吡非尼酮治疗硬皮病相关间质性肺病患者安全性和耐受性的开放标签II期研究：LOTUSS试验
An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial.
作者信息
Khanna Dinesh, Albera Carlo, Fischer Aryeh, Khalidi Nader, Raghu Ganesh, Chung Lorinda, Chen Dan, Schiopu Elena, Tagliaferri Margit, Seibold James R, Gorina Eduard
机构信息
From the University of Michigan, Ann Arbor, Michigan; University of Colorado, Denver, Colorado; University of Washington, Seattle, Washington; Stanford University School of Medicine; Jazz Pharmaceuticals, Palo Alto; InterMune Inc., Brisbane, California; Scleroderma Research Consultants LLC, Litchfield, Connecticut, USA; University of Turin, Turin, Italy; McMaster University, Hamilton, Ontario, Canada.D. Khanna, MD, MS, University of Michigan; C. Albera, MD, University of Turin; A. Fischer, MD, University of Colorado; N. Khalidi, MD, FRCPC, McMaster University; G. Raghu, MD, University of Washington; L. Chung, MD, Stanford University School of Medicine; D. Chen, MD, PhD, Jazz Pharmaceuticals, and formerly of InterMune; E. Schiopu, MD, University of Michigan; M. Tagliaferri, MD, formerly of InterMune; J.R. Seibold, MD, Scleroderma Research Consultants LLC; E. Gorina, MD, MS, formerly of InterMune.
出版信息
J Rheumatol. 2016 Sep;43(9):1672-9. doi: 10.3899/jrheum.151322. Epub 2016 Jul 1.
OBJECTIVE
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.
METHODS
All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.
RESULTS
Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.
CONCLUSION
Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD.
TRIAL REGISTRATION
ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.
目的
系统性硬化症相关间质性肺病（SSc-ILD）与特发性肺纤维化（IPF）具有许多临床特征和致病机制。本研究旨在评估抗纤维化药物吡非尼酮在SSc-ILD中的耐受性。鉴于这些器官在SSc中的受累情况，吡非尼酮已知的胃肠道、皮肤和肝脏不良事件（AE）具有重要意义。
方法
所有患者均接受吡非尼酮治疗，并按1:1随机分为两组，分别从801mg/天开始进行2周或4周的滴定，最终维持剂量为2403mg/天。患者总共接受吡非尼酮治疗16周。评估包括治疗中出现的不良事件（TEAE）和探索性疾病转归。
结果
63例患者被随机分组；96.8%的患者出现了TEAE，与维持期相比，更多患者在滴定期报告了TEAE。最常报告的TEAE与IPF中观察到的吡非尼酮相关不良事件一致（恶心、头痛、疲劳），且与滴定方案无关。与4周滴定组相比，2周滴定组中有更多患者因TEAE停药（分别为5例和1例）；所有停药事件均发生在达到吡非尼酮全剂量后3周以上。63.5%的患者除服用吡非尼酮外还服用霉酚酸酯（MMF），但MMF似乎未影响耐受性。探索性疾病转归基本保持不变。
结论
吡非尼酮在SSc-ILD中显示出可接受的耐受性，尽管较长的滴定时间可能与更好的耐受性相关。耐受性不受同时使用MMF的影响。本研究结果支持在未来针对SSc-ILD患者的临床试验中进一步研究吡非尼酮。
试验注册
ClinicalTrials.gov；www.clinicaltrials.gov NCT01933334。
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