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

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ClinicalTrials.gov Identifier: NCT03232073
Recruitment Status : Enrolling by invitation
First Posted : July 27, 2017
Last Update Posted : June 12, 2019
Sponsor:
Information provided by (Responsible Party):
Actelion

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Ponesimod Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 17, 2017
Estimated Primary Completion Date : April 2, 2022
Estimated Study Completion Date : April 2, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ponesimod
20 mg administered orally once daily
Drug: Ponesimod
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




Primary Outcome Measures :
  1. Annualized confirmed relapse rate (ARR) [ Time Frame: 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 ]
    defined as the number of confirmed relapses per subject-year

  2. Time from core study randomization to first confirmed relapse [ Time Frame: 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 enrollment in core study to first confirmed relapse

  3. Time to first 12-week confirmed disability accumulation (CDA) [ Time Frame: 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 baseline to first 12-week CDA

  4. Time to first 24-week confirmed disability accumulation (CDA) [ Time Frame: 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 baseline to first 24-week CDA

  5. Patients with absence of relapses [ Time Frame: 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 ]
    Number of patients with absence of relapses during study period

  6. Change from baseline in Expanded Disability Status Scale (EDSS) [ Time Frame: 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 EDSS at all assessments

  7. Assessment of no evidence of disease activity (NEDA) status at week 108 and end-of treatment (EOT) according to NEDA 3 [ Time Frame: 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 ]
    NEDA 3 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA

  8. Assessment of no evidence of disease activity (NEDA) status at week 108 and end-of treatment (EOT) according to NEDA 4 [ Time Frame: 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 ]
    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

  9. Percent change from baseline in brain volume (PCBV) measured by magnetic resonance imaging (MRI) [ Time Frame: 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 brain volume at all assessments

  10. Cumulative number of combined unique active lesions (CUAL) measured by MRI [ Time Frame: 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) defined as new Gd+ T1 lesions plus new or enlarging T2 lesions (without double-counting the lesions) at all assessments

  11. Determination of number of Gd+ T1 lesions by MRI [ Time Frame: 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 ]
    Number of Gd+ T1 lesions at all assessments

  12. Cumulative number of new or enlarging T2 lesions measured by MRI [ Time Frame: 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 (relative to baseline) at all assessments

  13. Assessment of volume of brain lesions measured by MRI [ Time Frame: 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 MRI lesions (T2 lesions, T1 hypointense lesions) at all assessments

  14. Absence of MRI lesions [ Time Frame: 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 (Gd+ T1 lesions, new or enlarging T2 lesions) at all assessments

  15. Determination of proportion of Gd+ lesions at baseline evolving to persistent black holes (PBHs) [ Time Frame: 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 ]
    Proportion of Gd+ lesions at baseline evolving to PBHs at all assessments

  16. Estimation of incidence rates of adverse events (AEs) [ Time Frame: 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 ]
    Incidence rates of treatment-emergent AEs, severe AEs, AEs of special interest and AEs leading to premature discontinuation of study treatment

  17. Estimation of incidence rates of treatment-emergent morphological ECG abnormalities [ Time Frame: 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 ]
    ECG abnormalities as defined by the ECG provider

  18. Assessment of cardiac rhythms measured by electrocardiogram (ECG) parameters [ Time Frame: 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 values by visit for 12-lead ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)

  19. Change from baseline values by visit for cardiac rhythms [ Time Frame: 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 ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)

  20. Change in ECG parameters from pre-dose to selected post-dose assessments [ Time Frame: Analysis period: From day 1 in extension study to end-of-treatment (EOT) in extension study, i.e. for up to 240 weeks ]
    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

  21. Absolute values and percent change from baseline in forced expiratory volume and forced vital capacity [ Time Frame: 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 values and percent change from baseline in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at all assessments

  22. Assessment of treatment-emergent decrease from baseline in forced expiratory volume and forced vital capacity [ Time Frame: 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 treatment-emergent decrease from baseline in FEV1 and FVC (absolute and % of predicted)

  23. 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 [ Time Frame: 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 FEV1 and FVC (absolute and % of predicted)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent
  2. Subjects with MS having completed the double-blind treatment in the core study as scheduled
  3. Compliance with teriflunomide elimination procedure
  4. 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:

  1. Any of the following cardiovascular conditions on Day 1 pre-dose:

    1. Resting heart rate (HR) < 50 bpm;
    2. Presence of second degree atrioventricular (AV) block or third degree AV block or a QTcF interval > 470 ms (females), > 450 ms (males);
  2. 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:

    1. Lymphocyte count: < 0.2 x 109/L;
    2. Neutrophil count <1.0 × 109/L;
    3. Platelet count < 50 × 109/L;
    4. Creatinine clearance < 30 mL/min
  3. At Visit 14 of the core study (EOT) >30% decrease from core study baseline FEV1 and/or FVC;
  4. Clinically significant, persistent respiratory AEs (e.g., dyspnea) not resolved prior to first dosing in the extension study.
  5. Macular edema at any time between Visit 1 (Screening) in the core study and Day 1 of the extension study.
  6. 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:

    1. Suspected opportunistic infection of the CNS or any other infection which, in the opinion of the investigator, contraindicates re-start of the study drug;
    2. Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms.
  7. Need for and intention to administer forbidden study treatment-concomitant therapy
  8. Women who are pregnant or lactating.
  9. Male subjects wishing to parent a child;
  10. Treatment with any MS Disease Modifying Therapies;
  11. 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;
  12. Subjects unlikely to comply with the extension study protocol based on investigator best judgment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03232073


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Sponsors and Collaborators
Actelion
Investigators
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Study Director: Tatiana Scherz, MD, PhD Actelion

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Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT03232073     History of Changes
Other Study ID Numbers: AC-058B303
First Posted: July 27, 2017    Key Record Dates
Last Update Posted: June 12, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases