Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.
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
Recurrence
Respiratory Tract Infections
/ etiology
Young Adult
Journal
The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
pubmed:
18
11
2020
medline:
22
1
2021
entrez:
17
11
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.).
Sections du résumé
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.).
Identifiants
pubmed: 33200890
doi: 10.1056/NEJMoa2027892
doi:
Substances chimiques
IL1A protein, human
0
IL1B protein, human
0
Interleukin-1alpha
0
Interleukin-1beta
0
Receptors, Interleukin-1 Type I
0
Recombinant Fusion Proteins
0
rilonacept
8K80YB5GMG
Banques de données
ClinicalTrials.gov
['NCT03737110']
Types de publication
Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
31-41Investigateurs
Antonio Abbate
(A)
Wael Abo-Auda
(W)
Asif Akhtar
(A)
Michael Arad
(M)
Shaul Atar
(S)
Bipul Baibhav
(B)
Karan Bhalla
(K)
Antonio Brucato
(A)
Sean Collins
(S)
David Colquhoun
(D)
Paul Cremer
(P)
David Cross
(D)
Girish Dwivedi
(G)
Alon Eisen
(A)
Nahum Freedberg
(N)
Shmuel Fuchs
(S)
Eliyazar Gaddam
(E)
Marco Gattorno
(M)
Eli Gelfand
(E)
Paul Grena
(P)
Majdi Halabi
(M)
David Harris
(D)
Massimo Imazio
(M)
Antonella Insalaco
(A)
Amin Karim
(A)
Allan Klein
(A)
Kirk Knowlton
(K)
Apostolos Kontzias
(A)
Robert Kornberg
(R)
Faisal Latif
(F)
David Leibowitz
(D)
Martin LeWinter
(M)
David Lin
(D)
Dor Lotan
(D)
Pey Wen Lou
(PW)
S Allen Luis
(SA)
Mady Moriel
(M)
Stephen Nicholls
(S)
John Petersen
(J)
Michael Portman
(M)
Philip Roberts-Thomson
(P)
Elad Schiff
(E)
Robert Siegel
(R)
Michael Stokes
(M)
Paul Sutej
(P)
Samuel Wittekind
(S)
Valentin Witzling
(V)
Robert Zukermann
(R)
Commentaires et corrections
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Informations de copyright
Copyright © 2020 Massachusetts Medical Society.