Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials
Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials
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DOI：
10.1016/s0140-6736(11)60405-4
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发表时间：
2011-05-21
期刊：
影响因子：
168.9
通讯作者：
du Bois, Roland M.
中科院分区：
文献类型：
--
作者：
Noble, Paul W.;Albera, Carlo;du Bois, Roland M.
研究背景特发性肺纤维化是一种进行性、致死性的肺部疾病，不可避免地伴随着肺功能的丧失。能力方案（研究004和006）旨在证实一项2期研究的结果，该研究表明吡非尼酮（一种新型抗纤维化和抗炎药物）可减轻特发性肺纤维化患者的肺功能恶化。（004和006），在澳大利亚、欧洲和北美的110个中心，特发性肺纤维化患者（年龄40 - 80岁）被随机分配接受口服吡非尼酮或安慰剂治疗至少72周。在研究004中，患者以2：1：2的比例分配至吡非尼酮2403 mg/天、吡非尼酮1197 mg/天或安慰剂组;在研究006中，患者以1：1的比例分配至吡非尼酮2403 mg/天或安慰剂组。计算机生成随机化代码（排列区组设计），并按地区分层。所有研究人员均对治疗组分配设盲，直至最终数据库锁定后。口服给药，801 mg或399 mg，每日三次。主要终点为第72周时用力肺活量（FVC）预测值百分比的变化。这些研究在www.example.com上注册，编号为NCT 00287729和NCT 00287716。结果在研究004中，435例患者中有174例被分配至吡非尼酮2403 mg/天组，87例被分配至吡非尼酮1197 mg/天组，174例被分配至安慰剂组。在研究006中，344例患者中的171例被分配至吡非尼酮2403 mg/天组，173例被分配至安慰剂组。对两项研究中的所有患者进行了分析。在研究004中，吡非尼酮降低了FVC的下降（p = 0.001）。第72周时，吡非尼酮2403 mg/天组的平均FVC变化为-8.0%（SD 16.5），安慰剂组为-12-4%（18.5）（差异4.4%，95% CI 0.7至9 - 1）; 174例患者中分别有35例（20%）和60例（35%）下降至少10%。从第24周开始的所有时间点和所有研究时间点的分析中均观察到显著的治疗效应（p = 0.0007）。吡非尼酮1197 mg/天组FVC百分比的平均变化介于吡非尼酮2403 mg/天组和安慰剂组之间。在研究006中，第72周时FVC变化的组间差异不显著（p = 0.501）。第72周时FVC的平均变化为-9.0%（SD 19.6），吡非尼酮组为-9.6%（19.1），第72周时FVC预测值变化的组间差异不显著（0.6%，-3.5至4.7）;然而，在第48周（p = 0.005）和所有研究时间点的分析中（p = 0.007），吡非尼酮效应一致。吡非尼酮2403 mg/天组患者的恶心发生率较高（125/345 [36%] vs 60/347 [17%]），消化不良（66 [19%] vs 26 [7%]），呕吐（47 [14%] vs 15 [4%]），厌食（37 [11%] vs 13 [4%]）、光敏性（42 [12%] vs 6 [2%]）、皮疹（111 [32%] vs 40 [12%]）和头晕（63 [18%] vs 35 [10%]）。与安慰剂组相比，吡非尼酮2403 mg/天组中发生的总体死亡（19 [6%] vs 29 [8%]）和与特发性肺纤维化相关的死亡（12 [3%] vs 25 [7%]）较少。
Background Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis.Methods In two concurrent trials (004 and 006), patients (aged 40-80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716.Findings In study 004,174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006,171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0.001). Mean FVC change at week 72 was -8.0% (SD 16.5) in the pirfenidone 2403 mg/day group and -12-4% (18.5) in the placebo group (difference 4.4%, 95% CI 0.7 to 9-1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0.0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0.501). Mean change in FVC at week 72 was -9.0% (SD 19.6) in the pirfenidone group and -9.6% (19.1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0.6%, -3.5 to 4.7); however, a consistent pirfenidone effect was apparent until week 48 (p=0.005) and in an analysis of all study timepoints (p=0.007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups.Interpretation The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis.