Hydroxychloroquin (HCQ) in chILD of Genetic Defect

Study Overview
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Brief Summary
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The purpose of this proposed research is to investigate the efficacy and safety of hydroxychloroquine sulfate (HCQ, Quensyl) for pediatric ILD(chILD) caused by pulmonary surfactant-associated genes mutations.

Detailed Description
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Children Interstitial lung disease (chILD) is a heterogeneous group of rare respiratory disorders of known and unknown etiologies that are mostly chronic and associated with high morbidity and mortality. ILD are characterized by inflammatory and fibrotic changes of the lung parenchyma structure that typically result in the presence of diffuse infiltrates on lung imaging, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect and/or impaired gas exchange. Genetic factors are important contributors to chILD. Genetic variations have been mainly described in genes encoding (or interacting with) the surfactant proteins (SP): SP-C (SFTPC) and the ATP-binding cassette-family A-member 3 (ABCA3) (ABCA3), and less frequently in the genes encoding NKX homeobox 2 (NKX2)-1 (NKX2-1), SP-B (SFTPB), SP-A (SFTPA) and other genes. To date, the therapeutic managements of such chILD remain limited and are mainly based of the use of corticosteroids, however, their efficacy is highly variable. An alternative approach to treatment was originally described by Tooley who reported a good response to treatment with chloroquine in a girl with ILD, and several case reports have shown a positive response to hydroxychloroquine(HCQ) alone or in combination with systemic steroids of the children with ILD. The exact mechanism of action of HCQ is unknown, but is probably due to its anti-inflammatory properties, HCQ have lysosomal activities such as diminished vesicle fusion, diminished exocytosis, decreased digestive efficiency of phagolysosomes and reversible lysosomal storage disease. This may be the mechanism by which HCQ tend to help in chILD, especially in those cases related to surfactant protein deficiency. SP-B and SP-C are synthesized in the endoplasmic reticulum (ER) of alveolar type II cells as large precursor proteins, are cleaved by proteolytic enzymes and transported through Golgi apparatus to multivesicular bodies that fuse with lamellar bodies. In chILD related to SP-C gene mutations, there is misfolding of proSP-C that accumulates within ER and Golgi apparatus in alveolar type II cells, resulting in cellular injury and apoptosis. Treatment with HCQ may interfere with this accumulation of pro-surfactant proteins within alveolar cells. The investigators propose to study the efficacy and safety of the therapy with HCQ for children with chILD suffered with genetic mutations, and its long-term effects. Through this study the investigators hope to confirm the benefits of HCQ in the treatment of this rare disease.

Official Title
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Hydroxychloroquine in Pediatric ILD With Genetic Surfactant Dysfunction Disorders: Cross-control, Prospective Study

Conditions
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Surfactant Dysfunction

Intervention / Treatment
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* Drug: Hydroxychloroquin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients should be clinically stable for inclusion into the study Mature newborn ≥ 37 weeks of gestation, Infants and children (≥2month and < 18y) or previously preterm (≤ 37 weeks of gestation) babies or children(≥2month and <18y) if chILD genetically diagnosed chILD genetically diagnosed surfactant dysfunction disorders including patients with mutations in SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), FOXF1 further extremely rare entities with specific mutations, for example in TBX4, NPC2, NPC1, NPB, COPA, LRBA and other genes no HCQ treatment in the last 3 months 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 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 alveolarization 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 Proven retinopathy or maculopathy Glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia Myasthenia gravis Hematopoetic disorders 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 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: 1 Month
Maximum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: cross-control
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCQ Therapy<br>Hydroxychloroquine Sulfate (HCQ, Quensyl) in a loading dose of 10 mg/kg*d, p.o., bid. After the illness gradually alleviate to maintain dose between 5mg/kg*d to 10mg/kg*d, p.o., bid ; the maximum daily dose is 400mg. Assess the efficacy and safety of HCQ after 6 months treatment compared with any other routine therapy before HCQ therapy (such as inhaling oxygen, corticosteroid, anti-infection therapy, nutritional support) | Drug: Hydroxychloroquin<br>* Hydroxychloroquine Sulfate (HCQ, Quensyl) in a loading dose of 10 mg/kg*d, p.o., bid. After the illness gradually alleviate to maintain dose between 5mg/kg*d to 10mg/kg*d, p.o., bid ; the maximum daily dose is 400mg.<br>* Other names: Hydroxychloroquine Sulfate; Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation change | Clinical judgment of oxygenation condition at 6 months compared with trial day 1 (demand of oxygen supplement while transcutaneous oxygen saturation no less than 92% and with no clinical manifestations of hypoxia) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen flow rate | O2 supplement(L/min) at 1 months compared with trial day 1 | 1 month | 
| Oxygen flow rate | O2 supplement(L/min) at 3 months compared with trial day 1 | 3 month | 
| Oxygen flow rate | O2 supplement(L/min) at 12 months compared with trial day 1 | 12 month | 
| Oxygen flow rate | O2 supplement(L/min) at 18 months compared with trial day 1 | 18 month | 
| Oxygen flow rate | O2 supplement(L/min) at 24 months compared with trial day 1 | 24 month | 
| Fraction of inspired oxygen(FiO2) | Fraction of inspired oxygen(FiO2) at 1 months compared with trial day 1 | 1 month | 
| Fraction of inspired oxygen | FiO2 at 3 months compared with trial day 1 | 3 month | 
| Fraction of inspired oxygen | FiO2 at 6 months compared with trial day 1 | 6 month | 
| Fraction of inspired oxygen | FiO2 at 12 months compared with trial day 1 | 12 month | 
| Fraction of inspired oxygen | FiO2 at 18 months compared with trial day 1 | 18 month | 
| Fraction of inspired oxygen | FiO2 at 24 months compared with trial day 1 | 24 month | 
| Number of subjects with oxygen inhalation | Number of subjects at 6 months compared with trial day 1 | 6 months | 
| Number of subjects with oxygen inhalation | Number of subjects at 12 months compared with trial day 1 | 12 months | 
| Number of subjects with oxygen inhalation | Number of subjects at 24 months compared with trial day 1 | 24 months | 
| Transcutaneous oxygen saturation | O2-sat at 1 months compared with trial day 1 | 1 months | 
| Transcutaneous oxygen saturation | O2-sat at 3 months compared with trial day 1 | 3 months | 
| Transcutaneous oxygen saturation | O2-sat at 12 months compared with trial day 1 | 12 months | 
| Transcutaneous oxygen saturation | O2-sat at 18 months compared with trial day 1 | 18 months | 
| Transcutaneous oxygen saturation | O2-sat at 24 months compared with trial day 1 | 24 months | 
| Respiratory rate | Respiratory rate(RR) at 1 months compared with trial day 1 | 1 months | 
| Respiratory rate | RR at 3 months compared with trial day 1 | 3 months | 
| Respiratory rate | RR at 6 months compared with trial day 1 | 6 months | 
| Respiratory rate | RR at 12 months compared with trial day 1 | 12 months | 
| Chronic cough | (yes/no) | 6 months | 
| Chronic cough | (yes/no) | 12 months | 
| Chronic cough | (yes/no) | 24 months | 
| Clubbing finger | (yes/no) | 6 months | 
| Clubbing finger | (yes/no) | 12 months | 
| Clubbing finger | (yes/no) | 24 months | 
| Functional lesion of liver and kidney | (yes/no) | 3 months | 
| Functional lesion of liver and kidney | (yes/no) | 6 months | 
| Functional lesion of liver and kidney | (yes/no) | 12 months | 
| Functional lesion of liver and kidney | (yes/no) | 24 months | 
| Malnutrition | (yes/no) at 3 months compared with trial day 1, based on Reference criteria for growth and development of children under 7 years old in China | 3 months | 
| Malnutrition | (yes/no) at 6 months compared with trial day 1, based on Reference criteria for growth and development of children under 7 years old in China | 6 months | 
| Malnutrition | (yes/no) at 12 months compared with trial day 1, based on Reference criteria for growth and development of children under 7 years old in China | 12 months | 
| Malnutrition | (yes/no) at 24 months compared with trial day 1, based on Reference criteria for growth and development of children under 7 years old in China | 24 months | 
| Deterioration of pulmonary imaging | (yes/no) Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 6 months | 6 months | 
| Deterioration of pulmonary imaging | Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 12 months | 12 months | 
| Deterioration of pulmonary imaging | Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 24 months | 24 months | 
| Lung function decline | (yes/no) Clinical judgment of Lung-function compared with that of last visit if lung-function testing were done at 3 years | 3 years | 
| Lung function decline | (yes/no) Clinical judgment of Lung-function compared with that of last visit if lung-function testing were done at 6 years | 6 years | 
| Abnormal myocardial zymogram | (yes/no) | 3 months | 
| Abnormal myocardial zymogram | (yes/no) | 6 months | 
| Abnormal myocardial zymogram | (yes/no) | 12 months | 
| Duration of oxygen inhalation | The time last from HCQ treatment to withdrawal of oxygen (months) | 36 months | 
| Mortality | Number of deaths at 3 months | 3 months | 
| Mortality | Number of deaths at 12 months | 12 months | 
| Mortality | Number of deaths at 24 months | 24 months | 
| Number of Treatment related adverse events | Measured on each visit | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interstitial lung disease, Hydroxychloroquine