Atrasentan in patients with IgA nephropathy (ALIGN): final 2·5-year results from a randomised, double-blind, placebo-controlled, phase 3 trial.

We assessed whether atrasentan slowed estimated glomerular filtration rate (eGFR) decline after 2·5 years' treatment.

我们评估了在2.5年的治疗后，Atrasentan是否减缓了估算的肾小球滤过率（eGFR）的下降。

Methods

We performed a randomised, double-blind, placebo-controlled, phase 3 trial (133 sites, 20 countries).

我们进行了一项随机、双盲、安慰剂对照的III期临床试验（133个试验地点，20个国家）。

Adults with biopsy-proven IgA nephropathy, eGFR of at least 30 mL/min per 1·73 m2, and urinary protein excretion of at least 1·0 g/day while receiving renin-angiotensin system inhibition were enrolled (main stratum).

纳入了经活检证实的IgA肾病成人患者，肾小球滤过率（eGFR）至少为30 mL/min每1.73平方米，且在使用肾素-血管紧张素系统抑制剂治疗的同时，尿蛋白排泄量至少为每天1.0克（主要队列）。

An exploratory stratum enrolled participants also receiving an SGLT2 inhibitor.

一个探索性分层纳入了同时接受SGLT2抑制剂治疗的参与者。

Participants were randomly assigned (1:1) to oral atrasentan 0·75 mg once daily or placebo for 132 weeks, followed by a 4-week off-treatment follow-up.

参与者被随机分配（1:1），分别接受每日一次口服0.75毫克阿特森坦或安慰剂治疗132周，随后进行为期4周的停药随访。

The key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum, assessed in all randomised patients (excluding data after intercurrent events, defined as initiation of restricted or alternative IgA nephropathy medications or kidney replacement therapy).

主要次要终点是主要队列中从基线到第136周的估算肾小球滤过率（eGFR）的变化，评估所有随机患者（排除间发事件后的数据，间发事件定义为开始使用受限或替代性IgA肾病药物或肾脏替代治疗）。

Safety was assessed in all randomised patients who received at least one dose of study treatment.

安全性评估是在所有至少接受一次研究治疗的随机患者中进行的。

ALIGN is registered with ClinicalTrials.gov, NCT04573478; the double-blindsection is complete, and the open-label extension is ongoing.

ALIGN已在ClinicalTrials.gov注册，编号为NCT04573478；双盲阶段已完成，开放标签扩展正在进行中。

Results

Between March 15, 2021, and April 28, 2023, 404 participants were randomly assigned (main stratum: 340; SGLT2 inhibitor stratum: 64).

从2021年3月15日至2023年4月28日，共有404名参与者被随机分配（主要队列：340人；SGLT2抑制剂队列：64人）。

In the main stratum, change from baseline in eGFR at week 136 was -7·5 mL/min per 1·73 m2 (95% CI -9·2 to -5·8) with atrasentan and -9·9 mL/min per 1·73 m2 (-11·7 to -8·1) with placebo (between-group difference 2·4 mL/min per 1·73 m2; 95% CI -0·1 to 4·8; p=0·057).

在主要分层中，第136周时与基线相比，阿曲生坦组的eGFR变化为-7.5 mL/min per 1.73 m2（95% 置信区间-9.2至-5.8），安慰剂组为-9.9 mL/min per 1.73 m2（-11.7至-8.1）（两组间差异为2.4 mL/min per 1.73 m2；95% 置信区间-0.1至4.8；p=0.057）。

The between-group difference in eGFR change from baseline at end of treatment (week 132) was 2·6 mL/min per 1·73 m2 (95% CI 0·1-5·0), and the difference in total eGFR slope (baseline to week 136) was 1·4 mL/min per 1·73 m2 per year (95% CI 0·5-2·3).

治疗结束时（第132周）eGFR从基线的变化在两组之间的差异为2.6 mL/min per 1.73 m2（95% 置信区间0.1-5.0），而从基线到第136周的总eGFR斜率差异为1.4 mL/min per 1.73 m2 per year（95% 置信区间0.5-2.3）。

In the SGLT2 inhibitor stratum, the difference in eGFR change from baseline at week 136 between atrasentan and placebo was 9·1 mL/min per 1·73 m2 (95% CI 3·0-15·2).

在SGLT2抑制剂组中，第136周时阿曲生坦与安慰剂相比，基线eGFR变化的差异为9.1 mL/min per 1.73 m2（95% 置信区间 3.0-15.2）。

Treatment-emergent adverse events were well balanced between atrasentan and placebo, with no new safety signals.

阿曲生坦与安慰剂之间的治疗后不良事件平衡良好，没有出现新的安全信号。

In the main stratum, fluid retention adverse events occurred in 24 (14%) of 169 patients receiving atrasentan and 20 (12%) of 170 receiving placebo.

在接受主要分层的患者中，有14%（24/169）的阿曲生坦治疗患者和12%（20/170）的安慰剂治疗患者出现了液体潴留不良事件。

interpretation

Atrasentan reduced proteinuria and preserved kidney function after 2·5 years.

阿曲生坦在2.5年后降低了蛋白尿并保持了肾功能。

This effect was present with or without concomitant SGLT2 inhibitor use.

无论是否同时使用SGLT2抑制剂，这种效果都存在。

Atrasentan was well tolerated.

阿特森坦耐受性良好。

funding

Novartis.

诺华制药公司。