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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.

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

Multiple Sclerosis

Autoantibody disorders (affecting the nervous system)

Brain and Nervous System Conditions

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.

Ponesimod

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

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 the absence of fever or infection. A confirmed relapse is identified when a patient's symptoms worsen as indicated by an increase in their Expanded Disability Status Scale (EDSS) or Functional Systems (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).

Time to first confirmed relapse: date of first confirmed relapse (in either core or extension study) minus date of randomization 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, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse are: 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).

Time to first 12-week CDA is defined as start date of the first 12-week CDA minus date of randomization 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 participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score >=5.5, confirmed after 12 weeks. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.

Time to first 24-week CDA was defined as start date of the first 24-week CDA minus date of randomization in the core study + 1 day. A 24-week CDA was defined as a 24-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 24-weeks. CDA was defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score >=5.5, confirmed after 24 weeks. EDSS was an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.

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. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse: 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). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.

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 randomization in the core study for each outcome measure and each participant individually.

NEDA-3 up to extension EOS is defined by the absence of confirmed relapse, gadolinium-enhancing (Gd+ T1) lesions, new or enlarging T2 lesions, and 12-week CDA. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant 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 defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.

NEDA-4 up to EOS is defined by the 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 participant discontinued treatment prematurely, the participant 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 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 defined as the last non-missing value recorded before or on randomization in core study for each outcome measure and each participant individually.

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 randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

CUALs was calculated as sum of new T1 Gadolinium-enhanced (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 randomization in the core study for each outcome measure and each participant individually.

Number of Gd+ T1 lesions measured by MRI 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 randomization in the core study for each outcome measure and each participant individually. For this outcome measure, results presented here are for the Extension end-of-treatment visit.

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 randomization in the core study for each outcome measure and each participant individually.

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 randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

Number of participants 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 randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

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 randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

Number of participants with TEAEs were reported. An AE is any untoward medical event that occurs in a participants 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 treatment end date + 15 days.

Number of participants 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.

Actual values of 12-lead ECG measurements up to end of study treatment: heart rate were reported. In this outcome measure, results were presented for extension end of treatment visit.

Actual values of 12-lead ECG measurements up to end of study treatment: PR, QRS, QT, QTcB, QTcF were reported. In this outcome measure, results were presented for extension end of treatment visit.

Change in heart rate (HR) from baseline up to end of study treatment were reported.

Change in PR, QRS, QT, QTcB, QTcF from baseline up to end of study treatment were reported.

Absolute values in FEV1 and FVC values 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.

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. In this outcome measure, results were presented for extension end of treatment visit.

Number of participants 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 participant, 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.

Number of participants 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.

Number of participants with AE leading to premature discontinuation of study treatment were reported. An AE is any untoward medical event that occurs in a participant 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 treatment end date + 15 days.

Number of participants 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).

Number of participants 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).

Number of participants 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. 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.

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.

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.

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.

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.

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 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.

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.

The Research Center of Southern California, LLC

The Neurology Group

Mountain View Clinical Research

Neurology Associates of Ormond Beach

University of South Florida

Josephson Wallack Munshower Neurology, PC

Raleigh Neurology Associates

Ohio Health

Advanced Neurosciences Institute

Grodno University Hospital

Minsk City Clinical Hospital 5

Republican Scientific Clinical Centre

Vitebsk Regional Diagnostic Center

Vitebsk Regional Clinical Hospital

University Clinicl Center Sarajevo

UMHAT Sveti Georgi

Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum

Multiprofile Hospital For Active Treatment National Cardiology Hospital, Ead

Acibadem City Clinic Tokuda Hospital

St Ivan Rilski University Multiprofile Hospital For Active Treatment

University Multiprofile Hospital for Active Treatment Alexandrovska EAD

Military Medical Academy, Multiprofile Hospital for Active Treatment -Sofia

University of Alberta

Royal Jubilee Hospital

Ottawa Hospital

Recherche Sepmus Inc.

Ch Osijek

University Hospital Center Zagreb

Fakultní nemocnici Brno

Fakultni nemocnice Hradec Kralove

Nemocnice Jihlava

Fakultni nemocnice Ostrava

Pardubicka krajska nemocnice a.s.

Vseobecna Fakultní Nemocnice

FN Motol

Krajska zdravotni, a.s. - Nemocnice Teplice, o.z.

Suomen Terveystalo Tampere

Mehilainen NEO

Hopital Pellegrin CHU Bordeaux

CHU Clermont-Ferrand - Hopital Gabriel Montpied

Hôpital Nord Laennec - CHU NANTES

Hopital PASTEUR

Nouvel Hôpital Civil

LTD 'Aversi Clinic'

P. Sarajishvili Institute of Neurology

Pineo Medical Ecosystem Ltd

S.Khechinashvili University Hospital

Curatio, Jsc

Universitätsklinikum Carl-Gustav-Carus Dresden

Helios Klinikum Erfurt

Panakeia - Arzneimittelforschung GmbH

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

401 Military Hospital

Naval Hospital of Athens

Medical Center of Athens

Uzsoki Utcai Korhaz

Jahn Ferenc Del-pesti Korhaz es Rendelointezet

Valeomed EGÉSZSÉGÜGYI KÖZPONT

Petz Aladar Megyei Oktato Korhaz

Pest Megyei Flor Ferenc Korhaz

Barzilai Medical Center

Rambam Medical Center

Hadassah Medical Center

Ziv Medical Center

Ospedale San Salvatore

Azienda Ospedaliera Sant Andrea

Pauls Stradins Clinical University Hospital

Latvias Juras medicinas centrs Ltd

Rīgas Austrumu klīniskā universitātes slimnīca

Hospital of Lithuanian University of Health Sciences Kaunas Clinics

VsI Respublikine Siauliu ligonine, V.

Unidad de Investigacion En Salud

CRI Centro Regiomontano de Investigacion SC

Neurocentrum Bydgoszcz Sp Z O O

Copernicus Podmiot Leczniczy Sp. z o.o

NeuroCentrum. Centrum Terapii SM

NEURO-MEDIC Janusz Zbrojkiewicz Poradnia Wielospecjalistyczna

Centrum Kompleksowej Rehabilitacji

Centrum Opieki Zdrowotnej Orkan-Med

Indywidualna Praktyka Lekarska Prof. Konrad Rejdak

Szpital Kliniczny im. Heliodora Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Po

Clinical Research Center sp. z o.o MEDIC-R s.k.

NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partnerska Lekarzy

WroMedica I.Bielicka, A.Strzałkowska s.c.

Hospital de Braga

Hospitais da universidade de Coimbra

Hosp. Cuf Descobertas

H. Santo António - Centro Hospitalar do Porto

Spitalul Universitar de Urgenta Militar Central 'Dr. Carol Davila'

Institutul Clinic Fundeni

Spitalul Universitar de Urgenta Bucuresti

Spitalul Clinic Judetean de Urgenta 'Pius Brinzeu'

Barnaul Territorial Clinical Hospital

St. Joseph Belgorod Regional Hospital

Bryansk Regional Hospital #1

Sverdlovsk Region Clinical Hospital #1

Research Medical Center Your Health

Federal State Budgetary Institution

State Budgetary Healthcare Institution Kursk Region Kursk Regional Clinical Hospital

Clinical City Hospital #1

defined as the number of confirmed relapses per subject-year

Time from enrollment in core study to first confirmed relapse

Time from core baseline to first 12-week CDA

Time from core baseline to first 24-week CDA

Number of patients with absence of relapses during study period

Change from baseline in EDSS at all assessments

NEDA 3 defined by the absence of confirmed relapse, GD+ T1 lesions, new or enlarging T2 lesions and 12-week CDA

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

Change from baseline in brain volume at all assessments

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

Number of Gd+ T1 lesions at all assessments

Cumulative number of new or enlarging T2 lesions (relative to baseline) at all assessments

Determination of MRI lesions (T2 lesions, T1 hypointense lesions) at all assessments

Absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) at all assessments

Proportion of Gd+ lesions at baseline evolving to PBHs at all assessments

Incidence rates of treatment-emergent AEs, severe AEs, AEs of special interest and AEs leading to premature discontinuation of study treatment

ECG abnormalities as defined by the ECG provider

Absolute values by visit for 12-lead ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)

Change from baseline values by visit for ECG parameters (HR, PR, QRS, QT, QTcB, QTcF)

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

Absolute values and percent change from baseline in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at all assessments

Determination of treatment-emergent decrease from baseline in FEV1 and FVC (absolute and % of predicted)

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)

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

Trials at a glance

Trials at a glance

Plain Language Summary