Efficacy and Safety of Selexipag in Adults With Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study

Abstract

Objective: To determine the effect of selexipag, an oral, selective IP prostacyclin receptor agonist, on the frequency of attacks of Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc).

Methods: Patients with SSc-related RP were randomized 1:1 to placebo (n = 38) or selexipag (n = 36) in individualized doses (maximum of 1,600 μg twice daily) during a 3-week titration period. The primary end point was the weekly average number of RP attacks during the study maintenance period, analyzed using a Bayesian approach with a negative binomial model adjusted for baseline number of RP attacks. Other outcome measures included Raynaud's Condition Score (RCS), RP attack duration, and treatment-emergent adverse events (AEs).

Results: Baseline characteristics were comparable between treatment groups. For 83.3% of patients, the individualized maintenance dosage of selexipag was ≤800 μg twice daily. No significant difference was observed between placebo and selexipag in weekly average number of electronic diary (eDiary)-recorded RP attacks during the maintenance period (14.2 attacks during the maintenance period and 21.5 attacks during the baseline week in the placebo group [n = 32] versus 18.0 attacks during the maintenance period and 22.4 attacks during the baseline week in the selexipag group [n = 27]; adjusted mean treatment difference of 3.4 in favor of placebo). No significant treatment effect was observed on RCS or RP attack duration. In the double-blind period, 86.8% of placebo-treated patients and 100% of selexipag-treated patients reported ≥1 AE; 55.3% and 91.7%, respectively, reported ≥1 prostacyclin-associated AE.

Conclusion: Treatment with selexipag did not reduce the number of RP attacks compared with placebo. The safety profile of selexipag was similar to that previously reported. This study provides important information about the feasibility of eDiary reporting of RP attacks in clinical trials.

Trial registration: ClinicalTrials.gov NCT02260557.

© 2017, American College of Rheumatology.

Figures

Figure 1

Patient disposition. * = Six patients were excluded from the placebo per‐protocol set (PPS), due to premature study treatment discontinuation (before day 30) (n = 2), ≥30% missing data for assessment of Raynaud's phenomenon (RP) during the maintenance period (n = 2), and the concomitant use of forbidden medication (n = 2). † = Nine patients were excluded from the selexipag per‐protocol set, due to premature study treatment discontinuation (before day 30) (n = 7), ≥30% missing data for RP assessment during the maintenance period (n = 1), and <7 RP attacks/RP attacks not experienced on ≥5 different days prior to randomization (n = 1). FAS = full analysis set (all randomized patients); SAE = serious adverse event.

Figure 2

Posterior distribution of weekly Raynaud's phenomenon (RP) attack rate in selexipag‐treated patients (A) and placebo‐treated patients (B), and difference in weekly RP attack rate between treatment arms (per‐protocol set) (C). The probabilities of observing a difference (selexipag minus placebo) of <0 (statistical significance; right vertical bar) and of <–4 (clinical efficacy; left vertical bar) in the mean weekly average number of RP attacks were below the proof‐of‐concept criteria of ≥0.95 and ≥0.5, respectively (observed probabilities 0.03 and 0.00, respectively).

Figure 3

Forest plot of summary statistics of weekly attacks of Raynaud's phenomenon (RP) from posterior distribution of negative binomial Bayesian model (subgroup analyses; per‐protocol set). np = number of patients receiving placebo; na = number of patients receiving active treatment; P† = probability that the difference between the treatment means (selexipag minus placebo) for weekly average number of RP attacks in the maintenance period is <0; 90% CI = 90% confidence interval; DU = digital ulcer; CCBs = calcium‐channel blockers.