Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis

Study Overview
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Brief Summary
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The study AC-058B301 (OPTIMUM; NCT02425644) has been designed to investigate the efficacy, safety and tolerability of ponesimod in subjects with relapsing multiple sclerosis (RMS). The AC-058B303 study is the long-term extension for the core study AC-058B301. The purpose of this long term extension of the core study AC-058B301 is to characterize the long-term safety, tolerability, and control of disease of ponesimod 20 mg in subjects with RMS.

Detailed Description
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The AC-058B303 study (extension study) is the long-term extension for the AC-058B301 study (core study). The core study has been designed to investigate the efficacy, safety and tolerability of ponesimod in subjects with RMS. The subjects are treated with either ponesimod or the active comparator, teriflunomide in the core study. The purpose of this long term extension of the core study is to characterize the long-term safety and control of disease of ponesimod in subjects with RMS. In particular, the study will allow to observe potential adverse events which may only occur after long term treatment with ponesimod. The study will also investigate the effect of re-initiation of ponesimod after a brief interruption in a relatively large population (all subjects treated with ponesimod in the core study and eligible for the extension study) on disease activity in terms of relapses and MS-related MRI lesions. There is currently limited guidance on when a new MS treatment should be started after discontinuation of teriflunomide and the study will contribute with data on safety and efficacy of switching from teriflunomide to ponesimod after an interruption as mandated by the protocol. The study will also allow confirmation of sustained efficacy of ponesimod in terms of relapses, MRI lesions and reduction of disability accumulation during long-term treatment. In addition, combined data from the core study together with the results of the current extension study will allow comparison of MS activity in subjects who were switched from teriflunomide to ponesimod versus those who were treated with ponesimod in both studies. A vaccination sub-study will be conducted in a sub-set of up to 50 eligible study participants from selected countries who consent to be vaccinated with the Janssen coronavirus disease-2019 (COVID-19) vaccine (Ad26.COV2.S) to investigate the immune response induced by the Janssen COVID-19 vaccine.

Official Title
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Multicenter, Non-comparative Extension of Study AC-058B301, to Investigate the Long-term Safety, Tolerability, and Control of Disease of Ponesimod 20 mg in Subjects With Relapsing Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Ponesimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Subjects with MS having completed the double-blind treatment in the core study as scheduled Compliance with teriflunomide elimination procedure Women of childbearing potential (WOCBP) must have a negative pre-treatment urine pregnancy test, must agree to undertake 4-weekly urine pregnancy tests, and must have been using reliable methods of contraception. Fertile male subjects participating in the study must agree to use a condom. Exclusion Criteria: Any of the following cardiovascular conditions on Day 1 pre-dose: Resting heart rate (HR) < 50 bpm; Presence of second degree atrioventricular (AV) block or third degree AV block or a QTcF interval > 470 ms (females), > 450 ms (males); Any of the following alerts from central laboratory at Visit 14 of the core study (EOT) which was confirmed as an alert at repeated testing or not repeated prior to FU1 of the core study: Lymphocyte count: < 0.2 x 109/L; Neutrophil count <1.0 × 109/L; Platelet count < 50 × 109/L; Creatinine clearance < 30 mL/min At Visit 14 of the core study (EOT) >30% decrease from core study baseline FEV1 and/or FVC; Clinically significant, persistent respiratory AEs (e.g., dyspnea) not resolved prior to first dosing in the extension study. Macular edema at any time between Visit 1 (Screening) in the core study and Day 1 of the extension study. Presence of the following at core study Visit 14 (EOT, Week 108), FU1, or abbreviated visit FU2, or on Day 1 of the extension study pre-dose: Suspected opportunistic infection of the CNS or any other infection which, in the opinion of the investigator, contraindicates re-start of the study drug; Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms. Need for and intention to administer forbidden study treatment-concomitant therapy Women who are pregnant or lactating. Male subjects wishing to parent a child; Treatment with any MS Disease Modifying Therapies; Any other clinically relevant medical or surgical condition, which, in the opinion of the investigator, would put the subject at risk by participating in the study; Subjects unlikely to comply with the extension study protocol based on investigator best judgment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-group open-label extension study to investigate long-term safety, tolerability and control of disease of ponesimod 20 mg in subjects with RMS. Statistical analyses will be descriptive and therefore all endpoints are exploratory in nature. All exploratory endpoints are listed under primary outcomes.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ponesimod<br>20 mg administered orally once daily | Drug: Ponesimod<br>* Ponesimod; Film-coated tablet; Oral use. From Day 1 to Day 14, ponesimod is gradually up-titrated until a maintenance dose of 20 mg is reached from Day 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized confirmed relapse rate (ARR) | defined as the number of confirmed relapses per subject-year | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Time from core study randomization to first confirmed relapse | Time from enrollment in core study to first confirmed relapse | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Time to first 12-week confirmed disability accumulation (CDA) | Time from core baseline to first 12-week CDA | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Time to first 24-week confirmed disability accumulation (CDA) | Time from core baseline to first 24-week CDA | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Patients with absence of relapses | Number of patients with absence of relapses during study period | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Change from baseline in Expanded Disability Status Scale (EDSS) | Change from baseline in EDSS at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Assessment of no evidence of disease activity (NEDA) status at end-of-study (EOS) according to NEDA 3 | NEDA 3 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA | Up to 354 weeks | 
| Assessment of no evidence of disease activity (NEDA) status at EOS according to NEDA 4 | NEDA 4 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA, and annual brain volume change ≥ -0.4% from baseline to all assessments | Up to 354 weeks | 
| Percent change from baseline in brain volume (PCBV) measured by magnetic resonance imaging (MRI) | Change from baseline in brain volume at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Cumulative number of combined unique active lesions (CUAL) measured by MRI | Cumulative number of combined unique active lesions (CUAL) defined as new Gd+ T1 lesions plus new or enlarging T2 lesions (without double-counting the lesions) at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Determination of number of Gd+ T1 lesions by MRI | Number of Gd+ T1 lesions at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Cumulative number of new or enlarging T2 lesions measured by MRI | Cumulative number of new or enlarging T2 lesions (relative to baseline) at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Assessment of volume of brain lesions measured by MRI | Determination of MRI lesions (T2 lesions, T1 hypointense lesions) at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Absence of MRI lesions | Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Determination of proportion of Gd+ lesions at baseline evolving to persistent black holes (PBHs) | Proportion of Gd+ lesions at baseline evolving to PBHs at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Estimation of incidence rates of adverse events (AEs) | Incidence rates of treatment-emergent AEs, severe AEs, AEs of special interest and AEs leading to premature discontinuation of study treatment | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Estimation of incidence rates of treatment-emergent morphological ECG abnormalities | ECG abnormalities as defined by the ECG provider | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Assessment of cardiac rhythms measured by electrocardiogram (ECG) parameters | Absolute values by visit for 12-lead ECG parameters (HR, PR, QRS, QT, QTcB, QTcF) | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Change from baseline values by visit for cardiac rhythms | Change from baseline values by visit for ECG parameters (HR, PR, QRS, QT, QTcB, QTcF) | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Change in ECG parameters from pre-dose to selected post-dose assessments | Change in ECG parameters (HR, PR, QRS, QT, QTcB, QTcF) from pre-dose to selected post-dose assessments (1h, 2h, 3h, 4h) on day 1 of extension study and on day of re-initiation of study treatment | Analysis period: From day 1 in extension study to end-of-treatment (EOT) in extension study, i.e. for up to 240 weeks | 
| Absolute values and percent change from baseline in forced expiratory volume and forced vital capacity | Absolute values and percent change from baseline in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at all assessments | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Assessment of treatment-emergent decrease from baseline in forced expiratory volume and forced vital capacity | Determination of treatment-emergent decrease from baseline in FEV1 and FVC (absolute and % of predicted) | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks | 
| Absolute change from baseline to end-of-study (EOS) versus change from baseline to end-of-treatment (EOT) in forced expiratory volume and forced vital capacity | Absolute change from baseline to end-of-study (EOS) versus change from baseline to end-of-treatment (EOT) in FEV1 and FVC (absolute and % of predicted) | Analysis period: From day 1 in core study (Enrollment) to end-of-treatment (EOT) in the extension study, i.e. for up to 354 weeks |