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)
Phase: PHASE2
Conditions: Interstitial Lung Disease, Diffuse Parenchymal Lung Disease, Children´s Interstitial Lung Disease
Sponsor: Matthias Griese

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
1 of 52 
 
CLINICAL TRIAL PROTOCOL 
 
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) 
Short Title: HCQ in pediatric ILD particularly 4surfdefect 
EudraCT: 2013-003714-40 
IZKS trial code: 2013-006 
final 
 
 
 
Version 
 
3.1 
Date 
 
 
27.07.2017 
Sponsor 
Coordinating/Principal investigator 
Institution      Klinikum der Universität München 
 
 
Address        Marchioninistraße 15, 81377 München 
 
Department/   Ludwig Maximilians University of Munich 
Institution       Paediatric Pneumology 
 
 
Name 
Prof. Dr. med. M. Griese 
Address Lindwurmstr. 4, 80337  Munich 
Phone +49 / 89 / 4400-57871 
Fax 
+49 / 89 / 4400-57872 
e-Mail 
Matthias.griese@med.uni-muenchen.de 
Study coordination 
Biometrician 
Department/ 
University Medical Center of the 
 
 
 
Johannes Gutenberg-University Mainz 
Institution 
Interdisciplinary Center for Clinical  
 
 
 
Trials (IZKS) 
Name 
 
Kai Kronfeld 
Address  
Langenbeckstr. 2, 55131 Mainz 
Phone  
+49/6131/17-9936 
Fax 
 
+49/6131/17-9925 
e-Mail 
 
kronfeld@izks-mainz.de 
Department/ 
University Medical Center of the 
 
 
 
Johannes Gutenberg-University Mainz 
Institution 
Interdisciplinary Center for Clinical  
 
 
 
Trials (IZKS) 
Name 
 
Christian Ruckes 
Address  
Langenbeckstr. 2, 55131 Mainz 
Phone  
+49/6131/17-9919 
Fax 
 
+49/6131/17-9914 
e-Mail 
 
ruckes@izks-mainz.de 
 
 
Details of further contact persons will be provided in the investigator site file at each study center. 
 
This protocol is confidential information and is intended solely for the guidance of the clinical trial. 
This protocol may not be disclosed to third parties not associated with the clinical trial or used for 
any other purpose without the prior written consent of the sponsor. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
2 of 52 
 
List of abbreviations 
6MWT  
6-minute-walk test 
ABCA3  
Human ATP-binding cassette transporter, sub-family A, member 3 
AE 
 
Adverse event 
AMG 
 
German drug law (Arzneimittelgesetz) 
AR 
 
Adverse reaction 
BAL 
 
Bronchoalveolar lavage 
BB 
 
Blood count 
BP 
 
Blood pressure 
BSPAR  
The British Society for Paediatric and Adolescent Rheumatology 
BW 
 
Body weight 
chILD  
Children’s interstitial lung disease 
CK 
 
Creatine kinase 
CO2 
 
Carbon dioxide 
CPI 
 
Chronic pneumonitis of infancy 
CQ 
 
Chloroquine 
Crea 
 
Creatinine 
CRF 
 
Case report form 
D 
 
Day 
DCF 
 
Data clarification form 
Diff 
 
Differential blood count 
DIP 
 
Desquamative interstitial pneumonitis 
DLCO  
Diffusing capacity of the lung for carbon monoxide 
DMC 
 
Data monitoring committee 
DMP 
 
Data management plan 
DPLD  
Diffuse parenchymal lung disease 
DZL 
 
German Center of lung research 
EC/IEC  
Ethics committee/Independent ethics committee 
ECG 
 
Electrocardiogram 
Echo 
 
Echocardiography 
ECLA  
Extracorporeal lung assist 
ECLS  
Extracorporeal Life Support System 
ECMO  
Extracorporeal membrane oxygenation 
e-CRF  
Electronic case report form 
EDC 
 
Electronic data capture 
EDTA  
Ethylene diamine tetraacetic acid  
EMEA  
European Medicines Agency 
FAF 
 
Fundus autofluorescence 
FDA 
 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second  
FiO2 
 
Fraction of inspired oxygen 
FVC 
 
Forced vital capacity 
GCP 
 
Good clinical practice 
GCP-V  
GCP regulation 
GFR 
 
Glomerular filtration rate 
gGT 
 
Gamma-glutamic transferase 
GIP 
 
Giant cell interstitial pneumonia 
GLI 
 
Global Lung function Initiative 
GMCSF 
Granulocyte macrophage colony-stimulating factor 
GMCSF-Ra/b Granulocyte macrophage colony-stimulating factor receptor subunit α and β 
GOT 
 
Glutamate oxaloacetate transaminase 
GPT 
 
Glutamate pyruvate transaminase 
GvHD  
Graft-versus-Host-Disease 
HCQ 
 
Hydroxychloroquine 
HP 
 
Hypersensitivity pneumonitis 
ICH 
 
International conference on harmonization of technical requirements for registration of 
 
 
pharmaceuticals for human use 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
3 of 52 
 
IgG 
 
Immunoglobulin G 
IMP 
 
Investigational medicinal product 
ILD 
 
Interstitial lung disease 
IRB 
 
Institutional review board 
ISRCTN 
International standard randomised controlled trial number 
INN 
 
International non-proprietary name 
ISF 
 
Investigator site file 
ITT 
 
Intention to treat 
IZKS 
 
Interdisciplinary centre for clinical trials  
Lab 
 
Laboratory 
LDH 
 
Lactatdehydrogenase 
LIP 
 
Lymphocytic interstitial pneumonia 
LKP 
 
Clinical Trial Director according (Leiter der Klinischen Prüfung) 
MedDRA 
Medical dictionary for regulatory activities terminology 
MDAT  
Medical database 
MPAW  
Mean airway pressure 
NEHI 
 
Neuroendocrine Hyperplasia of Infancy 
Nkx2-1  
NK2 homeobox 1 gene 
NO 
 
Nitrogen monoxide 
NSIP 
 
Nonspecific interstitial pneumonitis 
PaO2  
Partial pressure of oxygen in arterial blood 
PcapO2   
Partial pressure of oxygen in capillary blood 
PAP 
 
Pulmonary alveolar proteinosis  
pCO2  
Carbon dioxide partial pressure 
pO2 
 
Oxygen partial pressure 
O2 
 
Oxygen 
O2-sat  
Oxygen saturation 
OCT 
 
Ocular coherence tomography 
O.I. 
 
Oxygenation index 
PEEP  
Positive endexspiratory pressure 
PIP 
 
Positive inspiratory pressure 
p.o. 
 
Orally 
PP 
 
Per protocol 
QOL 
 
Quality of life 
QC 
 
Quality control 
QT 
 
QT-intervall in the ECG 
RDS 
 
Respiratory distress syndrome  
RR 
 
Respiratory rate 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SAR 
 
Serious adverse reaction 
SAS 
 
Statistical analysis system 
SDV 
 
Source data verification 
SFTPB  
Surfactant protein B 
SFTPC  
Surfactant protein C 
SmPC  
Summary of product characteristics 
SOP 
 
Standard operating procedure 
SPSS  
Statistics program 
SSL 
 
Secure Sockets Layer 
SUSAR 
Suspected unexpected serious adverse reaction 
Temp  
Body temperature 
Ti 
 
Inspiration Time 
TMF 
 
Trial master file 
TTF1 
 
Thyroid Transcription Factor-1 
UIP 
 
Usual interstitial pneumonitis 
VA 
 
veno-arterial 
VV 
 
veno-venous 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
4 of 52 
 
Overview Study plan HCQ 
 
This randomized controlled study is embedded into the European Management Platform for 
Children´s Interstitial Lung Diseases (chILD). Patients included into this register and biobank 
are eligible for inclusion into the trials (see 3.5.1).  
 
The study contains two different study blocks:  
 
 
 
 
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
5 of 52 
 
Typical examples for the indication of these blocks: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient already had been treated with HCQ longer than 3 months ago, it makes sense to include 
him/her into the START-HCQ block for several reasons among others, especially for : 
- 
It is not obvious, if there was an effect of the HCQ treatment or not 
- 
It is unclear which dose of HCQ was given or if the patient was compliant 
- 
There are new aspects of the course of the patient’s disease 
- 
The child has become substantially (e.g. > 1 year) older 
 
 
These blocks can be initiated in sequence as needed by the subjects. Each patient can 
participate in each block only once:  
 
 
 
                                  
 
                                  
               
               
       
 
or 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
6 of 52 
 
Synopsis 
 
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) 
Short title 
HCQ in pediatric ILD 
EudraCT 
2013-003714-40 
IZKS trial code 
2013-006 
Indication 
Diagnosed children´s interstitial lung disease (chILD) in children and adults 
Phase 
2a 
Treatments 
Test product: Hydroxychloroquine Sulfate (HCQ), one daily dose in the evening. 
 
Reference therapy: Placebo 
 
The treatments are organized in START and STOP blocks, which can be initiated in 
sequence, as needed by the subjects.  
 
 
START HCQ block 
Block specific 
inclusion criterion 
(others see 3.6.1) 
All subjects not currently on HCQ (last dose ≥ 3 months ago) and intention to widen 
treatment.  
Primary objective 
To evaluate the efficacy of HCQ after 28 days of treatment in chILD compared to placebo 
Secondary 
objectives 
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 
Trial design 
  
 
 
This is an exploratory Phase 2a, randomized, double-blind, placebo-controlled, parallel-
group study and switched placebo to active drug, multicentre, multinational study in 
subjects with chILD genetically, histologically or clinically diagnosed. 
 
This study includes: 
• Screening Period (Day -28 through Day -3) 
• Treatment Period (Day 1 through Day 56) 
 
 
 
 
 
 
 
 
 
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
7 of 52 
 
 
STOP HCQ block 
Block specific 
inclusion criterion 
(others see 3.6.1) 
All subjects on chronic (> 3 months) treatment with HCQ (usually 6-10 mg/kg/d or 
individually tolerated dose) and intention to reduce treatment. 
Primary objective 
To evaluate the efficacy of HCQ after 84 days of treatment in chILD compared to placebo 
Secondary 
objectives 
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 
Trial design 
 
 
 
This is an exploratory Phase 2a, randomized, double-blind, placebo-controlled, parallel-
group, multinational withdrawal study in subjects with chILD and treated with 
hydroxychloroquine. 
 
This study includes: 
• History of Open Treatment Period (total of at least 3 months of continuing HCQ   
   treatment until randomization) 
• Screening Period (Day -30 through Day -10) 
• Treatment Period (Day 1 through Day 84) 
• Open observation period (Day 85 through Day 168) 
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
 
8 of 52 
 
Trial population 
In addition to the block specific inclusion criterion the inclusion criteria are:  
See 3.6.1 in the protocol 
Allowed previous medication: see 4.1.10  
 
exclusion criteria: See 3.6.2 
Trial duration  
Until 2024/2025 
Number of 
subjects 
It is planned to enrol at least 80 subjects 
Number of sites 
Up to 100 trial sites are planned to participate 
Primary outcome 
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) active compared to change placebo 
 
STOP HCQ block 
Relative change day 1 (i.e. Visit 2) through day 84 (i.e. Visit 5): change active compound 
compared to change placebo 
 
Oxygenation (see Table 3.3-1) 
 
Secondary 
outcome 
See 3.4 
Statistical analysis 
 
START HCQ block and STOP HCQ block 
 
The variable assessing the primary outcome is the response rate measured by the 
oxygen saturation in room air. 
 
Both blocks separately 
 
a) A difference between the changes in placebo and active phases is considered 
significant, if the oxygen saturation increases by > 5%. 
 
b) Patients are defined as responder if the oxygen saturation is increased by 5% 
compared to baseline. The numbers of responders are counted and compared by Fisher 
exact test. 
 
Both blocks together 
 
c) oxygen saturation and the correspondent responder will be analysed by a linear mixed 
model (or logistic regression respectively). If indicated, a Bayesian approach will be 
employed. 
 
If appropriate, the analyses will be adjusted for the stratification factor of the 
randomization: age group. 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
9 of 52 
 
Trial schedule 
START HCQ block  
Table 1-1 
Visit 
Screening 
evaluations and 
Visit 1 
Visit 2 
Email-/Phone-
Visit 
Visit 3 
Email-/Phone-
Visit 
Visit 4 
Action 
„Start of 
baseline“ 
“End of 
baseline” + 
Day 1 of 
treatment 
Every 7 days at 
home 
End of 1st Tx 
period 
 
Every 7 days at 
home 
“End of trial” 
Trial day 
-28 to -3 
1 
7, 14, 21 (+/- 3) 
28 (-4, +7) 
35, 42, 49 (+/- 3) 
56 (-4, +7) 
Demographics (e.g. sex, age) 
X 
 
 
 
 
 
Patient information, informed consent 
X 
 
 
 
 
 
Previous (last 12 months) and concomitant 
diseases 
X 
X 
X 
X 
X 
X 
Previous (last 3 months) and concomitant 
treatments 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X*5 
 
 
 
 
Pregnancy test K 
X* 
 
 
X 
 
X 
Randomization a 
X 
 
 
 
 
 
Trial medication supply to patient 
 
X 
 
X 
 
 
History (cardiotoxicity, hypoglycaemia) 
X 
X 
 
X 
 
X 
Physical examination 
X 
X 
 
X 
 
X 
Vital signs (BP, pulse, temp) b 
X 
X 
 
X 
 
X 
ECGj 
X* 
 
 
X 
 
X 
Ophthalmologic review j 
X* 
 
 
 
 
X 
Lab c 
(GOT/GPT/Crea/Potassium/CK/gGT/LDH/BB/
DIFF / HCQ drug level, blood glucose) 
X* 
 
 
X 
 
X 
pO2, pCO2 (capillary) 
X 
X*3 
 
X*3 
 
X*3 
O2-sat e, in room air 
X 
X 
X  
X 
X  
X 
Respiratory rate, in room air 
X 
X 
X 
X 
X 
X 
Retractions 
X 
X 
X 
X 
X 
X 
Coughing  
X 
X 
X 
X 
X 
X 
Oxygen demand 
X 
X 
X 
X 
X 
X 
Chest x-ray  
X*2 
 
 
X*4 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
10 of 52 
 
Visit 
Screening 
evaluations and 
Visit 1 
Visit 2 
Email-/Phone-
Visit 
Visit 3 
Email-/Phone-
Visit 
Visit 4 
Pulmonary hypertension (Echo) j 
X* 
 
 
 
 
 
Quality-of-life i  
X* 
 
 
X 
 
X 
Health Economics h 
X* 
 
 
X 
 
X 
Weight for height b 
X* 
X 
 
X 
 
X 
Clinical course of lung disease 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
Exacerbation o 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
Adverse events 
X 
X 
X 
X 
X 
X 
Drug accountability 
 
 
 
X 
 
X 
Additionally in children > 5 years 
 
 
 
 
 
 
Spirometry / Bodyplethysmography d 
X 
X 
 
X 
 
X 
6 minute walking distance (meter) g 
X 
X 
 
X 
 
X 
O2-saturation before and after 6MWT 
X 
X 
 
X 
 
X 
Borg scale f 
X 
X 
 
X 
 
X 
Additionally in ventilated patients m 
 
 
 
 
 
 
Oxygenation index (OI) n 
X 
X 
X 
X 
X 
X 
Duration (h) of mechanical ventilation 
X 
X 
X 
X 
X 
X 
NO (%), ECLS (VV/VA/ECLA/Flow/time since 
insertion) 
X 
X 
X 
X 
X 
X 
 
X*  
Tests must be done before first drug dosing 
X*2  
Test can be done according to the opinion of the treating physician 
X*3 
Puncture site should be warm and well perfusedP. 
X*4 
Chest x-ray is recommended if clinically indicated e.g. to answer the question if the disease is stable 
X*5 
Re-check inclusion criteria 1 
X*6 
(since last visit): Healthy / Sick-better / Sick-same / Sick-worse / Patient died 
X*7 Pulmonary exacerbation is defined as sustained worsening of the patient’s condition from stable state and beyond normal day to day variations. The exacerbation is rated as 
indicated below o.  
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
11 of 52 
 
STOP HCQ block  
Table 1-2 
Visit 
Visit 1 
+ 
Screening 
Visit 2 
Email-
/Phone-
Visit 
Visit 3 
Email-/ 
Phone-
Visit 
Visit 4 
Email-/ 
Phone-
Visit 
Visit 5 
Email-/ 
Phone-
Visit 
Visit 6 
Email-
/Phone-
Visit 
Visit 7 
Email-
/Phone-
Visit 
Visit 8 
Action 
„Begin of 
baseline“ 
“End of 
baseline” 
+ Day 1 
of 
withdrawa
l 
treatment 
2 weeks 
of 
withdrawa
l, at home 
4 weeks 
of 
withdrawa
l 
treatment  
6 weeks 
of 
withdrawa
l, at home 
8 weeks 
of 
withdrawa
l 
treatment 
10 weeks 
of 
withdrawa
l, at home 
“End of 
trial” after 
12 weeks 
of 
withdrawa
l 
treatment 
2 
weeks 
of open 
observ
ation at 
home 
Follow up 
after 4 
weeks of 
open 
observati
on 
6 weeks 
of 
withdrawa
l, at home 
Follow up 
after 8 
weeks of 
open 
observati
on 
10 weeks 
of 
withdrawa
l, at home 
Follow up 
after 12 
weeks of 
open 
observati
on  
Trial day 
-30 to -10 
1 
14 (-7, 
+7) 
28 (-7, 
+7) 
42 (-7, 
+7) 
56 (-7, 
+7) 
70 (-7, 
+7) 
84 (-7, 
+7) 
98 (-7, 
+7) 
112 (-7, 
+7) 
126 (-
7,+7) 
140 (-7, 
+7) 
154 (-7, 
+7) 
168 (-7, 
+7) 
Demographics (e.g. sex, 
age) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient information, 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous (last 12 months) 
and concomitant 
diseases 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous (last 3 months) 
and concomitant 
treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion 
criteria 
X 
X*5 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test K 
X* 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Randomization a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial medication supply to 
patient 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
History (cardiotoxicity, 
hypoglycaemia) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical examination 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs (BP, pulse, 
temp) b 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ECGj 
X* 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Ophthalmologic reviewj 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
X *8 
Lab c 
(GOT/GPT/Crea/Potassi
um/CK/gGT/LDH/BB/DIF
F / HCQ drug level, blood 
glucose) 
X* 
 
 
X 
 
X 
 
X 
 
X 
(only 
HCQ drug 
level) 
 
X 
(only 
HCQ drug 
level) 
 
X  
(only 
HCQ drug 
level) 
pO2, pCO2 (capillary) 
X 
X*3 
 
X*3 
 
X*3 
 
X*3 
 
X*3 
 
X*3 
 
X*3 
O2-sat e, in room air 
 
X 
 
 
X 
 
 
X  
 
X 
 
 
X  
 
X 
 
 
X  
 
X 
 
 
X 
X 
 
X  
X 
 
X  
 
X 
 
Respiratory rate, in room 
air 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
12 of 52 
 
Visit 
Visit 1 
+ 
Screening 
Visit 2 
Email-
/Phone-
Visit 
Visit 3 
Email-/ 
Phone-
Visit 
Visit 4 
Email-/ 
Phone-
Visit 
Visit 5 
Email-/ 
Phone-
Visit 
Visit 6 
Email-
/Phone-
Visit 
Visit 7 
Email-
/Phone-
Visit 
Visit 8 
Retractions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coughing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen demand L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-ray 
X*2 
 
 
 
 
 
 
X*4 
 
 
 
 
 
 
Pulmonary hypertension 
(Echo) j 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality-of-life i 
X* 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Health Economics h 
X* 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Weight for height b 
X* 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Clinical course of lung 
disease 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
X*6 
Exacerbation o 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
X*7 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug accountability 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Additionally in children > 
5 years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry / 
Bodyplethysmography d 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
6 minute walking 
distance (meter)g 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
O2-saturation before and 
after 6MWT g 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Borg scale f 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Additionally in ventilated 
patients m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oxygenation index (OI) n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Duration (h) of 
mechanical ventilation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NO (%), ECLS 
(VV/VA/ECLA/Flow/time 
since insertion) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
13 of 52 
 
X*  
Tests must be done before first drug dosing 
X*2  
Test can be done according to the opinion of the treating physician 
X*3 
Puncture site should be warm and well perfusedP 
X*4 
Chest x-ray is recommended if clinically indicated e.g. to answer the question if the disease is stable 
X*5 
Re-check inclusion criteria 1 
X*6 
(since last visit): Healthy / Sick-better / Sick-same / Sick-worse / Patient died 
X*7 Pulmonary exacerbation is defined as sustained worsening of the patient’s condition from stable state and beyond normal day to day variations. The 
exacerbation is rated as indicated below o 
 
X*8 This ophthalmologic investigation may be used for patients entering the START block, if START HCQ block is done within 6 months and no HCQ was taken 
since end of STOP block and the ophthalmological investigation was normal. 
 
a Randomization must occur for logistic reasons as soon as possible after concluding all screening investigations and including the patient into the study. This 
secures delivery of the study medication in time to any study center. 
 
b Weight (kg) and height (cm) will be measured with shoes and clothes off. Vital signs will be collected after the patient has been at rest for 5 minutes.  
 
c Blood sample should include: Blood count with differential, GOT, GPT, gGT, Creatinine, LDH, Potassium, Creatine kinase, blood glucose.  
HCQ drug level (2 ml EDTA blood and 2 ml of Serum blood). Labor Manual will be provided. 
 
d Spirometry / Bodyplethysmography will be performed pre-bronchodilator in children age ≥ 5 years. (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 (%). SOP will be provided. 
 
e Measurement of O2-Saturation, respiratory rate and O2 flow (if necessary) in awake patient at rest: 
 
If not on O2: after 5 min at rest, room air, then measure twice over 1 min. each; the measurements have to be at least 1 min. apart; report the stable 
average value 
 
If on O2:  
- 
BEFORE withdrawal (after 5 min at rest with steady state O2 supplement, measure over 1 minute) 
- 
Then withdraw O2 to obtain steady state O2-Sat. in room air (at least 30 seconds without change). Then measure twice over 1 min. each; the 
measurements have to be at least 1 min. apart; report the stable average value.    If the O2-Sat falls below SpO2<80% place back in oxygen and note 
as exact value.  
Document the time of measurement and state of the patient, usually “awake, at rest”. Note: In babies avoid crying, eating, sleeping during measurement. 
Note: try to schedule patients at similar time of the day.  
 
f Borg-Scale: assessment of dyspnea (0 – 10: 0 = no dyspnea at all, 5 = severe dyspnea, 10 = extremely severe dyspnea)  

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
14 of 52 
 
g Standard exercise testing (6-minute-walk test): SOP will be provided 
 
h Health economics assessment with the use of a special questionnaire which has to be filled out by the parents or adult patients. 
 
I  Quality of Life assessment with the use of the questionnaire PedsQL for different age groups which has to be filled out by parents and/or patients  
 
j For Electrocardiography (ECG), ophthalmological review and Echocardiography (Echo) please see Chapter 5. If a routine ophthalmological examination was 
done within 3 month before Visit 1, no additional ophthalmological exam is required.  
 
k Pregnancy test only has to be performed in 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. The pregnancy test can be performed in the urine or serum. 
 
L The following parameter will also be assessed, if there is oxygen demand: 
1. 
O2 via nasal cannula or via face mask: O2-Flow (l/min)  
2. 
on high-flow nasal cannula: Flow air (l/min), O2-Flow (l/min), FiO2 
 
m The following parameter will also be assessed on ventilation: ventilation method, duration of ventilation (hours/day/only for non-invasive ventilation),  
PEEP (cmH2O), PIP (cmH2O), FiO2, Ti (sec), MPAW (cmH2O) and Oxygenation Index (OI);  
In addition, if patients on the heart lung machine (e.g. NO (%), ECLS (VV/VA/ECLA), Flow/time since insertion) will be documented descriptively. 
 
n Calculation of Oxygenation Index (OI): OI = (FiO2* MPAW)/PaO2  
with MPAW = ((frequency * inspiration time)/60) * ((inspiratory pressure (PIP) – PEEP) + PEEP))) ; If PaO2 is not available, PcapO2 can be used.) 
 
o Start date, End date, Patient returned to baseline function? Y/N 
1. Increase in respiratory rate? Y/N/not done.  
2. Increase or development of dyspnea ? Y/N 
3. Newly developing or increased abnormalities on chest imaging ? Y/N/not done 
4. Onset/increase of oxygen demand to attain the individual baseline saturation ? Y/N 
5. Need for an additional level of ventilatory support (in addition to oxygen) ? Y/N 
6. Decrease in lung function in children able to perform the tests? Y/N/not done. Give before and after  FEV1 (% predicted) _____, FVC (%)______ 
7. Reduced exercise tolerance (history or in tests)? Y/N 
Additional info: 1. Was the patient hospitalized? Y/N, 2. New feeding problem?  Y/N, 3. New failure to thrive/weight lost?  Y/N, 4. Was there a change in treatment 
?  Y/N 
Cause/trigger (multiple selection possible), 1. Infection? Y/N, 2. Exposure to environmental irritant? Y/N, 3. Aspiration ? Y/N, 4. Extra-pulmonary processes? Y/N, 
5. Changes of treatment prior worsening? Y/N, 6. Poor treatment adherence 
? Y/N, 7. Side effect of current medication? Y/N, 8. Psychosocial factors? Y/N. 9. 
Other? Y/N. Give detail:________ 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
                                                      CONFIDENTIAL 
 
15 of 52 
 
P Capillary blood sample is obtained by the use of a warm, moist towel at a temperature not higher than 42 °C on a puncture site not longer than three to five 
minutes or use of  other vasodilator agent (e.g. Finalgon). Puncture site: Fingertip is recommended (rarely ear lobe or in neonates/infants, heel). If an arterial 
sample is available, this can substitute the capillary sample.  

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
16 of 52 
 
 
Table of Contents 
Table of Contents ................................................................................................................... 16 
1 
INTRODUCTION .................................................................................................................. 18 
1.1 
Scientific background ..................................................................................................... 18 
1.2 
Trial rationale ................................................................................................................. 18 
1.3 
Treatments and rationale for dose selection ................................................................... 18 
1.4 
Summarized risk-benefit assessment ............................................................................. 19 
2 
TRIAL OBJECTIVES ............................................................................................................ 21 
2.1 
Primary objective ............................................................................................................ 21 
2.2 
Secondary objectives ..................................................................................................... 21 
3 
TRIAL DESIGN .................................................................................................................... 22 
3.1 
Trial duration and schedule ............................................................................................ 22 
3.2 
Number of subjects ........................................................................................................ 22 
3.3 
Primary outcome parameters ......................................................................................... 22 
3.4 
Secondary outcome parameters ..................................................................................... 23 
3.5 
Measures taken to minimize/avoid bias .......................................................................... 24 
3.5.1 
Randomization ...................................................................................................... 24 
3.5.2 
Blinding ................................................................................................................. 24 
3.6 
Selection and withdrawal of subjects .............................................................................. 25 
3.6.1 
Inclusion criteria .................................................................................................... 25 
3.6.2 
Exclusion criteria ................................................................................................... 26 
3.6.3 
Withdrawal criteria ................................................................................................ 27 
3.6.4 
Premature closure of the clinical trial .................................................................... 27 
4 
TRIAL TREATMENTS .......................................................................................................... 28 
4.1 
Investigational treatments............................................................................................... 28 
4.1.1 
HCQ ..................................................................................................................... 28 
4.1.1.1 
General information about investigational medicinal product (IMP) ................... 28 
4.1.1.2 
Therapeutic effects ........................................................................................... 28 
4.1.1.3 
Known important side effects ............................................................................ 28 
4.1.1.4 
Dosage schedule .............................................................................................. 29 
4.1.1.5 
Overdose instructions ....................................................................................... 29 
4.1.2 
Placebo ................................................................................................................. 29 
4.1.3 
Treatment assignment .......................................................................................... 29 
4.1.4 
Treatment after the end of the trial ........................................................................ 30 
4.1.5 
Packaging and labelling ........................................................................................ 30 
4.1.6 
Drug distribution to subjects .................................................................................. 30 
4.1.7 
Drug storage, supplies and accountability ............................................................. 30 
4.1.8 
Procedures for monitoring subject compliance ...................................................... 30 
4.1.9 
Medication intake .................................................................................................. 30 
4.1.10 
Not permitted medication ...................................................................................... 31 
4.2 
Rescue medication or emergency treatment .................................................................. 32 
5 
TRIAL SCHEDULE .............................................................................................................. 33 
5.1 
Ophthalmological review ................................................................................................ 33 
5.2 
Electrocardiogram (ECG) and echocardiography (Echo) ................................................ 33 
5.3 
Check for Hypoglycemia ................................................................................................ 33 
6 
TRIAL METHODS ................................................................................................................ 33 
6.1 
Assessment of efficacy ................................................................................................... 33 
7 
Safety ................................................................................................................................... 34 
7.1 
Definitions ...................................................................................................................... 34 
7.2 
Assessment of AEs by investigator ................................................................................ 36 
7.3 
Period of observation ..................................................................................................... 37 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
17 of 52 
 
7.4 
Documentation of AEs and Follow up ............................................................................. 37 
7.5 
Immediate reporting of SAEs by investigator .................................................................. 37 
7.6 
Safety evaluation and Reporting by sponsor .................................................................. 38 
7.7 
Immediate Reporting of pregnancy by investigator ......................................................... 38 
7.8 
Documentation of Abuse, Misuse, Overdose and Medication Error ................................ 38 
7.9 
Emergency procedures .................................................................................................. 39 
7.10 Other safety data ............................................................................................................ 39 
8 
STATISTICS ........................................................................................................................ 39 
8.1 
Sample size.................................................................................................................... 39 
8.2 
Analysis populations ....................................................................................................... 39 
8.3 
Efficacy analyses ........................................................................................................... 40 
8.3.1 
Definition and analysis of primary outcome ........................................................... 40 
8.3.2 
Analysis of secondary outcome ............................................................................ 41 
8.3.3 
Analysis of Subgroups .......................................................................................... 41 
8.3.4 
Interim analyses .................................................................................................... 41 
8.4 
Analysis of adverse events ............................................................................................. 41 
8.5 
Analysis of clinical laboratory findings ............................................................................ 41 
8.6 
Other .............................................................................................................................. 41 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................ 41 
9.1 
Requirements for investigational sites and staff .............................................................. 41 
9.2 
Direct entries .................................................................................................................. 42 
9.3 
Direct access to source data/documents ........................................................................ 42 
9.4 
Investigator site file and archiving ................................................................................... 42 
9.5 
Monitoring ...................................................................................................................... 42 
9.6 
Inspection by authorities and audits ............................................................................... 42 
9.7 
Audits ............................................................................................................................. 43 
10 
DATA MANAGEMENT ......................................................................................................... 44 
10.1 Medical Database / eCRF (MDAT) ................................................................................. 44 
10.2 Secure Hosting of the Medical database (MDAT) ........................................................... 44 
10.3 Data entry ...................................................................................................................... 45 
10.4 Data concealment for electronic transfer ........................................................................ 46 
10.5 Database quality control ................................................................................................. 46 
10.6 Storage and archiving of data ......................................................................................... 46 
11 
ETHICAL AND LEGAL ASPECTS ........................................................................................ 47 
11.1 Good clinical practice ..................................................................................................... 47 
11.2 Patient information and informed consent ...................................................................... 47 
11.3 Confidentiality ................................................................................................................. 47 
11.4 Responsibilities of investigator ....................................................................................... 48 
11.5 Approval of trial protocol and substantial amendments ................................................... 48 
11.6 Submission to local regulatory/competent authorities ..................................................... 48 
11.7 Data monitoring committee (DMC) ................................................................................. 48 
11.8 Insurance ....................................................................................................................... 48 
11.9 Agreements .................................................................................................................... 49 
11.9.1 
Financing of the trial.............................................................................................. 49 
11.9.2 
Report ................................................................................................................... 49 
11.9.3 
Publication policy .................................................................................................. 49 
12 
SIGNATURES ...................................................................................................................... 50 
13 
DECLARATION OF INVESTIGATOR .................................................................................. 51 
14 
REFERENCES ..................................................................................................................... 52 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
18 of 52 
 
1 INTRODUCTION 
1.1 Scientific background 
The problem 
Interstitial lung disease in children (chILD) is a very rare condition. It is a group of over 200 
different entities that affect the parenchyma of the lung and lead to a chronic lung disease. The 
natural course of many of these diseases is connected to a high morbidity and mortality. Often the 
children are dependent on oxygen for a long period of time or demand mechanical ventilation 
(Griese 2009). 
No successfully proven pharmacological treatments are available up-to-date. The symptomatic 
treatment in general consists of oxygen supplementation if necessary, adequate nutrition adapted 
to the high energy demand due to the increased breathing effort, as well as immunization against 
respiratory pathogens to prevent exacerbations through respiratory infections. 
The current pharmacological treatment regimens are mainly dependent on the treating physician’s 
expertise. Common treatment options include the treatment with steroids, hydroxychloroquine 
(HCQ) and macrolide antibiotics. All three substances are often used in chILD, although so far no 
controlled study has shown a benefit. In some cases treatment consist of other agents such as 
azathioprine, cyclophosphamide, cyclosporine or methotrexate (Clement 2010). 
 
1.2 Trial rationale 
The impact 
So far, there exist no controlled studies to evaluate the efficacy of the different treatment options in 
chILD. In practice beside steroids hydroxychloroquine and macrolide antibiotics are often used 
drugs for the treatment of chILD (Clement 2010). 
Due to the rareness of the diseases only international studies can collect sufficient numbers of 
patients. Therefore we will use the European wide project on chILD, the chILD-EU project, to 
implement a randomized controlled study to evaluate the pharmacological treatment of chILD. 
This international study will address all these issues and will help to create new knowledge for 
everyday care in this broad group of pediatric interstitial lung diseases. 
With this study we aim to  
- 
Evaluate the efficacy of hydroxychloroquine against placebo in chILD 
- 
Evaluate the safety of mid-term use of hydroxychloroquine  
- 
Be able to make a decision on the risk and benefit of the use of hydroxychloroquine 
- 
Help standardizing the pharmacological treatment of chILD 
Currently HCQ is used off-label in a wide range of clinical severity, ranging from respiratory 
insufficiency to minimal respiratory symptoms. So far it is not predictable which patients will 
respond to the treatment and which will not. Due to this fact and due to the rareness of the 
diseases the goal of this exploratory study is to include patients with different symptoms and a 
wide range of clinical severity to sample as much information about this topic as possible to 
improve the treatment of this group of patients. Therefore, the character of this study is explorative 
and not confirmative. 
 
1.3 Treatments and rationale for dose selection 
Pharmacological treatment of chILD – literature review 
Performing a literature review concerning the pharmacological treatment of chILD we found only 
case reports and small series. There exist no standards for the pharmacological treatment of 
patients with chILD, as well as randomized controlled studies are lacking (Bush 2009). 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
19 of 52 
 
The majority of patients have been treated with steroids alone or in combination with other 
medication. The positive effect of steroids in chILD is mainly presumed to be related to their 
immunosuppressive effect. In practice there are two common ways of steroid therapy. They can 
either be given as steroid pulse therapy or as long term oral administration over weeks and 
sometimes months, sometimes the two therapies are combined (Benedictis 2012). The main 
problem with the steroid therapy is that there are many dose dependent side effects, especially if 
given over a long period of time. To reduce the dose of steroids, they are often combined with one 
of the other anti-inflammatory medications mentioned above. 
 
To evaluate the use of hydroxychloroquine till now, we made a literature research to summarize all 
previously described cases of chILD starting from year 1984 that were treated with 
hydroxychloroquine alone or in combination with other drugs. We found 83 cases of chILD that 
were treated with chloroquine (CQ) or HCQ. Outcome from this treatment was very variable from 
case to case. There are reports about cases that were resistant to the treatment with steroids and 
responded very well to hydroxychloroquine. But there are also several cases that apparently did 
not benefit from the treatment with hydroxychloroquine. So far it is not possible to predict, which 
patient will benefit from the treatment with hydroxychloroquine and which will not.  
 
The dose given ranged from 3.5 – 10 mg/kg bw/d. In this context it is notable, that there exist two 
pharmaceutical 
forms 
of 
hydroxychloroquine, 
the 
hydroxychloroquine-base 
and 
the 
hydroxychloroquine-sulfate; the correction factor is 200 mg Sulfate = 155 mg Base. The majority of 
case reports and small series did not indicate which of the two pharmaceutical forms the dose is 
referring to. In Germany, the common pharmaceutical form is the hydroxychloroquine sulfate and 
the dose given in chILD is 10 mg/kg bw/d. After extensive discussion with the German competent 
authorities (BfArM) and the European group of experts, on the basis of available safety data 
available and possible efficacy, a dose of 6.5 mg/kg b.w./d, after an initial week of treatment with 
10 mg/kg b.w./d, was selected for the START study. In the STOP block, the individual dosage, a 
patient was on until enrollment, should be continued.  
 
Pharmakokinetic 
The half-life of HCQ is 30 to 60 days, the protein binding is 63% and the oral bioavailability is 74%. 
Kinetic and pharmacological effect and metabolism of chloroquine and hydroxychloroquine are 
quite similar. After oral application HCQ is resorbed quickly and nearly completely. The maximum 
drug level is achieved about 4 hours after the application. Elimination exists of two parts. The rapid 
elimination has a half-life of three days. The second part is a slow elimination from the deeper body 
compartments with a half-life of 18 days. The half-life is dependent on the dose and is lengthened 
by very high drug levels.  Excretion goes mainly via the stool and only to a smaller part via the 
kidney. 
Studies concerning the carcinogenicity have not been found in literature. There have been studies 
that analyzed the risk of HCQ during pregnancy. The authors concluded that the treatment with 
HCQ during pregnancy is without elevated teratogen risk (Diav-Citrin O, 2013). 
 
1.4 Summarized risk-benefit assessment 
The need for a trial: 
So far for children with chILD no randomized or controlled trials have been performed. As almost 
each individual symptomatic child is empirically treated with the entire spectrum of potential drugs, 
we urgently need to clarify which patients, and if any at all, might benefit from this treatment and 
which will not. This is necessary to improve the everyday care, and to direct treatment of the 
patients with the chILD. Such knowledge will also reduce treatment burden in children who are 
treated despite the fact that this might not be effective.  
 
As the type of diseases investigated in this trial, as well as the course of the diseases and the 
effects of the drug are not sufficiently similar in adults and pediatric patients, pediatric effectiveness 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
20 of 52 
 
cannot be extrapolated from studies in adults. Almost all disease in question are unique to infants 
and children. Thus studies in adults cannot (and do not) exist, as type and course of diseases is 
specific for children. Thus the studies must be done in the population primarily affected by the 
diseases (chILD). In other settings no relevant results can be expected. 
The clinical research interventions and procedures planned represent an appropriate balance of 
risk and potential benefit. Specific protections were implemented to ensure adequate protection for 
minors, including parental permission and assent of able children, assurance of direct benefit for 
the child or for the group of patients with the particular condition, and minimization of risk. The risks 
to which the children are exposed are low, both compared to the potential therapeutic benefit and 
the risk of the disease. Due to the cross-over design of the START trial, the children are neither 
placed at a disadvantage by being enrolled, nor failing to get necessary health care.  
The additional burden put on the children from participation in the study is minimal. Except for a 
sample for HCQ blood level measurements, no investigations or tests are performed which would 
not be performed outside the study setting, including ophthalmological investigation (Chapter 5.1), 
liver function tests, ECG testing (Chapter 5.2). Special thresholds cannot be given as they are 
heavily dependent on the initial condition and co-morbidities of the child. Any significant deviation 
from baseline (usually > 2 fold upper limit of normal) will be reported as adverse event. These data 
are monitiored systematically according to the protocol (Chapter 7) and the infants and children are 
very closely monitored by their physicians who decide withdrawal from the study depending on the 
condition of the subject. 
 
Summarized medical risk-benefit assessment: 
In clinical practice HCQ is very frequently used in almost any patient with chILD at one or more 
occasions. Clear positive clinical improvements, usually occurring within 4 weeks, have been 
reported in 15 of 16 cases, when HCQ was given alone, and in 37 of 53 cases, when given in 
combination with glucocorticosteroids. Thus almost any child with a symptomatic form of chILD is 
treated with HCQ based on an empirical base.  
The application, also for prolonged, uncontrolled periods over years, were obviously save with very 
few, if any reported side effects during off-label usage. Of course a significant underreporting may 
be associated; however from other conditions and situations, in which the drug was used for a very 
prolonged time, including pregnancy and rheumatologic disease at significant higher frequency 
application was apparently safe and without major side effects even if given over a long period of 
time. Appropriate baseline testing (ophthalmologist, liver function values, blood count, electrolytes) 
is recommended before starting treatment to obtain baseline values. Subsequent examinations are 
at the discretion of the ophthalmologist, routine blood monitoring is not required.  
Hydroxychloroquine may have potential for several side effects such as i.e. retinal changes and 
abdominal pain. The retinal changes are dose dependent and can be irreversible. In the 83 case 
reports of chILD that were treated with either chloroquine or hydroxychloroquine, there were only 
three cases in which retinal changes were reported. All three patients with retinal changes were 
treated with chloroquine over periods between 20 months and 9 years. In the case reports we 
retrieved, no retinal changes were reported in patients that received hydroxychloroquine. In one 
series of patients, who received hydroxychloroquine, abdominal pain in the first week of treatment 
with hydroxychloroquine was reported in a minority of cases. So the risk for major side effects 
seems to be much lower with the use of hydroxychloroquine instead of chloroquine. There are 
several case reports, where the patients received hydroxychloroquine safely over years.  
 
As it is not clear, if HCQ works in these conditions at all, a placebo controlled design is justified. 
The selected duration of the placebo phase was the result of a delphi questionnaire among 
European pediatric pneumologists and balanced the anticipated time point, when a treatment effect 
could be noted in a majority of patients if present, and the time period tolerated to withhold the drug 
from a placebo treated subject. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
21 of 52 
 
So we think, that in a patient with relatively stable disease it is justifiable to start the treatment with 
the study drug in the placebo arm four weeks later than in the study drug arm without relevant 
disadvantage for the patient, as till now we don’t even know, if he will benefit from the 
pharmacological treatment or not. Due to this fact, we believe, that all patients should receive HCQ 
at one point during the study to avoid that patients who might benefit from the treatment with HCQ 
are not treated. 
Due to the heterogeneity of the diseases with a wide spectrum of clinical symptoms and severity it 
is not possible to determine one specific HCQ treatment duration that will fit the majority of 
subjects. Physicians anticipate treatment of some patients that will be treated with HCQ only for 
some weeks and patients that will need HCQ treatment for several years. Due to the variety of 
conditions and our intention to be as inclusive as possible in this exploratory trial, we decided not 
to determine the time period patients are treated between the start and stop treatment with HCQ. 
However, we took the chance to investigate stopping HCQ in a double blind, placebo controlled 
fashion. As with longer treatment and the intention to terminate treatment the exact time point to 
stop the treatment does not matter, we suggest a placebo-controlled withdrawal of active drug. In 
this stop block patients on active drug are randomized in a blinded manner to either continue for 
three more months with their active treatment or to receive placebo. 
In summary the risk of major side effects in these already often used pharmacological treatments 
as well as the risk of giving placebo instead of the study drug seems acceptable regarding the gain 
of useful knowledge and the possibility to create adequate treatment strategies for chILD. 
 
2 TRIAL OBJECTIVES 
2.1 Primary objective 
The primary objective of the trial is to investigate the following: 
 
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. 
 
2.2 Secondary objectives 
Secondary objectives of the study are: 
 
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. 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
22 of 52 
 
3 TRIAL DESIGN 
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. 
3.1 Trial duration and schedule 
The duration of this trial is expected to be at least 36 months. The subject recruitment started in Q4 
2015 and should last as long as possible, at least till the end of the chILD-EU project or longer if 
possible. The actual overall trial duration or subject recruitment period may vary from this time 
period. 
3.2 Number of subjects 
It is planned to assess >100 subjects for eligibility and to allocate 80 subjects. Recruitment and 
treatment of subjects is expected to be performed in up to 100 trial centres. We expect an equal 
distribution between START and STOP blocks. 
3.3 Primary outcome parameters 
 
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 
 
Oxygenation 
As respiratory condition is also dependent on the support given to the patient this needs to 
be taken into consideration when assessing oxygenation. Therefore parameters to be 
measured were defined depending on the patient´s condition (Table 3.3-1). How to 
analyse these variables statistically is detailed in section 8.  
 
Tab 3.3-1: Oxygenation - specific measurements used to determine, depending on Patient´s condition 
Patient’s 
condition 
Measured parameters 
Assessment 
In room air  In room air 
O2 Saturation (mean 
value) 
Respiratory rate (mean 
value) 
After 5 min at rest room air, then measure twice 
over 1 minute each, at least 1 min apart 
On O2-
supplement 
In room air 
O2 Saturation (mean 
value) 
Respiratory rate (mean 
value) 
Before O2-withdrawal take same parameters, after 
5 min withdraw O2 and obtain steady state O2 Sat 
in air. Steady state minimum SpO2 should be at 
least 30 seconds without change. Then measure 
twice, over 1 minute each, at least 1 min apart. If 
SpO2 falls below 80%, place back on oxygen. 
On high-
O2-flow, air-flow 
After 5 min stable rest measure twice over 1 minute 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
23 of 52 
 
flow nasal 
cannula 
each, at least 1 min apart 
Ventilated 
Oxygenation index 
OI = (FiO2* MPAW)/PaO2; with FiO2 = Fraction of 
inspired oxygen;  
MPAW = Mean airway pressure (= ((frequency * 
inspiration time)/60) * ((inspiratory pressure (PIP) – 
PEEP) + PEEP))) 
PaO2 = Partial pressure of oxygen in arterial blood 
 
3.4 Secondary outcome parameters 
 
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 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
24 of 52 
 
3.5 Measures taken to minimize/avoid bias 
3.5.1 Randomization  
Patients will be allocated to the two treatments, i.e., oral hydroxychloroquine and placebo, in a ratio 
of 1:1 by central randomization within each age group.  
The age-matched stratification will be performed according to 2 age groups defined as infants > 3 
Wks, < 2 y and the age category Children > 2 y, because of an anticipated skewed frequency 
distribution of cases, the older ones being less frequent.  
The randomization procedure will not consider the sex of the patients, since no sex-specific 
responses to HCQ therapy have been reported yet and are not expected. The randomization list 
will be generated by an independent institute using a validated system, which involves a pseudo-
random number generator to ensure that the resulting treatment sequence will be both 
reproducible and non-predictable. 
Only patients who participate in the chILD EU register can be included in the HCQ study. Inclusion 
in the chILD EU register and in the HCQ study can be performed at the same day. 
Patients will not receive a distinct HCQ patient number. The HCQ patient number corresponds to 
the respective patient number of the chILD EU register. 
At screening, each patient to be included will receive the next consecutive random/ patient number 
from a block of randomization numbers per age group. Study medication will be packed and 
blinded according to the random list. Each patient medication box will be sent together with the 
sealed unblinding codes (i.e. envelopes) to the sites. The investigator has to take care that each 
patient will be provided with the study medication box bearing the correct randomization number.  
The randomization list is to be kept confidential and is only accessible to authorized personnel until 
the code is broken. At the end of the trial, any emergency opening of the envelopes will be 
controlled after collecting the explanations for unblinding and checking the unused treatment units. 
The code will be broken regularly only at the end of the study after freezing the statistics database 
(by checking the data, recording any protocol violations etc.) allowing the collected data to be 
analyzed. 
The randomization list will be kept in safe and confidential custody. 
3.5.2 Blinding 
Blinding will be achieved by providing the study-specific HCQ-powder/substance and placebo-
powder/substance in appropriately covered capsules to keep the content not visible both for the 
two study drugs hydroxychloroquine and placebo. 
In the case of a medical emergency requiring identification of the treatment taken by the patient, 
the investigator has the right to open the respective envelope, but every effort should be taken to 
avoid unblinding of patients except the information will be needed for the emergency treatment. 
Opened envelopes have to be signed, dated and the reason for unblinding has to be documented. 
The envelope has then to be filed in the ISF and the sponsor and/or the responsible monitor has to 
be informed. Unblinded patients have to be withdrawn from the study. No other reason than an 
emergency may justify unblinding. After unblinding the investigator must also note the date, time 
and reason in the case report form. 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
25 of 52 
 
3.6 Selection and withdrawal of subjects 
3.6.1 Inclusion criteria  
For block specific inclusion criteria please see synopsis. 
Subjects meeting the block specific inclusion criteria and all of the following criteria will be 
considered for admission to the trial: 
 
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 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
26 of 52 
 
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. 
 
*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. 
3.6.2 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 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 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
27 of 52 
 
3.6.3 Withdrawal criteria 
 
Subjects or/and representatives can withdraw their consent at their own request without given 
reasons at all time during the trial. This should be without disadvantages for the subject. However 
the investigator should try to perform a final visit to get concluding findings of investigation. 
Subjects may be withdrawn from the trial for the following reasons 
 
At their own request or at request of the legal representative. 
 
At the instigation of the sponsor. If, in the investigator’s opinion, continuation of the trial 
would be detrimental to the subject’s well-being. 
 
For women, if it becomes known that the subject is pregnant. 
 
Aggravation of disease with life threatening events 
 
Severe side effects (for example retinopathy, cardiomyopathy, ECG-modifications, liver   
value elevation) 
 
The subject/ patient is non-compliant or uncooperative 
 
The subject/ patient is not able to participate due to an Adverse Event 
 
The subject/ patient has to take any concomitant drugs interfering with the study medication 
 
The subject/ patient is no longer able to participate for other medical reasons (e.g., surgery,  
other diseases, or death) 
The investigator decides about withdrawal of subjects from the clinical trial in case of occurrence of 
criteria mentioned above. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject’s medical 
records. In case of withdrawal of a subject at his/her own request, as far as possible the reason 
should be asked for and documented. The subject must be followed up and as far as possible; all 
examinations scheduled for the final trial day should be performed and documented and all trial 
medication should be collected at site.  
All on-going serious adverse events of withdrawn subjects have to be followed up see 7.3. 
Withdrawn subjects will not be replaced.  
3.6.4 Premature closure of the clinical trial 
The whole trial may be discontinued at the discretion of the sponsor, e.g. for following reasons: 
• 
New risks for subjects become known. 
• 
Inefficacy of the trial medication becomes evident. 
• 
Occurrence of AEs unknown to date in respect of their nature, severity, and duration or the 
 
unexpected increase in the incidence of known AEs. 
• 
Medical or ethical reasons affecting disadvantageous the continued performance of the trial. 
• 
Difficulties in the recruitment of subjects. 
• 
The time schedule cannot be met (e.g., more than doubling of recruitment time) 
• 
The sponsor and the investigator decide to discontinue this study because of failure to meet 
expected goals 
 
The ethic committees (EC) and the competent authorities must then be informed. Should the trial 
be closed prematurely, all trial material must be returned to or fetched by the monitor. 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
28 of 52 
 
4 TRIAL TREATMENTS  
4.1 Investigational treatments 
4.1.1 HCQ 
4.1.1.1 General information about investigational medicinal product (IMP) 
International non-proprietary name (INN): hydroxychloroquine 
Formulation: Mannitol, Lactose-Monohydrate, Povidon (MW: ca. 25 000), maize starch, 
Magnesium stearate (Ph. Eur.), Hypromellose, Macrogol (4000), Titanium dioxide (E 171), Silicon 
dioxide, Sodium saccharine. Capsule 
Manufacturer: University Hospital Munich, Pharmacy, Marchioninistrasse 15, 81377 Munich, 
Germany. 
4.1.1.2 Therapeutic effects 
Hydroxychloroquine is an anti-malarial quinolone, which is used in rheumatologic disease as well 
as in interstitial lung disease. Its mechanism of action in interstitial lung disease is not yet 
understood. It is believed to change intracellular pH of organelles and affects trafficking of proteins 
through the cells. Several case reports of children with chILD describe the benefit of 
hydroxychloroquine either in combination with steroids or alone. This benefit was an improvement 
of the respiratory condition. In some cases treatment with hydroxychloroquine was successful even 
after the failure of treatment with steroids. 
 
4.1.1.3  Known important side effects 
Side effects: 
Hydroxychloroquine is considered to be a very safe drug. Nevertheless there is a low risk for 
several known side effects. The most important side effect is the change of vision.  
The incidence of hydroxychloroquine-induced retinopathy is very low with only 2 cases of a series 
of 400 patients developing irreversible retinopathy, both after having taken maximum dose 
(400mg) for 6 years. The maximum dose and duration of treatment both appear to have the most 
impact on the development of retinopathy. Quinolones may also precipitate in the cornea- however 
this is much less common with hydroxychloroquine than chloroquine. 
 
Further known side effects are 
- 
Gastrointestinal disturbance - nausea, diarrhea, anorexia abdominal cramps.  
- 
Headache  
- 
Skin reactions - rash, pruritus. Rarely pigmentary changes, bleaching of hair and hair loss.  
- 
ECG changes (especially conduction disorders (bundle branch block / atrio-ventricular 
heart block) as well as biventricular hypertrophy)  
- 
Heart failure, cardiomyopathy in individual cases leading to death 
- 
Severe hypoglycaemia with loss of consiousness 
- 
convulsions 
- 
ototoxicity 
- 
Blood disorders, psychological disturbance, sensomotoric disorders, extrapyramidal disorders, 
myopathy, Steven Johnson syndrome, acute generalized exanthematous pustulosis, 
exfoliative dermatitis, photosensitivity, hepatic damage  
 
(according to BSPAR guidance for hydroxychloroquine, October 2010 and Fachinformation 
Quensyl® January 2017)  
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
29 of 52 
 
For more detailed information please read the current country specific Summary of Product 
Characteristics of Hydroxychloroquinsulfate (SmPC). 
 
4.1.1.4 Dosage schedule 
Start HCQ block 
During trial: Hydroxychloroquine Sulfate (HCQ) in a loading dose of 10 mg/kg bw/d, p.o., one daily 
dose in the evening for 7 days, then reduction to 6,5 mg/kg bw/d; the maximum daily dose is 
400mg. 
 
Stop HCQ block 
Individual dose, usually Hydroxychloroquine Sulfate (HCQ) 6 - 10 mg/kg bw/d, p.o., one daily dose 
in the evening; the maximum daily dose is 400 mg. The dose, on which the patient is included into 
the trial, should be continued for the duration of the trial. 
 
4.1.1.5 Overdose instructions 
Symptoms of an overdose with hydroxychloroquine are headache, visual changes, seizures, 
hypokalaemia, cardiac arrhythmias (inclusive elongation of the QT-interval, Torsade de pointes, 
ventricular tachycardia, ventricular fibrillation) and cardiovascular failure. This can occur suddenly 
and can lead to death. As these symptoms can occur shortly after the overdose, an immediate 
medical treatment is necessary. 
There exist no specific antidotes against hydroxychloroquine. In case of an overdose the stomach 
should be emptied by induced vomiting or gastric lavage. If the time point of overdose is less than 
30 minutes ago, active coal - administered via gastric tube after the gastric lavage - can reduce 
further resorption of hydroxychloroquine. If necessary a support of pulmonary and cardiovascular 
function must be provided, e.g. adrenalin. Seizures have to be treated by benzodiazepines 
(diazepam), phenobarbital or if necessary by peripheral muscle relaxants and invasive ventilation. 
The cardiotoxicity of hydroxychloroquine can be reduced by the administration of parenteral 
diazepam. Haemodialysis is not suitable. Possibly a hypokalaemia has to be treated. 
If the acute phase is over and the patient remains without any symptoms a strict monitoring for at 
least 6 hours is necessary. 
(According to Fachinformation Quensyl®, January 2017) 
 
For overdose instructions please refer also to the current country specific Summary of Product 
Characteristics of Hydroxychloroquinsulfate (SmPC). 
 
4.1.2 Placebo 
Formulation: Mannitol, Maize starch, Silicon dioxide, Sucrose octaacetate, Sodium saccharine.  
Capsule 
Manufacturer: University Hospital Munich, Pharmacy, Marchioninistrasse 15, 81377 Munich, 
Germany. 
 
Warnings and precautions for placebo capsules: Patients with hypersensitivity against one of the 
ingredients of placebo (see formulation) should not take the placebo capsules.  
 
4.1.3 Treatment assignment 
The trial medication will be administered only to subjects included in this trial. Subjects withdrawn 
from the trial retain their identification codes. New subjects will always receive a new identification 
code. 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
30 of 52 
 
4.1.4 Treatment after the end of the trial 
Treatment after the end of the trial is at the discretion of the investigator. 
 
4.1.5 Packaging and labelling 
The trial medication will be labelled according to EU-GMP Annex 13.  
The trial medication will be packed by pharmacy university medical centre Munich. 
 
4.1.6 Drug distribution to subjects 
For all patients capsules with individual, body weight adjusted drug or placebo will be 
manufactured and shipped by the pharmacy within a week to the site for distribution to the patients 
or their caregivers. No adjustments of dose are necessary throughout the trial, as all patients will 
receive their body adjusted dose from the beginning. 
 
4.1.7 Drug storage, supplies and accountability 
The investigator will take inventory and acknowledge the receipt of all shipments of the trial 
medication. All trial medication must be kept in a locked area with access restricted to designated 
trial staff. The trial medication must be dryly stored in accordance with manufacturer’s instructions. 
The investigator will also keep accurate records of the quantities of trial medication dispensed, 
used, and returned by each subject on the drug accountability form. The site monitor will 
periodically check the supplies of trial medication held by the investigator to verify the correct 
accountability of all trial medication used. At the end of the trial, all unused trial medication and all 
medication containers will be disposed by the trial center according to the local regulations. It will 
be assured that a final drug accountability report is prepared and maintained by the investigator. 
 
4.1.8 Procedures for monitoring subject compliance 
Trial medication will be dispensed to the subjects by the investigator. Subjects will be instructed to 
bring all trial medication to the trial site at every visit (including all empty packages and unused trial 
medication), compliance will be assessed. Details will be recorded in the CRF and on the drug 
accountability form in the investigator site file. 
 
4.1.9 Medication intake 
Medication intake should take place with the meals or shortly after the meals. 
These application forms are possible: 
 
Patients that can take the capsules: 
 
Whole capsules will be taken with liquid (50-100ml water, tea or apple juice). 
 
Patient that can’t take the capsules: 
Capsules will be opened by the parents and content suspended in 5-20ml sweetened liquid 
(tea or apple juice) or taken with yogurt, jam, puree, apple sauce or pudding followed by 
liquid (50-100ml). 
 
Patient with feeding tube 
Capsules will be opened and content suspended in 5-20ml water and immediately 
administered. After this tube will be flushed by additional 2.5-10ml water. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
31 of 52 
 
4.1.10 Not permitted medication 
Each previous and concomitant medication has to be documented in detail.  
Systemetic steroids: pulsed glucocorticoids in the 4 weeks before entry into the study (day 1) and 
throughout the trail (V4 in START block and V6 in STOP block) are not allowed. A continous daily 
or alternate day oral dose of glucocorticoids is allowed and has to be stable in the 4 weeks before 
entry into the study (day 1) and troughout the trail. 
 
Not permitted medication 
Comedications very carefully to be 
considered (further explanation in the text) 
Hepatotoxic medications, also caution with alcohol 
Antiepileptics 
Inhibitors of the monoaminooxidase 
Digoxin 
Arrhythmogenic medications 
Cyclosporine 
Amiodarone 
Methotrexate 
Moxifloxacin 
Corticosteroids 
Halofantrin 
Aminoglycosides 
Metronidazole 
Agalsidase-beta 
Phenylbutazon 
laronidase 
Probenecid 
Neostigmine, Pyridostigmine 
Indomethacin 
Antacids 
Penicillamin 
Caolin 
Pyrimethamine/Sulfadoxine 
Cimetidine 
Other medications that decrease the convulsive 
threshold 
Praziquantel 
Bupropion 
Rabies vaccination with HDCV 
Mefloquine 
Insulin, antidiabetics 
Other antimalarial 
Ampicillin 
 
Azathioprin 
 
Other disease-modifying antirheumatic drugs 
 
Due to an increased risk of ventricular arrhythmias the use of arrhythmogenic medication, as for 
example amiodarone or moxifloxacin, is not permitted during the trial. Halofantrin can prolong the 
QT interval with increased risk of arrhythmias and is therefore not permitted during the trial.  
 
It is prohibited to use other hepatotoxic medication or inhibitors of the monoaminooxidase during 
the trial. Adolescent patients should be explained that no larger quantity of alcohol should be 
consumed during the treatment with HCQ. 
 
The use of medication, that lowers the convulsive threshold, as for example mefloquine and 
bupropion, is not allowed during the trial, as there is an increased risk for seizures. The effect of 
antiepileptics can be reduced by hydroxychloroquine.  
 
The use of digoxin and cyclosporine is not prohibited during the trial, but investigators must be 
aware that hydroxychloroquine may increase the plasma concentrations of digoxin and 
cyclosporine. So in this case a strict control of plasma-drug-level is necessary to avoid intoxication 
with digoxin or cyclosporine. 
 
The use of other antimalarial drugs is not allowed during the trial because of a higher risk of side 
effects. With the use of phenylbutazon there is an increased risk for exfoliative dermatitis. If 
probenecid and indomethacin are used simultaneously there is an increased risk for sensibilisation 
and retinopathy. All three drugs are therefore not permitted during the trial.  
The use of other disease-modifying antirheumatic drugs in patients who are already on the drugs is 
not prohibited during the trial, but the investigator must be aware of possible interactions and 
increased immunosuppression. 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
32 of 52 
 
If hydroxychloroquine is combined with corticosteroids myopathies and cardiomyopathies can 
deteriorate. A combination with aminoglycosides leads to an increased neuromuscular blockade.   
 
The combination with penicillamin can increase the risk for severe hematological and/or renal side 
effects and skin reactions. A combination with pyrimethamine/sulfadoxine increases the risk for 
skin reactions. Therefore these drugs must be avoided.  
 
Simultaneous medication, which is toxic to the retina (e.g. tamoxifen) is not recommended. 
 
Further, investigators must be aware, that hydroxychloroquine inhibits the effects of agalsidase 
beta (used in Fabrys disease), laronidase (used in mucopolysaccaridosis), neostigmine and 
pyridostigmine. It can also decrease the resorption of ampicillin. 
In contrast, the effect of methotrexate is increased by hydroxychloroquine. Hydroxychloroquine can 
lead to an increased effect of antidiabetics (insulin, oral antidiabetics), so reduction of amount 
given can be necessary.    
 
The effect of hydroxychloroquine can be reduced by caolin and antacids. If the use of antacids is 
necessary, there should be a time lag of 4 hours between the intake of hydroxychloroquine and 
antacids.  The plasma concentrations of hydroxychloroquine can be increased by cimetidine. 
 
Under the medication of the structural similar chloroquine-sulfate combined with metronidazole one 
acute dystonic reaction was observed, therefore the use of metronidazole during this trial is not 
permitted. The effect of praziquantel is reduced by chloroquine; so far it is not known if this is also 
the case with HCQ. In case of rabies vaccination with HDCV the production of antibodies can be 
reduced by HCQ.  
 
(According to BSPAR guidance for hydroxychloroquine, October 2010 and Fachinformation 
Quensyl®, January 2017) 
 
For interactions with other medications and further warnings and precautions please refer also to 
the current country specific Summary of Product Characteristics of Hydroxychloroquinsulfate  
(SmPC) for detailed information. 
 
4.2 Rescue medication or emergency treatment 
There exists no special rescue medication in this trial. Children with interstitial lung disease often 
are very sick. So far we do not know which patient will benefit from the use of hydroxychloroquine 
and which will not. It is possible, that some patients will deteriorate during the trial. As no evidence 
based standards for treating interstitial lung disease in children exist, it is in the responsibility of the 
treating physician to decide, what the further treatment will be. 
 
 
 
 
 
 
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
33 of 52 
 
5 TRIAL SCHEDULE 
Tables 1-1 and 1-2 on page 9 to 13 provide the detailed schedule of assessments during the trial, 
from the Screening Period through the last visit.  
 
5.1 Ophthalmological review 
Recommendation to consult ophthalmologist at baseline for baseline visual assessment and at the 
end of the initiation or withdrawal, including:  
1. 
Enquiry about any disturbance of central vision  
2. 
Check visual acuity and reading acuity  
3. 
Slit lamp examination from age 3 years onward 
4. 
Funduscopy 
 
Facultative, not requested by the study physician and only at the discretion of the ophthalmologist 
1. 
Ocular coherence tomography (OCT),  
2. 
Fundus auto fluorescence (FAF) imaging 
3. 
Stereoscopic slit lamp examination of the retina (e.g. with a 90D or 78 biconvex lens) 
4. 
Central visual field, using an Amsler Chart (preferably red on black) or automated perimetry 
5. 
Evaluation may need to be extended according to signs and symptoms to include retinal 
photography and visual electrophysiological tests.  
 
Subsequent examinations should be at the discretion of the ophthalmologist, but indefinite 
follow up is not likely to be required for most patients. For patients who have received continuous 
treatment for more than 5 years, an individual arrangement should be agreed with the local 
ophthalmologist.  
Visual side effects are dose related and the drug should be stopped if they develop. 
 
5.2 Electrocardiogram (ECG) and echocardiography (Echo) 
Any signs of conduction disorders (bundle branch block / atrio-ventricular heart block) as well as 
biventricular hypertrophy in the ECG can be a sign of cardiomyopathy, which has been described 
under the medication with HCQ. In this case further cardiologic workup is necessary. If there are 
any signs or symptoms of cardiomyopathy the medication with HCQ must be discontinued 
immediately. (Fachinformation Quensyl® 2017) The Echo is done to assess for pulmonary 
hypertension and to exclude cardiomyopathy at the beginning of the study. 
 
5.3 Check for Hypoglycemia 
Any signs of hypoglycaemia like low blood glucose levels or reports of potential hypoglycaemic 
episodes will lead to intensived observation of blood glucose levels and if persistant change of 
medication (e.g. reduction or stop). 
 
6 TRIAL METHODS 
6.1 Assessment of efficacy  
The primary outcome of the trial is the oxygen saturation, measured in room air. As the numbers of 
subjects that will be included into the trial will be low and cannot precisely be predicted, a spectrum 
of secondary outcome parameters will be interpreted exploratory, including patient oriented 
measures and outcomes, like quality of life.  
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
34 of 52 
 
7 Safety 
7.1 Definitions 
 
Adverse Event (AE) 
According to GCP, an adverse event (AE) is defined as any untoward medical occurrence in a 
subject treated with a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
 
An AE may be: 
 a new symptom or a new diagnosis 
 a new medical condition or an accident 
 a change in laboratory parameters 
 an intercurrent illness or accident 
 worsening of a medical condition/diseases existing before the start of the clinical trial 
 recurrence of a disease 
 an increase in frequency or intensity of episodic diseases. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical trial protocol and the condition(s) leading to these measures are 
not AEs, if the condition leading to the measure was present before inclusion in the trial. In the 
latter case the condition should be reported as medical history. 
Change in laboratory parameters: The criteria for determining whether an abnormal test finding 
should be reported as an adverse event are as follows: 
 Test result is associated with accompanying symptoms, and/ or 
 Test result requires additional diagnostic testing or medical/ surgical intervention, and/ or 
 Test result leads to a change in trial dosing outside of protocol-stipulated dose adjustments, or 
discontinuation from the trial, significant additional concomitant drug treatment, or other therapy, 
and/ or 
 Test result is considered to be an adverse event by the investigator or sponsor. 
 Progression of chILD under treatment should not be reported as an adverse event. However, if 
chILD leads to a fatal outcome during the trial or within the safety reporting period, then disease 
progression should be reported as an adverse event and as a serious adverse event with 
outcome “death”. 
 
Serious adverse event (SAE) 
A serious adverse event (SAE) is one that at any dose (including overdose): 
 results in death 
 is life-threatening1 
 requires subject hospitalization or prolongation of existing hospitalization² 
 results in persistent or significant disability/incapacity3 or 
 is a congenital anomaly/birth defect 
 is an important medical event4. 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
35 of 52 
 
 
Comment: 
Death is an outcome of an event. The event that resulted in death should be recorded and reported 
as an SAE. 
 
1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused 
death if it were more severe. 
2If the admission is pre-planned (i.e., elective or scheduled surgery arranged prior to start of the 
trial) or not associated with an adverse event (e.g., social hospitalisation for purpose) or results in a 
hospital stay less than 12 hours, the serious criterion “hospitalisation” is not fulfilled. However, it 
should be noted that invasive treatment during a hospitalisation may fulfil the criteria of “medically 
important” and may be reportable as a serious adverse event dependent on clinical judgement. 
An inpatient rehabilitation program per se does not fulfil the seriousness criterion “hospitalization”. 
In this case the investigator should evaluate carefully whether the reason for the inpatient 
rehabilitation program has to be documented as an AE/ SAE. 
3“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. The irreversible injury of an organ function (e.g., 
paresis, diabetes, cardiac arrhythmia) fulfils this criterion. 
4Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed in 
the definition above should also usually be considered serious. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
convulsions that do not result in subject hospitalization, or the development of drug dependency or 
drug abuse. A diagnosis of cancer during the course of a treatment should be considered as 
medically important.  
 
Clarification of the onset and end date of AEs and SAEs 
The onset date of the AE is defined as the onset of signs and symptoms or a change from 
baseline. The onset date of the SAE is defined as the date the signs and symptoms/diagnosis 
became serious, i.e., met at least one of the ICH criteria for seriousness.  
The end date of the AE is defined as the date when the symptoms resolve, or the event is 
considered stable. The end date of the SAE is defined as the time the seriousness criteria are no 
longer applicable. The end date of the SAE must not be later than the end date of the 
corresponding AE. AEs and SAEs that are on-going at the time of death are considered not 
resolved or resolving.  
 
Clarification of the difference in meaning between "serious" and "severe": 
The terms “serious” and “severe” are not synonymous but are often used interchangeably. The 
term ‘severe’ is often used to describe the intensity (severity) of a specific event; the event itself, 
however, may be of relatively minor significance (such as severe headache). This is not the same 
as “serious”, which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning. Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
36 of 52 
 
A SUSAR is every SAE with an at least possible relationship to the investigational medicinal 
product which is unexpected. An unexpected serious adverse reaction is any adverse reaction, the 
nature or severity of which is not consistent with the applicable product information of the current 
country specific Summary of Product Characteristics of Hydroxychloroquinsulfate (SmPC)).  
 
7.2 Assessment of AEs by investigator  
Subjects must be carefully monitored for adverse events by the investigator. The intensity of the 
adverse events and the causal relation to trial medication and/or procedures are to be assessed. 
 
Intensity/ Severity 
The intensity of an AE will be assessed by the investigator as follows: 
Mild: 
 
Temporary event which is tolerated well by the subject and does not interfere with 
 
 
normal daily activities. 
Moderate: 
Event which results in discomfort for the subject and impairs his/her normal activity. 
Severe: 
Event which results in substantial impairment of normal activities of subject. 
 
If the event is serious, the severity reported in the adverse event must be consistent with the 
severity included in the adverse event report. 
 
 
Causal relation to trial medication/procedures 
The assessment of the relationship of an adverse event to the administration of study drug is a 
clinical decision based on all available information at the time of the documentation. Factors to be 
considered in assessing the relationship of the adverse event to study drug include: 
• The temporal sequence from drug administration: The investigator has to consider, if the event 
occurred before first intake of study medication or long time after last intake. Additionally the length 
of time from drug exposure to event should be evaluated in the clinical context of the event. 
• Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge): 
Subject’s response after drug discontinuation (de-challenge) or subjects response after drug re-
introduction (re-challenge) should be considered in the view of the usual clinical course of the 
event in question. 
• Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the context of 
the natural history and course of the disease being treated and any other disease the subject may 
have. 
• Concomitant medication or treatment: The other drugs the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them may be suspected to 
cause the event in question. 
Positive causal relationship: 
An assessment of ‘related‘ implies a reasonable possibility of a causal relationship between the 
event and the investigational medicinal product (IMP).  
This means that there are facts (evidence) or arguments to suggest a causal relationship, such as: 
 
A close temporal relationship 
 
A common drug reaction to the IMP  
 
No plausible alternative cause 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
37 of 52 
 
 
Negative causal relationship: 
An assessment of ‘not related‘ means that there is no reasonable possibility of a causal 
relationship between the event and the investigational medicinal product. 
This includes for example:  
 
Another cause of the adverse event is more plausible  
 
A temporal sequence cannot be established with the onset of the adverse event and 
administration of the study treatment 
 
A causal relationship is considered biologically implausible. 
 
7.3 Period of observation 
In this trial, the period of observation for collection of adverse events extends from signing the 
inform consent up to the end of trial. If the investigator detects a serious adverse event in a trial 
subject after the end of the period of observation, and considers the event possibly related to the 
prior trial, he should contact the sponsor to determine how the adverse event should be 
documented and reported. 
 
7.4 Documentation of AEs and Follow up 
All AEs (whether serious or not) reported by the subject or detected by the investigator will be 
documented on the appropriate pages of the case report form (CRF). AEs must also be 
documented in the subject’s medical records. If the adverse event is serious (see Section 7.1), the 
investigator must complete, in addition to the “Adverse Event Page”, a “Serious Adverse Event 
Form” at the time the serious adverse event is detected. 
Every attempt should be made to describe the adverse event in terms of a diagnosis. If a clear 
diagnosis has been made, individual signs and symptoms will not be recorded unless they 
represent atypical or extreme manifestations of the diagnosis, in which case they should be 
reported as separate events. If a clear diagnosis cannot be established, each sign and symptom 
must be recorded individually. 
All subjects who have adverse events, whether considered associated with the use of the 
investigational products or not, must be monitored to determine the outcome. The clinical course of 
the adverse event will be followed up according to accepted standards of medical practice, even 
after the end of the period of observation, until a satisfactory explanation is found or the 
investigator considers it medically justifiable to terminate follow-up, but no longer than 90 days 
after the end of the trial. 
Should the adverse event result in death, a full pathologist’s report should be supplied, if possible. 
 
7.5 Immediate reporting of SAEs by investigator 
SAEs must immediately (within 24 hours of the investigator’s awareness) be reported to: 
 
IZKS Mainz 
Langenbeckstr 2 
55131 Mainz 
FAX 0049 6131/17-9916 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
38 of 52 
 
The initial SAE Report should be as complete as possible including the essential details of 
subject’s identification (screening number, random number), the serious adverse event (medical 
term, diagnosis), the trial medication and the assessment of the causal relationship between the 
event and the trial medication. The SAE report must be reviewed and signed by the investigator.  
The investigator should provide related additional information on the clinical course and the 
outcome of each SAE as soon as possible (Follow up report). The “Serious Adverse Event Form” 
will be provided. 
 
Worsening of a sign or symptom of the condition under treatment will normally be measured by 
efficacy parameters. However, if the outcome fulfils the definition of “serious adverse event”, it 
must be reported as such.  
 
7.6 Safety evaluation and Reporting by sponsor 
The sponsor will ensure that all legal reporting requirements are met. According to GCP the 
sponsor is responsible for the continuous safety evaluation of the investigational product(s) and the 
clinical trial. The IZKS on behalf of the sponsor will conduct the management of SAEs and the 
expedited reporting in Germany as required by German Drug Law (AMG) and GCP regulation 
(GCP-V). Suspected unexpected serious adverse reactions (SUSARs) and safety issues as 
defined by GCP-V are determined for expedited reporting: The competent authorities and the 
ethics committees should be notified as soon as possible but not later than 15 calendar days, and 
7 calendar days if it was fatal or life-threatening. All investigators will be informed within the same 
timeframe. The marketing authorization holder of the IMP should be informed too. Work flow and 
procedures concerning Safety management will be described in a separate document. 
During the clinical trial the sponsor will submit the Development Safety Update Report (DSUR) 
including a list of all serious adverse reactions to the ethics committee(s) and the competent 
authorities once a year. 
 
7.7 Immediate Reporting of pregnancy by investigator 
Any pregnancy diagnosed in a female subject during treatment with the investigational product 
must be reported immediately using the “Pregnancy Reporting Form” to: 
 
IZKS Mainz 
Langenbeckstr 2 
55131 Mainz 
FAX 0049 6131/17-9916 
 
Pregnancy occurring during the clinical trial, although not considered a SAE, must be reported 
within the same timelines as a serious adverse event. The outcome of a pregnancy should be 
followed up carefully and abnormal outcome of mother or child should be reported if any. 
When the outcome of the pregnancy and the definite condition of the child could be established, 
the investigator completes the “Pregnancy Outcome Form”, and faxes the completed Report Form 
II to IZKS. 
 
7.8 Documentation of Abuse, Misuse, Overdose and Medication Error 
All special events such as study medication abuse, misuse, overdose and medication errors 
including dilution errors and infusion rate errors have to be documented in the subject’s CRF and 
source documents. If any abuse, misuse, overdose, or medication errors lead to an (serious) 
adverse event, then the event has to be documented and reported as AE/SAE. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
39 of 52 
 
 
7.9 Emergency procedures 
During and following a subject’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to a subject for any AEs including clinically significant laboratory 
values.  
Emergency treatment: see 4.2 
Emergency unblinding: see 3.5.2  
 
7.10 Other safety data 
7.10.1 Previous and intercurrent illnesses 
Illnesses already known at the time of informed consent are to be documented in the CRF as 
medical history. Illnesses detected during the clinical trial are to be documented as Adverse Events 
(see above).  
 
7.10.2 Previous and intercurrent medical treatments 
All medical treatments with the exception of the Investigational Medical Products received by the 
participant at the beginning and / or during the clinical trial are to be documented in the CRF as 
concomitant medication. 
Routine physical examination and laboratory determination as specified above at study visits.  
 
 
8 STATISTICS  
Details of the statistical analysis of the data collected in this trial will be documented in a Statistical 
Analysis Plan (SAP) that will be generated by IZKS Mainz and finalized before closing the data 
base and prior to breaking the blind. The SAP is based on the protocol including all amendments. 
The document may modify the plans outlined in this protocol; however any major modifications of 
the primary outcome definition and/or its analysis will also be reflected in a protocol amendment. 
Any deviation from the original statistical plan must be described and justified in the final report. 
The statistical analysis will be conducted by means of SAS®. 
 
8.1 Sample size 
Due to the exploratory nature of the study there is no formal sample size calculation. The study 
aims to include 80 patients. 
 
8.2 Analysis populations 
All subjects with signed informed consent are considered as enrolled subjects, even if they did not 
receive any trial treatment. All randomised subjects will be included in the Intention-to-treat (ITT) 
population. This population is the primary analysis population. Within ITT population analyses 
subjects will be assigned to the treatment to which they were randomised. For the combined 
analysis the ITT Population consists of all patients that are at least in the START or the STOP 
block. The corresponding PP Populations consist of the patients from the ITT population without 
major protocol violations. Major protocol violations will be defined in the SAP. The safety 
population comprises all subjects who received at least one dose of trial treatment. In analyses of 
the safety population subjects will be assigned to the treatment which they actually received. The 
analysis populations will be defined prior to unblinding of the study.  
For analysis, subgroups of patients will be defined, based on age, categories of diagnosis and 
further appropriate factors. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
40 of 52 
 
 
8.3 Efficacy analyses 
The primary population for the analyses of efficacy are the ITT Populations (randomised patients) 
for each block. For the combined analysis the ITT Population consists of all patients that are at 
least in the START or the STOP block. For all hypotheses two-sided exploratory p-values will be 
provided. 
If appropriate, the analyses will be adjusted for the stratification factor of the randomization: age 
group. The final efficacy analysis will be described in the Statistical Analysis Plan (SAP). 
 
8.3.1 Definition and analysis of primary outcome  
The oxygenation of the patient is the primary outcome variable. The primary outcome will be 
assessed as the response rate of oxygenation to the intervention. As the patient´s respiratory 
condition can vary over a broad range, may necessitate variable external support, and as these 
changes may occur over relatively short time periods, it is necessary to take all this into 
consideration when assessing oxygenation. Therefore we defined the parameters to be measured 
depending on the patient´s condition to define a responder (Table 3.8-1). The majority of children 
included into the study are expected to be on supplemental oxygen or in room air. In these 
subjects oxygen saturation in room air will be assessed (for assessments please see 3.2). 
However to include the broad continuum of respiratory support possible in individual patients, an 
approach was chosen accommodating that need. Responses to treatment judged as significant 
were defined depending on Patient´s condition. How and when to assess the variables is further 
detailed in the study protocol. 
Oxygenation, the primary outcome parameter, was chosen as a dichotomous variable (response 
yes or no). Its components, i.e. O2-saturtation and respiratory rate, are also used continuously in a 
descriptive manner as secondary outcome variables.  
 
Tab 3.8-1: Definition of responders to treatment depending on Patient´s condition 
Patient’s 
condition 
Measured 
parameters 
Specific 
metric 
Definition of significant change 
or responder to the initiation 
of HCQ 
Definition of significant change 
or responder to the 
withdrawal of HCQ 
Method of 
aggregation 
In room air 
In room air 
O2 Sat (mean 
value) 
Respir rate (mean 
value) 
Change 
from 
baseline 
Increase ≥ 5% in O2 Sat, 
or 
Decrease in resp. rate ≥ 20% 
Decrease ≥ 5% in O2 Sat, 
or 
Increase in resp. rate ≥ 20% 
Proportion of 
responders 
On O2-
supple-
ment 
In room air 
O2 Sat (mean 
value) 
Respir rate (mean 
value) 
Change 
from 
baseline 
Increase ≥ 5% in O2 Sat 
or 
Decrease in resp. rate ≥ 20% 
or 
Support no more needed 
Decrease ≥ 5% in O2 Sat, 
or 
Increase in resp. rate ≥ 20% 
or 
Support newly needed 
Proportion of 
responders 
On high-
flow nasal 
cannula 
O2-flow, air-flow 
Change 
from 
baseline 
Decrease ≥ 20% 
or 
Support no more needed 
Increase ≥ 20% 
or 
Support newly needed 
Proportion of 
responders 
Ventilated 
Oxygenation index 
Change 
from 
baseline 
Decrease ≥ 20% 
or 
Support no more needed 
Increase ≥ 20% 
or 
Support newly needed 
Proportion of 
responders 
 
The definition of the threshold for a significant change or responder regarding oxygenation will be 
further assessed as a secondary outcome. 
 
Controlled initiation of HCQ 
Relative change trial day 1 (i.e. Visit 2), through day 28 (i.e. Visit 3) and relative change day 28 (i.e. 
Visit 3) to day 56 (i.e. Visit 4) active compared to change placebo 
Controlled withdrawal of HCQ 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
41 of 52 
 
Relative change trial day 1 (i.e. Visit 2) through day 84 (i.e. Visit 5): change active compound 
compared to change placebo 
 
8.3.2 Analysis of secondary outcome 
All analysis of secondary outcome will be interpreted purely exploratory. Continuous and quasi-
continuous variables will be displayed by the descriptive statistics: N (number of observations), 
mean, standard deviation, minimum, median, maximum and the number of missing observations. 
Categorical variables will be displayed by absolute and relative frequencies. Exploratory p-values 
will be calculated when appropriate. Time to event data will be displayed by Kaplan-Meier Plot 
when a reasonable number of events occur. 
 
8.3.3 Analysis of Subgroups 
If appropriate, subgroups will be defined in the SAP. 
 
8.3.4 Interim analyses 
No interim analyses are planned. 
 
8.4 Analysis of adverse events 
All summaries and listings of safety data will be performed for the safety population.  
Frequencies of subjects experiencing at least one adverse event (AE) will be displayed by body 
system and preferred term according to MedDRA terminology. Detailed information collected for 
each AE will include: A description of the event, duration, whether the AE was serious, intensity, 
relationship to trial drug, action taken, clinical outcome. Summary tables will present the number of 
subjects observed with AEs and corresponding percentages. Additional subcategories will be 
based on event intensity and relationship to trial drug. A subject listing of all AEs will be prepared. 
 
8.5 Analysis of clinical laboratory findings 
Listings will be prepared for each laboratory measure and will be structured to permit review of the 
data per subject as they progress on treatment. Summary tables will be prepared to examine the 
changes of laboratory measures over time. Additionally, shift tables will be provided to examine the 
changes of laboratory data from normal baseline to values outside the corresponding reference 
range during/after treatment. 
 
8.6 Other 
Steady state drug levels and ECGs will be monitored. Ophthalmologic exams will be done. 
 
9 
QUALITY CONTROL AND QUALITY ASSURANCE  
 
9.1 Requirements for investigational sites and staff 
The investigator should be able to demonstrate (e.g. based on retrospective data) a potential for 
recruiting the required number of suitable subjects within the agreed recruitment period. The 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
42 of 52 
 
investigator should have sufficient time to properly conduct and complete the trial within the agreed 
trial period. The investigator should have available an adequate number of qualified staff and 
adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.The 
investigator should ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the trials treatments, and their trial-
related duties and functions. 
 
9.2 Direct entries 
Data entries be entered in the CRF as Direct, are listed in the Monitor Manual in the section source 
data control. 
 
9.3 Direct access to source data/documents  
The investigator/institution must permit trial-related monitoring and auditing, as well as inspections 
by the appropriate competent authorities and Ethics committees, providing direct access to source 
data/documents (Confidentiality see 11.3). The subjects will be informed that representatives of the 
sponsor, independent ethics committee (IEC) or competent authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection laws. 
9.4 Investigator site file and archiving 
The investigator will be provided with an investigator site file (ISF) at the start of the trial. The 
investigator will archive all trial data and relevant correspondence in the ISF. The ISF, all source 
data and all documents will be kept filed according to the requirements of the ICH-GCP guidelines 
after termination of the trial. After the end of the trial related documents e.g. trial master file (TMF) 
and CRFs will be stored in the archive of the sponsor. It is the responsibility of the investigator to 
ensure that the subject-identification sheets are stored for at least 15 years beyond the end of the 
clinical trial. All original subject files must be stored for the longest possible time permitted by the 
regulations at the hospital, research institute, or practice in question. If archiving can no longer be 
maintained at the site, the investigator will notify the sponsor. 
 
9.5 Monitoring 
Monitoring will be done by personal visits from a clinical monitor according to SOPs of the IZKS 
Mainz in Germany. In the other planned countries (e.g. Italy, Spain, Portugal, Turkey, Poland and 
Austria), the monitoring will be done by the ECRIN partners according to SOPs provided by the 
Lead CTU (IZKS Mainz) and the ERCIN ERIC coordination in Paris/Cologne. Each site will be 
visited by the monitor at regular intervals to ensure compliance with the trial protocol, GCP and 
legal aspects. The monitor will review the entries into the CRFs for completeness and correctness 
and verify the entries on the basis of the source documents. The presence of correct informed 
consents will be checked for every subject. Details will be specified in the monitoring manual for 
this trial.The investigator must allow the monitor to look at all relevant documents and must provide 
support at all times to the monitor. By frequent communications (letters, telephone, fax), the 
monitor will ensure that the trial is conducted according to the protocol and regulatory 
requirements. 
 
9.6 Inspection by authorities and audits 
Competent authorities and by the sponsor authorised persons (auditor) may request access to all 
source documents, CRF, and other trial documentation in case of an inspection or audit. Direct 
access to these documents must be guaranteed by the investigator who must provide support at all 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
43 of 52 
 
times for these activities. Source data documents can be copied during inspection or audit in case 
the identity of the subject have been made unrecognizable. 
 
9.7 Audits  
No audits are planned for this trial. 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
44 of 52 
 
10 DATA MANAGEMENT 
 
The Central Information Office Marburg is responsible for data management. All data management 
activities will be done according to the current Standard Operating Procedures (SOPs) of Central 
Information Office Marburg. For reports and analysis the EDC system provides data export 
functionality for data management. The data can be exported in SAS or SPSS format for reports 
and analysis.  
 
10.1 Medical Database / eCRF (MDAT) 
 
The Central Information Office Marburg is responsible for programming the eCRF (electronic Case 
Report Form) and hosting the medical database (MDAT). The eCRF will be designed in 
accordance to the clinical trial protocol. As EDC system the secuTrial® system of the Central 
Information Office Marburg will be used. secuTrial® is an internet based system with connection to 
a rational ORACLE® database. The software serves as remote data entry system for 
pseudonymized medical data. It includes functions for data entry in electronic forms, for data view, 
analysis and export. 
The software development was strictly done in accordance to a standardized procedural model, 
meeting all ISPE GAMP4 requirements of software validation. SecuTrial® is permanently audited 
to meet all requirements according to GCP, AMG, EMEA and FDA (21 CFR Part 11). It includes 
three different audit trail systems for medical data, user management and eCRF changes. Audit 
trail includes all changes made through the eCRF system within the database with additional login 
information and timestamp. This assures that any documentation and/or changes to database, 
user roles and medical items are traceable anytime. Changes or corrections can only be made by 
persons who have access to the system with user specific, role based access rights. Last audit 
was in May 2013. 
Data management based on GCP refers to the activities defined to achieve safe routines to 
efficiently enter patient information into a database, avoiding errors. The data management 
routines include procedures for handling of CRF, database setup and management, data entry and 
verification, data validation, quality control (QC) of database, and documentation of the performed 
activities including information of discrepancies in the process.  
Subjects’ data are documented with the EDC (Electronic Data Capture) system directly by the sites 
via web browser and are transferred via SSL encryption to the central medical database (MDAT). 
The EDC system is 21 CFR Part 11 compliant and has an implemented audit trail.  
 
10.2 Secure Hosting of the Medical database (MDAT) 
 
The server-hardware of the Central Information Office Marburg is recently renewed in November 
2012 to a currently up-to-date high-level processing power and storage system state. The server 
system is housed in a cage-in-cage-room in the High Security Data Center Itenos of the T-Systems 
AG, Nürnberg (20000-1 and ITIL certified). For the secure system administration the I-Motion 
GmbH, Fürth, is responsible (ISO-9001 and KV-Safenet certified). Server support is provided 
exclusively by high qualified and experienced personal.  
The secure hosting concept includes the conception and implementation of the safety and security 
standard operating procedures, the professional audit of all formal processes of data security and 
the continuous support by competent personal.  

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
45 of 52 
 
Network traffic between the internet and the firewall systems, between the firewall systems and the 
application servers and between the application and the database servers is controlled by network 
based intrusion detection systems. All warnings and errors are logged in a separated database, 
located in the separated IT-center of the I-Motion GmbH, Fürth, permanently controlled and 
watched by internal implemented analysis tools.  
The high availability of the medical research data is guaranteed by redundant hard disk systems 
(RAID) and a generation based data backup strategy.  
All medical data on the database servers and all log files of the firewall systems are backuped 
daily. Exchange of the backup-tapes of the individual generations is weekly with a three-week 
rotation. Tapes of the last generation are stored in a bank safe-deposit box. 
All systems are secured from power failures by a redundant uninterruptable emergency power 
supply system (USV, NEA). 
The ASP-hosting and server connections (ISP-Connectivity) of the server farm, located in the T-
Systems Data Center Itenos, Nürnberg, and their system administration by the I-Motion GmbH, 
Fürth, is audited regularly by the Central Information Office Marburg.  
Audit is based on  
 
 
German 
National 
Institute 
of 
Security 
in 
Information 
Technology 
(BSI):  
            Safeguard catalogues 
 
ISO 27000 (Management systems for Information Security) 
 
ISO 27001 (Information security management systems requirements specifications) 
 
ISO 27005 (Information security risk management) 
 
FDA Guidance for industry: Computerized Systems used in Clinical Trials (CSUCT) 
 
Good Clinical Data Management practices, ver. 4 
 
Last audit was in June 2012. 
  
10.3 Data entry 
 
The investigator is responsible for the performance of the trial in accordance to the clinical trial 
protocol. All data collected during the trial have to be documented in the eCRF by authorized 
persons according to the personal log with delegation of authorities. Detailed requirements for 
using the EDC system are specified in an EDC-Manual. 
The eCRF should always reflect the latest observations on the patients participating in the study. 
Therefore, the eCRF are to be completed as soon as possible during or after the patient’s visit. To 
avoid inter-observer variability, every effort should be made to ensure that the same individual who 
made the initial baseline determinations completes all effect and safety evaluations. The 
investigator must verify that all data entries in the eCRF are accurate and correct. If some 
assessments are not done, or if certain information is not available, not applicable or unknown, the 
investigator should indicate this in the eCRF. The investigator will be required to electronically sign 
off adverse and serious adverse event reports in the medical study database. 
In order to use the EDC system all participants entering and monitoring data are provided with 
training materials and required documentation before start of the trial by IZKS Mainz. Every person 
using the EDC system has to complete a registration form (User-ID request) to confirm that they 
have received the training material and have been trained for data entry. For training of data entry 
a test/training database will be provided. 
For support with data entry the Data management team of the national chILD-EU centers can be 
contacted. Each trial site has one responsible person who supports the national chILD-EU center 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
46 of 52 
 
in implementation of technical and organisational processes. A list of these persons is enclosed to 
DMP. 
Users with monitoring function are not able to enter or change data. They have the possibility to 
view the data write protected (review function) and they can raise discrepancies and/or SDV marks 
in case of queries. Discrepancies which appear at data management are forwarded to the site 
directly. 
 
10.4 Data concealment for electronic transfer 
 
Every investigator, study nurse, monitor or other person involved in the trial receives her or his 
personal login data (username and password). Access rights to the database will depend on the 
group affiliation. Every person who gets access to the system has to fill in a registration form (User-
ID request) and has to confirm that they have been adequately trained. Thus it is guaranteed that 
only authorized persons have access to the EDC system to document subjects in the trial. 
 
10.5 Database quality control 
 
Data have to be entered into the Medical database by the clinical investigator’s staff, using single 
data entry with electronic verification. The Medical database contains several completeness and 
plausibility data checks. During data entry these integrity checks help to minimize entry failures. 
They are programmed according to the data validation plan, signed by the coordinating 
investigator.Case report forms can only be stored after answer completeness and plausibility errors 
with correct data entries.  
The data entry system allows the trial monitors to control the entry process with the help of several 
eCRF-internal review functions. Comments and requests can be processed by the trial site just in 
time. Subsequently, the entered data are systematically checked by the monitors, using the 
internal query system of the Medical database, completeness reports and printable queries details 
lists. 
The investigator or a designated sub investigator, following review of the data in the eCRF, will 
confirm the validity of each subject’s data by electronic signature. The EDC system is capable to 
make exact copies of data in legible paper form for inspections and audits. Quality control audits of 
all key safety and efficacy data in the database are made prior to locking the database. 
Concomitant medications, medical history, current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
At the conclusion of the clinical trial, the occurrence of any protocol violations will be determined.  
After these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked for additional data entries and final checks for plausibility, consistency 
and completeness of the data will be performed. Based on these checks, final queries can be 
produced. Any missing data or inconsistencies will be reported back to the respective site and 
clarified by the responsible investigator. A database audit will be accomplished to ensure and 
document the high-quality trial database. If no further corrections are to be made in the database it 
will be declared closed and used for statistical analysis. 
 
10.6 Storage and archiving of data 
 
According to GCP, the investigator will archive all trial data (subject identification list, source data) 
and relevant correspondence in the Investigator Site File (ISF). The ISF, all source data and all 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
47 of 52 
 
documents itemized in section 8 of the ICH Consolidated Guideline on GCP will be archived after 
finalization of the trial according to the legal regulations. 
Responsible for storage and archiving of other trial data will be the Coordinating investigator. 
Storage and archiving of the electronic data during the trial will be assured by the Central 
Information Office Marburg. After completion of the trial all electronic data will be handed over to 
the sponsor. 
 
11 ETHICAL AND LEGAL ASPECTS  
11.1 Good clinical practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
good clinical practice (GCP) and the ethical principles described in the Declaration of Helsinki. The 
trial will be carried out in keeping with local legal and regulatory requirements. 
 
11.2 Patient information and informed consent 
Before being admitted to the clinical trial, the subject and/or the representatives must consent to 
participate after being fully informed about the nature, scope, and possible consequences of the 
clinical trial. The documents must be in a language understandable to the subject and 
representatives and must specify who informed the subject and the representatives. A copy of the 
signed informed consent document must be given to the subject or representative. The original 
signed consent document will be retained by the investigator. 
The investigator will not undertake any measures specifically required only for the clinical trial until 
valid consent has been obtained. If the subject has a primary physician the investigator should 
inform the subject’s primary physician about the subject’s participation in the trial and if the subject 
or his representatives agrees to the primary physician being informed. 
After reading the informed consent document, the subject must give consent in writing. The 
subject's consent must be confirmed by the personally dated signature of the subject and by the 
personally dated signature of the person conducting the informed consent discussions. 
 
Since the subjects in this trial are mostly children, the consent of both legally authorized 
representatives must be sought. Children who are able to understand the nature, scope, and 
possible consequences of the clinical trial must also give their informed consent. The consent must 
be confirmed by the personally dated signature of the representatives (and child, if applicable) and 
the personally dated signature of the person conducting the informed consent discussions. A copy 
or one of two originals of the signed consent document must be given to the representatives. The 
original signed consent document will be retained by the investigator. 
 
11.3 Confidentiality 
The name of the subjects and other confidential information will not be supplied to the sponsor. 
During the clinical trial, subjects will be identified solely by means of an individual identification 
code (e.g. subject number, randomization number). Trial findings stored on a computer will be 
stored in accordance with local data protection laws and will be handled in strictest confidence. For 
protection of these data, organizational procedures are implemented to prevent distribution of data 
to unauthorized persons. The appropriate regulations of data legislation will be fulfilled in its 
entirety. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
48 of 52 
 
The subject will declare in the written consent to release the investigator from the medical 
professional secrecy to allow identification of subject’s name and/or inspection of original data for 
monitoring purposes by health authorities and authorized persons (monitors). 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
11.4 Responsibilities of investigator 
The investigator will ensure that all persons assisting in the trial are adequately informed about the 
protocol, any amendments to the protocol, the trial treatments, and their trial-related duties and 
functions. The investigator will maintain a list of sub investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties. 
 
11.5 Approval of trial protocol and substantial amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents will be submitted to the independent ethics committee (IEC) for approval. 
The documents will also be submitted to the competent authorities (in Germany approval by 
BfArM), in accordance with the respective local legal requirements. 
Investigational products can only be supplied to the investigator after documentation on all ethical 
and legal requirements for starting the clinical trial has been received by the sponsor (“regulatory 
green light”). Before the first subject is enrolled in the trial, all ethical and legal requirements must 
be met. The IEC and, if applicable, the competent authorities must be informed of all subsequent 
protocol amendments, in accordance with the respective local legal requirements. The sponsor 
must keep a record of all communications with the IEC and the competent authorities. The EC 
must be informed of the end of the trial in accordance with legal requirements. 
 
11.6 Submission to local regulatory/competent authorities 
Before the start of trial, the sponsor is responsible for submission of all documents necessary to 
the competent authorities for approval, in accordance to the respective local legal requirements.  
 
11.7 Data monitoring committee (DMC) 
Details will be specified in the charter of the DMC. 
 
11.8 Insurance 
According to legal requirements, the sponsor has to subscribe an insurance policy covering, in its 
terms and provisions, its legal liability for injuries caused to participating persons and arising out of 
this research performed strictly in accordance with the scientific protocol as well as with applicable 
law and professional standards.  
Any impairment of health which might occur in consequence of trial participation must be notified to 
the insurance company. The subject is responsible for notification. The insured person will be 
agreed to all appropriate measures serving for clarification of the cause and the extent of damage 
as well as the reduction of damage. 
During the conduct of the trial, the subject must not undergo other clinical treatment except for 
cases of emergency. The subject is bound to inform the investigator immediately about any 
adverse events and additionally drugs taken. The terms and conditions of the insurance should be 
delivered to the subject. 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
49 of 52 
 
Insurance provisions for this clinical trial are given in separate agreements. 
11.9 Agreements 
11.9.1 Financing of the trial 
The trial is part of the EU research projects chILD EU, E-Rare 2016 and the DZL 2.0. 
The general conditions of financing for this trial are given in separate agreements. 
 
11.9.2 Report 
After conclusion of the trial, a report shall be written by the sponsor, in cooperation with the 
coordinating investigator. The report will include a statistical analysis and an appraisal of the 
results from a medical viewpoint. It will be based on the items listed in this trial protocol. 
 
11.9.3 Publication policy  
It is planned to publish the results of the trial as an original article in an appropriate medical journal 
as well as presentation at congresses. The Principal Investigator is first author of the article and 
will present the data at the major congresses. The choice of the journal for the publication will be 
made by the Principal Investigator in agreement with the co-authors. Besides the Principal 
Investigator, further authors of this article have to meet the following points: 
 Substantial contribution to the recruitment of subjects, i.e. one of the five best recruiting centers 
within the trial. 
 Substantial contribution to interpretation of the data. 
 Substantial contribution to drafting the article or revising it critically for important intellectual 
content. 
All details regarding authorship are given in the Contract with Participants in the European child 
Registry (chILD-EU) Research Project, which was signed by each participant involved in the 
study 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
50 of 52 
 
12 SIGNATURES 
The present trial protocol was subject to critical review and has been approved in the present 
version by the persons undersigned. The information contained is consistent with: 
 The current risk-benefit assessment of the investigational medicinal product.  
 The moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP. 
 
 
 
Coordinating/Principal Investigator 
Prof. Dr. M. Griese 
 
 
 
 
_________________  
_____________________________________ 
Date 
 
 
 
Signature 
 
 
Trial coordination 
Dr. Kai Kronfeld 
 
 
 
 
_________________  
_____________________________________ 
Date 
 
 
 
Signature 
 
 
Biometrician 
Christian Ruckes, MSc 
 
 
 
_________________  
_____________________________________ 
Date 
 
 
 
Signature 
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
51 of 52 
 
13 DECLARATION OF INVESTIGATOR 
I have read the above trial protocol and I confirm that it contains all information to accordingly 
conduct the clinical trial. I pledge to conduct the clinical trial according to the protocol. 
I will enrol the first subject only after all ethical and regulatory requirements are fulfilled. I pledge to 
obtain written consent for trial participation from all subjects. 
I know the requirements for accurate notification of serious adverse events and I pledge to 
document and notify such events as described in the protocol. 
I pledge to retain all trial-related documents and source data as described. I will provide a 
Curriculum Vitae (CV) before trial start. I agree that the CV may be submitted to the responsible 
competent authorities. 
I will conduct the trial in compliance with the protocol, GCP and the applicable regulatory 
requirements.  
 
 
 
Investigator 
Name  
Address 
 
Phone  
Fax 
 
e-Mail  
 
 
_________________  
_____________________________________ 
Date 
 
 
 
Signature 
 
 
Sub investigator 
Name  
Address 
 
Phone  
Fax 
 
e-Mail  
 
 
_________________  
_____________________________________ 
Date 
 
 
 
Signature 
 
 
 
 
 

EudraCT: 2013-003714-40 
IZKS Trial Code: 2013-006 
Version 3.1 Date 27.07.2017 
final 
 
 
CONFIDENTIAL 
52 of 52 
 
14 REFERENCES 
 
1. Bush A, Nicholson A.G.. Paediatric interstitial lung disease. Eur Respir Mon, 2009, 46, 1–
36. 
2. Clement A, Nathan N, Epaud R, Fauroux B, Corvol H. Interstitial lung diseases in children. 
Orphanet J Rare Dis. 2010 Aug 20;5:22.  
3. de Benedictis FM, Bush A. Corticosteroids in respiratory diseases in children.  
Am J Respir Crit Care Med. 2012 Jan 1;185(1):12-23.  
4. Diav-Citrin O, Blyakhman S, Shechtman S, Ornoy A. Pregnancy outcome following in utero 
exposure to hydroxychloroquine: A prospective comparative observational study. Reprod 
Toxicol. 2013;39C:58-62. 
5. Fachinformation Quensyl®. Sanofi-Aventis Deutschland GmbH 2017. 
6. Griese M, Haug M, Brasch F, Freihorst A, Lohse P, von Kries R, Zimmermann T, Hartl D. 
Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany. 
Orphanet J Rare Dis. 2009 Dec 12;4:26.  
7. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. Kidney Int Suppl 2013; 3:1. 
8. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: 
evaluation, classification, and stratification. Am J Kidney Dis 2002; 39(Suppl 1):S1-S266. 
Table 24 (page S56).