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 Clinical Trial

— OPTIMUM-LT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03232073
• Other study ID #: AC-058B303
• Secondary ID: 2016-004719-10
• Status: Completed
• Phase: Phase 3
• Start date: July 5, 2017
• Est. completion date: January 16, 2024

Study information

• Verified date: February 2024
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 877
• Est. completion date: January 16, 2024
• Est. primary completion date: January 16, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

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

Locations

Country	Name	City	State
Belarus	Grodno University Hospital	Grodno
Belarus	Minsk City Clinical Hospital 5	Minsk
Belarus	Republican Scientific Clinical Centre	Minsk
Belarus	Vitebsk Regional Clinical Hospital	Vitebsk
Belarus	Vitebsk Regional Diagnostic Center	Vitebsk
Bosnia and Herzegovina	University Clinicl Center Sarajevo	Sarajevo
Bulgaria	UMHAT Sveti Georgi	Plovdiv
Bulgaria	Acibadem City Clinic Tokuda Hospital	Sofia
Bulgaria	Military Medical Academy, Multiprofile Hospital for Active Treatment -Sofia	Sofia
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	St Ivan Rilski University Multiprofile Hospital For Active Treatment	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment Alexandrovska EAD	Sofia
Canada	University of Alberta	Edmonton	Alberta
Canada	Recherche Sepmus Inc.	Greenfield Park	Quebec
Canada	Ottawa Hospital	Ottawa	Ontario
Canada	Royal Jubilee Hospital	Victoria	British Columbia
Croatia	Ch Osijek	Osijek
Croatia	University Hospital Center Zagreb	Zagreb
Czechia	Fakultní nemocnici Brno	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Králové
Czechia	Nemocnice Jihlava	Jihlava
Czechia	Fakultni nemocnice Ostrava	Ostrava-Poruba
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
Finland	Suomen Terveystalo Tampere	Tampere
Finland	Mehilainen NEO	Turku
France	Hopital Pellegrin CHU Bordeaux	Bordeaux cedex
France	CHU Clermont-Ferrand - Hopital Gabriel Montpied	Clermont Ferrand Cedex 1
France	Hôpital Nord Laennec - CHU NANTES	Nantes Cedex 1
France	Hopital PASTEUR	Nice
France	Nouvel Hopital Civil	Strasbourg CEDEX
Georgia	LTD 'Aversi Clinic'	T'bilisi
Georgia	Curatio, Jsc	Tbilisi
Georgia	P. Sarajishvili Institute of Neurology	Tbilisi
Georgia	Pineo Medical Ecosystem Ltd	Tbilisi
Georgia	S.Khechinashvili University Hospital	Tbilisi
Germany	Universitätsklinikum Carl-Gustav-Carus Dresden	Dresden
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Panakeia - Arzneimittelforschung GmbH	Leipzig
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Greece	401 Military Hospital	Athens
Greece	Naval Hospital of Athens	Athens
Greece	Medical Center of Athens	Marousi
Hungary	Jahn Ferenc Del-pesti Korhaz es Rendelointezet	Budapest
Hungary	Uzsoki Utcai Korhaz	Budapest
Hungary	Valeomed EGÉSZSÉGÜGYI KÖZPONT	Esztergom
Hungary	Petz Aladar Megyei Oktato Korhaz	Gyor
Hungary	Pest Megyei Flor Ferenc Korhaz	Kistarcsa
Israel	Barzilai Medical Center	Ashkelon
Israel	Rambam Medical Center	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Ziv Medical Center	Safed
Italy	Ospedale San Salvatore	L' Aquila
Italy	Azienda Ospedaliera Sant Andrea	Roma
Latvia	Latvias Juras medicinas centrs Ltd	Riga
Latvia	Pauls Stradins Clinical University Hospital	Riga
Latvia	Rigas Austrumu kliniska universitates slimnica	Riga
Lithuania	VsI Respublikine Siauliu ligonine, V.	Šiauliai
Lithuania	Hospital of Lithuanian University of Health Sciences Kaunas Clinics	Kaunas
Mexico	Unidad de Investigacion En Salud	Chihuahua
Mexico	CRI Centro Regiomontano de Investigacion SC	Nuevo Leon
Poland	Neurocentrum Bydgoszcz Sp Z O O	Bydgoszcz
Poland	Copernicus Podmiot Leczniczy Sp. z o.o	Gdansk
Poland	NEURO-MEDIC Janusz Zbrojkiewicz Poradnia Wielospecjalistyczna	Katowice
Poland	NeuroCentrum. Centrum Terapii SM	Katowice
Poland	Centrum Kompleksowej Rehabilitacji	Konstancin-Jeziorna
Poland	Centrum Opieki Zdrowotnej Orkan-Med	Ksawerow
Poland	Indywidualna Praktyka Lekarska Prof. Konrad Rejdak	Lublin
Poland	Clinical Research Center sp. z o.o MEDIC-R s.k.	Poznan
Poland	NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partnerska Lekarzy	Poznan
Poland	Szpital Kliniczny im. Heliodora Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Po	Poznan
Poland	WroMedica I.Bielicka, A.Strzalkowska s.c.	Wroclaw
Portugal	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
Romania	Institutul Clinic Fundeni	Bucuresti
Romania	Spitalul Universitar de Urgenta Bucuresti	Bucuresti
Romania	Spitalul Universitar de Urgenta Militar Central 'Dr. Carol Davila'	Bucuresti
Romania	Spitalul Clinic Judetean de Urgenta 'Pius Brinzeu'	Timisoara
Russian Federation	Barnaul Territorial Clinical Hospital	Barnaul, Altai Krai
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	Central Clinical Hospital N.A.Semashko	Moscow
Russian Federation	Clinical City Hospital #1	Moscow
Russian Federation	State Health Care Institution Of Moscow	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	City Clinical Hospital #31	St. Petersburg
Russian Federation	Institute of Human Brain Ras	St. Petersburg
Russian Federation	Municipal Multi-Specialty Hospital # 2	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
Serbia	Clinical Hospital Center Zvezdara	Belgrade
Serbia	Vojnomedicinska Akademija	Belgrade
Serbia	University Clinical Center Kragujevac	Kragujevac
Serbia	University Clinical Center NIS	Nis
Spain	Hospital Clinic I Provincial	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Vall d'Hebron	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
Sweden	Sahlgrenska Universitetsjukhuset	Göteborg
Sweden	Centrum för Neurologi	Stockholm
Turkey	Karadeniz Teknik University Medical Faculty	Trabzon
Ukraine	Municipal health care institution Chernihiv Regional Hospital	Chernihiv
Ukraine	Public Non-profit Enterprise: Chernihiv City Hospital #4 under Chernihiv City Council	Chernihiv
Ukraine	Ivano-Frankivsk Regional Clinical Hospital	Ivano-Frankivsk
Ukraine	Limited Liability Company 'Neuro Global'	Ivano-Frankivsk
Ukraine	Kharkiv Postgrad Academy, Dept of Neurology #1 At Hosp #7	Kharkiv
Ukraine	Kharkiv Railway Clinical Hospital N1 Of Brance 'Health Center'	Kharkiv
Ukraine	National Research Center for Radiation Medicine	Kyiv
Ukraine	Lviv Clinical Regional Hospital	Lviv
Ukraine	Public Non-Profit Enterprise: Lviv City Clinical Hospital #5	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
United Kingdom	Royal Preston Hospital	Preston
United Kingdom	Salford Royal NHS Foundation Trust	Salford
United States	The Research Center of Southern California, LLC	Carlsbad	California
United States	Ohio Health	Columbus	Ohio
United States	Mountain View Clinical Research	Denver	Colorado
United States	Advanced Neurosciences Institute	Franklin	Tennessee
United States	Josephson Wallack Munshower Neurology, PC	Indianapolis	Indiana
United States	Neurology Associates of Ormond Beach	Ormond Beach	Florida
United States	The Neurology Group	Pomona	California
United States	Raleigh Neurology Associates	Raleigh	North Carolina
United States	University of South Florida	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Belarus,  Bosnia and Herzegovina,  Bulgaria,  Canada,  Croatia,  Czechia,  Finland,  France,  Georgia,  Germany,  Greece,  Hungary,  Israel,  Italy,  Latvia,  Lithuania,  Mexico,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Spain,  Sweden,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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