In the event of discontinuation of treatment before Week 96 (whatever the reason), all assessments planned at Visit E13 (EOT2) must be carried out as soon as possible, but no later than 5 days after the date of the last dose of study drug. For premature discontinuations, EOT3 should be performed as soon as possible, but no later than 5 days after the last dose of study drug.
Multiple sclerosis
Several therapies are currently approved for the treatment of MS in at least one country. In addition, there are drugs in late-stage development for the treatment of relapsing multiple sclerosis (RMS), including AIN457 (secukinumab).
Sphingosine-1-Phosphate receptors
The first S1P receptor modulator, fingolimod (FTY720), which has been approved worldwide for the treatment of MS, is not selective for the S1P1 receptor, but also interacts with S1P3, S1P4 and S1P5 [Brinkmann 2007]. Two other S1P receptor modulators - siponimod (which binds to S1P1 and S1P5) and ozanimod (which binds to S1P1) have also been approved for MS in some countries.
Ponesimod
- Clinical pharmacology
- Pharmacodynamics in humans
- Efficacy in humans
- Safety and tolerability
In the long-term clinical studies, an increased incidence of adverse events (AEs) of hypertension was observed in patients with hypertension at baseline, who were treated with ponesimod. In the interim analysis of AC-058B202 (cut-off date of March 31, 2019), long-term treatment with ponesimod was not associated with new safety or tolerability issues.
Study rationale
The maximum number of patients in this extension study corresponds to the number of randomized patients in the core study. All patients who have been on placebo during the core study will be randomized 1:1:1 to 10, 20 or 40 mg ponesimod during TP1 in the extension study.
Overall study design and plan
Patients who received placebo in the core study will be randomized 1:1:1 to 10, 20 or 40 mg ponesimod during TP1. All patients receiving 40 mg ponesimod during TP1 will be re-randomized to 10 or 20 mg ponesimod in a 1:1 ratio.
Study committees
A Major Adverse Cardiovascular Events (MACE) Review Board will review and evaluate the MACE reported in the study. The composition and activities of the MACE Review Board are described in the MACE Review Board Charter.
Role of key site personnel throughout the study
During the open-label phase of the study (TP3), the role of assessing neurologist may be fulfilled by the primary investigator/treating neurologist [see section 3.3.3]. Preferably, the same physician would maintain the role of treating neurologist for a given patient throughout the study.
Study population
Recommended concomitant medications
Allowed concomitant medications
Prohibited concomitant medications
The day of the first open dose of ponesimod 20 mg will correspond to the start of TP3. The day of the first open dose of ponesimod 20 mg will correspond to the start of TP3.
Study drugs
Since this study was initially conducted in a double-blind fashion during TP1 and TP2, all patients, regardless of whether they were on placebo or ponesimod during the baseline study, needed to complete a titration scheme.
Study drug discontinuation and study withdrawal
Patients
Centers
Treatment exposure and compliance
Treatment assignment and blinding
Patients who received placebo in the core study will be randomized in a 1:1:1 ratio to receive 10, 20, or 40 mg of ponesimod. Patients on 40 mg ponesimod will then be re-randomized to 10 or 20 mg ponesimod in a 1:1 ratio.
Study drug packaging and labeling
Any code breach must be documented in a detailed report with date and time of code breach and signed by the primary investigator. Three bottles each at all visits from the earliest visit after approval of protocol version 8 by ECs/IRBs and health authorities and signature of the revised Informed Consent Form by the patients and when switching to TP3 is possible.
Study endpoints
Pharmacokinetic analyses
Pharmacodynamic analyses
Study assessments
- Brain magnetic resonance imaging parameters
- Relapses
- Expanded Disability Status Scale and Functional System
- Ancillary study: Ophthalmological assessments
- Ancillary study: Doppler echocardiography
- Blood pressure
- Pulmonary function test
- Bronchodilator assessment
- Ophthalmological assessments
- Weight
- Physical examination
- Laboratory assessments
- Pharmacokinetic assessments
- Pharmacodynamic assessments
- Informed consent
- Demographics and disease characteristics
- Concomitant medications
Incidental findings unrelated to multiple sclerosis detected by the central reader will be reported to the primary investigator/treating neurologist. The patient number assigned in the baseline study will be retained and will identify patients in the extension study.
Visit and assessment schedule
Visit E1 (Day 1) / Randomization and study drug
Visit E2 (Day 8) / first uptitration
Visit E3 (Day 15) / second uptitration
Phone call on Day 22
Visits E4, E5 and E6 (Weeks 4, 8 and 12)
Visits E7, E9 and E11 (Weeks 24, 48 and 72)
Visits E8, E10 and E12 (Weeks 36, 60 and 84)
Visit E13 (Week 96) – EOT2
Visit P1 (Day 1)
Transition from treatment period 2 to treatment period 3
EOT3 (Week 540)
Visit E14: EOT2 + 7 days (Follow-up Visit E1)
Visit E15: EOT2 + 30 days (Follow-up visit E2)
Follow-up visit 1 (FU1): 8 days after the last dose of study
Follow-up visit 2 (FU2): 30 days after the last dose of study
Follow-up visit 3 (FU3): 90 days after the last dose of study
Unscheduled relapse visit
Unscheduled visits (any other assessment)
Additional visits for re-initiation or re-uptitration of study drug
Additional unscheduled visit for eligibility assessment for re-
Unscheduled visits for re-initiation of the study drug after
Summary table
The patient will be instructed to take the study drug every morning, with or without breakfast (preferably always in the same way and at approximately the same time). When the patient has completed all scheduled assessments, Visit E14 (Follow-up Visit E1) will be scheduled 8 days after the last dose of study drug. When the patient has completed all scheduled assessments, follow-up visit 1 will be scheduled 8 days after the last dose of study drug.
Adverse events
Treatment period (including transition period and study drug
Follow-up period
In the event of an opportunistic infection, the study drug should be permanently discontinued [Appendix 3]. The assessments during this visit will be divided into two parts: before (pre-dose) and after (post-dose) administration of the study drug. When the patient has completed all scheduled assessments, follow-up visit 2 (FU2) is scheduled 30 days after the last dose of study drug.
Serious adverse events
- Serious adverse events
- Hospitalization - Prolongation of existing hospitalization
- Serious adverse events related to study-mandated procedures
- Treatment period (including transition period and study drug
- Follow-up period
- Reporting procedures
All adverse reactions, regardless of causal relationship, occurring from 16 days after discontinuation of the study drug until 30 or 90 days (as applicable) after discontinuation of the study drug must be recorded on a specific eCRF adverse event form for the extension study. All SAEs, regardless of causal relationship, occurring from 16 days after discontinuation of study drug to 30 or 90 days (as appropriate) after discontinuation of study drug should be reported.
Pregnancy
Special reporting situations
The patient will come to the clinic early in the morning and receive the study medication. However, on the morning of your next visit, you should not take any study medication before the visit. Sponsored study drug overdose (defined as ingestion of > 1 tablet on the same calendar day).
Product quality complaint handling
Medication error, missed medication error, or potential medication error involving a Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & Johnson medicinal product, eg, product name confusion, product label confusion , errors intercepted during description or distribution). Any special reporting situation that meets the criteria of an SAE must be recorded as an SAE.
Statistical analysis plan
Analysis sets
Efficacy endpoints
Dose response assessment
Sample size
Safety and tolerability endpoints
Absolute values and changes during the study of ECG numerical parameters will be summarized with descriptive statistics. Absolute percentage and change in left ventricular ejection fraction over the course of the study will be summarized with descriptive statistics.
Pharmacokinetic and pharmacodynamic endpoints
Treatment-emergent laboratory abnormalities will be summarized for each laboratory parameter, indicating their incidence and frequency. Absolute values and changes during the study of laboratory parameter values converted into standardized units will be summarized descriptively at the relevant time points.
Exposure to study drug
Treatment-emergent abnormalities assessed by standard 2D/Doppler echocardiography will be summarized by treatment group and presented similarly to the AEs. AEs, SAEs, and abnormalities are defined as treatment-emergent when they occur during administration of study drug up to 15 days after discontinuation of study drug.
Baseline parameters and concomitant medications
Additional periodic analyses
Procedures
Data collection
A baseline visit will be performed before the first patient is included in the study.
Database management and quality control
Both the sponsor and the researcher reserve the right to terminate the study at any time. Early termination or termination of the study must be discussed between the IDMC (until the IDMC is dissolved) and the sponsor.
Good Clinical Practice
In the event of permanent discontinuation of study drug due to infection, adequate treatment should be provided and the patient monitored until complete resolution of the infection. In the event of macular edema confirmed by the local ophthalmologist, treatment with the study drug should be permanently discontinued and the patient will be treated and monitored until resolution of the problem.
Criteria for discharge from hospital
Guidance on monitoring of patients for opportunistic infections
If the MRI shows signs atypical of multiple sclerosis, PML, or other opportunistic infection at the scheduled visit, clinical signs and symptoms, MRI results, prior exposure to natalizumab or immunosuppressants, and laboratory tests, including CSF analysis if indicated, should be considered. As long as PML or other opportunistic infection is suspected, study drug should be discontinued and should not be reintroduced until this suspicion is ruled out.
Guidance for skin examination
Macule A flat, colored lesion, <2 cm in diameter, not raised above the surface of the surrounding skin. Vesicle A small, fluid-filled lesion, <0.5 cm in diameter, raised above the level of surrounding skin.
Guidance for re-initiation of study drug in the event of drug interruption
Patients who do not meet the criteria for on-site cardiac monitoring (as confirmed during a pre-dose ECG assessment) can resume study drug at home after receiving a gradual up-titration blister with a starting dose of 2 mg from the carton. or restart the study drug in situ using the blister pack with the 2 mg starting dose and monitored for at least 4 hours post-dose, at the discretion of the investigator/treating neurologist [see section 3.12.5.3]. The additional visit 14 days (±1 day) after the day of restart (day 15) [see section 3.12.5.3] can be scheduled at the discretion of the investigator/treating neurologist.
Diagnostic criteria for MS (2005 revision of McDonald Criteria)
Kurtzke Expanded Disability Status Scale (EDSS)
Or a moderate decrease in touch or pain and/or severe proprioceptive decrease in more than two limbs. Or a moderate decrease in touch or pain and/or loss of proprioception for most of the body below the head.
Prohibited anti-arrhythmic and HR-lowering therapy
List of medications with risk of torsades de pointes (TdP)
Marketed drugs with new reported TdP or new marketed drugs with risk of TdP in their labels should not be administered unless the benefit-risk is acceptable as assessed by the investigator.
Guidance on study conduct during the COVID-19 (coronavirus) pandemic
There are 4 main types of COVID-19 vaccines (all non-live) currently available (see below). If a patient is eligible for COVID-19 vaccination according to their local regulations, their participation in the study should be modified as necessary.
Considerations for Optical Coherence Tomography assessments
Only in centers selected to perform OCT will the assessment of best-corrected visual acuity be standardized and the number of letters correctly identified for each eye will be recorded in the CRF. For each eye, the number of letters correctly identified is recorded in the subject's files as source data and in the CRF.
Considerations for pulmonary function tests
Calibration checks for volume accuracy should be performed at least daily using a 3-L or 2-L syringe. The result should be reported at BTPS conditions and adjusted for altitude (using any method of measuring temperature and barometric pressure proven effective by the manufacturer).