Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study.

Ralinepag is an oral, once-daily, selective prostacyclin IP receptor agonist developed to treat PAH.

Ralinapag是一种口服、每日一次的、选择性的前列环素IP受体激动剂，用于治疗PAH。

We aimed to evaluate the efficacy and safety of ralinepag in patients with PAH.

我们旨在评估ralinepag在肺动脉高压（PAH）患者中的疗效和安全性。

Methods

ADVANCE OUTCOMES was a randomised, double-blind, placebo-controlled, event-driven, phase 3 trial of ralinepag in patients with PAH.

ADVANCE OUTCOMES是一项针对肺动脉高压（PAH）患者的随机、双盲、安慰剂对照、事件驱动的ralinepag的3期临床试验。

Eligible patients were aged 18 years or older and PAH was diagnosed on the basis of the 2022 European Society of Cardiology and European Respiratory Society guidelines (mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and pulmonary vascular resistance of >2 Wood units).

符合条件的患者年龄在18岁或以上，并且根据2022年欧洲心脏病学会和欧洲呼吸学会的指南诊断为肺动脉高压（平均肺动脉压>20毫米汞柱，肺动脉楔压≤15毫米汞柱，肺血管阻力>2伍德单位）。

Patients were randomly assigned (1:1) to ralinepag or placebo, initiated at a dose of 50 μg once daily and titrated weekly until the highest tolerated individualised dose was reached.

患者被随机分配（1:1）到ralinepag或安慰剂组，起始剂量为每日一次50微克，并每周调整剂量直至达到最高耐受的个体化剂量。

Randomisation was stratified by baseline 6-minute walk distance (6MWD), PAH aetiology, and oral background therapy.

随机分组根据基线6分钟步行距离（6MWD）、肺动脉高压（PAH）病因和口服背景治疗进行分层。

A block size of four was used within each combination of stratification factors.

在每个分层因素组合内使用了四个的块大小。

The sponsor, patients, and all personnel directly involved with the conduct of the study were masked to study drug identity and randomisation assignments.

赞助商、患者以及所有直接参与研究执行的人员对研究药物的身份和随机分配情况进行了盲法处理。

The primary outcome was time to first clinical worsening event, a composite of death from any cause, admission to hospital due to worsening PAH or right heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response.

主要结果是首次临床恶化事件的时间，这是一个由任何原因导致的死亡、因肺动脉高压或右心衰竭恶化而住院、开始使用静脉或吸入的前列环素途径治疗、疾病进展或长期临床反应不满意等组成的复合终点。

Efficacy analyses were done in the full analysis set and safety analyses in the safety set; both sets comprised 687 patients after exclusion of 41 randomly assigned and treated patients from sites in China (exclusions due to regulatory challenges and data integrity concerns).

疗效分析在全分析集（full analysis set）中进行，安全性分析在安全性集（safety set）中进行；在排除了41名随机分配并接受治疗的中国研究点患者后（排除原因包括监管挑战和数据完整性问题），这两个集合均包含了687名患者。

This study is registered with ClinicalTrials.gov (NCT03626688) and euclinicaltrials.eu (2023-509304-16-00) and is complete.

该研究已在ClinicalTrials.gov（NCT03626688）和euclinicaltrials.eu（2023-509304-16-00）注册，并已完成。

Results

Patients were enrolled between Jan 24, 2019, and June 20, 2025.

患者在2019年1月24日至2025年6月20日期间被纳入研究。

Of 1037 patients screened for eligibility, 728 were randomly assigned and received at least one dose of ralinepag or placebo; 687 were included in the full analysis and safety sets, of whom 350 received ralinepag and 337 received placebo.

在1037名接受资格筛查的患者中，有728名被随机分配并至少接受了一剂ralinepag或安慰剂；687名被纳入完整分析和安全集，其中350名接受了ralinepag治疗，337名接受了安慰剂。

Median follow-up from randomisation to clinical worsening event, censoring, or study closure was 85·0 weeks (IQR 27·6-160·9) in the ralinepag group and 78·4 weeks (34·6-137) in the placebo group.

从随机分组到临床恶化事件、删失或研究结束的中位随访时间为85.0周（四分位数间距27.6-160.9）在ralinepag组，而在安慰剂组为78.4周（四分位数间距34.6-137）。

At baseline, patients had a mean 6MWD of 438·9 m (SD 104·8) and 548 (80%) of 687 patients were receiving dual background PAH therapy.

在基线时，患者的平均6分钟步行距离（6MWD）为438.9米（标准差104.8），并且在687名患者中有548名（80%）正在接受双背景肺动脉高压（PAH）治疗。

Overall, 64 (18%) of 350 patients in the ralinepag group and 121 (36%) of 337 patients in the placebo group had a first clinical worsening event (hazard ratio0·45 [95% CI 0·33-0·62]; p<0·0001).

总体而言，350名ralinepag组患者中有64名（18%）和337名安慰剂组患者中有121名（36%）发生了首次临床恶化事件（风险比0·45 [95% 置信区间0·33-0·62]；p<0·0001）。

The largest numerical between-group differences in components of the composite outcome were observed for disease progression, initiation of parenteral or inhaled prostacyclin-pathway therapy, and unsatisfactory long-term clinical response.

复合结果各组成部分中，两组间最大的数值差异观察到疾病进展、开始使用静脉或吸入的前列环素途径治疗以及长期临床反应不满意。

Adverse eventwas the primary reason for treatment discontinuation in 65 (19%) of 350 patients in the ralinepag group and ten (3%) of 337 patients in the placebo group.

不良事件是ralinepag组350名患者中65名（19%）和安慰剂组337名患者中10名（3%）停药的主要原因。

Serious adverse events occurred in 98 (28%) patients in the ralinepag group and 104 (31%) patients in the placebo group.

ralinepag组有98名（28%）患者和安慰剂组有104名（31%）患者发生了严重不良事件。

Adverse events leading to death occurred in 15 (4%) and 14 (4%) patients, respectively.

分别有15名（4%）和14名（4%）患者发生了导致死亡的不良事件。

interpretation

In patients with PAH receiving contemporary background therapy, ralinepag significantly reduced the risk of first clinical worsening compared with placebo, but was associated with more adverse-event-related treatment discontinuations.

在接受现代背景治疗的肺动脉高压（PAH）患者中，与安慰剂相比，ralinepag显著降低了首次临床恶化风险，但与更多与不良事件相关的治疗中断有关。

These results support the use of ralinepag as an oral, once-daily prostacyclin-pathway treatment option for PAH.

这些结果支持将ralinepag作为PAH的口服每日一次的前列环素途径治疗选择。

funding

United Therapeutics Corporation.

联合治疗公司。