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    Summary
    EudraCT Number:2013-003714-40
    Sponsor's Protocol Code Number:HCQinpediatricILD
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-07-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2013-003714-40
    A.3Full title of the trial
    Hydroxychloroquine in pediatric ILD START randomized controlled in parallel-group, then switch placebo to active drug, and STOP randomized controlled in parallel-group
    to evaluate the efficacy and safety of hydroxychloroquine (HCQ)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    HCQ in pediatric ILD
    A.4.1Sponsor's protocol code numberHCQinpediatricILD
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02615938
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKlinikum der Ludwig-Maximilian-Universität München
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEUROPEAN COMMISSION DIRECTORATE-GENERAL FOR RESEARCH & INNOVATION
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Ludwig-Maximilian-Universität München
    B.5.2Functional name of contact pointMatthias Griese
    B.5.3 Address:
    B.5.3.1Street AddressLindwurmstr. 4
    B.5.3.2Town/ cityMünchen
    B.5.3.3Post code80337
    B.5.3.4CountryGermany
    B.5.4Telephone number4989440057871
    B.5.5Fax number4989440057872
    B.5.6E-mailMatthias.griese@med.uni-muenchen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namehydrochloroquine
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNhydroxychloroquine
    D.3.9.1CAS number 118-42-3
    D.3.9.4EV Substance CodeSUB04018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namehydrochloroquine
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNhydroxychloroquine
    D.3.9.1CAS number 118-42-3
    D.3.9.4EV Substance CodeSUB04018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    interstitial lung disease
    E.1.1.1Medical condition in easily understood language
    interstititial lung disease
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10022611
    E.1.2Term Interstitial lung disease
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    START HCQ block
    To evaluate the efficacy of HCQ after 28 days of treatment in chILD compared to placebo.

    STOP HCQ block
    To evaluate the efficacy of HCQ after 84 days of treatment in chILD compared to Placebo
    E.2.2Secondary objectives of the trial
    START HCQ block
    - To evaluate the efficacy of HCQ after 56 days of treatment in chILD compared to 28 days.
    - To evaluate the safety of HCQ after 28 and 56 days of treatment in chILD.
    - To evaluate blood levels of HCQ after 28 and 56 days of treatment in chILD.

    STOP HCQ block
    - To evaluate the efficacy of chronic (> 3 months) HCQ treatment in chILD compared to placebo.
    - To evaluate the safety of HCQ after > 3 months of treatment in chILD.
    - To evaluate blood levels of HCQ before and after treatment in chILD
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)Patients should be clinically stable during baseline (between Visit 1 and 2) for inclusion into the study
    a) To determine this, attending physicians can use SpO2 in room air for patients on room air or on O2-supplement; the absolute difference on SpO2 is expected not to be ≥ 5% between Visit 1 and 2. For patients on respiratory support, the summary key parameters should not change ≥ 20% between Visit 1 and 2
    and
    b) No major changes in other medications between Visit 1 and 2
    2)Mature newborn ≥ 37 weeks of gestation, age ≥ 3 wks and < 2y
    or
    Infants and children (≥ 2 y and < 18 y)
    or
    Adults (≥18 and ≤30 y)
    or
    Previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages if chILD genetically diagnosed (see inclusion criterion 3.)
    3) Diagnosis of chronic (≥ 3 wks of duration) diffuse parenchymal lung disease (DPLD = chILD), defined in at least one of the following ways:
    a) chILD genetically diagnosed
    Surfactant dysfunction disorders including patients with mutations in SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), further extremely rare entities with specific mutations, for example in TBX4, NPC2, NPC1, NPB, COPA, LRBA and other genes. In this case, also previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages can be included into the study.
    b) chILD histologically diagnosed
    • Chronic pneumonitis of infancy (CPI)
    • Desquamative interstitial pneumonia (DIP)
    • Lipoid pneumonitis / Cholesterol pneumonia
    • Nonspecific interstitial pneumonia (NSIP)
    • PAP after the exclusion of mutations in GMCSF-Ra/b and GMCSF autoantibodies*
    • Usual interstitial pneumonia (UIP)
    • Follicular bronchitis/ bronchiolitis/ Lymphogenic interstitial pneumonia (LIP)
    • Storage disease with primary pulmonary involvement (e.g. Nieman Pick)
    • Hermansky Pudlak Syndrome
    • Idiopathic pulmonary haemorrhage (haemosiderosis)*
    • Other histology diagnosing chILD, in particular combination of the above pattern, but not exclusively
    4) Start block: no HCQ treatment in the last 12 weeks
    Stop block: stable HCQ treatment for at least the last 12 weeks
    5) Ability of subject or/and legal representatives to understand character and individual consequences of clinical trial.
    6) Signed and dated informed consent of the subject (if the subject has the ability) and the representatives (of underaged children) must be available before start of any specific trial procedures.
    E.4Principal 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 alveolarisation
    - hILD 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 capsules (lactose-monohydrate, povidone, maize starch, magnesium stearate, hypromellose, macrogol or titanium dioxide (E 171), silicon dioxide or mannitol), to sucrose-octaacetate or sodium saccharine.
    - Proven retinopathy or maculopathy
    - Glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia
    - Myasthenia gravis
    - Hematopoetic disorders
    - Pregnancy and lactation (Women with childbearing potential have to practice a medically accepted contraception during trial and till three months after the end of the treatment with HCQ, and a negative pregnancy test (serum or urine) should be existent on Visit 1, if girls of childbearing age and only if sexual relations are known or probable. It is at the discretion and responsibility of the attending physician to decide, whether a pregnancy test is necessary or not. Reliable contraception are systematic contraceptives (oral, implant, injection). Women that are sterile by surgery can participate in the trial. At the discretion of the investigator, sexual abstinence is also accepted as contraceptive method. Girls after menarche have to receive a counselling about birth control methods in presence of at least one parent, which has to be documented in the patient notes.
    - 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
    - Renal insufficiency at screening, defined as glomerular filtration rate (GFR)
    o < 40 mL/min/1.73 m2 in patients age 3 to 8 weeks
    o < 60 mL/min/1.73 m2 in patients ≥ 8 weeks of Age (KDIGO guideline 2012, K/DOQI guideline 2002)
    - Liver disease, gastrointestinal disorder, haematological disorder, epilepsy or other neurological disorder, psoriasis, porphyria at the discretion of the treating physician
    - Simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication at the discretion of the treating physician
    E.5 End points
    E.5.1Primary end point(s)
    START HCQ block
    Relative change trial day 1 (i.e. Visit 2) through day 28 (i.e. Visit 3) and relative change day 28 to day 56, (i.e. Visit 4): change active compound compared to change placebo

    STOP HCQ block
    Relative change trial day 1 (i.e. Visit 2) through day 84 (i.e. Visit 5): change active compound compared to change placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    28/56 / 84 days
    E.5.2Secondary end point(s)
    - For both, START and STOP HCQ blocks absolute and relative change under the active compound from trial day 1 (i.e. Visit 2), to START block: day 28 (i.e. Visit 3), STOP block: day 84 (i.e. Visit 5) each, will be compared to change under placebo. The following variables will be investigated:

    - Oxygen saturation (O2-sat, in room air) (only absolute, as relative already primary outcome)
    - Respiratory rate (RR, in room air) (relative and absolute)

    - Retractions (yes/no)
    - Coughing (yes/no)
    - Oxygen demand

    - pO2, pCO2 (capillary, in room air)
    - Chest x-ray
    - Quality-of-life
    - Health economics
    - Overall survival
    - Weight for height
    - Cumulative amounts of steroid equivalents. Clinical course of lung disease (since last visit): Healthy/ Sick-better/ Sick-same/ Sick-worse/ Patient died
    - Pulmonary exacerbation (since last visit)
    If > 5y old (If a child ≤ 5 years is already able to perform the listed investigations (spirometry or bodyplethysmography), these should also be performed and documented at the discretion of the investigator.)
    The following lung function parameters will be assessed:
    FEV1 % predicted (recorded in L), FEV 1 (L), FVC % predicted (recorded in L), FVC (L); MEF 75 (L/s); MEF 50 (L/s); MEF 25 (L/s); TLC (L); ITGV (L); RV (L); R eff (kPa*s/L); R eff predicted (%).
    reference values according to the GLI 2012 lung function regression equations

    - 6 minute walking distance (meter)
    - O2-saturation before and after 6MWT
    - Borg scale

    - If ventilated:
    Duration (h) of mechanical ventilation
    NO (%), ECMO yes/no, if yes VA/VV, double lumen vs. single lumen, Flow-rate.

    - Safety monitoring
    Adverse events, clinical laboratory values (GOT, Creatinine, gGT, blood count, differential, LDH, potassium, steady state drug level), ECG, ophthalmologic review
    E.5.2.1Timepoint(s) of evaluation of this end point
    56 / 84 days
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Italy
    Poland
    Portugal
    Spain
    Turkey
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months36
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 60
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 5
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects in this trial are mostly children, consent of both legally authorized representatives must be sought, Children who are able to understand nature, scope, and possible consequences of the clinical trial must also give their informed consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 10
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Treatment after the end of the trial is at the discretion of the investigator.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-20
    P. End of Trial
    P.End of Trial StatusOngoing
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