随机对照 2 期羟氯喹治疗儿童间质性肺疾病试验。

Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease.

机构信息

Dr. von Hauner Children´s Hospital, University of Munich, German Center for Lung Research (DZL), Lindwurmstraße 4, 80337, Munich, Germany.

Uniklinikum Essen Pädiatrische Pneumologie, Kinderheilkunde III, Hufelandstr. 55, 45122, Essen, Germany.

出版信息

Orphanet J Rare Dis. 2022 Jul 23;17(1):289. doi: 10.1186/s13023-022-02399-2.

DOI:10.1186/s13023-022-02399-2

PMID:35871071

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9308121/

Abstract

BACKGROUND

No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks.

RESULTS

26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O-saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O-saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ.

CONCLUSIONS

Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).

摘要

背景

对于患有间质性肺疾病（chILD）的儿童，目前尚无任何治疗方法的对照试验结果。我们评估了羟氯喹（HCQ）在一项 2 期、前瞻性、多中心、1:1 随机、双盲、安慰剂对照、平行组/交叉试验中的疗效。HCQ（起始组）或安慰剂治疗 4 周。然后所有受试者均接受 HCQ 治疗 4 周。在停药组中，已接受 HCQ 治疗的受试者被随机分为 HCQ 或安慰剂（=停止 HCQ）治疗 12 周。然后所有受试者停止治疗并观察 12 周。

结果

26 名受试者进入起始组，9 名受试者进入停药组，其中 4 名受试者同时参加了两组。主要终点为治疗反应的有无，通过经皮氧饱和度变化（计算为经皮氧饱和度增加≥5%、呼吸频率增加≥20%或呼吸支持水平）评估，安慰剂组与 HCQ 组之间无差异。次要终点包括氧饱和度增加≥3%、健康相关生活质量、肺功能和 6 分钟步行试验距离，两组之间也无差异。最后，合并所有安慰剂和所有 HCQ 治疗期并未发现有显著的治疗效果。总体效应量较小。HCQ 耐受性良好，安慰剂组和 HCQ 组的不良反应无差异。

结论

鉴于研究存在重要缺陷，包括研究人群小、治疗时间短、6 岁以下儿童肺功能检测结果缺失等，观察到的 HCQ 治疗效果较小，这需要对日常实践中的处方进行重新评估（EudraCT-Nr.：2013-003714-40，www.clinicaltrialsregister.eu，于 2013 年 7 月 2 日注册）。

该研究于 2013 年 7 月 2 日（Eudra-CT 编号：2013-003714-40）在欧洲药品管理局注册，2014 年 11 月 24 日获得联邦药物和医疗器械管理局的批准，随后于 2015 年 1 月 20 日获得慕尼黑大学附属医院主要伦理委员会的批准。在美国临床试验注册中心（ClinicalTrials.gov），该试验于 2015 年 11 月 8 日（NCT02615938）进行了额外的注册。