口服曲前列尼尔治疗背景内皮素受体拮抗剂和磷酸二酯酶 5 抑制剂治疗的肺动脉高压患者（FREEDOM-C2 研究）：一项随机对照试验。

Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial.

机构信息

Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC.

Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

出版信息

Chest. 2013 Sep;144(3):952-958. doi: 10.1378/chest.12-2875.

DOI:10.1378/chest.12-2875

PMID:23669822

Abstract

BACKGROUND

Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both.

METHODS

A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening.

RESULTS

One hundred thirty-two patients (84%) receiving oral treprostinil and 138 (90%) receiving placebo completed the study. The mean ± SD dose of oral treprostinil at week 16 was 3.1 ± 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, -2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%).

CONCLUSIONS

The addition of oral treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects.

TRIAL REGISTRY

ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov.

摘要

背景

曲前列尼尔是一种稳定的前列环素类似物，已被批准用于治疗肺动脉高压（PAH），可采用注射或吸入给药。曲前列尼尔二醇胺是曲前列尼尔的一种持续释放口服制剂，研究其是否可为病情较轻的 PAH 患者提供更为便捷的前列环素治疗选择。本研究旨在评估口服曲前列尼尔治疗接受稳定背景内皮素受体拮抗剂（ERA）和/或磷酸二酯酶 5 抑制剂（PDE-5I）治疗的 PAH 患者的疗效和安全性。

方法

这是一项在 310 例 PAH 患者中开展的、为期 16 周、多中心、双盲、安慰剂对照研究，比较了口服曲前列尼尔（n=157）与安慰剂（n=153）的疗效。主要终点为第 16 周 6 分钟步行距离的变化。次要疗效终点包括世界卫生组织（WHO）功能分级、Borg 呼吸困难评分、呼吸困难-疲劳指数、PAH 体征和症状以及临床恶化情况。

结果

132 例（84%）接受口服曲前列尼尔治疗的患者和 138 例（90%）接受安慰剂治疗的患者完成了研究。第 16 周时，口服曲前列尼尔的平均（±SD）剂量为 3.1±1.9 mg，每日 2 次。Hodges-Lehmann 校正的安慰剂组差值的中位值（95%CI）为 10.0 m（-2 至 22 m；P=0.089）。次要终点未见显著变化。最常与口服曲前列尼尔相关的不良反应为头痛（71%）、腹泻（55%）、恶心（46%）、潮红（35%）和下颌痛（25%）。