Hydroxychloroquin (HCQ) in chILD of Genetic Defect

NCT ID: NCT03822780

Last Updated: 2024-05-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-01
• Study Completion Date: 2026-07-30

Brief 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.

Detailed 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.

Conditions

Surfactant Dysfunction

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HCQ Therapy

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)

Group Type: EXPERIMENTAL

Hydroxychloroquin

Intervention Type: DRUG

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.

Interventions

Hydroxychloroquin

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.

Intervention Type: DRUG

Other Intervention Names

Hydroxychloroquine Sulfate; Plaquenil

Eligibility Criteria

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

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Children's Hospital of Fudan University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's hospital of Fudan University

Shanghai, Shanghai Municipality, China

Site Status: RECRUITING

Countries

China

Facility Contacts

Ling Li Qian, Doctor

Role: primary

llqian@126.com

021-64931913

References

Clement A, Nathan N, Epaud R, Fauroux B, Corvol H. Interstitial lung diseases in children. Orphanet J Rare Dis. 2010 Aug 20;5:22. doi: 10.1186/1750-1172-5-22.

Reference Type: BACKGROUND

PMID: 20727133 (View on PubMed)

Nathan N, Borensztajn K, Clement A. Genetic causes and clinical management of pediatric interstitial lung diseases. Curr Opin Pulm Med. 2018 May;24(3):253-259. doi: 10.1097/MCP.0000000000000471.

Reference Type: BACKGROUND

PMID: 29517585 (View on PubMed)

Barnett HL. editor. Pediatrics. 15th edition. New York: Appleton Century-Crofts; 1972. pp 1315-1316.

Reference Type: BACKGROUND

Rosen DM, Waltz DA. Hydroxychloroquine and surfactant protein C deficiency. N Engl J Med. 2005 Jan 13;352(2):207-8. doi: 10.1056/NEJM200501133520223. No abstract available.

Reference Type: BACKGROUND

PMID: 15647591 (View on PubMed)

Kroner C, Reu S, Teusch V, Schams A, Grimmelt AC, Barker M, Brand J, Gappa M, Kitz R, Kramer BW, Lange L, Lau S, Pfannenstiel C, Proesmans M, Seidenberg J, Sismanlar T, Aslan AT, Werner C, Zielen S, Zarbock R, Brasch F, Lohse P, Griese M. Genotype alone does not predict the clinical course of SFTPC deficiency in paediatric patients. Eur Respir J. 2015 Jul;46(1):197-206. doi: 10.1183/09031936.00129414. Epub 2015 Feb 5.

Reference Type: BACKGROUND

PMID: 25657025 (View on PubMed)

Hevroni A, Goldman A, Springer C. Infant pulmonary function testing in chronic pneumonitis of infancy due to surfactant protein C mutation. Pediatr Pulmonol. 2015 Jun;50(6):E17-23. doi: 10.1002/ppul.23166. Epub 2015 Mar 9.

Reference Type: BACKGROUND

PMID: 25755194 (View on PubMed)

Avital A, Hevroni A, Godfrey S, Cohen S, Maayan C, Nusair S, Nogee LM, Springer C. Natural history of five children with surfactant protein C mutations and interstitial lung disease. Pediatr Pulmonol. 2014 Nov;49(11):1097-105. doi: 10.1002/ppul.22971. Epub 2013 Dec 17.

Reference Type: BACKGROUND

PMID: 24347114 (View on PubMed)

Thouvenin G, Abou Taam R, Flamein F, Guillot L, Le Bourgeois M, Reix P, Fayon M, Counil F, Depontbriand U, Feldmann D, Pointe HD, de Blic J, Clement A, Epaud R. Characteristics of disorders associated with genetic mutations of surfactant protein C. Arch Dis Child. 2010 Jun;95(6):449-54. doi: 10.1136/adc.2009.171553. Epub 2010 Apr 19.

Reference Type: BACKGROUND

PMID: 20403820 (View on PubMed)

Hepping N, Griese M, Lohse P, Garbe W, Lange L. Successful treatment of neonatal respiratory failure caused by a novel surfactant protein C p.Cys121Gly mutation with hydroxychloroquine. J Perinatol. 2013 Jun;33(6):492-4. doi: 10.1038/jp.2012.131.

Reference Type: BACKGROUND

PMID: 23719253 (View on PubMed)

Arikan-Ayyildiz Z, Caglayan-Sozmen S, Isik S, Deterding R, Dishop MK, Couderc R, Epaud R, Louha M, Uzuner N. Survival of an infant with homozygous surfactant protein C (SFTPC) mutation. Pediatr Pulmonol. 2014 Mar;49(3):E112-5. doi: 10.1002/ppul.22976. Epub 2013 Dec 17.

Reference Type: BACKGROUND

PMID: 24347240 (View on PubMed)

Other Identifiers

jzxfb-qlv

Identifier Type: -

Identifier Source: org_study_id