Hydroxychloroquin (HCQ) in Pediatric Interstitial Lung Disease (ILD)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Interstitial Lung Disease, Diffuse Parenchymal Lung Disease, Children´s Interstitial Lung Disease

Intervention / Treatment
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* Drug: Hydroxychloroquine sulfate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients should be clinically stable during baseline (between Visit 1 and 2) for inclusion into the study 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 No major changes in other medications between Visit 1 and 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.) Diagnosis of chronic (≥ 3 wks of duration) diffuse parenchymal lung disease (DPLD = chILD), defined in at least one of the following ways: 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. 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 Start block: no HCQ treatment in the last 12 weeks Stop block: stable HCQ treatment for at least the last 12 weeks Ability of subject or/and legal representatives to understand character and individual consequences of clinical trial. 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

Ages Eligible for Study
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Minimum Age: 3 Weeks
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Start HCQ block Verum<br>During trial: Hydroxychloroquine Sulfate (HCQ, Quensyl) 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 400mg. | Drug: Hydroxychloroquine sulfate<br>* Apply drug to modify lysosomal pH<br>* Other names: Quensyl;|
| Placebo Comparator: Start HCQ block Placebo<br>At the beginning of the trial: Placebo for 4 weeks then Hydroxychloroquine Sulfate (HCQ, Quensyl) 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 400mg. | Other: Placebo<br>* Apply Placebo not to modify lysosomal pH<br>* Other names: no other name;|
| Experimental: Stop HCQ block Verum<br>Individual dose, usually Hydroxychloroquine Sulfate (HCQ, Quensyl) 6-10 mg/kg bw/d, p.o., one daily dose in the evening; the maximum daily dose is 400 mg. The dose, on which the patient is included into the trial, should be continued for 3 months. After therapy of 3 months the medication will be stopped. The patients will be followed up for additional 3 months. | Drug: Hydroxychloroquine sulfate<br>* Apply drug to modify lysosomal pH<br>* Other names: Quensyl;|
| Placebo Comparator: Stop HCQ block Placebo<br>Patients will receive Placebo for 3 months and will be followed up for additional 3 months. | Other: Placebo<br>* Apply Placebo not to modify lysosomal pH<br>* Other names: no other name;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Oxygenation | Start HCQ block: relative Change Trial day 1 through day 28 and relative Change day 28 to day 56; Change active compound compared to Change Placebo. Stop HCQ block: Relative change trail day 1 through day 84: change active compound compared to change Placebo. | Start HCQ block: 28 and 56 days; Stop HCQ block: 84 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Oxygen Saturation | (O2-sat, in room air) (only absolute, as relative already Primary outcome) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Respiratory rate | (RR, in room air) (relative and absolute) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Retraction, Coughing | (yes/no) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Lab values | (GOT, Creatinine, gGT, blood count, differential, LDH, potassium, steady state drug level) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Oxygen demand | in room air, on Os-supplement or O2 flow | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of QoL | (PedsQl™ generic and chILD specific module) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Health economics | specific questionaire | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Overall survival | death or not | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Weight to Height ratio | Weight measured in kg and Height measured in cm | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Cumulative amounts of Steroid equivalents | Clinical course of lung disease (since last visit): Healthy/ Sick-better/ Sick-same/ Sick-worse/ Patient died | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of x-ray | if x-ray were done | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of pO2, pCO2 | (capillary, in room air) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Pulmonary exacerbation | (since last visit) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Forced vital capacity | measured by spirometry or bodyplethysmography; If > 5y old (If a child ≤ 5 years is already able to perform the listed investigations (spirometry or bodyplethysmography), these should also be performed and documented at the discretion of the investigator.) | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Number of abnormal changes in Electrocardiographie (ECG) | measured on start and end of trial | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of 6 minute walking distance (6MWT) (in meter) | O2-saturation will be measured before and after 6MWT | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Change of Borg Scale | Measured after 6MWT | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Number of subjects with ophthalmologic abnormalities | Ophthalmologic review on start and end of trial | Start HCQ block: 28 days; Stop HCQ block: 84 days | 
| Number of Treatment related advers events | measured on each visit | Start HCQ block: 28 days; Stop HCQ block: 84 days |