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

Phase 3

Completed

• Conditions: Multiple Sclerosis
• Interventions: Drug: Ponesimod

• 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.

Study Timeline

• Study Start: 2017-07-05
• Study First Submitted: 2017-07-20
• Study First Submitted QC: 2017-07-26
• Study First Posted: 2017-07-27
• Primary Completion: 2024-01-16
• Study Completion: 2024-01-16
• Results First Submitted: 2025-01-14
• Results First Submitted QC: 2025-01-30
• Results First Posted: 2025-02-21
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-24
• Last Update Posted: 2025-04-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 877

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

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
Annualized Confirmed Relapse Rate (ARR)	From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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 From Core Study Randomization to First Confirmed Relapse	From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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 Confirmed Disability Accumulation (CDA)	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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 Confirmed Disability Accumulation (CDA)	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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.
Percentage of Participants With Absence of Relapses	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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.
Change From Baseline in Expanded Disability Status Scale (EDSS)	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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.
Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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.
Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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 Magnetic Resonance Imaging (MRI)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	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.
Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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 Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	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	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	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 and T1 Hypointense Lesions)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	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)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	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 Persistent Black Holes (PBHs)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	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 Treatment-emergent Adverse Events (TEAEs)	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	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 Electrocardiogram (ECG) Abnormalities	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 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	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Change in PR, QRS, QT, QTcB, QTcF from baseline up to end of study treatment were reported.
Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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 Forced Vital Capacity (FVC) From Baseline (%)	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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 Serious Adverse Events (SAEs)	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	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 Adverse Events of Special Interest (AESIs)	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 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	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 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	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 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	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	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	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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 End of Treatment (EOT)	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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 End of Study (EOS)	From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months	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 Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline	From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months	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	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	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	From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months	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.

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