慢性哮喘患者单次吸入孟鲁司特的I期临床试验：随机、安慰剂对照、剂量探索性研究
2010/12/17
摘要
背景：已经证实，口服孟鲁司特能治疗成人和儿童哮喘和过敏性鼻炎。本研究旨在评价吸入孟鲁司特治疗的剂量相关性支气管扩张和安全性。
方法：本试验为随机、双盲、交叉、适应性设计研究，比较单次孟鲁司特吸入与安慰剂在治疗15～65岁患者(n = 68)慢性哮喘中的疗效。采用干粉吸入器，孟鲁司特吸入剂量分别为25, 250和1000 μg，基于预先设计的剂量反应原则，必要时可采用50, 100和500 μg。每次给药后连续4～7天的洗脱期，而后进行接下来的交叉试验。首要终点为第一秒用力呼气体积（FEV1）在给药后4小时内变化，计算时间加权平均值（ΔFEV1 [0–4 h]）。其他终点包括支气管扩张的出现时间和持续时间，吸入孟鲁司联合沙丁胺醇治疗的疗效。
结果：给药后4小时，与安慰剂组相比（最小二乘平均值0.03 L），吸入孟鲁司特100 μg (0.13 L; P≤ 0.001)、250 μg (0.10 L; P≤0.01)和1000 μg (0.12 L; P≤0.001) 后ΔFEV1显著增加（0～4 h）。给药24小时后，与安慰剂组相比(0.02 L; P≤ 0.05 vs. 孟鲁司特).，吸入孟鲁司特100 μg (0.10 L)和1000 μg (0.09 L)具有显著的支气管扩张。与安慰剂相比，孟鲁司特1000 μg能在给药后20 分钟内产生显著的支气管扩张效应（0.03 L vs. –0.05 L），而孟鲁司特100 μg在给药后2小时，与安慰剂相比，也能产生显著的支气管扩张。基于ΔFEV1，孟鲁司特（累计剂量）联合沙丁胺醇对哮喘的疗效，优于孟鲁司特联合安慰剂(0～90分钟) (0.34 L vs. 0.15 L; p = 0.015)。孟鲁司特吸入的耐受性与安慰剂相当。无严重不良事件出现。
结论：吸入孟鲁司特在20分钟之内就能产生明显的支气管扩张，而且该效应能持续24小时，加用沙丁胺醇能增加其支气管扩张效应。
（林江涛 审校）
J Asthma. 2010 Oct 12. [Epub ahead of print]
A Phase I Randomized, Placebo-Controlled, Dose-Exploration Study of Single-Dose Inhaled Montelukast in Patients with Chronic Asthma.
Philip G, Pedinoff A, Vandormael K, Tymofyeyev Y, Smugar SS, Reiss TF, Korenblat PE.
Merck Research Laboratories, North Wales, PA, USA.
Abstract
Background. The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast. Methods. Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15–65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 μg, and doses of 50, 100, and 500 μg could be used if needed based on a prespecified dose–response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV1) over the first 4 hours after administration, calculated as a time-weighted average (ΔFEV1 [0–4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast.
Results. Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 μg (0.13 L; p ≤ .001), 250 μg (0.10 L; p < .01), and 1000 μg (0.12 L; p ≤ .001) had significantly greater ΔFEV1 (0–4 hours). At 24 hours postdose, inhaled montelukast 100 μg (0.10 L) and 1000 μg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p < .05 vs. montelukast). Montelukast 1000 μg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. –0.05 L), whereas montelukast 100 μg provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for ΔFEV1 (0–90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported. Conclusions. Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.
J Asthma. 2010 Oct 12. [Epub ahead of print]
背景：已经证实，口服孟鲁司特能治疗成人和儿童哮喘和过敏性鼻炎。本研究旨在评价吸入孟鲁司特治疗的剂量相关性支气管扩张和安全性。
方法：本试验为随机、双盲、交叉、适应性设计研究，比较单次孟鲁司特吸入与安慰剂在治疗15～65岁患者(n = 68)慢性哮喘中的疗效。采用干粉吸入器，孟鲁司特吸入剂量分别为25, 250和1000 μg，基于预先设计的剂量反应原则，必要时可采用50, 100和500 μg。每次给药后连续4～7天的洗脱期，而后进行接下来的交叉试验。首要终点为第一秒用力呼气体积（FEV1）在给药后4小时内变化，计算时间加权平均值（ΔFEV1 [0–4 h]）。其他终点包括支气管扩张的出现时间和持续时间，吸入孟鲁司联合沙丁胺醇治疗的疗效。
结果：给药后4小时，与安慰剂组相比（最小二乘平均值0.03 L），吸入孟鲁司特100 μg (0.13 L; P≤ 0.001)、250 μg (0.10 L; P≤0.01)和1000 μg (0.12 L; P≤0.001) 后ΔFEV1显著增加（0～4 h）。给药24小时后，与安慰剂组相比(0.02 L; P≤ 0.05 vs. 孟鲁司特).，吸入孟鲁司特100 μg (0.10 L)和1000 μg (0.09 L)具有显著的支气管扩张。与安慰剂相比，孟鲁司特1000 μg能在给药后20 分钟内产生显著的支气管扩张效应（0.03 L vs. –0.05 L），而孟鲁司特100 μg在给药后2小时，与安慰剂相比，也能产生显著的支气管扩张。基于ΔFEV1，孟鲁司特（累计剂量）联合沙丁胺醇对哮喘的疗效，优于孟鲁司特联合安慰剂(0～90分钟) (0.34 L vs. 0.15 L; p = 0.015)。孟鲁司特吸入的耐受性与安慰剂相当。无严重不良事件出现。
结论：吸入孟鲁司特在20分钟之内就能产生明显的支气管扩张，而且该效应能持续24小时，加用沙丁胺醇能增加其支气管扩张效应。
（林江涛 审校）
J Asthma. 2010 Oct 12. [Epub ahead of print]
A Phase I Randomized, Placebo-Controlled, Dose-Exploration Study of Single-Dose Inhaled Montelukast in Patients with Chronic Asthma.
Philip G, Pedinoff A, Vandormael K, Tymofyeyev Y, Smugar SS, Reiss TF, Korenblat PE.
Merck Research Laboratories, North Wales, PA, USA.
Abstract
Background. The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast. Methods. Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15–65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 μg, and doses of 50, 100, and 500 μg could be used if needed based on a prespecified dose–response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV1) over the first 4 hours after administration, calculated as a time-weighted average (ΔFEV1 [0–4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast.
Results. Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 μg (0.13 L; p ≤ .001), 250 μg (0.10 L; p < .01), and 1000 μg (0.12 L; p ≤ .001) had significantly greater ΔFEV1 (0–4 hours). At 24 hours postdose, inhaled montelukast 100 μg (0.10 L) and 1000 μg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p < .05 vs. montelukast). Montelukast 1000 μg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. –0.05 L), whereas montelukast 100 μg provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for ΔFEV1 (0–90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported. Conclusions. Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.
J Asthma. 2010 Oct 12. [Epub ahead of print]
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