Hydroxychloroquin (HCQ) in chILD of Genetic Defect

  • STATUS
    Recruiting
  • End date
    Jul 30, 2026
  • participants needed
    25
  • sponsor
    Children's Hospital of Fudan University
Updated on 17 March 2021

Summary

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.

Description

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.

Details
Condition Surfactant Dysfunction
Treatment Hydroxychloroquin
Clinical Study IdentifierNCT03822780
SponsorChildren's Hospital of Fudan University
Last Modified on17 March 2021

Eligibility

Yes No Not Sure

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-galactosemalabsorption
Simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication at the discretion of the treating physician
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