<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03822780</url>
  </required_header>
  <id_info>
    <org_study_id>jzxfb-qlv</org_study_id>
    <nct_id>NCT03822780</nct_id>
  </id_info>
  <brief_title>Hydroxychloroquin (HCQ) in chILD of Genetic Defect</brief_title>
  <official_title>Hydroxychloroquine in Pediatric ILD With Genetic Surfactant Dysfunction Disorders: Cross-control, Prospective Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital of Fudan University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Hospital of Fudan University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this proposed research is to investigate the efficacy and safety of&#xD;
      hydroxychloroquine sulfate (HCQ, Quensyl) for pediatric ILD(chILD) caused by pulmonary&#xD;
      surfactant-associated genes mutations.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Children Interstitial lung disease (chILD) is a heterogeneous group of rare respiratory&#xD;
      disorders of known and unknown etiologies that are mostly chronic and associated with high&#xD;
      morbidity and mortality. ILD are characterized by inflammatory and fibrotic changes of the&#xD;
      lung parenchyma structure that typically result in the presence of diffuse infiltrates on&#xD;
      lung imaging, and abnormal pulmonary function tests with evidence of a restrictive&#xD;
      ventilatory defect and/or impaired gas exchange.&#xD;
&#xD;
      Genetic factors are important contributors to chILD. Genetic variations have been mainly&#xD;
      described in genes encoding (or interacting with) the surfactant proteins (SP): SP-C (SFTPC)&#xD;
      and the ATP-binding cassette-family A-member 3 (ABCA3) (ABCA3), and less frequently in the&#xD;
      genes encoding NKX homeobox 2 (NKX2)-1 (NKX2-1), SP-B (SFTPB), SP-A (SFTPA) and other genes.&#xD;
&#xD;
      To date, the therapeutic managements of such chILD remain limited and are mainly based of the&#xD;
      use of corticosteroids, however, their efficacy is highly variable. An alternative approach&#xD;
      to treatment was originally described by Tooley who reported a good response to treatment&#xD;
      with chloroquine in a girl with ILD, and several case reports have shown a positive response&#xD;
      to hydroxychloroquine(HCQ) alone or in combination with systemic steroids of the children&#xD;
      with ILD.&#xD;
&#xD;
      The exact mechanism of action of HCQ is unknown, but is probably due to its anti-inflammatory&#xD;
      properties, HCQ have lysosomal activities such as diminished vesicle fusion, diminished&#xD;
      exocytosis, decreased digestive efficiency of phagolysosomes and reversible &quot;lysosomal&#xD;
      storage disease. This may be the mechanism by which HCQ tend to help in chILD, especially in&#xD;
      those cases related to surfactant protein deficiency. SP-B and SP-C are synthesized in the&#xD;
      endoplasmic reticulum (ER) of alveolar type II cells as large precursor proteins, are cleaved&#xD;
      by proteolytic enzymes and transported through Golgi apparatus to multivesicular bodies that&#xD;
      fuse with lamellar bodies. In chILD related to SP-C gene mutations, there is misfolding of&#xD;
      proSP-C that accumulates within ER and Golgi apparatus in alveolar type II cells, resulting&#xD;
      in cellular injury and apoptosis. Treatment with HCQ may interfere with this accumulation of&#xD;
      pro-surfactant proteins within alveolar cells.&#xD;
&#xD;
      The investigators propose to study the efficacy and safety of the therapy with HCQ for&#xD;
      children with chILD suffered with genetic mutations, and its long-term effects. Through this&#xD;
      study the investigators hope to confirm the benefits of HCQ in the treatment of this rare&#xD;
      disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 1, 2017</start_date>
  <completion_date type="Anticipated">July 30, 2026</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2025</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>cross-control</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Oxygenation change</measure>
    <time_frame>6 months</time_frame>
    <description>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)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Oxygen flow rate</measure>
    <time_frame>1 month</time_frame>
    <description>O2 supplement(L/min) at 1 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen flow rate</measure>
    <time_frame>3 month</time_frame>
    <description>O2 supplement(L/min) at 3 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen flow rate</measure>
    <time_frame>12 month</time_frame>
    <description>O2 supplement(L/min) at 12 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen flow rate</measure>
    <time_frame>18 month</time_frame>
    <description>O2 supplement(L/min) at 18 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen flow rate</measure>
    <time_frame>24 month</time_frame>
    <description>O2 supplement(L/min) at 24 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of inspired oxygen(FiO2)</measure>
    <time_frame>1 month</time_frame>
    <description>Fraction of inspired oxygen(FiO2) at 1 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of inspired oxygen</measure>
    <time_frame>3 month</time_frame>
    <description>FiO2 at 3 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of inspired oxygen</measure>
    <time_frame>6 month</time_frame>
    <description>FiO2 at 6 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of inspired oxygen</measure>
    <time_frame>12 month</time_frame>
    <description>FiO2 at 12 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of inspired oxygen</measure>
    <time_frame>18 month</time_frame>
    <description>FiO2 at 18 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of inspired oxygen</measure>
    <time_frame>24 month</time_frame>
    <description>FiO2 at 24 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with oxygen inhalation</measure>
    <time_frame>6 months</time_frame>
    <description>Number of subjects at 6 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with oxygen inhalation</measure>
    <time_frame>12 months</time_frame>
    <description>Number of subjects at 12 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with oxygen inhalation</measure>
    <time_frame>24 months</time_frame>
    <description>Number of subjects at 24 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcutaneous oxygen saturation</measure>
    <time_frame>1 months</time_frame>
    <description>O2-sat at 1 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcutaneous oxygen saturation</measure>
    <time_frame>3 months</time_frame>
    <description>O2-sat at 3 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcutaneous oxygen saturation</measure>
    <time_frame>12 months</time_frame>
    <description>O2-sat at 12 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcutaneous oxygen saturation</measure>
    <time_frame>18 months</time_frame>
    <description>O2-sat at 18 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Transcutaneous oxygen saturation</measure>
    <time_frame>24 months</time_frame>
    <description>O2-sat at 24 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory rate</measure>
    <time_frame>1 months</time_frame>
    <description>Respiratory rate(RR) at 1 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory rate</measure>
    <time_frame>3 months</time_frame>
    <description>RR at 3 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory rate</measure>
    <time_frame>6 months</time_frame>
    <description>RR at 6 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory rate</measure>
    <time_frame>12 months</time_frame>
    <description>RR at 12 months compared with trial day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chronic cough</measure>
    <time_frame>6 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chronic cough</measure>
    <time_frame>12 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chronic cough</measure>
    <time_frame>24 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clubbing finger</measure>
    <time_frame>6 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clubbing finger</measure>
    <time_frame>12 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clubbing finger</measure>
    <time_frame>24 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional lesion of liver and kidney</measure>
    <time_frame>3 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional lesion of liver and kidney</measure>
    <time_frame>6 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional lesion of liver and kidney</measure>
    <time_frame>12 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional lesion of liver and kidney</measure>
    <time_frame>24 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malnutrition</measure>
    <time_frame>3 months</time_frame>
    <description>(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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malnutrition</measure>
    <time_frame>6 months</time_frame>
    <description>(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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malnutrition</measure>
    <time_frame>12 months</time_frame>
    <description>(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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malnutrition</measure>
    <time_frame>24 months</time_frame>
    <description>(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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deterioration of pulmonary imaging</measure>
    <time_frame>6 months</time_frame>
    <description>(yes/no) Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deterioration of pulmonary imaging</measure>
    <time_frame>12 months</time_frame>
    <description>Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deterioration of pulmonary imaging</measure>
    <time_frame>24 months</time_frame>
    <description>Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lung function decline</measure>
    <time_frame>3 years</time_frame>
    <description>(yes/no) Clinical judgment of Lung-function compared with that of last visit if lung-function testing were done at 3 years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lung function decline</measure>
    <time_frame>6 years</time_frame>
    <description>(yes/no) Clinical judgment of Lung-function compared with that of last visit if lung-function testing were done at 6 years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abnormal myocardial zymogram</measure>
    <time_frame>3 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abnormal myocardial zymogram</measure>
    <time_frame>6 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Abnormal myocardial zymogram</measure>
    <time_frame>12 months</time_frame>
    <description>(yes/no)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of oxygen inhalation</measure>
    <time_frame>36 months</time_frame>
    <description>The time last from HCQ treatment to withdrawal of oxygen (months)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>3 months</time_frame>
    <description>Number of deaths at 3 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>12 months</time_frame>
    <description>Number of deaths at 12 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>24 months</time_frame>
    <description>Number of deaths at 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Treatment related adverse events</measure>
    <time_frame>36 months</time_frame>
    <description>Measured on each visit</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Surfactant Dysfunction</condition>
  <arm_group>
    <arm_group_label>HCQ Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxychloroquin</intervention_name>
    <description>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.</description>
    <arm_group_label>HCQ Therapy</arm_group_label>
    <other_name>Hydroxychloroquine Sulfate; Plaquenil</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients should be clinically stable for inclusion into the study&#xD;
&#xD;
          -  Mature newborn ≥ 37 weeks of gestation, Infants and children (≥2month and &lt; 18y) or&#xD;
             previously preterm (≤ 37 weeks of gestation) babies or children(≥2month and &lt;18y) if&#xD;
             chILD genetically diagnosed&#xD;
&#xD;
          -  chILD genetically diagnosed surfactant dysfunction disorders including patients with&#xD;
             mutations in SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), FOXF1 further extremely rare entities&#xD;
             with specific mutations, for example in TBX4, NPC2, NPC1, NPB, COPA, LRBA and other&#xD;
             genes&#xD;
&#xD;
          -  no HCQ treatment in the last 3 months&#xD;
&#xD;
          -  Ability of subject or/and legal representatives to understand character and individual&#xD;
             consequences of clinical trial&#xD;
&#xD;
          -  Signed and dated informed consent of the subject (if subject has the ability) and the&#xD;
             representatives (of underaged children) must be available before start of any specific&#xD;
             trial procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects presenting with any of the following criteria will not be included in the trial:&#xD;
&#xD;
          -  chILD primarily related to developmental disorders&#xD;
&#xD;
          -  chILD primarily related to growth abnormalities reflecting deficient alveolarization&#xD;
&#xD;
          -  chILD related to chronic aspiration&#xD;
&#xD;
          -  chILD related to immunodeficiency&#xD;
&#xD;
          -  chILD related to abnormalities in lung vessel structure&#xD;
&#xD;
          -  chILD related to organ transplantation/organ rejection/GvHD&#xD;
&#xD;
          -  chILD related to recurrent infections&#xD;
&#xD;
          -  Acute severe infectious exacerbations&#xD;
&#xD;
          -  Known hypersensitivity to HCQ, or other ingredients of the tablets&#xD;
&#xD;
          -  Proven retinopathy or maculopathy&#xD;
&#xD;
          -  Glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia&#xD;
&#xD;
          -  Myasthenia gravis&#xD;
&#xD;
          -  Hematopoetic disorders&#xD;
&#xD;
          -  Participation in other clinical trials during the present clinical trial or not beyond&#xD;
             the time of 4 half-lives of the medication used, at least one week&#xD;
&#xD;
          -  Hereditary galactose intolerance, lactase deficiency or glucose-galactose-&#xD;
             malabsorption&#xD;
&#xD;
          -  Simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication&#xD;
             at the discretion of the treating physician&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Children's hospital of Fudan University</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>201102</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ling Li Qian, Doctor</last_name>
      <phone>021-64931913</phone>
      <email>llqian@126.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>20727133</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>29517585</PMID>
  </reference>
  <reference>
    <citation>Barnett HL. editor. Pediatrics. 15th edition. New York: Appleton Century-Crofts; 1972. pp 1315-1316.</citation>
  </reference>
  <reference>
    <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.</citation>
    <PMID>15647591</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>25657025</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>25755194</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>24347114</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>20403820</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>23719253</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>24347240</PMID>
  </reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>January 15, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>April 3, 2023</last_update_submitted>
  <last_update_submitted_qc>April 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Interstitial lung disease</keyword>
  <keyword>Hydroxychloroquine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Interstitial</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxychloroquine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03822780
org study id: jzxfb-qlv
nct id: NCT03822780
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: cross-control
primary purpose: Treatment
masking: None (Open Label)
measure: Oxygenation change
time frame: 6 months
description: 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)
measure: Oxygen flow rate
time frame: 1 month
description: O2 supplement(L/min) at 1 months compared with trial day 1
measure: Oxygen flow rate
time frame: 3 month
description: O2 supplement(L/min) at 3 months compared with trial day 1
measure: Oxygen flow rate
time frame: 12 month
description: O2 supplement(L/min) at 12 months compared with trial day 1
measure: Oxygen flow rate
time frame: 18 month
description: O2 supplement(L/min) at 18 months compared with trial day 1
measure: Oxygen flow rate
time frame: 24 month
description: O2 supplement(L/min) at 24 months compared with trial day 1
measure: Fraction of inspired oxygen(FiO2)
time frame: 1 month
description: Fraction of inspired oxygen(FiO2) at 1 months compared with trial day 1
measure: Fraction of inspired oxygen
time frame: 3 month
description: FiO2 at 3 months compared with trial day 1
measure: Fraction of inspired oxygen
time frame: 6 month
description: FiO2 at 6 months compared with trial day 1
measure: Fraction of inspired oxygen
time frame: 12 month
description: FiO2 at 12 months compared with trial day 1
measure: Fraction of inspired oxygen
time frame: 18 month
description: FiO2 at 18 months compared with trial day 1
measure: Fraction of inspired oxygen
time frame: 24 month
description: FiO2 at 24 months compared with trial day 1
measure: Number of subjects with oxygen inhalation
time frame: 6 months
description: Number of subjects at 6 months compared with trial day 1
measure: Number of subjects with oxygen inhalation
time frame: 12 months
description: Number of subjects at 12 months compared with trial day 1
measure: Number of subjects with oxygen inhalation
time frame: 24 months
description: Number of subjects at 24 months compared with trial day 1
measure: Transcutaneous oxygen saturation
time frame: 1 months
description: O2-sat at 1 months compared with trial day 1
measure: Transcutaneous oxygen saturation
time frame: 3 months
description: O2-sat at 3 months compared with trial day 1
measure: Transcutaneous oxygen saturation
time frame: 12 months
description: O2-sat at 12 months compared with trial day 1
measure: Transcutaneous oxygen saturation
time frame: 18 months
description: O2-sat at 18 months compared with trial day 1
measure: Transcutaneous oxygen saturation
time frame: 24 months
description: O2-sat at 24 months compared with trial day 1
measure: Respiratory rate
time frame: 1 months
description: Respiratory rate(RR) at 1 months compared with trial day 1
measure: Respiratory rate
time frame: 3 months
description: RR at 3 months compared with trial day 1
measure: Respiratory rate
time frame: 6 months
description: RR at 6 months compared with trial day 1
measure: Respiratory rate
time frame: 12 months
description: RR at 12 months compared with trial day 1
measure: Chronic cough
time frame: 6 months
description: (yes/no)
measure: Chronic cough
time frame: 12 months
description: (yes/no)
measure: Chronic cough
time frame: 24 months
description: (yes/no)
measure: Clubbing finger
time frame: 6 months
description: (yes/no)
measure: Clubbing finger
time frame: 12 months
description: (yes/no)
measure: Clubbing finger
time frame: 24 months
description: (yes/no)
measure: Functional lesion of liver and kidney
time frame: 3 months
description: (yes/no)
measure: Functional lesion of liver and kidney
time frame: 6 months
description: (yes/no)
measure: Functional lesion of liver and kidney
time frame: 12 months
description: (yes/no)
measure: Functional lesion of liver and kidney
time frame: 24 months
description: (yes/no)
measure: Malnutrition
time frame: 3 months
description: (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
measure: Malnutrition
time frame: 6 months
description: (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
measure: Malnutrition
time frame: 12 months
description: (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
measure: Malnutrition
time frame: 24 months
description: (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
measure: Deterioration of pulmonary imaging
time frame: 6 months
description: (yes/no) Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 6 months
measure: Deterioration of pulmonary imaging
time frame: 12 months
description: Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 12 months
measure: Deterioration of pulmonary imaging
time frame: 24 months
description: Clinical judgment of pulmonary imaging compared with that of last visit if X-ray or CT were done at 24 months
measure: Lung function decline
time frame: 3 years
description: (yes/no) Clinical judgment of Lung-function compared with that of last visit if lung-function testing were done at 3 years
measure: Lung function decline
time frame: 6 years
description: (yes/no) Clinical judgment of Lung-function compared with that of last visit if lung-function testing were done at 6 years
measure: Abnormal myocardial zymogram
time frame: 3 months
description: (yes/no)
measure: Abnormal myocardial zymogram
time frame: 6 months
description: (yes/no)
measure: Abnormal myocardial zymogram
time frame: 12 months
description: (yes/no)
measure: Duration of oxygen inhalation
time frame: 36 months
description: The time last from HCQ treatment to withdrawal of oxygen (months)
measure: Mortality
time frame: 3 months
description: Number of deaths at 3 months
measure: Mortality
time frame: 12 months
description: Number of deaths at 12 months
measure: Mortality
time frame: 24 months
description: Number of deaths at 24 months
measure: Number of Treatment related adverse events
time frame: 36 months
description: Measured on each visit
arm group label: HCQ Therapy
arm group type: Experimental
description: 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)
intervention type: Drug
intervention name: Hydroxychloroquin
description: 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.
arm group label: HCQ Therapy
other name: Hydroxychloroquine Sulfate; Plaquenil
criteria: 
gender: All
minimum age: 1 Month
maximum age: 18 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
country: China
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PMID: 20727133
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.
PMID: 29517585
citation: Barnett HL. editor. Pediatrics. 15th edition. New York: Appleton Century-Crofts; 1972. pp 1315-1316.
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.
PMID: 15647591
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PMID: 25657025
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PMID: 25755194
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.
PMID: 24347114
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PMID: 20403820
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.
PMID: 23719253
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PMID: 24347240
responsible party type: Sponsor
mesh term: Lung Diseases, Interstitial
mesh term: Hydroxychloroquine