Prospective evaluation of hydroxychloroquine in pediatric interstitial lung diseases: Study protocol for an investigator-initiated, randomized controlled, parallel-group clinical trial
Matthias Griese, Meike Köhler, Sabine Witt, Daniela Sebah, Matthias Kappler, Martin Wetzke, Nicolaus Schwerk, Nagehan Emiralioglu, Nural Kiper, Kai Kronfeld, Christian Ruckes, Hans Rock, Gisela Anthony, Elias Seidl, Matthias Griese, Meike Köhler, Sabine Witt, Daniela Sebah, Matthias Kappler, Martin Wetzke, Nicolaus Schwerk, Nagehan Emiralioglu, Nural Kiper, Kai Kronfeld, Christian Ruckes, Hans Rock, Gisela Anthony, Elias Seidl
Abstract
Background: Interstitial lung diseases in children (chILD) are rare and consist of many different entities that affect the parenchyma of the lungs, leading to a chronic lung disease. The natural course of many of these diseases is connected with a high morbidity and significant mortality. Symptomatic treatment consists of oxygen supplementation, adequate nutrition adapted to the high energy demand generated by the disease due to the increased breathing effort required, as well as immunization against respiratory pathogens to prevent exacerbations through respiratory infections. No proven pharmacological treatments are available to date. This placebo-controlled study aims to evaluate the efficacy and safety of the mid-term use of hydroxychloroquine in chILD.
Methods and design: The study is an explorative, prospective, randomized, double-blind, placebo-controlled investigation of hydroxychloroquine (HCQ) in chILD. Patients can be included into the trial when diagnosed with a chronic (≥ 3 weeks' duration) diffuse parenchymal lung disease (chILD) (1) genetically defined, (2) histologically defined or (3) diagnosed with idiopathic pulmonary hemorrhage (hemosiderosis). The study contains of two different study blocks, a START and a STOP block, which can be initiated in any sequence. Each patient can participate in each block only once. In the START block subjects are randomized to parallel groups for 4 weeks treatment, then the placebo group is switched to the active drug. In the STOP block, subjects taking HCQ are randomized into parallel groups treated with placebo or HCQ.
Discussion: This study is the first international, investigator-initiated, prospective and controlled investigation of a pharmacological treatment in chILD. The block design was selected as it has the advantage of accommodating patients who are initiating or withdrawing from HCQ therapy, thus allowing the participation of those who were previously started on off-label HCQ. The cross-over design and selected outcome parameters enables us to include appropriate numbers of patients of all age groups from neonates to adults suffering from these rare diseases.
Trial registration: This is an exploratory, Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD. Study title: Hydroxychloroquine in pediatric ILD: START randomized controlled in parallel groups, then switch placebo to the active drug, and STOP randomized controlled in parallel groups to evaluate the efficacy and safety of hydroxychloroquine (HCQ). Short title: HCQ in pediatric ILD, particularly 4surfdefect. EudraCT, ID: 2013-003714-40. Registered on 2 July 2013. ClinicalTrials.gov, ID: NCT02615938. Registered on 8 November 2015. IZKS trial code: 2013-006; Sponsor: University Hospital, Ludwig-Maximilians University of Munich. Responsible Party: Prof. Dr. med. Matthias Griese, University Hospital, Ludwig-Maximilians University of Munich, Germany.
Keywords: Hydroxychloroquine; Interstitial lung disease; chILD.
Conflict of interest statement
The authors declare that they have no competing interests.
Figures
References
- Deutsch GH, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176(11):1120–1128. doi: 10.1164/rccm.200703-393OC.
- Das S, Langston C, Fan LL. Interstitial lung disease in children. Curr Opin Pediatr. 2011;23(3):325–331. doi: 10.1097/MOP.0b013e3283464a37.
- Griese M, et al. Categorizing diffuse parenchymal lung disease in children. Orphanet J Rare Dis. 2015;10:122. doi: 10.1186/s13023-015-0339-1.
- Griese M, et al. Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany. Orphanet J Rare Dis. 2009;4:26. doi: 10.1186/1750-1172-4-26.
- Bush A, et al. European protocols for the diagnosis and initial treatment of interstitial lung disease in children. Thorax. 2015;70(11):1078–1084. doi: 10.1136/thoraxjnl-2015-207349.
- Clement A, et al. Interstitial lung diseases in children. Orphanet J Rare Dis. 2010;5:22. doi: 10.1186/1750-1172-5-22.
- Griese M, et al. International management platform for children's interstitial lung disease (chILD-EU) Thorax. 2018;73(3):231–239. doi: 10.1136/thoraxjnl-2017-210519.
- Zentiva, Plaquenil-Hydroxychloroquine sulfate – Summary of Product Characteristics, in , Zentiva, Editor. 2017: Guildford.
- Braun S, et al. Hydroxychloroquine in children with interstitial (diffuse parenchymal) lung diseases. Pediatr Pulmonol. 2015;50(4):410–419. doi: 10.1002/ppul.23133.
- Pandya HK, et al. Hydroxychloroquine retinopathy: a review of imaging. Indian J Ophthalmol. 2015;63(7):570–574. doi: 10.4103/0301-4738.167120.
- Dinwiddie R, Sharief N, Crawford O. Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland. Pediatr Pulmonol. 2002;34(1):23–29. doi: 10.1002/ppul.10125.
- Bush A, Sheppard MN, Warner JO. Chloroquine in idiopathic pulmonary haemosiderosis. Arch Dis Child. 1992;67(5):625–627. doi: 10.1136/adc.67.5.625.
- Travis WD, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–748. doi: 10.1164/rccm.201308-1483ST.
Source: PubMed