Phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis

RHAPSODY Investigators

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195 Scopus citations

Abstract

BACKGROUND Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis. METHODS We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed. RESULTS A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. CONCLUSIONS Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).

Original languageEnglish (US)
Pages (from-to)31-41
Number of pages11
JournalNew England Journal of Medicine
Volume384
Issue number1
DOIs
StatePublished - Jan 7 2021

Funding

We conducted this multicenter, double-blind, placebo-controlled, randomized-withdrawal trial of rilonacept in Australia, Israel, Italy, and the United States. Full details of the trial design have been published previously.18 The trial was funded by Kiniksa Pharmaceuticals. The protocol, which is available with the full text of this article at NEJM.org, was designed by the first four authors and by the sixth and last authors (employees of Kiniksa Pharmaceuticals) and was conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guide- lines of the International Council for Harmonisation, and all relevant regulations. The protocol was approved by the relevant institutional review boards or independent ethics committees for all participating centers. The sponsor directed all aspects of the trial, held the data, and performed the statistical analyses. The academic research organization C5Research provided independent confirmation of the trial analyses. The first two authors and the sixth and last two authors (employees of Kiniksa Pharmaceuticals) vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol. Supported by Kiniksa Pharmaceuticals.

ASJC Scopus subject areas

  • General Medicine

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