Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.

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.).

• Authors: Allan L Klein, Massimo Imazio, Paul Cremer, Antonio Brucato, Antonio Abbate, Fang Fang, Antonella Insalaco, Martin LeWinter, Basil S Lewis, David Lin, Sushil A Luis, Stephen J Nicholls, Arian Pano, Alistair Wheeler, John F Paolini, RHAPSODY Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 384 Issue 1 Pg. 31-41 (01 07 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 33200890 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Massachusetts Medical Society.

Chemical References

• IL1A protein, human
• IL1B protein, human
• Interleukin-1alpha
• Interleukin-1beta
• Receptors, Interleukin-1 Type I
• Recombinant Fusion Proteins
• rilonacept

Topics

• Adolescent
• Adult
• Aged
• Double-Blind Method
• Female
• Humans
• Injections, Subcutaneous (adverse effects)
• Interleukin-1alpha
• Interleukin-1beta
• Male
• Middle Aged
• Pericarditis (drug therapy)
• Proportional Hazards Models
• Receptors, Interleukin-1 Type I (antagonists & inhibitors)
• Recombinant Fusion Proteins (adverse effects, therapeutic use)
• Recurrence
• Respiratory Tract Infections (etiology)
• Young Adult