the visit during which the transition from TP2 to TP3 takes place (i.e., the day of the first open-label dose of 20 mg), re-initiation, and re-uptitration visits. She/he will assess eligibility for discharge or continued patient management on Visits E1, E2, E3, P1 re-initiation, and re-uptitration visits.
She/he will support the primary investigator in making a decision on eligibility of the patients (based on cardiac results) prior to randomization in the extension study by alerting the primary investigator to any significant cardiac abnormalities, and providing adequate treatment in cases of cardiac events.
Significant findings (e.g., new ECG abnormalities, bradycardia), which in the view of the physician evaluating cardiac safety meet the definition of an AE, must be reported to the primary investigator / treating neurologist and recorded on the Adverse Event form of the eCRF.
Any cardiac events of potential clinical concern at any time during the study, including AV blocks, must be assessed for seriousness by the physician evaluating cardiac safety and reported accordingly. In addition, the physician evaluating cardiac safety assessments should determine the need for medical management, and assist the treating neurologist in deciding what actions should be taken on study treatment, if any.
Treatment for bradycardia, if any, will be reported to the primary investigator / treating neurologist and recorded as concomitant medication on the appropriate eCRF form.
MRI staff
The MRI staff will be responsible for performing the scheduled and unscheduled MRI investigations according to the study MRI Technology Manual (separate document). They will export the original data to the MIAC, c/o University Hospital Basel, Switzerland, and ensure storage of the primary data at the study site.
Ophthalmologist
The ophthalmologist will perform the ophthalmological examinations as scheduled in the study protocol.
Pulmonary function laboratory technician or expert
The PFTs must be performed by qualified staff, such as a pulmonary function technician or expert according to the American Thoracic Society/European Respiratory Society guidelines and study protocol schedule.
3.4 Study population
maximum number of patients in the extension study equals the number of randomized patients in the core study.
Inclusion criteria
Eligible patients must meet all of the following inclusion criteria:
1. Patients who completed study treatment at their regular Week 24 (EOT) Visit within the core study.
2. Women of childbearing potential must:
Have a negative urine pregnancy test at their regular Week 24 visit within the core study.
Use reliable methods of contraception for up to at least 30 days after study drug discontinuation as described in Section4.4.2.
3. Signed informed consent for participating in the extension study prior to administration of the first dose in the transition period (i.e., prior to continuation of dosing at Visit 11 (Week 24) of the core study).
Exclusion criteria
Eligible patients must meet none of the following exclusion criteria:
1. Patients meeting at their regular Week 24 (EOT) Visit, during the transition period, and/or at Visit E1 any of the study-specific criteria for permanent discontinuation of study drug as defined in Appendix 1, or patients receiving any of the prohibited concomitant medication as outlined in Section 3.4.4.3and Appendix 8.
2. Any other clinically relevant medical or surgical condition, which, in the opinion of the investigator, would put the patient at risk by participating in the extension study.
Concomitant medications
3.4.4.1 Recommended concomitant medications
Acute exacerbations of MS should be treated with methylprednisolone 1 g intravenously daily for 3 to 5 days. Oral taper with corticosteroids is not permitted.
3.4.4.2 Allowed concomitant medications
Administration of intravenous (i.v.) atropine in the event of symptomatic bradycardia.
Vaccination with non-live vaccines is allowed while on study treatment if the vaccination is advised by the primary investigator / treating neurologist, based on her/his clinical assessment of the risk/benefit for the individual patient, and if supported by guidelines for vaccination relevant to this patient population, as applicable.
Patients receiving non-live vaccination while on study treatment will have 5 mL of blood drawn prior to and at least 3 weeks after vaccination in order to explore changes in vaccine- specific antibody titers from pre- to post vaccination. Samples will be analyzed at the end of the study at the latest. In case of a vaccine requiring the administration of multiple doses, the post-vaccination sample should be collected at least 3 weeks after the administration of the last dose.
Glatiramer acetate and IFN β-1a are allowed only during study drug interruptions for planned pregnancy. These treatments may be started 7 days after study drug interruption and must be stopped 7 days before study drug re-initiation.
Low dose of corticosteroids (up to 10 mg of prednisone equivalent daily), given as short- term treatment (up to 2 weeks per treatment cycle with at least 8 weeks’ interval between treatment cycles and no more than 8 weeks during the whole study duration), and inhaled corticosteroids for pulmonary conditions.
Other treatments considered necessary for the patient’s benefit and not categorized as prohibited concomitant medications.
3.4.4.3 Prohibited concomitant medications
Systemic corticosteroids or adrenocorticotropic hormone (ACTH), except for: the treatment of acute MS exacerbations [see Section 3.4.4.1]; short-term treatment with a low dose of corticosteroid; and inhaled corticosteroids for pulmonary conditions [see Section 3.4.4.2].
Immunomodulating treatment (e.g., IFN β, glatiramer acetate, natalizumab or other monoclonal antibody therapy [except glatiramer acetate or IFN β-1a during study drug interruptions for planned pregnancy as described under “Allowed”]).
Immunosuppressive treatment (e.g., cladribine, mitoxantrone or other systemic immunosuppressive drugs such as azathioprine, cyclophosphamide, cyclosporine or methotrexate).
i.v. immunoglobulin.
Plasmapheresis, cytapheresis, or total lymphoid irradiation.
Vaccination with live vaccines, except if performed during a temporary treatment interruption period. In this case it must be performed not earlier than 1 week after the last dose of study treatment, and treatment can be re-initiated only after at least 4 weeks from completion of vaccination.
β-blockers, diltiazem, verapamil, digoxin, or any other anti-arrhythmic or HR -lowering systemic therapy [non-exhaustive list provided in Appendix 8] during the titration (i.e., during the first 14 days after re-initiation of study treatment).
Treatment with any of these therapies is also not recommended during maintenance treatment with ponesimod (i.e., 20 mg) and should be considered with caution if an alternative medication cannot be used.
Medications with risk of torsades de pointes (TdP) should not be administered unless the benefit-risk is acceptable, as judged by the investigator [non-exhaustive list provided in Appendix 9].
Any investigational drug.
3.5 Study drugs