Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis
- Registration Number
- NCT03232073
- Lead Sponsor
- 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 877
- 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.
-
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
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Women who are pregnant or lactating.
-
Male subjects wishing to parent a child;
-
Treatment with any MS Disease Modifying Therapies;
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ponesimod Ponesimod 20 mg administered orally once daily
- Primary Outcome Measures
Name Time Method Time to first 24-week confirmed disability accumulation (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 from core baseline to first 24-week CDA
Assessment of no evidence of disease activity (NEDA) status at end-of-study (EOS) according to NEDA 3 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
Annualized confirmed relapse rate (ARR) 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
Assessment of volume of brain lesions measured by MRI 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
Estimation of incidence rates of adverse events (AEs) 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
Estimation of incidence rates of treatment-emergent morphological ECG abnormalities 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
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 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)
Time from core study randomization 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 from enrollment in core study to first confirmed relapse
Patients with absence of relapses 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
Assessment of no evidence of disease activity (NEDA) status at EOS according to NEDA 4 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
Time to first 12-week confirmed disability accumulation (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 from core baseline to first 12-week CDA
Cumulative number of new or enlarging T2 lesions measured by MRI 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
Change from baseline in Expanded Disability Status Scale (EDSS) 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
Absence of MRI lesions 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
Absolute values and percent change from baseline in forced expiratory volume and forced vital capacity 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
Percent change from baseline in brain volume (PCBV) measured by magnetic resonance imaging (MRI) 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
Cumulative number of combined unique active lesions (CUAL) measured by MRI 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
Determination of number of Gd+ T1 lesions by MRI 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
Determination of proportion of Gd+ lesions at baseline evolving to persistent black holes (PBHs) 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
Assessment of cardiac rhythms measured by electrocardiogram (ECG) parameters 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)
Change from baseline values by visit for cardiac rhythms 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)
Change in ECG parameters from pre-dose to selected post-dose assessments 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
Assessment of treatment-emergent decrease from baseline in forced expiratory volume and forced vital capacity 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)
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (148)
Hopital Nord Laennec - CHU NANTES
🇫🇷Nantes Cedex 1, France
NEURO MEDIC Janusz Zbrojkiewicz Poradnia Wielospecjalistyczna
🇵🇱Katowice, Poland
Centrum Opieki Zdrowotnej Orkan Med
🇵🇱Ksawerow, Poland
Szpital Kliniczny im Heliodora Swiecickiego Uniwersytetu Medycznego im Karola Marcinkowskiego w Po
🇵🇱Poznan, Poland
NZOZ NEURO KARD Ilkowski i Partnerzy Sp Partnerska Lekarzy
🇵🇱Poznan, Poland
WroMedica I Bielicka A Strzalkowska s c
🇵🇱Wroclaw, Poland
The Research Center of Southern California, LLC
🇺🇸Carlsbad, California, United States
The Neurology Group
🇺🇸Pomona, California, United States
Mountain View Clinical Research
🇺🇸Denver, Colorado, United States
Neurology Associates of Ormond Beach
🇺🇸Ormond Beach, Florida, United States
University of South Florida
🇺🇸Tampa, Florida, United States
Josephson Wallack Munshower Neurology, PC
🇺🇸Indianapolis, Indiana, United States
Raleigh Neurology Associates
🇺🇸Raleigh, North Carolina, United States
Ohio Health
🇺🇸Columbus, Ohio, United States
Advanced Neurosciences Institute
🇺🇸Franklin, Tennessee, United States
Grodno University Hospital
🇧🇾Grodno, Belarus
Minsk City Clinical Hospital 5
🇧🇾Minsk, Belarus
Republican Scientific Clinical Centre
🇧🇾Minsk, Belarus
Vitebsk Regional Diagnostic Center
🇧🇾Vitebsk, Belarus
Vitebsk Regional Clinical Hospital
🇧🇾Vitebsk, Belarus
University Clinicl Center Sarajevo
🇧🇦Sarajevo, Bosnia and Herzegovina
UMHAT Sveti Georgi
🇧🇬Plovdiv, Bulgaria
Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum
🇧🇬Sofia, Bulgaria
Multiprofile Hospital For Active Treatment National Cardiology Hospital, Ead
🇧🇬Sofia, Bulgaria
Acibadem City Clinic Tokuda Hospital
🇧🇬Sofia, Bulgaria
St Ivan Rilski University Multiprofile Hospital For Active Treatment
🇧🇬Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment Alexandrovska EAD
🇧🇬Sofia, Bulgaria
Military Medical Academy Multiprofile Hospital for Active Treatment Sofia
🇧🇬Sofia, Bulgaria
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Royal Jubilee Hospital
🇨🇦Victoria, British Columbia, Canada
Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada
Recherche Sepmus Inc.
🇨🇦Greenfield Park, Quebec, Canada
Ch Osijek
🇭🇷Osijek, Croatia
University Hospital Center Zagreb
🇭🇷Zagreb, Croatia
Fakultní nemocnici Brno
🇨🇿Brno, Czechia
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Králové, Czechia
Fakultni Nemocnice Ostrava
🇨🇿Ostrava-Poruba, Czechia
Nemocnice Jihlava
🇨🇿Jihlava, Czechia
Pardubicka krajska nemocnice a s
🇨🇿Pardubice, Czechia
Vseobecna Fakultní Nemocnice
🇨🇿Praha 2, Czechia
FN Motol
🇨🇿Praha 5, Czechia
Krajska zdravotni, a.s. - Nemocnice Teplice, o.z.
🇨🇿Teplice, Czechia
Suomen Terveystalo Tampere
🇫🇮Tampere, Finland
Mehilainen NEO
🇫🇮Turku, Finland
Hopital Pellegrin CHU Bordeaux
🇫🇷Bordeaux cedex, France
CHU Clermont-Ferrand - Hopital Gabriel Montpied
🇫🇷Clermont Ferrand Cedex 1, France
Hopital PASTEUR
🇫🇷Nice, France
Nouvel Hopital Civil
🇫🇷Strasbourg CEDEX, France
LTD 'Aversi Clinic'
🇬🇪T'bilisi, Georgia
P. Sarajishvili Institute of Neurology
🇬🇪Tbilisi, Georgia
S.Khechinashvili University Hospital
🇬🇪Tbilisi, Georgia
Pineo Medical Ecosystem Ltd
🇬🇪Tbilisi, Georgia
Curatio, Jsc
🇬🇪Tbilisi, Georgia
Universitätsklinikum Carl-Gustav-Carus Dresden
🇩🇪Dresden, Germany
Helios Klinikum Erfurt
🇩🇪Erfurt, Germany
Panakeia - Arzneimittelforschung GmbH
🇩🇪Leipzig, Germany
Universitatsmedizin der Johannes Gutenberg Universitat Mainz
🇩🇪Mainz, Germany
401 Military Hospital
🇬🇷Athens, Greece
Naval Hospital of Athens
🇬🇷Athens, Greece
Medical Center of Athens
🇬🇷Marousi, Greece
Uzsoki Utcai Korhaz
🇭🇺Budapest, Hungary
Jahn Ferenc Del-pesti Korhaz es Rendelointezet
🇭🇺Budapest, Hungary
Valeomed EGÉSZSÉGÜGYI KÖZPONT
🇭🇺Esztergom, Hungary
Petz Aladar Megyei Oktato Korhaz
🇭🇺Győr, Hungary
Kistarcsai Flor Ferenc Korhaz
🇭🇺Kistarcsa, Hungary
Barzilai Medical Center
🇮🇱Ashkelon, Israel
Rambam Medical Center
🇮🇱Haifa, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Ziv Medical Center
🇮🇱Safed, Israel
Ospedale San Salvatore
🇮🇹L' Aquila, Italy
Azienda Ospedaliera Sant Andrea
🇮🇹Roma, Italy
Pauls Stradins Clinical University Hospital
🇱🇻Riga, Latvia
Latvias Juras medicinas centrs Ltd
🇱🇻Riga, Latvia
Rīgas Austrumu klīniskā universitātes slimnīca
🇱🇻Riga, Latvia
Hospital of Lithuanian University of Health Sciences Kaunas Clinics
🇱🇹Kaunas, Lithuania
VsI Respublikine Siauliu ligonine, V.
🇱🇹Šiauliai, Lithuania
Unidad de Investigacion En Salud
🇲🇽Chihuahua, Mexico
CRI Centro Regiomontano de Investigacion SC
🇲🇽Nuevo Leon, Mexico
Neurocentrum Bydgoszcz Sp Z O O
🇵🇱Bydgoszcz, Poland
Copernicus Podmiot Leczniczy Sp. z o.o
🇵🇱Gdansk, Poland
Neuro Centrum Centrum Terapii SM
🇵🇱Katowice, Poland
Centrum Kompleksowej Rehabilitacji
🇵🇱Konstancin Jeziorna, Poland
Indywidualna Praktyka Lekarska Prof. Konrad Rejdak
🇵🇱Lublin, Poland
Clinical Research Center sp z o o MEDIC R s k
🇵🇱Poznan, Poland
Hospital de Braga
🇵🇹Braga, Portugal
Hospitais da universidade de Coimbra
🇵🇹Coimbra, Portugal
Hosp. Cuf Descobertas
🇵🇹Lisboa, Portugal
H. Santo António - Centro Hospitalar do Porto
🇵🇹Porto, Portugal
Spitalul Universitar de Urgenta Militar Central 'Dr. Carol Davila'
🇷🇴Bucuresti, Romania
Institutul Clinic Fundeni
🇷🇴Bucuresti, Romania
Spitalul Universitar de Urgenta Bucuresti
🇷🇴Bucuresti, Romania
Spitalul Clinic Judetean de Urgenta Pius Brinzeu
🇷🇴Timisoara, Romania
Barnaul Territorial Clinical Hospital
🇷🇺Barnaul, Russian Federation
St. Joseph Belgorod Regional Hospital
🇷🇺Belgorod, Russian Federation
Bryansk Regional Hospital #1
🇷🇺Bryansk, Russian Federation
Sverdlovsk Region Clinical Hospital #1
🇷🇺Ekaterinburg, Russian Federation
Research Medical Center Your Health
🇷🇺Kazan, Russian Federation
Federal State Budgetary Institution
🇷🇺Krasnoyarsk, Russian Federation
State Budgetary Healthcare Institution Kursk Region Kursk Regional Clinical Hospital
🇷🇺Kursk, Russian Federation
Clinical City Hospital #1
🇷🇺Moscow, Russian Federation
State Health Care Institution Of Moscow
🇷🇺Moscow, Russian Federation
Central Clinical Hospital N.A.Semashko
🇷🇺Moscow, Russian Federation
Municipal Clinical Hospital # 3
🇷🇺Nizhniy Novgorod, Russian Federation
Siberian District Medical Center of Federal Medical-Biological Agency
🇷🇺Novosibirsk, Russian Federation
Federal Scientific Clinical Center of Physico-Chemical Medicine
🇷🇺Odintsovo, Russian Federation
Perm State Medical Academy n.a. E. A. Vagner
🇷🇺Perm, Russian Federation
City Clinical Hospital # 2
🇷🇺Pyatigorsk, Russian Federation
Pavlov First Saint Petersburg State Medical University
🇷🇺Saint Petersburg, Russian Federation
State Healthcare Institution Samara Regional Clinical Hospital named after V.D.Seredavin
🇷🇺Samara, Russian Federation
Smolensk Regional Clinical Hospital
🇷🇺Smolensk, Russian Federation
Municipal Multi-Specialty Hospital # 2
🇷🇺St. Petersburg, Russian Federation
City Clinical Hospital #31
🇷🇺St. Petersburg, Russian Federation
Institute of Human Brain Ras
🇷🇺St. Petersburg, Russian Federation
City Hospital# 40
🇷🇺St.Petersburg, Russian Federation
Siberian State Medical University
🇷🇺Tomsk, Russian Federation
Tver Regional Clinical Hospital
🇷🇺Tver, Russian Federation
GUZ Novgorod Regional Clinical Hospital
🇷🇺Velikiy Novgorod, Russian Federation
Yaroslavl Clinical Hospital #8
🇷🇺Yaroslavl, Russian Federation
Clinical Hospital Center Zvezdara
🇷🇸Belgrade, Serbia
Vojnomedicinska Akademija
🇷🇸Belgrade, Serbia
University Clinical Center Kragujevac
🇷🇸Kragujevac, Serbia
University Clinical Center NIS
🇷🇸Nis, Serbia
Hospital del Mar
🇪🇸Barcelona, Spain
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Clinic I Provincial
🇪🇸Barcelona, Spain
Hospital Universitario de La Princesa
🇪🇸Madrid, Spain
Hospital Regional Universitario de Malaga
🇪🇸Malaga, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain
Hospital Vithas Nisa Sevilla
🇪🇸Sevilla, Spain
Sahlgrenska Universitetsjukhuset
🇸🇪Göteborg, Sweden
Centrum för Neurologi
🇸🇪Stockholm, Sweden
Karadeniz Teknik University Medical Faculty
🇹🇷Trabzon, Turkey
Public Non-profit Enterprise: Chernihiv City Hospital #4 under Chernihiv City Council
🇺🇦Chernihiv, Ukraine
Municipal health care institution Chernihiv Regional Hospital
🇺🇦Chernihiv, Ukraine
Ivano-Frankivsk Regional Clinical Hospital
🇺🇦Ivano-Frankivsk, Ukraine
Limited Liability Company 'Neuro Global'
🇺🇦Ivano-Frankivsk, Ukraine
Kharkiv Railway Clinical Hospital N1 Of Brance 'Health Center'
🇺🇦Kharkiv, Ukraine
Kharkiv Postgrad Academy, Dept of Neurology #1 At Hosp #7
🇺🇦Kharkiv, Ukraine
National Research Center for Radiation Medicine
🇺🇦Kyiv, Ukraine
Public Non-Profit Enterprise: Lviv City Clinical Hospital #5
🇺🇦Lviv, Ukraine
Lviv Clinical Regional Hospital
🇺🇦Lviv, Ukraine
Odessa National Medical University
🇺🇦Odesa, Ukraine
ME 'Poltava Regional Clinical Hospital n.a. M.V. Sklifosovsky of the Poltava Regional Council'
🇺🇦Poltava, Ukraine
Mnce 'Ternopil Regional Clinical Psychoneurology Hospital' of Trb
🇺🇦Ternopil, Ukraine
Medical Center Salutem LLC
🇺🇦Vinnytsia, Ukraine
O.F. Herbachevskyi Regional Clinical Hospital
🇺🇦Zhytomyr, Ukraine
Royal Preston Hospital
🇬🇧Preston, United Kingdom
Salford Royal NHS Foundation Trust
🇬🇧Salford, United Kingdom