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A patient will be considered as withdrawn from the study if, and only if, she/he is lost to follow-up after all means of contact have been exhausted.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.
Patients who received placebo during the core study will be randomized in a 1:1:1 ratio to 10, 20, or 40 mg of ponesimod.
During TP2:
All patients on 10 and 20 mg ponesimod will continue with these maintenance doses.
Patients on 40 mg ponesimod will be re-randomized to 10 or 20 mg ponesimod centrally via Interactive Voice Response System (IVRS). Each of the study sites will keep the unique site number assigned for the core study.
Every patient will keep the patient number assigned during the core study, which will identify the patient throughout the extension study.
After entering the transition period and continuing administration of core study treatment, a CRF is assigned to each patient. The unique CRF number is preprinted on each CRF page.
Randomization will be performed by IVRS or Interactive Web Response System (IWRS) at Visit E1 (Day 1) for TP1. Patients who received one of the three active doses (10, 20, or 40 mg ponesimod) within the core study will be assigned to their current dose. Patients who received placebo within the core study will be randomized in a 1:1:1 ratio to receive 10, 20, or 40 mg ponesimod. Randomization via IVRS will be performed also for TP2 starting at Visit P1. Patients on 40 mg ponesimod will be then re-randomized to 10 or 20 mg ponesimod in a 1:1 ratio. Patients on 10 and 20 mg ponesimod will continue to receive their current dose. The dispensed study drug is labeled with a preprinted medication bottle number, also assigned by the IVRS/IWRS.
The IVRS/IWRS will allocate medication bottles containing medication that corresponds to the treatment designated. Each patient will receive one bottle with 10 capsules at Visit E1 (Day 1) and Visit E2 (Day 8), and a bottle with 36 capsules at Visit E3 (Day 15), and at Visits E4 and E5 (Weeks 4 and 8). At Visits E6 through E12 (Weeks 12, 24, 36, 48, 60, 72, and 84 respectively) each patient will receive three bottles with 36 capsules each. At Visits P1 through P36 each patient will receive three bottles with 36 tablets each. All tear-off labels of dispensed study drug bottles will be attached to the appropriate drug label dispensing log.
If drug packages are damaged, the center must immediately contact the monitor upon receipt of the shipment. The damage will be discussed and it will be mutually agreed if these bottles can be used or not. A written confirmation from the sponsor will be required. In addition, the receipt of damaged drug packages needs to be confirmed via IVRS/IWRS.
The randomization code will be kept strictly confidential. Actelion Quality Management will keep a sealed randomization code in a secure location. A second set will be provided to the statistician of the IDMC by Actelion Quality Management. See Section 3.8.2for further details on blinding.
The randomization code was revealed to the sponsor at the time of the AC-058B202 study interim analyses.
During TP3:
Patients receiving 20 mg ponesimod will continue with 20 mg ponesimod as maintenance dose. Patients on 10 mg ponesimod during TP2 will be re-allocated to 20 mg ponesimod centrally via an IVRS. Each of the study sites will keep the unique site number assigned for the core study.
Every patient will keep the patient number assigned during the core study, which will identify the patient throughout the extension study.
When feasible, re-allocation will be performed by IVRS or IWRS at the earliest visit following approval of protocol version 8 by ECs/IRBs and health authorities and after the patient has signed the revised Informed Consent Form. Patients on 20 mg ponesimod will continue to receive their current dose. The dispensed study drug is labeled with a preprinted medication bottle number, also assigned by the IVRS/IWRS.
At this visit, patient will receive three bottles with 36 tablets of ponesimod 20 mg each.
All tear-off labels of dispensed study drug bottles will be attached to the appropriate drug label dispensing log.
If drug packages are damaged, the site must immediately contact the monitor upon receipt of the shipment. The damage will be discussed and it will be mutually agreed if these bottles can be used or not. A written confirmation from the sponsor will be required. In addition, the receipt of damaged drug packages needs to be confirmed via the IVRS/IWRS.
Blinding
The study was initially conducted in a double-blind fashion during TP1 and TP2. The primary investigator/ treating neurologist, evaluating neurologist, clinical coordinator/ study nurse, physician evaluating cardiac safety assessments, PFT and MRI staff, patients, and CRO staff remained blinded to the previous treatment allocation during TP1 and TP2. The different doses of ponesimod were indistinguishable and were packaged in the same way. During TP3, blinding rules are not applicable because only one dose of ponesimod (i.e., 20 mg) will be dispensed to all patients until the end of the study.
The IDMC was unblinded (the IDMC Charter is a stand-alone document separate from the study protocol).
During TP1 and TP2, the following measures were taken to ensure that the efficacy assessments (i.e., EDSS/FS) were done independently and that cardiac safety assessments were performed without the potential to reveal the treatment assignment, in order to avoid potential bias:
An independent evaluating neurologist, not involved in any other aspects of patient care and management, was responsible for performing the neurological assessments for obtaining the EDSS/FS scores throughout the study.
The patient was instructed not to discuss AEs (other than those required for EDSS assessments), HR, pulmonary function and/or concomitant medications with the independent evaluating neurologist.
During TP1, the primary investigator / treating neurologist and independent physician evaluating cardiac safety assessments were not to discuss any issues related to patient care and management unless mandated for reasons of patient safety.
Potentially unblinding information was not be shared with the independent evaluating neurologist under any circumstances.
Data analyses of the ongoing extension study have been performed periodically for strategic planning of the future development of ponesimod. For such analyses, it was necessary to unblind the TP1 treatment assignment of patients who received placebo in the core study, AC-058B201.
Patients who were randomized to 10, 20 or 40 mg ponesimod in the core study received the same dose in TP1 of this extension study. Therefore, these patients’ treatment assignments were unblinded when the core study data were analyzed and the clinical study report published.
The potential for this sponsor’s unblinding to introduce bias in the conduct of the extension study was evaluated. This potential bias was considered minimal and without consequences for the scientific validity of the trial for the following reasons:
AC-058B202 study is an exploratory study.
Individual treatment allocation in the extension study was unblinded by the sponsor when performing interim analyses, but remained blinded to investigators (including the independent evaluating neurologist and the physician evaluating the cardiac safety assessments), CROs and patients during TP1 and TP2.
Data monitoring of the study was performed independently by the IDMC.
The analysis of the MRI scans performed by a central reading facility showed results consistent with the clinical parameters (ARR and confirmed disability accumulation).
Emergency procedure for unblinding
The investigator and the study staff must remain blinded to the dose of ponesimod assigned to the patient during TP1 and TP2, even if the patient refuses to participate in any study
procedures, or prematurely discontinues the study drug or experiences an AE, or if the patient dies.
The dose of ponesimod may be revealed only if the patient experiences a medical emergency the management of which would be improved by knowledge of the assigned dose of ponesimod.
The IVRS/IWRS will be set up to allow the primary investigator / treating neurologist to receive the dose assignment of ponesimod of her/his study patients at any time. The occurrence of any code break during the study must be clearly justified and explained by the primary investigator / treating neurologist. Before breaking the code, every attempt must be made by the investigator to discuss the intended code break with the sponsor. In all cases, the sponsor must be informed as soon as possible before or after the code break.
Any code break must be documented in a detailed report with the date and time of the code break, and signed by the primary investigator. This report is to be attached to the CRF. At the end of the study, the monitor will collect all code break reports and will return them to the sponsor for filing.
3.9 Study drug packaging and labeling