Clinical trial NCT02615938: Hydroxychloroquin (HCQ) in Pediatric Interstitial Lung Disease (ILD)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Interstitial Lung Disease
Diffuse Parenchymal Lung Disease
Children´s Interstitial Lung Disease
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
First posted: 2015-11-26
Enrollment: 80
Sex: ALL
Minimum age (years): 3
Maximum age (years): 99
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an exploratory Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD.

Detailed description: This study is an explorative, prospective, randomized, double-blind, placebo controlled investigation of hydroxychloroquine (HCQ) in pediatric ILD. The treatments are organized in START and STOP blocks, which can be initiated in sequence, as needed by the subjects. Each patient can participate in each block only once. In the START block subjects are randomized to parallel-groups, then the placebo group is switched to active drug. In the STOP block, subjects on HCQ are randomized into parallel-groups treated with placebo or HCQ to investigate the withdrawal of HCQ for assessment of its efficacy.

Eligibility criteria: Inclusion criteria:

1. Patients should be clinically stable during baseline (between Visit 1 and 2) for inclusion into the study

   1. 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
   2. 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 (≥2y and \< 18y) or Adults (≥18 and ≤30y) 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:

   1. 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.
   2. 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/Lymphocytic interstitial pneumonia (LIP)
      * Storage disease with primary pulmonary involvement (e.g. Niemann 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 subject has the ability) and the representatives (of underaged children) must be available before start of any specific trial procedures.

(\*may be diagnosed in the absence of a lung biopsy by characteristic lung lavage cytology (PAS stain, Fe stain), CT pattern or autoantibodies (gliadin, endomysium; cANCA) and clinical course.)

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
* 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 (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)

  * \< 40 mL/min/1.73 m2 in patients age 3 to 8 weeks
  * \< 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

Primary outcomes:
measure: Change of Oxygenation
timeFrame: Start HCQ block: 28 and 56 days; Stop HCQ block: 84 days
Secondary outcomes:
measure: Change of Oxygen Saturation
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Respiratory rate
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Retraction, Coughing
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Lab values
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Oxygen demand
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of QoL
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Health economics
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Overall survival
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Weight to Height ratio
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Cumulative amounts of Steroid equivalents
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of x-ray
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of pO2, pCO2
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Pulmonary exacerbation
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Forced vital capacity
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Number of abnormal changes in Electrocardiographie (ECG)
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of 6 minute walking distance (6MWT) (in meter)
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Change of Borg Scale
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Number of subjects with ophthalmologic abnormalities
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
measure: Number of Treatment related advers events
timeFrame: Start HCQ block: 28 days; Stop HCQ block: 84 days
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: Universitätsklinik für Kinder- und Jugendmedizin Tübingen
state: Baden-Württemberg
city: München
country: Germany
facility: Klinikum der Universität München, Haunersches Kinderspital
state: Bayern
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt, Pneumologie, Allergologie, Mukoviszidose
state: Hessen
city: Gießen
country: Germany
facility: Justus-Liebig-Universität, Allgemeine Pädiatrie u. Neonatologie
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Bochum
country: Germany
facility: St. Joseph- und St. Elisabeth Hospital gGmbH
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Uniklinikum Essen, Pädiatrische Pneumologie
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: Klinik u. Poliklinik für Kinder- u. Jugendmedizin der Universität Leipzig
state: Sachsen
city: Berlin
country: Germany
facility: Charité Berlin, Klinik für Pädiatrie
Study officials:
affiliation: Pediatric Pneumology, Ludwig-Maximilians-University Munich
name: Matthias Griese, Prof., MD
role: STUDY_DIRECTOR
affiliation: Pediatric Pneumology, Ludwig-Maximilians University Munich
name: Elias Seidl, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Griese M, Kappler M, Stehling F, Schulze J, Baden W, Koerner-Rettberg C, Carlens J, Prenzel F, Nahrlich L, Thalmeier A, Sebah D, Kronfeld K, Rock H, Ruckes C; HCQ-study group; Wetzke M, Seidl E, Schwerk N. Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease. Orphanet J Rare Dis. 2022 Jul 23;17(1):289. doi: 10.1186/s13023-022-02399-2.
citation: Griese M, Kohler M, Witt S, Sebah D, Kappler M, Wetzke M, Schwerk N, Emiralioglu N, Kiper N, Kronfeld K, Ruckes C, Rock H, Anthony G, Seidl E. Prospective evaluation of hydroxychloroquine in pediatric interstitial lung diseases: Study protocol for an investigator-initiated, randomized controlled, parallel-group clinical trial. Trials. 2020 Apr 3;21(1):307. doi: 10.1186/s13063-020-4188-4.