Only exploratory efficacy endpoints will be investigated.
Exploratory efficacy endpoints will be analyzed over the combined treatment period with ponesimod within studies AC-058B201 and AC-058B202 (i.e., starting from the first administration of ponesimod and ending with the EOT visit 2 or 3, as applicable). For
“changes from baseline to all assessments” as well as for all numerical endpoints, all assessments available after initiation of ponesimod are considered in the combined treatment period. For time to event endpoints, the start is defined as initiation of study treatment, and patients without events are censored at the end of the combined treatment period.
The following exploratory endpoints will be analyzed:
1. Annualized confirmed relapse rate.
2. Time to first confirmed relapse.
Definition of relapse
A relapse is defined as the occurrence of an acute episode of one or more new symptoms, or worsening of existing symptoms of MS, not associated with fever or infection, and lasting for at least 24 hours after a stable period of at least 30 days.
A “confirmed relapse” is a relapse accompanied by an increase from the previous clinically stable assessment (i.e., performed at least 30 days after the onset of any previous relapse) of at least 0.5 point in the EDSS score, or one point in the score for at least one of the FS scores, excluding the bowel and bladder, and mental FS. The confirmatory EDSS must be performed within 7 days of the onset of a new symptom or worsening of an existing symptom of MS.
Symptoms of transient neurological worsening that do not meet the criteria for “confirmed relapse” because unaccompanied by objective findings, but still judged to constitute a relapse by the treating neurologist, will be recorded as “unconfirmed relapse” and included in the number of total relapses.
Confirmed and unconfirmed relapse will be recorded in the CRF. Start/end date and dose of corticosteroid treatment will also be recorded in the CRF.
For exploratory efficacy endpoints both confirmed and total relapses are analyzed.
The severity of relapse will be calculated for each relapse according to the algorithm defined in Table 7.
Table 7: Severity of relapse
Mild relapse Moderate relapse Severe relapse
EDSS increase of 0.5 point or
1-point increase in 1 to 3 FS*
EDSS increase of 1 or 2 points or
2-point increase in 1 or 2 FS* or
1-point increase in 4 or more FS*
Exceeding moderate relapse criteria:
EDSS increase of 2.5 points or
2-point increase in 3 FS* or
3-point increase in 1 FS* or
2-point increase in more than 2 FS*
* excluding the bowel and bladder, and mental FS.
Note: The EDSS increase is the increase observed at the EDSS assessment associated with the relapse, as compared the preceding EDSS assessment (performed prior to the relapse).
3. Time to 24-week confirmed disability progression up to end of the study.
Disability progression is defined as an increase of at least one full point in the EDSS score (or 1.5 points if the baseline EDSS was 0, or 0.5 points if the baseline EDSS was equal or greater than 5.5) with or without relapse, confirmed at the next scheduled EDSS assessment at least 24 weeks later (or if missing, at the next available scheduled
EDSS assessment). The time to event is defined as the time from initiation of study treatment until the first EDSS assessment meeting the criteria for disability progression.
4. Other relapse-related endpoints:
Annualized total relapse rate.
Time to first (total) relapse.
Number of (confirmed and total) relapses.
Number of patients without any (confirmed and total) relapse.
Number of patients with a relapse requiring corticosteroid treatment.
5. MRI-related endpoints:
Number of Gd+ lesions per patient recorded on T1-weighted MRI scans at all assessments.
Number of patients with no Gd+ lesions on T1-weighted MRI scans at all assessments.
Total volume of Gd+ lesions per patient on T1-weighted MRI scans at all assessments.
Number of new or enlarging lesions per patient on T2-weighted MRI scans at all assessments.
Change from baseline to all assessments in total lesion volume per patient on T2-weighted MRI scans.
Number of combined unique active lesions (Gd+ lesions plus new or enlarging T2
lesions without gadolinium-enhancement) per patient on MRI scans at all assessments.
Percentage change of brain volume from Visit 2 (from AC-058B201) up to the end of the study.
Percentage change of brain volume from Visit 11 (from AC-058B201) up to the end of the study.
6. Neurological endpoints:
Categorical change from baseline to all assessments in EDSS and FS scores.
7. Ophthalmological endpoints:
Change from baseline to all assessments of average retinal nerve fiber layer (RNFL) thickness, central foveal thickness and total macular volume as measured by optical coherence tomography (OCT) at selected centers.
Change from baseline to all assessments of average number of letters correctly read in a best corrected visual acuity test (recorded only at the centers that also perform OCT).
8. Changes in vaccine-specific antibody titers from pre- to post vaccination will be explored at the end of the study, at the latest, for patients having received non-live vaccination while on study treatment.
Safety and tolerability endpoints
The following safety and tolerability endpoints will be analyzed on treatment as described for the exploratory efficacy endpoints:
Change in ECG parameters (HR, PR, QRS, QT, QTc) from baseline to all pre-dose assessments, and from pre-dose to post-dose at selected time points during the study.
Treatment-emergent clinically relevant abnormalities as assessed by 12-lead ECG (central reading).
Change in left ventricular ejection fraction as assessed by Standard 2D echocardiography (at selected centers) from baseline to all assessments.
Treatment-emergent clinically relevant abnormalities as assessed by Standard 2D/Doppler echocardiography (at selected centers).
Change in PFTs (FEV1, forced vital capacity [FVC], FEV1/FVC ratio, and FEV1and FVC in percent of predicted value) from baseline to all assessments.
Change in ophthalmological exam (best corrected visual acuity, low contrast visual acuity, visual fields, dilated ophthalmoscopy, and at selected centers, OCT) from baseline to all assessments.
Change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to all pre-dose assessments and from pre-dose to post-dose at selected time points during the study.
Change in laboratory parameters (hematology, blood chemistry, and urinalysis) from baseline to all assessments.
Treatment-emergent laboratory abnormalities.
Change in body weight from baseline to all assessments.
In addition, the following safety and tolerability parameters will be analyzed:
Treatment-emergent AEs, until 15 days after study drug discontinuation.
Post-treatment AEs, from 16 days until up to 90 days after study drug discontinuation.
AEs leading to premature discontinuation of study drug.
Treatment-emergent serious adverse events (SAEs) until 15 days after study drug discontinuation.
Post-treatment SAEs from 16 days until up to 90 days after study drug discontinuation.
Pharmacokinetic and pharmacodynamic analyses 3.10.3.1 Pharmacokinetic analyses
Plasma concentrations of ponesimod will be determined at trough (pre-dose):
− TP1: on Days 8 and 15 (Visits E2 and E3) and at Visits E4, E7, E9, and E13 (EOT2),
− TP2 and TP3:P2, P7, P14 and P22, as applicable.
3.10.3.2 Pharmacodynamic analyses
Absolute count and percent change in peripheral blood lymphocyte counts as a function of ponesimod dose and plasma concentrations at trough level (pre-dose) on Days 8 and 15 (Visits E2 and E3) and at Visits E4, E7, E9, E13 (EOT2), P2, P7, P14, P22, P30 and EOT3, as applicable.
Post-treatment lymphocyte recovery 8, 30, and 90 days (at 90 days for patients performing TP2 and TP3, if applicable) after study drug discontinuation.
Efficacy and safety parameters will be correlated with absolute lymphocyte counts and magnitude of reduction of lymphocyte counts on an exploratory basis.
Additional PK and PD relationships to efficacy and safety parameters may be investigated.
3.11 Study assessments