低剂量白细胞介素-2 治疗活动期系统性红斑狼疮（LUPIL-2）：一项多中心、双盲、随机、安慰剂对照的 II 期临床试验。
Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial.
机构信息
Department of Rheumatology and Clinical Immunology, University Hospital Schleswig-Holstein, Lübeck, Germany.
Service de médecine interne et immunologie clinique, Hopital Pitie-Salpetriere, Paris, France.
出版信息
Ann Rheum Dis. 2022 Dec;81(12):1685-1694. doi: 10.1136/ard-2022-222501. Epub 2022 Aug 16.
OBJECTIVES
A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment.
METHODS
We randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points.
RESULTS
The primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies.
CONCLUSIONS
The post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE.
TRIAL REGISTRATION NUMBER
NCT02955615.
目的
由于白细胞介素-2（IL-2）的缺乏导致调节性 T 细胞（Treg）不足，这是系统性红斑狼疮（SLE）病理生理学的核心。我们进行了一项多中心、双盲、随机、安慰剂对照的 II 期概念验证试验，以评估低剂量 IL-2 治疗在接受标准治疗的中度至重度疾病活动的 SLE 患者中的疗效。
方法
我们将 100 名患者以 1:1 的比例随机分配，每天接受 150 万 IU 皮下注射 IL-2（ILT-101）或安慰剂，连续 5 天，然后每周注射 12 周。在预先设定的分层分析中，在第 12 周评估临床疗效：（1）SLE 反应指数-4（SRI-4）反应作为主要终点，以及（2）安全性雌激素在狼疮红斑中的评估-系统性红斑狼疮疾病活动指数评分的相对和（3）绝对变化作为关键次要终点。
结果
意向治疗人群中主要终点未达到（ILT-101：68%，安慰剂：58%；p=0.3439），由于保加利亚的两个站点的安慰剂组有 100%的 SRI-4 反应率。在预先指定的人群中进行的事后协议分析排除了来自这两个站点的患者（n=53），对于 SRI-4 反应率显示出统计学上的显著差异（ILT-101：83.3%；安慰剂：51.7%；p=0.0168），以及两个关键次要终点，同时伴有多个次要探索终点的差异。ILT-101 耐受性良好，没有产生抗药物抗体。
结论
事后分层分析主要和关键次要终点在协议人群中，辅以对多个其他次要终点的探索性分析，支持低剂量 IL-2对活动性 SLE 有益。
试验注册号
NCT02955615。
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