Background

Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study.

Methods

In a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on a modified intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT03616912.

Findings

760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (142 [57%]; odds ratio 1·57 [95% CI 1·09 to 2·27]; difference with placebo 10·8 [2·0 to 19·6]; p=0·016), but not baricitinib 2 mg (126 [50%]; 1·14 [0·79 to 1·65]; 3·9 [–4·9 to 12·6]; p=0·47), reached SRI-4 response compared with placebo (116 [46%]). There were no significant differences between the proportions of participants in either baricitinib group reaching any of the major secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. 26 (10%) participants receiving baricitinib 4 mg had serious adverse events, 24 (9%) participants receiving baricitinib 2 mg, and 18 (7%) participants receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile.

Interpretation

The primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed.

Funding

Eli Lilly and Company.

中文翻译：

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Baricitinib 治疗系统性红斑狼疮：一项双盲、随机、安慰剂对照的 3 期试验 (SLE-BRAVE-I)

背景

Baricitinib 是一种 Janus 激酶 1 和 2 的口服选择性抑制剂，被批准用于治疗类风湿性关节炎、特应性皮炎和斑秃。在一项针对系统性红斑狼疮 (SLE) 患者的为期 24 周的 2 期研究中，巴瑞克替尼 4 mg 与安慰剂相比显着改善了 SLE 疾病活动。该试验的目的是在为期 52 周的 3 期研究中评估巴瑞克替尼对活动性 SLE 患者的疗效和安全性。

方法

在一项多中心、双盲、随机、安慰剂对照、平行组、3 期研究 SLE-BRAVE-I 中，接受稳定背景治疗的活动性 SLE 患者（年龄≥18 岁）按 1:1:1 随机分配巴瑞克替尼 4 毫克、2 毫克或安慰剂，每天一次，持续 52 周，并采用标准护理。鼓励糖皮质激素逐渐减量，但不是每个方案都要求的。主要终点是与安慰剂组相比，巴瑞克替尼 4 mg 治疗组在第 52 周时达到 SLE 反应指数（SRI）-4 反应的患者比例。主要终点通过逻辑回归分析评估模型中的基线疾病活动、基线皮质类固醇剂量、区域和治疗组。对改良的意向性治疗人群进行了疗效分析，包括所有被随机分配并接受至少一剂研究产品的参与者。对所有随机分配的参与者进行了安全性分析，这些参与者接受了至少一剂研究产品，并且在第一次基线后访视时没有因失访而停止研究。本研究注册于临床试验.gov，NCT03616912。

发现

760 名参与者被随机分配并接受至少一剂巴瑞克替尼 4 毫克（n=252）、巴瑞克替尼 2 毫克（n=255）或安慰剂（n=253）。接受巴瑞克替尼 4 mg 的参与者比例显着增加（142 [57%]；比值比 1·57 [95% CI 1·09 至 2·27]；与安慰剂的差异为 10·8 [2·0 至 19·6 ]；p=0·016），但巴瑞克替尼 2 mg（126 [50%]；1·14 [0·79 至 1·65]；3·9 [–4·9 至 12·6]；p= 0·47)，与安慰剂相比达到 SRI-4 反应 (116 [46%])。与安慰剂组相比，巴瑞克替尼组达到任何主要次要终点（包括糖皮质激素逐渐减量和首次严重发作时间）的参与者比例没有显着差异。26 名 (10%) 接受巴瑞克替尼 4 mg 的参与者出现严重不良事件，24 名 (9%) 接受巴瑞克替尼 2 mg 的参与者，18 名 (7%) 参与者接受安慰剂。baricitinib 在 SLE 参与者中的安全性与已知的 baricitinib 安全性一致。

解释

4 mg baricitinib 组达到了本研究的主要终点。然而，关键的次要终点却没有。没有观察到新的安全信号。

资金

礼来公司。