白细胞介素-1受体拮抗剂rilonacept治疗复发性心包炎的3期试验

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

作者信息

Klein Allan L, Imazio Massimo, Cremer Paul, Brucato Antonio, Abbate Antonio, Fang Fang, Insalaco Antonella, LeWinter Martin, Lewis Basil S, Lin David, Luis Sushil A, Nicholls Stephen J, Pano Arian, Wheeler Alistair, Paolini John F

机构信息

From the Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland (A.L.K., P.C.); University Cardiology, Cardiovascular, and Thoracic Department, Azienda Ospedaliero-Universitaria (AOU) Città della Salute e della Scienza di Torino and University of Turin, Turin (M.I.), the Department of Biomedical and Clinical Science, University of Milan, Fatebenefratelli Hospital, Milan (A.B.), and the Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome (A.I.) - all in Italy; Pauley Heart Center, Virginia Commonwealth University, Richmond (A.A.); Kiniksa Pharmaceuticals, Lexington, MA (F.F., A.P., J.F.P.); the Cardiology Unit, University of Vermont Medical Center, Burlington (M.L.); the Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel (B.S.L.); the Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis (D.L.), and the Division of Cardiovascular Ultrasound, Department of Cardiovascular Medicine, Mayo Clinic, Rochester (S.A.L.) - both in Minnesota; the Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, VIC, Australia (S.J.N.); and Kiniksa Pharmaceuticals, Hamilton, Bermuda (A.W.).

出版信息

N Engl J Med. 2021 Jan 7;384(1):31-41. doi: 10.1056/NEJMoa2027892. Epub 2020 Nov 16.

DOI:10.1056/NEJMoa2027892

PMID:33200890

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.).

摘要

背景

白细胞介素-1被认为是复发性心包炎的介质。rilonacept是一种白细胞介素-1α和白细胞介素-1β细胞因子陷阱，先前在一项涉及复发性心包炎患者的2期试验中研究了其疗效和安全性。

方法

我们对rilonacept进行了一项3期多中心、双盲、事件驱动、随机撤药试验，研究对象为有复发性心包炎急性症状（根据患者报告量表评估）和全身炎症（如C反应蛋白[CRP]水平升高所示）的患者。在接受标准治疗时出现心包炎复发的患者进入为期12周的导入期，在此期间开始使用rilonacept并停用背景药物。有临床反应（即符合预先设定的反应标准）的患者按1:1的比例随机分配，接受持续的rilonacept单药治疗或安慰剂治疗，每周皮下注射一次。使用Cox比例风险模型评估的主要疗效终点是首次心包炎复发的时间。同时也评估了安全性。

结果

共有86例有心包炎疼痛且CRP水平升高的患者进入导入期。在导入期，疼痛缓解或接近缓解的中位时间为5天，CRP水平恢复正常的中位时间为7天。共有61例患者进行了随机分组。在随机撤药期，rilonacept组的复发事件太少，无法计算首次经判定的复发的中位时间；安慰剂组首次经判定的复发的中位时间为8.6周（95%置信区间[CI]，4.0至11.7；Cox比例风险模型中的风险比为0.04；95%CI，0.01至0.18；对数秩检验P<0.001）。在此期间，rilonacept组30例患者中有2例（7%）发生心包炎复发，而安慰剂组31例患者中有23例（74%）发生复发。在导入期，有4例患者因不良事件导致rilonacept治疗中断。rilonacept最常见的不良事件是注射部位反应和上呼吸道感染。