From the Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati (B.C.T.); National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (Y.I.), Aichi Medical University Hospital, Nagakute, Aichi (E.Y.), and Kanagawa Cardiovascular and Respiratory Center, Yokohama (T.B.) - all in Japan; Outpatients Clinic for Interstitial and Rare Lung Disease, Ruhrlandklinik University Hospital, Essen (F.B.), and Center for Interstitial and Rare Lung Diseases, Pulmonology, Thoraxklinik, Heidelberg University Hospital, and German Center for Lung Research, Heidelberg (M.K.) - all in Germany; the Departments of Critical Care and Respiratory Medicine, Royal Brompton Hospital, London (C.M.); Respiratory Diseases Department, Pontchaillou Hospital, IRSET UMR 1085, Rennes 1 University, Rennes, France (S.J.); the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus (E.B.), and Savara, Horsholm (C.G., I.T.) - both in Denmark; the Pneumology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (I.C.); the 2nd Pulmonary Medicine Department, General University Hospital "Attikon," Medical School, National and Kapodistrian University of Athens, Athens (S.A.P.); University of Health Sciences Turkey, Yedikule Chest Diseases and Thoracic Surgery Education and Research Hospital, Istanbul (E.C.); Pulmonary Clinic of St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (M.M.I.); Institute of Pulmonary and Allergy Medicine, Rabin Medical Center, Petah Tikva, Israel (M.R.K.); ILD Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands (M.V.); the University of Western Australia, Royal Perth Hospital, Perth, Australia (G.W.); and Savara, Austin, TX (T.J.).
N Engl J Med. 2020 Oct 22;383(17):1635-1644. doi: 10.1056/NEJMoa1913590. Epub 2020 Sep 7.
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.
In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo) at week 24.
In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.
In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).
自身免疫性肺泡蛋白沉积症（aPAP）是一种罕见的疾病，其特征是表面活性剂逐渐积累和低氧血症。它是由粒细胞-巨噬细胞集落刺激因子（GM-CSF）信号中断引起的，肺泡巨噬细胞需要 GM-CSF 来清除表面活性剂。最近，吸入 GM-CSF 被证明可以改善 aPAP 患者的动脉血氧分压。
在一项双盲、安慰剂对照的三组分试验中，我们将 aPAP 患者随机分为三组，分别接受重组 GM-CSF 莫拉司亭（每日 300μg，通过吸入给药），连续或间断（每两周一次）给药，或匹配安慰剂。24 周的干预期后是开放标签的治疗延长期。主要终点是 24 周时肺泡-动脉氧差（A-aDo）的基线变化。
共有 138 名患者接受了随机分组；46 名患者接受连续莫拉司亭治疗，45 名患者接受间歇莫拉司亭治疗，47 名患者接受安慰剂治疗。4 名患者（每个莫拉司亭组 1 名，安慰剂组 2 名）在进行动脉血气测量时接受了鼻氧疗，其无效的 A-aDo 数据通过插补法进行了替换。对于主要终点 - 24 周时 A-aDo 的基线变化 - 连续莫拉司亭治疗组的改善大于安慰剂组（-12.8mmHg 与-6.6mmHg；估计治疗差异，-6.2mmHg；最小二乘法均值比较的 P=0.03）。接受连续莫拉司亭治疗的患者在次要终点方面也比安慰剂组有更大的改善，包括 24 周时圣乔治呼吸问卷总分的基线变化（-12.4 分与-5.1 分；估计治疗差异，-7.4 分；最小二乘法均值比较的 P=0.01）。对于多个终点，连续莫拉司亭治疗的改善大于间歇莫拉司亭治疗。除胸痛发生率外，三组患者的不良事件和严重不良事件发生率相似，而连续莫拉司亭组的胸痛发生率较高。
在 aPAP 患者中，每日给予吸入莫拉司亭治疗比安慰剂治疗能更显著地改善肺气体转移和功能健康状况，且不良事件发生率相似。（由 Savara 制药公司资助；IMPALA ClinicalTrials.gov 编号，NCT02702180）。
