ordinal clinical rating scales ranging from 0-5 or 6 with higher scale indicates overall functional impairment assessing Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel/Bladder and Cerebral functions. Rating individual FS scores is used to rate EDSS in conjunction with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10(death due to MS).
Time frame: Through study completion, an average of 68 weeks
Population: Full Analysis Set (FAS) included all randomized participants who were treated with at least one dose of study treatment and had at least one post baseline efficacy assessment. Participants were analyzed according to randomized treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ponesimod Plus Dimethyl Fumarate (DMF) | Annualized Confirmed Relapse Rate (ARR) | 0.237 Relapses per year |
| Placebo Plus Dimethyl Fumarate (DMF) | Annualized Confirmed Relapse Rate (ARR) | 0.187 Relapses per year |
p-value: 0.525295% CI: [0.608, 2.654]Negative binomial regression
Secondary
Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability
An AE is any untoward medical event that occurs in a participants administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time frame: Up to 147 Weeks
Population: Safety Analysis Set (SAF) includes all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ponesimod Plus Dimethyl Fumarate (DMF) | Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability | 48 Participants |
| Placebo Plus Dimethyl Fumarate (DMF) | Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability | 53 Participants |
Secondary
Percentage of Participants Experiencing a Confirmed Relapse as Assessed by Kaplan Meier Estimate at Week 96
Percentage of participants experiencing a confirmed relapse as assessed by Kaplan Meier estimate at week 96 was reported. The time to first confirmed relapse (in days) is defined as \[Date of first confirmed relapse minus Date of randomization plus 1\] in days. Relapse: Occurrence of acute episode of one or more new symptoms or worsened symptoms of Multiple sclerosis (MS), not related with fever/infection and lasting 24 hours after 30 days stable period.
Time frame: Week 96
Population: FAS included all randomized participants who were treated with at least one dose of study treatment and had at least one post baseline efficacy assessment. Participants were analyzed according to randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponesimod Plus Dimethyl Fumarate (DMF) | Percentage of Participants Experiencing a Confirmed Relapse as Assessed by Kaplan Meier Estimate at Week 96 | 33.6 Percentage of Participants |
| Placebo Plus Dimethyl Fumarate (DMF) | Percentage of Participants Experiencing a Confirmed Relapse as Assessed by Kaplan Meier Estimate at Week 96 | 25.7 Percentage of Participants |
Secondary
Percentage of Participants With 12-Week Confirmed Disability Accumulation (CDA) as Assessed by Kaplan Meier Estimate at Week 96
Percentage of participants with 12-week CDA as assessed by Kaplan Meier estimate at week 96 was defined as an increase of at least 1.5 in Expanded Disability Status Scale (EDSS) for participants with a baseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS for participants with a baseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 in EDSS for participants with a baseline EDSS score greater than or equal to (\>=) 5.5, which was confirmed after 12 weeks. Baseline EDSS was defined as the last EDSS score recorded prior to randomization. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS).
Time frame: Week 96
Population: FAS included all randomized participants who were treated with at least one dose of study treatment and had at least one post baseline efficacy assessment. Participants were analyzed according to randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponesimod Plus Dimethyl Fumarate (DMF) | Percentage of Participants With 12-Week Confirmed Disability Accumulation (CDA) as Assessed by Kaplan Meier Estimate at Week 96 | 18.7 Percentage of participants with a CDA. |
| Placebo Plus Dimethyl Fumarate (DMF) | Percentage of Participants With 12-Week Confirmed Disability Accumulation (CDA) as Assessed by Kaplan Meier Estimate at Week 96 | 11.9 Percentage of participants with a CDA. |