From Brigham and Women's Hospital, Boston (A.W.); the University of South Florida, Tampa (R.R.-J.), and St. Vincent's Lung, Sleep, and Critical Care Specialists, Jacksonville (A.B.) - both in FL; the University of Minnesota, Minneapolis (T.T.); St. Vincent Medical Group, Indianapolis (A.R.); the Carl and Edyth Lindner Research Center at the Christ Hospital, Cincinnati (P.E.); University of California Davis Medical Center, Sacramento (R. Allen), and Cedars-Sinai, Los Angeles (V.T.); Arizona Pulmonary Specialists, Phoenix (J.F.); the Medical University of South Carolina, Charleston (R. Argula); United Therapeutics Corporation, Silver Spring, MD (P.S., K.R., C.D., L.P., H.B.); and Inova Fairfax Hospital, Falls Church, VA (S.D.N.).
N Engl J Med. 2021 Jan 28;384(4):325-334. doi: 10.1056/NEJMoa2008470. Epub 2021 Jan 13.
BACKGROUND: No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear. METHODS: We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening. RESULTS: A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. CONCLUSIONS: In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).
背景：目前尚无治疗特发性肺纤维化相关性肺动脉高压的疗法。吸入性曲前列尼尔治疗此类患者的安全性和疗效尚不明确。
方法：我们开展了一项多中心、随机、双盲、安慰剂对照的 16 周临床试验，纳入了特发性肺纤维化合并肺动脉高压（经右心导管检查确诊）患者。将患者按照 1:1 的比例随机分组，分别接受超声脉冲式射流雾化吸入器给药的吸入性曲前列尼尔（最多 12 次呼吸，共 72μg），每日 4 次，或安慰剂治疗。主要疗效终点为两组患者在 16 周时 6 分钟步行试验峰值距离自基线的变化差值。次要终点包括 16 周时 N 末端 pro-B 型利钠肽（NT-proBNP）水平的变化以及临床恶化的时间。
结果：共有 326 例患者接受了随机分组，其中 163 例接受吸入性曲前列尼尔治疗，163 例接受安慰剂治疗。两组患者的基线特征相似。在 16 周时，与安慰剂组相比，曲前列尼尔组患者 6 分钟步行试验峰值距离自基线的变化差值的最小二乘均数为 31.12m（95%置信区间[CI]，16.85 至 45.39；P<0.001）。与安慰剂组相比，曲前列尼尔组患者的 NT-proBNP 水平自基线降低了 15%（治疗比，0.58；95%CI，0.47 至 0.72；P<0.001）。曲前列尼尔组有 37 例（22.7%）患者发生临床恶化，安慰剂组有 54 例（33.1%）患者发生临床恶化（风险比，0.61；95%CI，0.40 至 0.92；对数秩检验 P=0.04）。最常报告的不良事件为咳嗽、头痛、呼吸困难、头晕、恶心、疲劳和腹泻。
结论：与安慰剂相比，吸入性曲前列尼尔可改善特发性肺纤维化相关性肺动脉高压患者的运动能力（通过 6 分钟步行试验评估）。（由 United Therapeutics 公司资助；INCREASE 临床试验.gov 编号：NCT02630316。）
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