The investigator must permanently discontinue the study drug if continued administration of the study drug is believed to be contrary to the best interests of the patient.
The premature discontinuation of study drug might be triggered by an AE, a diagnostic or therapeutic procedure, an abnormal assessment (e.g., ECG, PFTs or laboratory abnormalities), or for administrative reasons, in particular withdrawal of the patient’s consent.
In addition, study drug must be discontinued if any of the specific discontinuation criteria listed in Appendix 1 is met, including cardiac and pulmonary parameters, arterial hypertension, lymphocyte counts, infection, macular edema and pregnancy.
Heightened vigilance is required for opportunistic infections, particularly viral infections with neurological symptoms such as reactivation of human herpes viruses (herpes simplex
viruses, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus) and reactivation of John Cunningham virus (JCV) causing progressive multifocal leukoencephalopathy (PML). The patient must be instructed to contact the investigator immediately if symptoms of infection occur. In the event of an opportunistic infection, the study drug must be permanently discontinued [Appendix 3].
If for any reason a patient has to be treated with immunomodulators, immunosuppressants, immunoglobulins or investigational drugs, or has to undergo plasmapheresis, cytapheresis or total lymphoid irradiation, the study drug must be permanently discontinued.
If treatment with prohibited medications is needed (e.g., for elective surgery), the patient must discontinue study drug temporarily until treatment with prohibited medication can be stopped. The study drug can be re-initiated after the corresponding wash-out period of the administered treatment, see below.
30 days of wash-out period for:
Systemic corticosteroids except for the treatment of MS relapses [see Section3.4.4.1]
ACTH
β-blockers, diltiazem, verapamil or digoxin or QT-prolonging drugs [as listed in Appendix 9]
Patients already treated during the core study with any of the concomitant medications listed inAppendix 9may continue treatment with the medications while being monitored in this study under close supervision of the physician responsible for cardiac safety assessment. In the event of a QTc prolongation of concern, the use of concomitant medications and the continuation in the study should be re-evaluated.
The date and reason for premature study drug discontinuation must be documented in the CRF.
Study drug interruption
Study drug interruption should be avoided.
If study drug intake is interrupted by the patient for any reason, she/he must immediately inform the primary investigator / treating neurologist.
Study drug may be temporarily interrupted in response to an AE, a diagnostic or therapeutic procedure, a laboratory abnormality, a planned pregnancy, or for administrative reasons.
The permitted maximum duration of the study drug interruption is 81 weeks for planned pregnancies and 12 weeks for other reasons (if exceeded, the patient will then be prematurely discontinued from the study).
In the event of a re-initiation of study drug, one tablet of ponesimod 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg will be taken orally o.d. during the uptitration period (Day 1 to 14). During the
maintenance period, patients will continue to take one tablet of ponesimod 20 mg orally o.d. [Table 6]. If a blister kit with the starting dose of 2 mg is not available at the site, re-initiation should be delayed until it becomes available (temporary treatment interruption).
Detailed guidance on how to re-initiate study drug in the event of drug interruption is provided in Appendix 5.
In the event of a re-initiation of study drug, one tablet of ponesimod 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg will be taken orally o.d. during the uptitration period (Day 1 to 14). During the maintenance period, patients will continue to take one tablet of ponesimod 20 mg orally o.d. [Table 6].
Table 6: 2-week gradual uptitration regimen
Treatment period Duration Dose regimen
Titration Day 1 and 2 2 mg
Titration Day 3 and 4 3 mg
Titration Day 5 and 6 4 mg
Titration Day 7 5 mg
Titration Day 8 6 mg
Titration Day 9 7 mg
Titration Day 10 8 mg
Titration Day 11 9 mg
Titration Day 12 to 14* 10 mg
Maintenance Day 15 until EOT3 20 mg
* An additional visit 14 days (±1 day) after the day of re-initiation (Re-initiation Day 15) is mandated for patients with cardiovascular risk factors [see Appendix 5], but may be scheduled for any patient at the discretion of the investigator / treating neurologist. The titration kit will therefore include 3 additional tablets (to be used if applicable) for treatment on Day 15-17 (i.e., dose regimen = 20 mg).
EOT3 = End-of-Treatment
Patients’ follow-up after study drug discontinuation
All randomized patients who received the study drug (for any length of time) must perform all protocol-mandated assessments of the corresponding EOT visit at the time of premature study drug discontinuation, i.e., as soon as possible but no later than 5 days after the last dose of study drug. In addition, the corresponding Safety Follow-up visits must be performed.
For TP1:
The corresponding EOT visit is EOT2.
In case of study drug discontinuation during or after completion of TP1, Follow-up Visit E1 and Follow-up visit E2 should be done 8 and 30 days respectively after the day of the last dose of study drug, regardless of the timing of the EOT2 visit.
For TP2 and TP3:
The corresponding EOT visit is EOT3.
Follow-up visits 1, 2 and 3 should be done 8, 30, and 90 days, respectively, after the day of the last dose of study drug, regardless of the timing of the EOT3 visit.
Patients will follow the standard of care after completing the study.
Study withdrawal
A patient will be considered as withdrawn from the study if, and only if, she/he is lost to follow-up after all means of contact have been exhausted.
The potential follow-up of patients after their withdrawal of consent will be subject to local regulations.
Replacement policy 3.6.5.1 Patients
Randomized patients discontinued from the study drug for any reason will not be replaced.
3.6.5.2 Centers
All centers with patients who are on study drug at their regular Week 24 (EOT) visit of the core study can participate in the extension study.