Hydroxychloroquin (HCQ) in chILD of Genetic Defect

Surfactant Dysfunction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03822780
• Other study ID #: jzxfb-qlv
• Status: Recruiting
• Phase: N/A
• Start date: July 1, 2017
• Est. completion date: July 30, 2026

Study information

• Verified date: May 2024
• Source: Children's Hospital of Fudan University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: July 30, 2026
• Est. primary completion date: December 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Lung Diseases, Interstitial
• Surfactant Dysfunction

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
China	Children's hospital of Fudan University	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital of Fudan University

Country where clinical trial is conducted

China, 

References & Publications (10)

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Oxygen flow rate	O2 supplement(L/min) at 1 months compared with trial day 1	1 month
Secondary	Oxygen flow rate	O2 supplement(L/min) at 3 months compared with trial day 1	3 month
Secondary	Oxygen flow rate	O2 supplement(L/min) at 12 months compared with trial day 1	12 month
Secondary	Oxygen flow rate	O2 supplement(L/min) at 18 months compared with trial day 1	18 month
Secondary	Oxygen flow rate	O2 supplement(L/min) at 24 months compared with trial day 1	24 month
Secondary	Fraction of inspired oxygen(FiO2)	Fraction of inspired oxygen(FiO2) at 1 months compared with trial day 1	1 month
Secondary	Fraction of inspired oxygen	FiO2 at 3 months compared with trial day 1	3 month
Secondary	Fraction of inspired oxygen	FiO2 at 6 months compared with trial day 1	6 month
Secondary	Fraction of inspired oxygen	FiO2 at 12 months compared with trial day 1	12 month
Secondary	Fraction of inspired oxygen	FiO2 at 18 months compared with trial day 1	18 month
Secondary	Fraction of inspired oxygen	FiO2 at 24 months compared with trial day 1	24 month
Secondary	Number of subjects with oxygen inhalation	Number of subjects at 6 months compared with trial day 1	6 months
Secondary	Number of subjects with oxygen inhalation	Number of subjects at 12 months compared with trial day 1	12 months
Secondary	Number of subjects with oxygen inhalation	Number of subjects at 24 months compared with trial day 1	24 months
Secondary	Transcutaneous oxygen saturation	O2-sat at 1 months compared with trial day 1	1 months
Secondary	Transcutaneous oxygen saturation	O2-sat at 3 months compared with trial day 1	3 months
Secondary	Transcutaneous oxygen saturation	O2-sat at 12 months compared with trial day 1	12 months
Secondary	Transcutaneous oxygen saturation	O2-sat at 18 months compared with trial day 1	18 months
Secondary	Transcutaneous oxygen saturation	O2-sat at 24 months compared with trial day 1	24 months
Secondary	Respiratory rate	Respiratory rate(RR) at 1 months compared with trial day 1	1 months
Secondary	Respiratory rate	RR at 3 months compared with trial day 1	3 months
Secondary	Respiratory rate	RR at 6 months compared with trial day 1	6 months
Secondary	Respiratory rate	RR at 12 months compared with trial day 1	12 months
Secondary	Chronic cough	(yes/no)	6 months
Secondary	Chronic cough	(yes/no)	12 months
Secondary	Chronic cough	(yes/no)	24 months
Secondary	Clubbing finger	(yes/no)	6 months
Secondary	Clubbing finger	(yes/no)	12 months
Secondary	Clubbing finger	(yes/no)	24 months
Secondary	Functional lesion of liver and kidney	(yes/no)	3 months
Secondary	Functional lesion of liver and kidney	(yes/no)	6 months
Secondary	Functional lesion of liver and kidney	(yes/no)	12 months
Secondary	Functional lesion of liver and kidney	(yes/no)	24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Abnormal myocardial zymogram	(yes/no)	3 months
Secondary	Abnormal myocardial zymogram	(yes/no)	6 months
Secondary	Abnormal myocardial zymogram	(yes/no)	12 months
Secondary	Duration of oxygen inhalation	The time last from HCQ treatment to withdrawal of oxygen (months)	36 months
Secondary	Mortality	Number of deaths at 3 months	3 months
Secondary	Mortality	Number of deaths at 12 months	12 months
Secondary	Mortality	Number of deaths at 24 months	24 months
Secondary	Number of Treatment related adverse events	Measured on each visit	36 months