Hydroxychloroquine (HCQ) in Pediatric Interstitial Lung Disease (ILD) (HCQ-chILD-EU)

Hydroxychloroquine in Pediatric ILD: START Randomized Controlled in Parallel-group, Then Switch Placebo to Active Drug, and STOP Randomized Controlled in Parallel-Group to Evaluate the Efficacy and Safety of Hydroxychloroquine (HCQ)

This is an exploratory Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD.

Study Overview

• Status: Terminated
• Conditions: Interstitial Lung Disease; Diffuse Parenchymal Lung Disease; Children´s Interstitial Lung Disease
• Intervention / Treatment: Drug: Hydroxychloroquine sulfate; Other: Placebo

Detailed Description

This study is an explorative, prospective, randomized, double-blind, placebo controlled investigation of hydroxychloroquine (HCQ) in pediatric ILD. The treatments are organized in START and STOP blocks, which can be initiated in sequence, as needed by the subjects. Each patient can participate in each block only once. In the START block subjects are randomized to parallel-groups, then the placebo group is switched to active drug. In the STOP block, subjects on HCQ are randomized into parallel-groups treated with placebo or HCQ to investigate the withdrawal of HCQ for assessment of its efficacy.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charité Berlin, Klinik für Pädiatrie
  • Baden-Wurttemberg
    • Tübingen, Baden-Wurttemberg, Germany, 72076
      • Universitätsklinik für Kinder- und Jugendmedizin Tübingen
  • Bavaria
    • München, Bavaria, Germany, 80337
      • Klinikum der Universität München, Haunersches Kinderspital
  • Hesse
    • Frankfurt am Main, Hesse, Germany, 60590
      • Universitätsklinikum Frankfurt, Pneumologie, Allergologie, Mukoviszidose
    • Giessen, Hesse, Germany, 35385
      • Justus-Liebig-Universität, Allgemeine Pädiatrie u. Neonatologie
  • Lower Saxony
    • Hanover, Lower Saxony, Germany, 30625
      • Medizinische Hochschule Hannover
  • North Rhine-Westphalia
    • Bochum, North Rhine-Westphalia, Germany, 44791
      • St. Joseph- und St. Elisabeth Hospital gGmbH
    • Essen, North Rhine-Westphalia, Germany, 45122
      • Uniklinikum Essen, Pädiatrische Pneumologie
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Klinik u. Poliklinik für Kinder- u. Jugendmedizin der Universität Leipzig

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 95 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Patients should be clinically stable during baseline (between Visit 1 and 2) for inclusion into the study

   1. To determine this, attending physicians can use SpO2 in room air for patients on room air or on O2-supplement; the absolute difference on SpO2 is expected not to be ≥ 5% between Visit 1 and 2. For patients on respiratory support, the summary key parameters should not change ≥ 20% between Visit 1 and 2 and
   2. No major changes in other medications between Visit 1 and 2
2. Mature newborn ≥ 37 weeks of gestation, age ≥ 3 wks and <2y or Infants and children (≥2y and < 18y) or Adults (≥18 and ≤30y) or Previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages if chILD genetically diagnosed (see inclusion criterion 3.)

3. Diagnosis of chronic (≥ 3 wks of duration) diffuse parenchymal lung disease (DPLD = chILD), defined in at least one of the following ways:

   1. chILD genetically diagnosed surfactant dysfunction disorders including patients with mutations in SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), further extremely rare entities with specific mutations, for example in TBX4, NPC2, NPC1, NPB, COPA, LRBA and other genes. In this case, also previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages can be included into the study.

   2. chILD histologically diagnosed

      • Chronic pneumonitis of infancy (CPI)
      • Desquamative interstitial pneumonia (DIP)
      • Lipoid pneumonitis / Cholesterol pneumonia
      • Nonspecific interstitial pneumonia (NSIP)
      • PAP after the exclusion of mutations in GMCSF-Ra/b and GMCSF autoantibodies*
      • Usual interstitial pneumonia (UIP)
      • Follicular bronchitis/bronchiolitis/Lymphocytic interstitial pneumonia (LIP)
      • Storage disease with primary pulmonary involvement (e.g. Niemann Pick)
      • Hermansky-Pudlak Syndrome
      • Idiopathic pulmonary haemorrhage (haemosiderosis)*
      • Other histology diagnosing chILD, in particular combination of the above pattern, but not exclusively
4. Start block: no HCQ treatment in the last 12 weeks Stop block: stable HCQ treatment for at least the last 12 weeks
5. Ability of subject or/and legal representatives to understand character and individual consequences of clinical trial.
6. Signed and dated informed consent of the subject (if subject has the ability) and the representatives (of underaged children) must be available before start of any specific trial procedures.

(*may be diagnosed in the absence of a lung biopsy by characteristic lung lavage cytology (PAS stain, Fe stain), CT pattern or autoantibodies (gliadin, endomysium; cANCA) and clinical course.)

Exclusion criteria:

Subjects presenting with any of the following criteria will not be included in the trial:

• chILD primarily related to developmental disorders
• chILD primarily related to growth abnormalities reflecting deficient alveolarisation
• chILD related to chronic aspiration
• chILD related to immunodeficiency
• chILD related to abnormalities in lung vessel structure
• chILD related to organ transplantation/organ rejection/GvHD
• chILD related to recurrent infections
• Acute severe infectious exacerbations
• Known hypersensitivity to HCQ, or other ingredients of the tablets (lactose-monohydrate, povidone, maize starch, magnesium stearate, hypromellose, macrogol or titanium dioxide (E 171), silicon dioxide or mannitol), to sucrose-octaacetate or sodium saccharine.
• Proven retinopathy or maculopathy
• Glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia
• Myasthenia gravis
• Hematopoetic disorders
• Pregnancy and lactation (Women with childbearing potential have to practice a medically accepted contraception during trial and till three months after the end of the treatment with HCQ, and a negative pregnancy test (serum or urine) should be existent on Visit 1, if girls of childbearing age and only if sexual relations are known or probable. It is at the discretion and responsibility of the attending physician to decide, whether a pregnancy test is necessary or not. Reliable contraception are systematic contraceptives (oral, implant, injection). Women that are sterile by surgery can participate in the trial. At the discretion of the investigator, sexual abstinence is also accepted as contraceptive method. Girls after menarche have to receive a counselling about birth control methods in presence of at least one parent, which has to be documented in the patient notes.
• Participation in other clinical trials during the present clinical trial or not beyond the time of 4 half-lives of the medication used, at least one week.
• Hereditary galactose intolerance, lactase deficiency or glucose-galactose- malabsorption

• Renal insufficiency at screening, defined as glomerular filtration rate (GFR)

  • < 40 mL/min/1.73 m2 in patients age 3 to 8 weeks
  • < 60 mL/min/1.73 m2 in patients ≥ 8 weeks of age (KDIGO guideline 2012, K/DOQI guideline 2002)
• Liver disease, gastrointestinal disorder, haematological disorder, epilepsy or other neurological disorder, psoriasis, porphyria at the discretion of the treating physician
• Simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication at the discretion of the treating physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Start HCQ block Verum; 4 weeks of Hydroxychloroquine Sulfate (HCQ, Quensyl) in a loading dose of 10 mg/kg bw/d, p.o., once daily dose in the evening for 7 days, then reduction to 6.5 mg/kg bw/d for 3 weeks; the maximum daily dose is 400 mg. Then 4 weeks Hydroxychloroquine Sulfate (HCQ, Quensyl). First week loading dose 10 mg/kg bw/d, p.o., once daily in the evening, followed by 6.5 mg/kg bw/d for 3 weeks.	Drug: Hydroxychloroquine sulfate; Apply drug to modify lysosomal pH; Other Names: Quensyl
Placebo Comparator: Start HCQ block Placebo; 4 weeks of Placebo in a loading dose of 10 mg/kg bw/d, p.o., one daily dose in the evening for 7 days, then reduction to 6.5 mg/kg bw/d for 3 weeks; the maximum daily dose is 400 mg. Then 4 weeks Hydroxychloroquine Sulfate (HCQ, Quensyl). First week loading dose 10 mg/kg bw/d, p.o., once daily in the evening, followed by 6.5 mg/kg bw/d for 3 weeks.	Other: Placebo; Apply Placebo not to modify lysosomal pH; Other Names: no other name
Experimental: Stop HCQ block Verum; Individual dose of Hydroxychloroquine Sulfate (HCQ, Quensyl) 6-10 mg/kg bw/d, p.o., once daily in the evening; the maximum daily dose is 400 mg. The dose on which the patient was included into the trial was continued for 3 months. Then the medication was stopped and the patient followed for additional 3 months.	Drug: Hydroxychloroquine sulfate; Apply drug to modify lysosomal pH; Other Names: Quensyl
Placebo Comparator: Stop HCQ block Placebo; Individual dose of Placebo 6-10 mg/kg bw/d, p.o., once daily in the evening; the maximum daily dose is 400 mg. The dose on which the patient was included into the trial was continued for 3 months. Then the medication was stopped and the patient wo received HCQ will be followed up for additional 3 months with no medication.	Other: Placebo; Apply Placebo not to modify lysosomal pH; Other Names: no other name

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary	O2 saturation measured after 5 min at rest and after withdrawal of oxygen if supplied. Change in Oxygenation (presence or absence of response to treatment) defined as change in O2 saturation >=5%, or change in respiratory rate >=20%, or change in respiratory support necessary	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary	O2 saturation measured after 5 min at rest and after withdrawal of oxygen if supplied. Change in Oxygenation (presence or absence of response to treatment) defined as change in O2 saturation >=3%, or change in respiratory rate >=20%, or change in respiratory support necessary	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Change of O2-sat in Room Air (%)	Oxygen saturation in room air at rest	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Change of Respiratory Rate in Room Air (Breaths/Min)	Respiratory rate in room air at rest measured in breaths per minute	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Change of Quality of Life (chILD Specific)	Quality of life (chILD specific) questionaire. A 5-point response scale was utilized (0 = never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Higher scores indicate better HrQoL.	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Change of Quality of Life (Total Score)	Quality of life (total score) questionaire. A 5-point response scale was utilized (0 = never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Higher scores indicate better HrQoL.	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Change of BMI Percentile	BMI percentile to adapt for age and sex related differences	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Change of LDH (U/ml)	Lactate dehydrogenase	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population)	FVC predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.) The absolute change in FVC % predicited between two measurements is reported.	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population)	FEV1 predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.). The absolute change in FEV1 % predicited between two measurements is reported.	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population)	MEF25-75 predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.). The absolute change in MEF25-75 % predicited between two measurements is reported.	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population)	6 Minute walking distance expressed as % of the predicted distance for age and sex. Ulrich et al, Reference values for the 6-minute walk test. BMC Pulm Med. 2013 Aug 5:13:49. doi: 10.1186/1471-2466-13-49. The absolute difference of two measuremnts between two time points is reported.	Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks

Collaborators and Investigators

• Sponsor: Matthias Griese
• Investigators: Principal Investigator: Matthias Griese, Hauner Children´s Hospital, LMU

Publications and helpful links

General Publications

• Griese M, Kohler M, Witt S, Sebah D, Kappler M, Wetzke M, Schwerk N, Emiralioglu N, Kiper N, Kronfeld K, Ruckes C, Rock H, Anthony G, Seidl E. Prospective evaluation of hydroxychloroquine in pediatric interstitial lung diseases: Study protocol for an investigator-initiated, randomized controlled, parallel-group clinical trial. Trials. 2020 Apr 3;21(1):307. doi: 10.1186/s13063-020-4188-4.
• Braun S, Ferner M, Kronfeld K, Griese M. Hydroxychloroquine in children with interstitial (diffuse parenchymal) lung diseases. Pediatr Pulmonol. 2015 Apr;50(4):410-9. doi: 10.1002/ppul.23133. Epub 2014 Dec 9.
• Griese M, Kappler M, Stehling F, Schulze J, Baden W, Koerner-Rettberg C, Carlens J, Prenzel F, Nahrlich L, Thalmeier A, Sebah D, Kronfeld K, Rock H, Ruckes C; HCQ-study group; Wetzke M, Seidl E, Schwerk N. Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease. Orphanet J Rare Dis. 2022 Jul 23;17(1):289. doi: 10.1186/s13023-022-02399-2.

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2015
• Primary Completion (Actual): June 27, 2019
• Study Completion (Actual): September 9, 2020

Study Registration Dates

• First Submitted: November 8, 2015
• First Submitted That Met QC Criteria: November 24, 2015
• First Posted (Estimated): November 26, 2015

Study Record Updates

• Last Update Posted (Estimated): December 3, 2025
• Last Update Submitted That Met QC Criteria: November 18, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Childhood ILD; Fibrosing lung disease
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Quinolines; Aminoquinolines; Chloroquine; Hydroxychloroquine
• Other Study ID Numbers: EudratCT:2013-003714-40

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO