Conditions: Neuroblastoma
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: no

Brief summary:
An open label, randomised, multiple dose, cross-over relative bioavailability and pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered to patients from 0 months - \< 21 years.

Detailed description:
All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment into the trial.

13-CRA will be prescribed to patients according to local treatment protocols at each clinical site. The dose administered will be 200mg/m2/day for both test and reference product. Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2/day.

The pharmacokinetics of 13-CRA liquid (test product) and extracted from capsule (reference product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as part of the trial, patients will be randomised to receive either liquid or capsule formulation in "My-CRA month 1". The patients will then cross-over to the alternative formulation in "My-CRA month 2". The patients on the trial who require further treatment will revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.

Arms:
arm 1: Oral liquid formulation of 13-Cis Retinoic Acid - test product. arm 2: Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.

Interventions: intervention 1: Liquid 13-Cis Retinoic Acid intervention 2: Extracted capsules 13-CRA
Intervention descriptions: intervention 1: Liquid 13-Cis Retinoic Acid intervention 2: Extracted capsules 13-CRA

Protocol document:
Prot_000.pdf: 














CONFIDENTIAL                             Nova Laboratories Limited                                            Page 8 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
TABLE OF CONTENTS 
ADMINISTRATIVE STRUCTURE ................................................................................................................... 2 
SPONSOR SIGNATURE SHEET ...................................................................................................................... 4 
MEDICAL ADVISOR SIGNATURE SHEET ................................................................................................... 5 
STATISTICS SIGNATURE SHEET .................................................................................................................. 6 
CHIEF INVESTIGATOR SIGNATURE SHEET ............................................................................................. 7 
TABLE OF CONTENTS ..................................................................................................................................... 8 
SYNOPSIS ........................................................................................................................................................... 10 
ABBREVIATIONS ............................................................................................................................................. 14 
1. 
INTRODUCTION ....................................................................................................................................... 15 
THE NEED FOR A LIQUID FORMULATION ....................................................................................................................15 
LIQUID FORMULATION OF 13-CIS-RETINOIC ACID .....................................................................................................15 
BENEFITS AND RISKS ................................................................................................................................................16 
JUSTIFICATION FOR THE ROUTE OF ADMINISTRATION, DOSAGE AND TREATMENT PERIOD ........................................16 
1.1.1. 
Route ......................................................................................................................................................16 
1.1.2. 
Dosage ...................................................................................................................................................16 
1.1.3. 
Treatment period ...................................................................................................................................17 
2. 
AIM AND OBJECTIVES .......................................................................................................................... 17 
2.1 
PRIMARY OBJECTIVE .......................................................................................................................................17 
2.2 
SECONDARY OBJECTIVES ................................................................................................................................17 
3. 
TRIAL DESIGN .......................................................................................................................................... 17 
3.1 
EXIT POINTS ....................................................................................................................................................17 
3.2 
TYPE OF TRIAL ................................................................................................................................................17 
3.3 
EXPECTED DURATION OF PATIENT PARTICIPATION ..........................................................................................18 
3.4 
TRIAL SCHEMATIC AND SCHEDULE .................................................................................................................18 
3.5 
DATA TO BE RECORDED ON THE CASE REPORT FORM ......................................................................................19 
4. 
TRIAL PROCEDURES ............................................................................................................................. 20 
4.1 
DEMOGRAPHY .................................................................................................................................................20 
4.2 
MEDICAL HISTORY .........................................................................................................................................20 
4.3  
PHYSICAL EXAMINATION ...............................................................................................................................20 
4.4 
SAFETY LABORATORY ASSESSMENTS .............................................................................................................20 
4.5 
PREGNANCY PREVENTION ...............................................................................................................................21 
4.6 
13-CRA DOSING AND BLOOD SAMPLING FOR PHARMACOKINETIC ANALYSES ...............................................21 
4.7 
VITAL SIGNS ...................................................................................................................................................22 
4.8 
PALATABILITY ASSESSMENTS .........................................................................................................................22 
4.9 
TOLERABILITY ASSESSMENTS .........................................................................................................................22 
4.10 
OROPHARYNGEAL TOLERABILITY ................................................................................................................23 
5. 
SELECTION OF PATIENTS .................................................................................................................... 23 
5.1 
INCLUSION CRITERIA .......................................................................................................................................23 
5.2 
EXCLUSION CRITERIA ......................................................................................................................................23 
5.2 
CRITERIA PRIOR TO STARTING EACH CYCLE OF 13-CRA ................................................................................24 
5.3 
WITHDRAWAL CRITERIA .................................................................................................................................24 
6 
TREATMENT OF PATIENTS .................................................................................................................. 24 
6.1 
EVALUATION OF TEST AND REFERENCE TREATMENT ......................................................................................24 
6.2 
PERMITTED MEDICATIONS ...............................................................................................................................25 
6.3 
MONITORING COMPLIANCE .............................................................................................................................25 
6.4 
EXIT POINTS ....................................................................................................................................................25 
6.5 
EXPECTED DURATION OF PATIENT PARTICIPATION ..........................................................................................25 
7 
INVESTIGATIONAL MEDICINAL PRODUCT .................................................................................... 26 
7.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................................................26 
7.3 
13-CRA DOSING .............................................................................................................................................26 
7.4 
PACKAGING AND LABELLING ..........................................................................................................................27 
7.5 
PREPARATION, HANDLING AND STORAGE .......................................................................................................27 
7.6 
INVESTIGATIONAL MEDICINAL PRODUCT ACCOUNTABILITY ...........................................................................27 
8 
PREMATURE DISCONTINUATION FROM TRIAL ........................................................................... 28 
8.1 
EARLY DISCONTINUATION OF AN INDIVIDUAL PATIENT .................................................................................28 
8.2 
EARLY DISCONTINUATION OF THE TRIAL .......................................................................................................28 
8.3 
PATIENT AND TRIAL COMPLETION ..................................................................................................................28 
9 
ASSESSMENT OF SAFETY ...................................................................................................................... 28 
9.1 
DEFINITION OF ADVERSE EVENTS ....................................................................................................................29 
9.2 
EXPECTED AE IN 13-CIS-RETINOIC ACID RECIPIENTS ......................................................................................29 






CONFIDENTIAL                             Nova Laboratories Limited                                            Page 11 of 50 
 
 
 
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Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
more than seven days before initiation of treatment, and sexually 
active patients and partners agreeing to undertake adequate 
contraceptive measures (see section 4.5). 
6. Provision of a single or double lumen central venous catheter for 
sampling (i.e. already in place). 
7. Parent(s)/legal guardian able and willing to provide written 
informed consent for the patient to take part in the trial.  
8. Where applicable, the patient should assent to undergo blood 
sampling for pharmacokinetic purposes and to allow physiological 
measurements to be made. 
EXCLUSION CRITERIA: 
1. Any clinically significant medical condition or abnormality, 
which, in the opinion of the investigator, might compromise the 
safety of the patient or which might interfere with the trial. 
2. Diagnosis of high-risk neuroblastoma (HRNBL) which is 
currently being treated on the SIOPEN HRNBL trial (patients who 
have exited this trial will be eligible). 
3. Known allergy to 13-CRA or any of the excipients. 
4. Inadequate contraception measures in females of childbearing age. 
5. Receiving concomitant treatment with tetracyclines. 
CRITERIA PRIOR TO 
STARTING EACH CYCLE OF 
13-CIS-RA 
1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. 
Veno-occlusive disease if present, should be stable or improving. 
2. Skin toxicity no greater than CTCAE Grade 1(10) 
3. Serum triglycerides <5.65mmol/L. 
4. No haematuria and / or proteinuria on urinalysis. 
5. Serum calcium ≥ 2.0mmol/L to ≤ 2.9mmol/L. 
6. Serum creatinine based on age / gender as follows: 
Age 
Maximum Serum Creatinine 
µmol/L 
  
Male 
Female 
1 month to < 6 months 
35 
35 
6 months to < 1 year 
44 
44 
1 to < 2 years 
53 
53 
2 to < 6 years 
70 
70 
6 to < 10 years 
88 
88 
10 to < 13 years 
106 
106 
13 to < 16 years 
132 
124 
≥ 16 years 
150 
124 
 
7. Patients with a seizure disorder must be well controlled and taking 
anticonvulsants.  CNS toxicity < grade 2 (CTCAE). 
WITHDRAWAL CRITERIA: 
1. Positive pregnancy test - pregnancy testing will be undertaken no 
more than seven days before treatment commences and routinely 
no more than seven days before each course of treatment in 
females of childbearing potential.  If a patient is found to be 
pregnant during the trial, the next course of treatment will not be 
given until the pregnancy has been discussed with the treating 
clinician, and the patient will be withdrawn from the trial whether 
or not treatment is continued. 
2. Request of the patient, for any reason. 
3. Discretion of the investigator. 
TREATMENT STRATEGY: 
All patients requiring at least two cycles of 13–CRA therapy will be 
eligible for recruitment into the trial. 
 
13–CRA will be prescribed to patients according to local treatment 
protocols at each clinical site. The dose administered will be 
200mg/m2/day for both test and reference product. Patients with a body 
weight of ≤12kg will receive a dose of 160 mg/m2. 
 
The pharmacokinetics of 13–CRA liquid (test product) and extracted 
capsule (reference product) will be evaluated over two months.  Prior 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 12 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
to the initiation of 13–CRA treatment as part of the trial, patients will 
be randomised to receive either liquid or capsule formulation in “My-
CRA month 1”. The patients will then cross-over to the alternative 
formulation in “My-CRA month 2”. The patients on the trial who 
require further treatment will revert to standard therapy i.e. extracted 
capsules according to local practice. 
ENDPOINTS: 
Primary Endpoints: 
Pharmacokinetic parameters (13-CRA) 
Primary parameters: 
• 
Relative bioavailability 
• 
Clearance (CL/F), 
• 
Volume of distribution (V/F) 
Secondary parameters: 
• 
Time to maximum concentration (Tmax), 
• 
Maximum plasma concentration (Cmax), 
• 
Area under plasma concentration time curve (AUC), 
• 
Half-life (t1/2) 
• 
Levels of the metabolite 4-oxo-13-cis-RA. 
  
Secondary Endpoints: 
Safety parameters 
• 
Evaluate the local (oro–pharyngeal) tolerability 
• 
Skin toxicity 
• 
Hypercalcaemia 
• 
Hepatotoxicity 
• 
Triglycerides  
 
Oro-pharyngeal adverse event data will be listed as adverse events and 
separately summarised. 
 
Palatability and Acceptability:  
Evaluate the taste acceptability of the new oral liquid formulation of 
13-CRA. 
ADVERSE EVENTS 
All adverse events that occur during the duration of therapy will be 
recorded and reports per regulatory health authority requirements.  All 
serious adverse events (SAEs) will be followed until resolution or 
stabilisation. 
 
PROCEDURE 
It is anticipated that all patients recruited into the trial will have a 
central line in situ. 
 
Patients will attend the site clinic on Pharmacokinetic Trial Days: 
 
Month 1: Day 1 and Day 14 
Month 2: Day 1 and Day 14 
 
On the day of sampling, 13-CRA (reference or test) will be 
administered in the clinic by a research nurse. Blood (2 ml) will be 
sampled post-dose at time points selected as follows: 
 
Time point (h) 
0.5 (Day 1 and Day 14) 
1 
1.5 
*2 
3 
4 
5 
*6 
**24-48 (Day 15 or 16) 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 13 of 50 
 
 
 
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Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
*The 2 hour and 6 hour samples are mandatory, with at least three 
further samples (where possible) selected over 0.5 to 5 hours.  
**Sample at 24-48 hours applies only to the final dose administered on 
Day 14 to allow the elimination phase of 13-CRA to be calculated.  For 
individual patients sampling times should remain the same across each 
of the four PK days, where possible.  
 
PATIENTS DURATION: 
Patients will be administered twice daily doses of 13-CRA for the 
duration of the trial.  Evaluation of the test and reference product will 
occur over two months of therapy.  Individual patient’s participation 
will therefore be for 2 months.  The whole trial recruitment period is 
estimated to be approximately 12 to 18 months from initiation. 
 
STATISTICAL METHODS 
The data from all patients taking part in the trial will be pooled and 
analysed simultaneously to avoid excessive blood sampling. 
Population pharmacokinetic parameters will be estimated by using a 
non-linear, mixed effects modelling approach.   
In the population approach all data from different individuals are fitted 
simultaneously using a non-linear, mixed effects modelling approach 
and post hoc individual kinetic parameters can be calculated with as 
few samples as one per individual. An appropriate software package 
such as NONMEM will be used to conduct the analysis.  
 
Preliminary analyses will focus on the structural and variance models. 
One and two compartment models with first and zero order inputs will 
be implemented. Between patient variability will be assumed to be log-
normally distributed, and residual error will be modelled using 
additive, proportional and combined error structures. 
 
Adverse events will be coded according to the current version of 
MedDRA.  Reporting of the safety data will be of a descriptive nature 
and presented using summary statistics. 
 
Analysis will be planned and documented in the Statistical Analysis 
Plan.  
 
Data Safety Monitoring 
Committee (DSMC) 
An independent Data Safety Monitoring Committee will be formed to 
alert and/or make recommendations to The Sponsor about any existing 
or potential safety issues. 
 
 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 14 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
ABBREVIATIONS 
13-CRA 
13-Cis Retinoic Acid 
AE 
 
Adverse event 
AUC 
 
Area under the plasma drug concentration-time curve extrapolated to infinity 
AUC0-24  
Area under the plasma drug concentration-time curve from zero to 24 hours 
 
Cmax 
 
Maximum observed plasma concentration 
CL/F 
 
Apparent plasma clearance following intranasal administration 
CRF 
 
Case report form 
CQC 
 
Care Quality Commission  
%CV 
Coefficient of Variation calculated using 
, where s2 is the variance of the 
log transformed data 
 
FBC 
 
Full blood count 
 
GCP 
 
Good clinical practice 
GLP 
 
Good laboratory practice 
 
HRNBL 
High Risk Neuroblastoma 
HR-NBL-1.7/SIOPEN current treatment trial for HRNBL 
 
IEC 
 
Independent ethics committee 
IM 
 
Intramuscular 
IMP 
 
Investigational medicinal product 
IV 
 
Intravenous 
 
kg 
 
kilogram 
 
LFT’s  
Liver function tests 
 
MHRA Medicines & Healthcare products Regulatory Agency 
ml 
 
millilitre 
 
NHS 
 
National Health Service 
NPSA  
National Patient Safety Agency 
 
PD 
 
Pharmacodynamics 
PK 
 
Pharmacokinetics 
 
SAE 
 
Serious adverse event 
SIOPEN 
International Society of Paediatric Oncology Europe Neuroblastoma 
Sponsor 
Nova Laboratories Limited 
SUSAR Suspected unexpected serious adverse reaction 
 
TEAE  
Treatment emergent adverse event 
t½ 
 
The terminal half-life of the drug in plasma 
 
VAS 
Visual Analogue Scale 
V / F 
Apparent central compartment volume of distribution 
 
WHO  
World Health Organisation 
1
100
2 −
×
se


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 15 of 50 
 
 
 
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Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
1. 
INTRODUCTION  
The need for a liquid formulation 
Neuroblastoma (NBL) is an aggressive cancer that predominantly affects children aged 5 years 
or less.  It is an orphan disease (incidence ~ 10 cases per million children; 1 case per 500,000 
general population) that still has poor outcomes. 
Children who present with metastatic NBL (approximately 50% of cases) are most commonly 
treated with myelo-ablative chemotherapy followed by stem-cell rescue and, to eradicate 
‘minimal residual disease’ post rescue, 13-cis-retinoic acid (13-CRA, isotretinoin) usually 
alongside immunotherapy.  Given by the enteral route, at a dose of 80 mg/m2 twice daily, in 2-
week cycles for 6 months 13-CRA has been shown in clinical trials to improve event-free 
survival.  Thus, most clinicians accept 13-CRA as frontline therapy for patients with NBL in 
remission.  
However, 13-CRA is not licensed for NBL in any region or country in the world and is currently 
available only as a gelatin capsule that children are often unwilling and / or unable to swallow. 
Presently, carers have to ‘open’ capsules of 13-CRA, and squeeze the contents into foods.  As 
few young children will take capsules, carers often have to administer 13-CRA by first extracting 
liquid out of the capsule.  Studies show that the current method of administration results in 
marked variability in drug exposure between patients and significantly lower plasma 
concentrations in patients receiving the extracted drug as compared to those able to swallow the 
capsules whole (1).  Furthermore, since 13-CRA can cause birth defects, pregnant women (e.g. 
parent of a child with NBL) risk accidently exposing their unborn babies when extracting 13-
CRA from capsules. 
No manufacturer has yet developed a child-friendly preparation of 13-CRA. Nova Laboratories 
Limited is developing a new oral liquid dosage form of 13-CRA, which will facilitate more 
consistent and accurate dosing and improve palatability for children.   
This trial aims to investigate the relative bioavailability and comparative pharmacokinetics of the 
new oral liquid and existing capsule formulations of 13-CRA in patients. Any patient requiring at 
least two treatment cycles with 13-CRA will be eligible for the trial.  The local oropharyngeal 
tolerability, the palatability and acceptability of the formulation will also be assessed. 
The trial will be conducted in compliance with the protocol, ICH GCP and the applicable 
regulatory requirement(s). 
Liquid formulation of 13-cis-retinoic acid 
13-CRA is a derivative of vitamin A.  It induces differentiation and growth arrest of malignant 
NBL cells in vitro through binding to retinoid acid receptors and altered gene transcription (2).  
Currently, the only licensed formulation of 13-CRA is a gelatin capsule with an indication for 
severe acne.   
In patients with NBL the optimal therapeutic blood level for 13-CRA is thought to lie between 2-
10 µM (3,4,5).  At blood concentrations above 10µM, there is an increased frequency of toxicity 
reactions (6).   Studies indicate that children able to chew and / or swallow 13-CRA capsules are 
significantly more likely to achieve target concentrations than those who have the drug extracted 
from capsules prior to administration.  Hence, ‘method of administration’ is a key factor in 
achieving adequate blood levels of 13-CRA.  Since dosing with 13-CRA is not adjusted 
according to blood levels, inherent variability in dose delivery associated with extracting drug 
from capsule runs the risk of under- and over- dosing of drug (1). A child appropriate oral liquid 
formulation of 13-CRA should reduce inter- and intra- patient variability in blood 13-CRA levels 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 16 of 50 
 
 
 
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Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
currently seen in patients dosed using the “drug extraction method”.  Since 13-CRA is a known 
teratogen, women of childbearing age are required to have a negative no more than seven days 
test prior to starting 13-CRA and use of effective contraception during therapy and for 3 months 
after cessation of treatment. The oral liquid product will also not pose the same level of 
teratogenic risk for mothers who currently have to extract drug from capsules. Hence, an oral 
liquid 13-CRA formulation for enteral use would be flexible and child- and carer- friendly. It 
would also allow for dosing by oral and naso-gastric routes. 
Benefits and Risks 
The importance and potential benefits of this work to parents, carers and healthcare professionals 
is clear.  The burden of accurately dosing and administering 13-CRA extracted from capsules 
can only really be described by those intimately involved in this practice.  Many healthcare 
professionals would struggle to perform this task even under ideal conditions.  
Any risks associated with taking blood samples from the central line for pharmacokinetic 
analysis are minimised by following the established aseptic guidelines practiced by the paediatric 
oncology unit. The number of pharmacokinetic blood samples have been minimised by utilising 
a sparse sampling population pharmacokinetic modelling approach. However, if the number of 
samples does cause disruption or irritation to the patient, the patient may be withdrawn from the 
trial. 
Justification for the route of administration, dosage and treatment period 
1.1.1. Route 
13-CRA is administered during the remission phase in the treatment of HRNBL between cycles 
of immunotherapy and also in patients with unresectable, intermediate risk neuroblastoma with 
unfavourable INPC histology and in patients with relapsed and refractory disease who have not 
already received 13-CRA. It is administered orally, currently using the capsule form licensed for 
severe acne.   
It is clear that many young children will not take solid medicines (tablets, capsules).  Potential 
solutions to this issue include developing a liquid for parenteral use, a medicine to be 
administered by the rectal route and a transdermal drug.    While there are other potential 
solutions, the oral liquid preparation meets important criteria for this medicine including flexible 
dosing, ease of use, minimal additional risk to patient and carer and patient comfort.  
1.1.2. Dosage 
The dose administered is in accordance with approved practice for 13-CRA extracted capsules. 
This is based on previous studies have shown that the dose obtained from extracted capsules 
needs to be adjusted to 200mg/m2/day in order to achieve the same blood level as that seen for 
capsules that have been swallowed whole (1).  Therefore the dose used in this trial will be 
200mg/m2/day for both test and reference product. Patients with a body weight of ≤12kg will 
receive a dose of 160 mg/m2. 
Patients with HRNBL may be included in the European SIOPEN HRNBL trial (7), which 
includes treatment with 13-CRA during the maintenance phase.  These patients will be excluded 
from the My-CRA trial in order to ensure that the trial endpoints for the SIOPEN clinical trial 
are not compromised.  Patients who are ineligible for the SIOPEN high risk trial, have exited the 
SIOPEN trial, or patients ≥ 18 months with unresectable, intermediate risk neuroblastoma with 
unfavourable INPC histology who may benefit from at least two cycles of 13-CRA will be dosed 
according to the currently approved local guidelines.  
 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 17 of 50 
 
 
 
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1.1.3. Treatment period 
All patients requiring 13-CRA therapy, who are unable to swallow 13-CRA capsules, will be 
eligible for recruitment into the trial. 
The pharmacokinetics of 13-CRA liquid (test product) and extracted capsule (reference product) 
will be evaluated in over a two month period to allow for two cycles of treatment in a cross over 
design (one test treatment period and one reference treatment period).  The 14-day treatment 
period and two week break between treatment cycles is based upon previous studies (7) and is 
the standard treatment period for cycles of 13-CRA. If patients require a longer period of time 
between treatments then this will be acceptable within the visit windows (i.e. treatment period 2 
will be within 14 +up to 7 days of completion of treatment period 1). 
Prior to the initiation of the trial 13-CRA, patients will be randomised to receive either liquid or 
extracted capsule formulation in “My –CRA month 1”.  The patients will then cross-over to the 
alternative formulation in “My-CRA month 2”.  After the trial if a patient requires additional 
cycles of 13-CRA, the patient will revert to standard 13-CRA therapy i.e. extracted capsules 
according to local practice. 
2. 
AIM AND OBJECTIVES 
The aim of this trial is to investigate the pharmacokinetics, safety, tolerability and palatability of 
oral liquid 13-CRA in patients aged from 0 months – < 21 years.   
2.1 
Primary objective 
• To determine the relative bioavailability and pharmacokinetics of 13-CRA administered 
as oral liquid and extracted capsule formulations. 
2.2 
Secondary objectives 
• To determine the safety and tolerability. 
• To assess palatability and acceptability. 
3. 
TRIAL DESIGN 
3.1 Exit points 
The normal exit point from this trial will be when the patient completes the follow up of the 
second treatment period, i.e. when the patient returns to clinic for their next treatment course or 
for their next clinic review (it is anticipated that this will be approximately two to three weeks 
following 13-CRA treatment), all adverse events will be followed up to conclusion. 
All patients who have at least one blood sample taken for the pharmacokinetic trial will be 
included in the population pharmacokinetic analysis.  If the parent(s)/legal guardian or patient 
refuses further blood sampling the patient will be withdrawn from the trial. 
3.2 Type of trial 
This is an open label, randomised, multiple dose, cross-over relative bioavailability and 
pharmacokinetics trial of oral 13–CRA liquid administered to patients aged from 0-< 21 years. 
The decision to initiate 13-CRA therapy will be taken independently of this trial protocol.  The 
trial will be conducted in patients who are attending the hospital for treatment for neuroblastoma 
requiring at least two cycles of 13-CRA.  13–CRA will be prescribed to patients according to the 
locally approved treatment protocols at a dose of 200mg/m2/day for both test and reference 
product.  Oral 13–CRA is administered for NBL (this is usually at a dose of 160mg/m2) for 14 
days, every 4 weeks, for 6 months, however where the dose is extracted from capsules this dose 


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Protocol Number: INV500                                       
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is increased to 200mg/m2.  In this trial the dose of 13-CRA will be 200mg/m2 as patients able to 
swallow the capsules will not be recruited to the trial.  Patients with a body weight of ≤12kg will 
receive a dose of 160 mg/m2. Patients who require their dose through a nasogastric tube or 
gastromy will be included in the trial, this will be recorded in the case record form. 
When an appointment is made for the patient to attend the hospital clinic for initiation of 13-
CRA treatment the parent(s)/legal guardian of the patient will be approached to discuss the 
pharmacokinetic trial and the possibility of the patient’s entry into the trial; information 
regarding the trial may be sent to parents and patients prior to them attending.  The 
parent(s)/legal guardian’s consent to take these additional blood samples and record 
physiological information (local [oro-pharyngeal] tolerability, skin toxicity, adverse events) will 
be sought.  Following parental consent, the patient will be approached and the trial procedures 
explained to them in order to receive their verbal and/or written assent to participate in the trial, 
if applicable (usually where the patient is over 7 years of age).  Parents and patients may still 
refuse to participate in the trial at any stage prior to or during their treatment with 13-CRA.  
Parents and patients will be given as much time as they need to consider participation in the trial. 
Patients and parents may choose to share information about the research with their family or GP 
before they decide if they would like to take part in the trial.  Investigators will ensure that 
families have at least 24 hours to consider involvement in the trial.  In practice this is likely to be 
longer as parents and patients are most likely to be approached well in advance of their 13-CRA 
treatment period.  If the parent(s)/legal guardian decide that they would not like their patient to 
participate in the trial then this will in no way affect the onward care of the patient. 
When the patient attends hospital for initiation of 13-CRA treatment, it is anticipated that they 
will have a central line in situ.  Patients will attend the clinic on Pharmacokinetic days; these will 
be Day 1 and Day 14 for each of the trial treatment periods.  Blood samples for pharmacokinetic 
analysis will be taken over the course of six hours after which the patients will leave the clinic.  
Parents and patients will be asked if they are willing to return for an additional sample at 24-48 
hours following their final dose on Day 14 of treatment. 
Additional assessments will be made according to the trial procedures (section 4). 
A trial schedule is presented in Appendix I. 
3.3 Expected duration of patient participation 
Patients will be administered twice-daily doses of 13-CRA for the duration of the trial.  
Evaluation of the test and reference product will occur over two months of therapy.  Individual 
patient’s participation will therefore be 2 months, including a two-week follow-up. 
3.4 
Trial schematic and schedule 
A trial schematic for individual patients is presented in Figure 3.4 and a full schedule is 
presented in Appendix I.  




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• 
Precise time of blood sampling. 
• 
Details of any local oro-pharyngeal tolerability (recorded as adverse events if 
appropriate).  Oro-pharyngeal tolerability will be assessed before and after dosing.  Any 
oro-pharyngeal adverse events will be recorded on the trial diary card. 
• 
Palatability.  This will be assessed at Day 14 in the clinic using a palatability 
questionnaire that will be completed by the patient/patient’s parents (depending on the 
age of the patient). 
• 
Adverse events – all events occurring during the timeframe of the trial and for a period 
of 14 days afterwards (on the trial diary card). 
• 
Serious adverse events – all events regarded as serious during course of trial and until 
resolution. 
• 
Trial withdrawal information, if applicable. 
• 
Date and time of trial discharge (i.e. when the patient completes the period of follow up). 
4. 
TRIAL PROCEDURES 
4.1 
Demography 
The following demographic characteristics will be recorded at the visit: age, sex, race, height, 
weight. 
4.2 
Medical History  
Oncology history and treatment will be recorded to confirm eligibility.  Additional relevant 
medical history during the four weeks prior to the trial will be recorded. This will include all 
current conditions by diagnosis (where possible) and any concomitant medication. 
4.3  
Physical Examination  
A qualified medical practitioner will carry out a general physical examination.  This will involve 
an external examination of the cardiovascular, respiratory and gastro-intestinal systems.  This 
will be performed at baseline prior to treatment to ensure no concurrent conditions exist that may 
exclude the patient from the trial.  
4.4 
Safety Laboratory Assessments 
Measurement of the haematological and biochemical parameters will be carried out prior to each 
course of 13-CRA treatment in line with standard of care.  Additional and/or more frequent 
clinical assessments and laboratory tests may be carried out at the discretion of the investigator 
in line with standard of care.  Safety laboratory tests will not be undertaken as part of the trial 
protocol, however results of routine laboratory tests may be collected as part of the safety 
assessment of the two treatment periods.  Any findings that the investigator considers to be an 
adverse event* will be recorded on the case record form (specifically for the following 
parameters): 
• 
Full blood count including haemoglobin, white blood cell, neutrophil, lymphocyte and 
platelet counts.  
• 
Renal and liver function (Na, K, Ca, Mg, PO4, urea, creatinine, glucose, total protein, 
bilirubin, transaminases) 
• 
Serum lactate dehydrogenase (LDH) 
* Abnormal laboratory values or test results will generally constitute adverse events only if they 
induce clinical signs or symptoms or require therapy, although investigators may report any 
laboratory finding or test result that they consider to be clinically relevant.  


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4.5 
Pregnancy Prevention 
For women of childbearing potential all conditions of the Pregnancy Prevention Programme 
should be met (8). Patients of childbearing potential, their partners and parents must understand 
and accept the need for effective contraception, be informed and understand the potential 
consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.  
Female patients of childbearing age must be provided with comprehensive information on 
pregnancy prevention and should be referred for contraceptive advice if appropriate. As part of 
the standard clinical care, female patients of childbearing potential will undergo a pregnancy test 
no more than seven days prior to the start of treatment and routinely no more than seven days 
before each course of treatment. Although the likelihood of pregnancy in patients receiving 13-
CRA is extremely low, if a positive pregnancy test does result during the trial, the next course of 
treatment will not be given until the pregnancy has been discussed with the treating clinician, and 
the patient will be withdrawn from the trial whether or not treatment is continued. 
4.6 
13-CRA Dosing and Blood sampling for Pharmacokinetic analyses 
All patients recruited into the trial will already have a central line in situ.  
Patients will receive their first morning dose of 13-CRA according to standard practice (for 
capsules by extracting the medicine from the capsule), or according to liquid dosing instructions, 
and will include a drink of water (volume to be included in dosing instructions) after dosing.  
Dosing instructions (including which foods such as yogurt or ice cream can be given with the 
medicine) for both medicine extracted from capsules and liquid will be provided to the site in a 
separate dosing manual, this document will be version controlled and retained in the trial files at 
site. 
The pharmacokinetic profile of 13-CRA post dosing will be evaluated.   
At least five blood samples (2ml) will be (where possible) taken post-dose at the time-points 
specified in Table 4.6 below.  In patients under two years of age, up to three samples at 
appropriate sampling times will be taken.  Sampling times in the patients under 2 years of age 
will be discussed with the Sponsor prior to the trial PK sampling days in order to ensure an even 
spread of sampling times in this younger population of patients.  Arrangements will be discussed 
and agreed in writing (or by email) on an individual basis for this group. 
Table 4.6 Blood Sampling Schedule 
 Time point (h) 
Requirements 
 0.5 (Day 1 and Day 14) 
*Two and six hour samples are mandatory.  
 
At least three further samples will be selected  
over 0.5 to 5 hours (where possible).  
 
**Sample at 24-48 hours applies only to the final dose 
administered on Day 14 to allow the elimination phase of 
parent and metabolite(s) to be calculated.  For individual 
patients sampling times should remain the same across 
each of the four PK days, where possible. 
1 
1.5 
2 
3 
4 
5 
6 
24-48 (Day 15 or 16) 
 
Flushing of the central line with normal saline and allowance for dead space will be performed 
according to local practice. 


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2.0 ml blood samples will be taken and processed immediately according to the technical manual 
and laboratory kit provided to the trial staff.  This technical manual will be version controlled 
and retained in the trial files at site 
4.7 
Vital Signs 
At baseline an assessment of vital signs will be made: Systolic and diastolic blood pressure, pulse 
and body temperature at baseline (in older patients this will be following 5 mins rest in supine 
position).  Following dosing vital signs will be monitored according to routine standard of care, 
any unexpected measurements will be recorded as adverse events and reported in the normal 
way. 
4.8 
Palatability assessments 
At the end of each of the two treatment cycles patients (together with their parents) will be 
surveyed using a standard questionnaire for their views of the palatability and acceptability of the 
13-CRA.  In the case of patients <6 years of age, the researcher will survey the view of one or 
both parents.  For patients from 6 years of age, the researcher will seek the views of one or both 
parents and the patient.  
The questionnaire will probe the taste and general acceptability (willingness to continue with 
treatment, ease of dose administration etc.).  After five patients have completed the survey the 
use of the questionnaire will be reviewed, by both the investigator and Nova, to ensure that it is 
working satisfactorily.  If the questionnaire needs to be adjusted (in terms of its administration or 
the ability/age groups of the patients), then this will be done.  Minor amendments only will be 
made.  All minor edits will be documented and a copy of the amended questionnaire will be 
provided to the Ethics Committee.  If significant adjustment is required Ethical Committee 
Approval will be sought before administering the amended questionnaire. 
Data on the following will be collected using a visual (hedonic) analogue scale and verbal 
responses. 
• Taste on first administration 
• Residual after taste 
• Smell 
• Any incidences of spitting medicine out or vomiting 
• Willingness to take 13-CRA on a daily basis 
• Ease of dose administration using the bottle and oral syringe 
• Preference between extracted capsule and liquid medicines 
The survey will be conducted by a trained research nurse.  The survey will be face to face with 
patient and/or parent and will be conducted on Day 14 of each treatment cycle and take no longer 
than 5 minutes.  In addition aspects of palatability may be included in the patient diary card if 
appropriate.  Diary cards will be provided to the Ethics Committee for approval prior to use. 
4.9 
Tolerability assessments 
All adverse events will be collected and recorded during the trial and for the 14 day follow up 
period.  Patients and parents will be provided with a trial diary card and will be asked to record 
adverse events. 
Common adverse events associated with 13-CRA include dry or peeling skin, cracked lips and 
dry eyes, skin may also become more sensitive to sunlight.  Therefore these adverse events 
collected during the trial will be separately listed.   
13-CRA can cause some mild changes in liver function and hypercalcemia, therefore standard of 
care laboratory assessments will be made to monitor liver function and serum calcium levels.   


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4.10 
Oropharyngeal Tolerability 
Oro-pharyngeal tolerability and symptoms will be separately assessed.  Dry skin, peeling skin, 
cracked lips and dry eyes will be assessed by the investigator on a four point scale (0 = none, 
1 = mild, 2 = moderate, and 3 = severe). 
Oro-pharyngeal symptoms will be assessed at baseline and following administration of 13-CRA 
during the Pharmacokinetic Day 14.  Patients and parents will be provided with a diary to record 
any oro-pharyngeal events during the two weeks treatment.  This diary card will be reviewed and 
discussed with the parents (and patient if appropriate) on Day 14 for each of the treatment cycles.  
Any local clinically relevant changes will be recorded as adverse events, classified by type of 
event (e.g. lesion, and/or other) and severity. 
5. 
SELECTION OF PATIENTS 
Up to 20 patients will be enrolled into the trial depending on the number of pharmacokinetic 
blood samples that are obtained from each patient.  A minimum of 150 pharmacokinetic blood 
samples are required for adequate analysis of the patient population. 
To ensure each age cohort is appropriately represented by age the trial will aim to include a 
minimum number of patients to the following age groups: 
Age 1 - <2 years:  
4 patients 
Age 2 - < 6 years:  
4 patients 
5.1 
Inclusion criteria 
To be eligible for inclusion into this trial the patients must fulfil all of the following criteria: 
1. Male or female aged from 0 years to < 21 years of age. 
2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology 
intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis 
3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA. 
4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from 
the capsules). 
5. Negative pregnancy test for females of childbearing potential no more than seven days 
before initiation of treatment, and sexually active patients and partners agreeing to 
undertake adequate contraceptive measures (see section 4.5). 
6. Provision of a single or double lumen central venous catheter for sampling (i.e. already in 
place). 
7. Parent(s)/legal guardian able and willing to provide written informed consent for the 
patient to take part in the trial.  
8. Where applicable, the patient should assent to undergo blood sampling for 
pharmacokinetic purposes and to allow physiological measurements to be made. 
5.2 
Exclusion criteria 
To be eligible for inclusion in this trial the patients must not meet any of the following criteria: 
1. Any clinically significant medical condition or abnormality, which, in the opinion of the 
investigator, might compromise the safety of the patient or which might interfere with the 
trial. 
2. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the 
SIOPEN HRNBL trial (patients who have exited this trial will be eligible). 
3. Known allergy to 13-CRA or any of the excipients. 
4. Inadequate contraception measures in females of childbearing age. 
5. Receiving concomitant treatment with tetracyclines. 


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5.2 
Criteria Prior to starting each cycle of 13-CRA 
1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if 
present, should be stable or improving. 
2. Skin toxicity no greater than CTCAE Grade 1(10) 
3. Serum triglycerides <5.65mmol/L. 
4. No haematuria and / or proteinuria on urinalysis. 
5. Serum calcium ≥2.0mmol/L to ≤ 2.9mmol/L. 
6. Serum creatinine based on age / gender as follows: 
  
Age 
Maximum Serum Creatinine µmol/L 
  
Male 
Female 
1 month to < 6 months 
35 
35 
6 months to < 1 year 
44 
44 
1 to < 2 years 
53 
53 
2 to < 6 years 
70 
70 
6 to < 10 years 
88 
88 
10 to < 13 years 
106 
106 
13 to < 16 years 
132 
124 
≥ 16 years 
150 
124 
 
7. Patients with a seizure disorder must be well controlled and taking anticonvulsants.  CNS 
toxicity < grade 2 (CTCAE). 
5.3 
Withdrawal criteria 
Parent(s)/legal guardian and patients may withdraw from the trial at any time without their care 
being affected and continue on existing route of 13-CRA administration for remainder of cycles.   
1. Positive pregnancy test - pregnancy testing will be undertaken no more than seven days 
before treatment commences and routinely no more than seven days before each course of 
treatment in females of childbearing potential.  If a patient is found to be pregnant during the 
trial, the next course of treatment will not be given until the pregnancy has been discussed 
with the treating clinician, and the patient will be withdrawn from the trial whether or not 
treatment is continued. 
2. Request of the patient, for any reason. 
3. Discretion of the investigator. 
 
6 
TREATMENT OF PATIENTS 
6.1 
Evaluation of test and reference treatment 
Evaluation of the test and reference product will occur during two months of the therapy only.  
Consent to take part in the trial will be obtained before any trial procedures are undertaken.  
Patients who are already receiving 13-CRA treatment will also be eligible for the trial, so long as 
they are able to commit to two cycles of trial 13-CRA.  The next planned 14-day treatment cycle 
will be classed as My-CRA Month 1.  After consent to take part has been obtained and prior to 
the initiation of the next 14 day treatment patients will be randomised to receive either13-CRA 
liquid (test product) or liquid extracted from capsule (reference product) in My-CRA Month 1.  
Randomisation will be done once eligibility has been confirmed and their next scheduled 
treatment visit is booked, in order that the appropriate medication can be made available for the 


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patient’s visit.  Randomisation will be done centrally by Nova according to a randomisation list 
generated be the trial statistician, investigators will email (or telephone) Nova to receive 
randomisation details, this will be confirmed by email as “liquid first” or “extracted capsules 
first”, pharmacy contacts will also be notified.  After My-CRA month 1, patients will then cross 
over to the alternative formulation in My-CRA Month 2.  In all other treatment cycles patients 
will revert to standard therapy i.e. liquid extracted from capsules.  The pharmacokinetics of 13-
CRA will be evaluated during test and reference treatments (My-CRA Month 1 and 2). 
6.2 
Permitted medications 
Concomitant medication is defined as any medication, other than the trial drug, which is taken 
during the trial (i.e. before the patient completes the 14 day follow up visit after My-CRA cycle 
2), including prescription and over-the-counter medicines. 
For the purposes of the trial, nutritional supplements including vitamins and minerals are not 
considered concomitant medications, although vitamin A supplements will not be allowed 
(according to standard practice). The generic names of medications should be used where 
possible.  Concomitant medication will be recorded in the CRF with indication, dose 
information, and dates of administration. Any new medications taken or any changes to the form, 
frequency or dose of existing medication occurring during the trial will also be recorded.  The 
use of concomitant medications is based upon the experience of the clinical investigator. 
6.3 
Monitoring compliance 
Medication will be prescribed and dispensed by the pharmacy.  On pharmacokinetic days (Day 1 
and 14) morning doses of medication will be administered in the clinic.  All additional doses of 
medication will be recorded fully on the patient’s diary card.  Prescription, dispensing and 
accountability of 13-CRA will be accurately recorded in the drug accountability log provided by 
the Sponsor.  The trial monitor will verify that the data have been accurately recorded and 
transferred. 
6.4 
Exit points 
The normal exit point from this trial will be when the patient completes the 14 day follow up 
visit in My-CRA month 2, all adverse events will be followed up to conclusion. 
6.5 
Expected duration of patient participation 
Patients will be in the trial for a 2 month period. 
 
 


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7 
INVESTIGATIONAL MEDICINAL PRODUCT 
The term ‘Investigational Medicinal Product’ will refer to the 13-CRA liquid administered to the 
patient as part of the pharmacokinetic trial. 
7.1 
Description of investigational medicinal product 
 
Drug Substance  
13-Cis Retinoic Acid 
Manufacturer of 
Drug Product 
The test drug product will be manufactured and batch released by: 
Nova Limited, Martin House, Gloucester Crescent, Wigston, Leicester, 
LE18 4YL. 
 
The reference drug product will be an approved, commercial product 
that will be purchased by the Sponsor and supplied to the local 
pharmacy, the manufacturer is: 
Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden 
City, AL7 1TW.  Product License: PL 00031/0160 
 
Test Drug Product 
Novel oral liquid formulation of 13-Cis Retinoic Acid 
Reference Drug 
Product 
Isotretinoin capsules-Roaccutane® 20 mg soft capsules (to be 
extracted per dosing instructions provided) 
Daily dose 
The dose administered will be 200mg/m2/day for both test and 
reference product.  Patients with a body weight of ≤12kg will receive a 
dose of 160 mg/m2. 
Frequency 
100 mg/m2 twice daily (morning and evening) for 14 days per patient 
Packaging, Test Drug 
Product 
50 ml Amber type III glass bottle with tamper evident child-resistant 
closure. Packaged with oral dosing syringes. 
Storage at room temperature (15 to 25oC) 
The medicinal product is photosensitive and should be protected from 
light and stored in the original carton at all times 
Shake the bottle vigorously for at least 30 seconds before use  
Packaging, Reference 
Drug Product 
Capsules, soft 10 and 20 mg capsules: Oval, opaque, brown-red and 
white capsules imprinted with ROA 20 in black ink. 
Duplex (PVC/PVDC) aluminium blister packs containing 20, 30, 50 or 
100 capsules. 
Storage at room temperature (15 to 25oC) 
The product will be prepared and dosing on the pharmacokinetic days will be by the site staff or 
by parents supervised by site staff, and will be according to instructions provided by The 
Sponsor (separate document to be version controlled).  Remaining doses will be given to the 
patients by their parents/guardians, and will be according to instructions provided to them.  
Parents will be trained according to these instructions and local hospital standard procedures. 
13-CRA dosing will be prescribed by qualified medical personnel. 
7.3 
13-CRA dosing  
The appropriate dose will be delivered to each patient, according to the weight of the patient to 
deliver approximately 200 mg/m2 13-CRA. Patients with a body weight of ≤12kg will receive a 
dose of 160 mg/m2. 
Each patient enrolled in the trial will receive 13-CRA in accordance with the dosing 
requirements. 


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Initial doses will be administered and checked by trained medical/nursing staff and recorded 
accurately in a controlled drug accountability log provided by the Sponsor.  Remaining doses 
will be recorded by the parents/guardians in the diary card.  
The Sponsor monitors will check the accuracy of the pharmacy and site for receipt of IMP, 
confirmation of receipt, pharmacy storage of the IMP packages, distribution records to the clinic 
and records of return to pharmacy and destruction of IMP.  Any anomalies will be queried and 
clearly documented.  All records will be maintained in the hospital pharmacy files with 
anonymised copies retained for the Sponsor trial master file. 
7.4 
Packaging and labelling 
The Sponsor will provide sufficient quantities of IMP in accordance with Good Manufacturing 
Practice (GMP).  The clinical trial supplies will be properly packaged and labelled in accordance 
with applicable local regulatory requirements. 
7.5 
Preparation, handling and storage 
The IMP will be accounted for in a drug inventory and stored in a locked area in the pharmacy or 
in the hospital clinic until used in the trial.  Storage information and batch characteristics will be 
supplied at the time of delivery.  At the end of the trial the site will be contacted about the 
handling procedures for unused trial drug. The IMP will be destroyed by the site according to 
local procedures, this will be appropriately documented. 
7.6 
Investigational medicinal product accountability 
The principal investigator at each site is responsible for ensuring the investigational medicinal 
product (IMP) accountability, including reconciliation of the IMP and maintenance of IMP 
records. 
• Upon receipt of the IMP the principal investigator (or delegated pharmacist) will check for 
accurate delivery and acknowledge receipt by signing (or initialling) and dating the 
documentation provided by the supplier and faxing/scanning a copy back to the supplier.  
The original will be retained in the investigator/pharmacy file. 
• The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
forms provided by the Sponsor. An accurate account will be made available for verification 
by the Sponsor monitor at each monitoring visit. 
• IMP accountability records will include: 
Release of the IMP by the supplier’s Qualified Person. 
Confirmation of IMP delivery to the trial site. 
The inventory at the site of IMP provided by the supplier. 
Details of pharmacy dispensing.   
Administration of IMP to patients (in clinic, and on diary cards).   
Destruction of excess IMP.  All unused IMP will be destroyed by pharmacy personnel 
according to normal hospital policy, destruction will be clearly recorded, documented and 
checked by The Sponsor monitors.  
Return to the supplier or alternative disposition of unused IMP. 
• The principal investigator should maintain records that adequately document that: 
Patients were treated with the dose specified in the protocol. 
Preparation/administration and return/destruction of IMP was properly conducted. 
 
Unused IMP must not be discarded without prior permission from the Sponsor or used for any 
purpose other than the present trial.  IMP that has been dispensed must be accurately recorded 
for each patient.  


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The Sponsor monitor will periodically collect the IMP accountability forms and check all IMP 
data (both used and unused) prior to making arrangements for the return of unused IMP to the 
supplier or authorising their destruction by the trial site. 
8 
PREMATURE DISCONTINUATION FROM TRIAL 
8.1 
Early Discontinuation of an Individual Patient 
Patients and their parent(s)/legal guardian will be informed that they have the right to withdraw 
from the trial at any time, without prejudice to their medical care and that they are not obliged to 
state their reasons.  In addition, the investigator may remove a patient from the trial if, in the 
investigator’s opinion, it is not in the best interest of the patient to continue in the trial. 
Any withdrawal from the trial must be fully documented in the CRF and source.   
The date of discontinuation from the trial and reason (where possible) for discontinuation will be 
recorded on the CRF and in the patient’s medical records. 
• Patients may be discontinued from the trial for the following reasons: 
• Withdrawal of consent  
• AE 
• Deviation from protocol 
• Other (to be specified on the CRF by the investigator if possible) 
 
The data recorded (including PK samples) until the time of withdrawal will be used as part of the 
clinical trial unless the parent(s)/legal guardian or patient requests that it is not used. 
Withdrawn patients may be replaced if the overall target number of samples has not been 
reached (i.e. a total of 150 samples). 
8.2 
Early Discontinuation of the Trial 
If, in the opinion of the investigator, the clinical observations in the trial suggest that it might not 
be justifiable to continue, he may terminate the trial following consultation with the Sponsor.  
Alternatively, the Sponsor may give written notification to the investigator, regulatory authorities 
and ethics committees of the early discontinuation of the trial, including reasons. 
In case of early discontinuation of the trial, safety assessments should be performed for each 
patient, as far as possible.  
8.3 
Patient and Trial Completion 
Patients will be considered to have completed the trial when the patient has completed the 14 
day’s follow up at the end of the My-CRA Month 2 dosing period.  Patients who consent for the 
trial but who do not, for whatever reason, receive trial medication will be considered to be 
screening failures and their data will be recorded on a screening failure list.  Patients who 
provide at least one pharmacokinetic blood sample for trial purposes will be deemed to have 
entered the trial and will be included in the PK analyses.  All patients who receive trial 
medication will be considered for the safety analyses.     
The trial will be considered to be completed 14 days after the last patient’s has completed their 
My-CRA Month 2 dosing. 
9 
ASSESSMENT OF SAFETY 
Assessments of safety will be performed throughout the time that the patient is in clinic and for 
the 14 days that the patient receives medication at home (and for 14 days between dosing cycles 


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if adverse events are recorded in the diary card or are spontaneously reported by the patient to 
hospital staff) and 14 days from the time that the patient receives their last dose (Two weeks 
follow up after Day 14 of the treatment). 
The on-going safety of the investigational medicinal product will be assessed through the 
recording, reporting and clinical assessment of baseline medical conditions, and adverse events 
recorded until discharged (and for 14 days follow up between cycles or post last dose if recorded 
in the diary card or spontaneously reported by the patient to hospital staff).  Trial site personnel 
will report any adverse event (AE), whether observed by the research staff or reported by the 
patient. 
Oro-praryngeal tolerability will be assessed at baseline and following dosing until a patient has 
completed the trial.  Any local clinically relevant changes will be recorded as adverse events. 
9.1 
Definition of adverse events 
An AE is any untoward medical occurrence in a patient or clinical trial patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether 
or not related to the IMP. 
During the trial, any worsening of conditions, signs or symptoms noted from the time of 
consenting to take part in the trial will be recorded as an AE. 
All AEs that occur (whether treatment related or not) will be recorded in the CRF throughout the 
duration of the visit  (and for 14 days post dosing if recorded on the diary card or spontaneously 
reported to hospital staff). 
As far as possible, each AE must be described by its duration (start and end time and date or 
ongoing), its frequency (single episode, intermittent, continuous), its severity (mild, moderate, 
severe - see section 9.2), a causality assessment (coexisting disease, concomitant medication, the 
IMP, or other cause), its relationship to the IMP (unrelated, unlikely, possibly, probably, 
definitely – see Section 9.2), whether this influenced the course of the IMP, whether it required 
specific action or therapy, and outcome. 
All medical conditions present at baseline should not be considered as AEs unless these have 
worsened during the trial phase. In cases of surgical or diagnostic procedures the 
condition/illness leading to such a procedure is considered as the AE rather than the procedure 
itself.  
9.2 
Expected AE in 13-cis-retinoic acid recipients 
Refer to Investigator Brochure. 
9.3 
Adverse events 
Using the WHO toxicity criteria as a guide, the principal investigator will assess the severity of 
all AEs according to the following definitions: 
Mild:  
The patient is aware of the event or symptom but it is easily tolerated. 
Moderate: 
The patient experiences sufficient discomfort to interfere with or reduce his / her 
usual level of activity  
Severe: 
Significant impairment of functioning – the patient is unable to carry out usual 
activities and/or the patient’s life is at risk from the event. 
The principal investigator will assess the relationship of AEs to the investigational medicinal 
product using the following definitions: 


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Definite: 
There is a definite clinical/biological relationship and time sequence between the 
onset of the AE and the administration of the investigational medicinal product. 
Probable: 
A causal relationship is clinically/biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product and there is a reasonable response on 
withdrawal. 
Possible: 
A causal relationship is clinically/biologically plausible and there is a plausible 
time sequence between onset of the AE and administration of IMP. 
Unlikely: 
A causal relationship is improbable and another documented cause of the AE is 
most plausible. 
Unrelated: 
A causal relationship can be definitively excluded and another documented cause 
of the AE is most plausible. 
In case of a fatality the cause of death is captured as the AE and the death is its outcome. 
 
10 
PROCEDURE 
FOR 
RECORDING AND 
REPORTING 
ADVERSE EVENTS 
Adverse event data will be recorded throughout the patient’s stay in the clinic/hospital (and for 
14 days post dosing if recorded in the diary card or if reported spontaneously to hospital staff).   
10.1 
Recording of adverse events in the case report form  
As quality and precision of AE data collected is of key importance, the principal investigator or 
his designee should use the AE definitions provided in the above sections and follow the 
guidelines below when completing the AE pages of the CRF: 
• Whenever possible recognised medical terms should be used to describe AEs rather than 
colloquialisms (e.g. ‘influenza’ rather than ‘flu’).  Abbreviations should be avoided. An 
adverse event term needs to be provided for each adverse event, preferably using the Short 
Name as listed in the Common Terminology Criteria for Adverse Events version 4 (CTCAE, 
current version 4.02), available online (10). 
• AEs should be described using a specific clinical diagnosis rather than component signs and 
symptoms where possible (e.g. ‘congestive heart failure’ rather than ‘dyspnoea, rales and 
cyanosis’).  
• Signs and symptoms that are considered unrelated to a specific disease or syndrome should 
be reported as individual AEs on the CRF (e.g. ‘nausea’ and ‘vomiting’ should be recorded 
separately and not as ‘nausea and vomiting’). 
• Provisional diagnoses (e.g. ‘suspected asthma’) are acceptable but should be followed up by 
a definite diagnosis when/if finally available. 
• AEs that are secondary to other events (e.g. ‘sequelae or complications) should be identified 
by the primary cause.  A primary AE, if clearly identifiable, generally represents the most 
accurate clinical term to be recorded on the AE pages of the CRF. The principal investigator 
should be invited to provide his/her own opinion of which is the primary AE. 
10.2 
Reporting of adverse events 
Complete and appropriate data on all AEs experienced during the clinical trial will be reported in 
the AE pages of the CRF on an ongoing basis for the duration of the reporting period. 
It is important that each AE report includes a description of the event, its seriousness status and 
criteria, duration, severity, relationship to the investigational medicinal product, other causality 
factors (if any), any concomitant medications dispensed, concomitant procedures prescribed or 
other actions taken and its outcome at the end of the reporting period. 




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SAE, should follow the initial fax report. Where applicable, information from relevant hospital 
case records and post-mortem reports should be obtained. 
Any SAE that is both unexpected and suspected to be related to treatment (SUSAR) must be 
reported by the Sponsor to the regulatory authorities and the REC (via the investigator) within 
the following time limits: 
• A SUSAR that is fatal or life-threatening is to be reported to the regulatory authorities and 
the REC as soon as possible, and in any case no later than seven days after the Sponsor first 
becomes aware of it. Relevant follow-up information must be reported within an additional 8 
days. 
• All other SUSARs are to be reported to the regulatory authorities and the REC as soon as 
possible, but within a maximum of 15 days of the Sponsor first becoming aware of it. 
10.4.1 Reporting procedures  
 
The Serious Adverse Event Form must be completed as fully as possible with information 
relevant to the serious adverse event(s) being reported. All fields should be populated or 
marked accordingly if no information is available. If it is not possible to complete all sections 
of the Serious Adverse Event Form within 24 hours, transmission of the form must not be 
delayed and the outstanding information should be sent on a follow-up Serious Adverse 
Event Form. The investigator must complete the Serious Adverse Event Report Form as fully as 
possible, assess causal relationship to trial treatment and send the completed form by fax within 
24 hours to the Sponsor. In cases of death reported as a serious adverse event, the report 
should detail the main and contributory causes of death. This information should also be 
accompanied by a death certificate or autopsy report, if available. The Sponsor will in any case 
report any death or life-threatening event to the authorities (MHRA and REC) within 7 calendar 
days, if it is both unexpected and considered to be drug-related, with any follow up reports 
within a further 8 calendar days. Any other serious adverse event that is both unexpected and 
considered drug-related will be reported within 15 calendar days. The original and the duplicate 
copies of the Serious Adverse Event Form, and the fax confirmation sheet must be kept with the 
case report forms at the trial site. The monitor will collect a copy of the Serious Adverse Event 
Form and deliver it to the Sponsor. For all serious adverse events where important or relevant 
information is missing, active follow-up should be undertaken. Investigators or other site 
personnel should inform Safety contact of any follow-up information on a previously reported 
serious adverse event. The follow-up information must be presented on a Serious Adverse Event 
Form marked as follow-up. It is necessary only to provide the new information, with the Serious 
Adverse Event Form signed by an investigator. 
Investigators or other site personnel should send relevant or requested supporting 
documentation (e.g. electrocardiogram (ECG), laboratory results, autopsy report to Safety 
contact.) 
The investigator will ensure that all the necessary information is provided within the 
timelines stipulated by Safety contact when the request for information is made. 
Follow-up reports should be completed and transmitted following the same procedure as for the 
initial report. The follow-up should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or discontinued trial participation. The 
form and fax confirmation sheet must be retained. The Sponsor may also request further follow-
up information following review of the Serious Adverse Event Form. The investigator will make 
all reasonable attempts to obtain the follow-up information requested and forward it to the 
Sponsor as detailed above. Pregnancy follow-up should describe the outcome of the pregnancy, 
including any voluntary or spontaneous termination, details of the birth, and the presence or 
absence of any congenital abnormalities or birth defects. The investigator will provide these 
details via completion of a Pregnancy Follow-up form. 


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11 
EVALUATION OF RESULTS 
Changes in the conduct of the trial or planned analyses will be reported in the corresponding 
section of the trial report. 
A Statistical Analysis Plan (SAP) will be developed by a qualified statistician together with a 
pharmacokinetic modeller.  Pharmacokinetic and Statistical analysis will be performed according 
to this document.  The SAP will specifically include details of how all: Analysis Populations, 
Demographic and Baseline Characteristics, Completion and Discontinuation information, 
Medication details, Pharmacokinetic analyses as well as Safety analyses (including oro-
pharyngeal tolerability) and Palatability will be classified and described.  The SAP will be 
reviewed and approved prior to analysis.   
The sample size chosen for the trial is considered appropriate based on previous experience.  No 
formal sample size calculations have been performed.  In order to develop a robust population 
pharmacokinetic model (i.e. precisely estimated parameters), data from a minimum of 150 blood 
samples will be required.  It is hoped that the required number of samples may be obtained from 
12-18 patients.  However, if problems are encountered in obtaining samples further patients may 
be included in the trial.  In order to accommodate these problems without having to submit 
repeated protocol amendments the protocol states up to 18 patients for inclusion in the trial. 
11.1 
Pharmacokinetic analysis 
Since a sparse sampling approach is to be employed in the present trial it is not possible to use a 
classical analysis to obtain PK parameter estimates.  Therefore, a population-PK approach will 
be applied.  In the population approach all data from different individuals are fitted 
simultaneously using a non-linear, mixed effects modelling approach and post hoc individual 
kinetic parameters can be calculated with as few samples as one per individual.  
Data will be analysed using the mixed effects non-linear regression modelling programme, 
NONMEM (version V II; ICON).  Post processing of NONMEM output will be undertaken with 
an appropriate statistical package such as R (current version). 
Preliminary analyses will focus on the structural and variance models.  One and two 
compartment models with first and zero order inputs will be implemented.  Between patient 
variability will be assumed to be log-normally distributed, and residual error will be modelled 
using additive, proportional and combined error structures. 
Biologically plausible covariates will be included in the model for analysis e.g. age, weight.  A 
multivariate analysis will be performed, details of this analysis will be included in the SAP.   
Several criteria can be used to evaluate the improvement in the model performance and thus 
select the final model.  Comparisons of hierarchical models are based on the objective function 
value, i.e. two times the negative log likelihood value.  Changes in the objective function value > 
7.88 (p<0.005) are accepted as statistically significant.  The other selection criteria used include 
improvement in the goodness of fit and residual plots, increased precision in parameter 
estimation, and reduced variance of between patient and residual errors.  An assessment of model 
appropriateness will be undertaken using visual predictive checks and posterior predictive 
checks.  This will be based on the final covariate model. 
The metabolite 4-oxo-13-cis-retanoic acid will also be evaluated.  The absorption function, 
CL/F, V/F will be considered as primary PK parameters; secondary PK parameters (such as 
Tmax, Cmax, AUC and half-life) will be calculated from the primary model parameters. .  
11.2 
Safety, tolerability and palatability analyses  
Reporting of the safety data will be of a descriptive nature and presented using appropriate 
summary statistics (e.g. n, mean, SD, %CV, median, minimum, maximum) or frequency 


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distributions (n%) by age group (age 1-11 years, age 12-< 21 years). Unless otherwise stated 
these tabulations will be supported by data listings. 
Safety summaries will include all patients irrespective of whether or not they completed the trial. 
AEs will be coded according to the current version of MedDRA (version to be identified in trial 
report). 
Treatment emergent adverse events (TEAEs) will be determined and only these will be included 
in the statistical analysis report.  Details of the criteria of classifying an AE as a TEAE will be 
provided in the Statistical Analysis Plan.   
The incidence of adverse events will be summarised by system organ class, preferred term and 
maximum severity.  Adverse events will also be summarised by strongest relationship to 
Investigational Medicinal Product by event and system organ class. If a patient experiences an 
adverse event more than once the event with the worst severity or at the most related to IMP 
occurrence will be considered. Patients will be included only once at each level where they 
experienced one or more events.  
A summary of the incidence of serious adverse events will be presented by event and system 
organ class. 
Adverse events relating to oro-pharyngeal tolerability data will be additionally listed separately 
and appropriately summarised.  
All results for other safety will be appropriately summarised.   
Palatability data will be appropriately summarised. 
11.3 
Data Safety Monitoring Committee (DSMC) 
An independent Data Safety Monitoring Committee will be formed to alert and/or make 
recommendations to The Sponsor about any existing or potential safety issues. 
11.4 
Reporting urgent safety measures  
If any urgent safety measures are taken the Investigator/Sponsor shall immediately and in any 
event no later than 3 days from the date the measures are taken, give written notice to the MHRA 
and the relevant REC of the measures taken and the circumstances giving rise to those measures. 
Please refer to the following website for details on clinical trials safety reporting: 
http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyr
eporting-SUSARSandASRs/index.htm 
11.3 
Statistical analysis  
11.3.1 Analysis Populations 
 
The primary trial population will be the Pharmacokinetic (PK) population.  The PK population 
will include those patients who had at least one successful blood sample taken and complete the 
trial without significant protocol deviations/violations which are likely to affect the 
determination of the pharmacokinetic parameters.  Further details on what is deemed a 
significant protocol deviation/violation will be documented in the Statistical Analysis Plan.  This 
population will be used for the analysis of the primary variable. 
 
Safety data will be presented for the Safety population, that is, it will include all patients who 
received trial medication. 
 


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11.3.2 Sample Size  
 
Up to 20 patients, both male and female, aged 0 – < 21 years of age will be recruited. 
 
There are no power calculations in this trial. The objective of this trial is to estimate the 
population pharmacokinetics of 13-CRA following the administration of 13-CRA liquid (test 
product) and extracted capsule (reference product). From a statistical point of view, the collected 
plasma 13-CRA concentration data are expected to relate to a non-linear, mixed effects model 
involving repeated measures.  The developed pharmacokinetic model will estimate the 
parameters of the model and their associated within- and between-patient variability. 
 
11.3.3 Data Analysis 
Statistical analyses will be performed after all patients have ended their participation in the trial, 
protocol deviations reviewed, populations have been agreed and the database has been locked.  
Details of this analysis will be included in the SAP.  
Patients withdrawn before treatment administration will not be assessed for outcome variables or 
safety. 
Continuous variables will be summarised using descriptive statistics; n, mean, standard 
deviation, %CV, median, minimum and maximum, while categorical variables will be 
summarised as the number (and percentage) of patients in each category. 
Baseline and demographic data will be summarised overall and by age group (age 1-11 years, 
age 12-< 21 years) as appropriate. 
Concomitant medications will be tabulated by age group along with the current available WHO 
drug dictionary coding by primary term and generic drug name. 
As part of the pharmacokinetic analysis, statistical significance will be declared at the 5% level 
(two- sided). All other safety analyses will be simply summarised. 
11.3.4 Missing, Unused or Spurious Data  
The handling of missing, unused and spurious data will be described in the Statistical Analysis 
Plan. 
11.3.5 Deviations from the Planned Statistical Analyses 
Any changes to the planned analysis (as described in the protocol and Statistical Analysis Plan) 
will be documented in the statistical and clinical trial reports. 
12 
 
REGULATORY AND ETHICAL CONSIDERATIONS  
12.1 
Good Clinical Practice 
The investigator and Sponsor will ensure that this trial will be performed in accordance with the 
protocol, the Declaration of Helsinki (9), and all applicable regulatory requirements.  The trial 
will be conducted according to the protocol and to Standard Operating procedures (SOPs) that 
meet the guidelines laid down by the International Conference on Harmonisation (ICH) for Good 
Clinical Practice (GCP) in clinical trials. The Sponsor has implemented a quality management 
system to manage quality throughout all stages of the trial process, using a risk-based approach.  
A Study Management Plan will be developed and will include a risk analysis for identification, 
evaluation, control, communication, review and reporting of the risks to the safety and integrity 
of the patients and the scientific integrity of the trial.  This risk analysis will identify processes 
and data that are critical to ensure human subject protection and reliability of results, this risk 
assessment will be reviewed as appropriate during the study. 


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12.2 
Informed consent 
Before a patient can participate in the trial their parent(s)/legal guardian must give written 
informed consent to participation.  Where applicable, the patient themselves will provide assent 
for the trial (generally in patients over 7 years of age).  The informed consent process will be in 
accordance with ICH GCP, the Declaration of Helsinki and local regulatory requirements. 
Patient information leaflets/informed consent forms will be based on master documents provided 
by the Sponsor and submitted and approved by the Independent Ethical Committee (IEC).  
Patient information leaflets will be designed to target specific age groups and levels of 
understanding in order to obtain patient assent for the trial as well as parental/legal guardian 
consent.  The Sponsor must approve and retain copies of any changes requested by the IEC 
before the documents are used. 
12.3 
Regulatory authority approval 
Before the trial is initiated at a site the Sponsor will obtain approval to conduct the trial from the 
appropriate regulatory authority in accordance with any applicable country specific 
requirements. Regulatory authority approval for the clinical trial will be obtained prior to 
recruitment of patients into the trial and shipment of IMP. 
12.4 
Independent ethics committee requirements 
Before initiation of the trial at a given site written approval of the protocol, informed consent 
forms and patient information leaflets will be obtained from the appropriate independent ethics 
committee.  If any amendments to any of these documents occur during the trial, written 
approval must be obtained prior to their implementation.  The site will also apply to their Local 
Authority and IEC as appropriate for approval to participate in the trial.  The principal 
investigator at each site is responsible for ensuring that these actions occur.   
12.5 
Data Safety Monitoring Committee (DSMC) 
Before initiation of the trial the final trial protocol will be supplied to the independent Data 
Safety Monitoring Committee who will make recommendations to The Sponsor about any 
existing or potential safety issues. 
12.6 
Indemnity and Insurance 
With respect to any liability directly or indirectly caused by the IMP in connection with this 
clinical trial the Sponsor assumes liability on behalf of the investigator for possible injury to the 
patient, provided the investigator has followed the instructions of the Sponsor in accordance with 
this protocol and any amendments thereto, that the IMP has been supplied by the Sponsor, and 
that the investigator has performed the clinical trial in accordance with scientific practice and 
currently acceptable techniques and knowledge.  The Sponsor’s liability is covered by liability 
insurance.  
12.7 
Patient Confidentiality 
The principal investigator must ensure that the patient’s anonymity is maintained.  On the CRFs 
or other documents submitted to the Sponsor, patients should not be identified by their names, 
but by their assigned identification number.  If patient names are included on copies of 
documents submitted to the Sponsor, the names must be obliterated and replaced with the 
assigned trial patient numbers. 
The principal investigator should keep a separate log of patient identification numbers, names, 
addresses, telephone numbers and hospital numbers (if applicable).  Documents not for 


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submission to the Sponsor, such as signed informed consent forms, should be maintained in strict 
confidence by the principal investigator in the trial site file. 
A screening failure log will be maintained for patients who have consented to participate in the 
trial but who, for whatever reason, are not eligible, withdrawn or decide to withdraw prior to 
taking part. This log will contain the following information: 
• Patient trial number 
• Patient initials 
• Reason for trial withdrawal (if available) 
CRF pages will not be completed for these patients. 
The investigator shall permit authorised representatives of the Sponsor, regulatory authorities 
and IECs to review that portion of the patient’s medical record that is directly related to the trial. 
As part of the required content of informed consent, the patient must be informed that his/her 
records will be reviewed in this manner.  The Sponsor will have access to patients information 
on site during monitoring or auditing, no identifying information other than patient number will 
be transferred to the Sponsor. 
12.8 
Trial Documentation and Storage 
The investigator/institution should maintain the trial documents in a comprehensive and 
centralised filing system that is suitable for inspection by representatives of the Sponsor and 
regulatory authorities. The investigator/institution should take measures to prevent accidental or 
premature destruction of these documents. 
Essential documents as defined by ICH GCP include the signed protocol and any amendment(s), 
copies of the completed CRFs, signed informed consent forms from the parent(s)/legal guardians 
of all patients for whom consent was obtained, hospital records and other source documents, IEC 
approvals and all related correspondence including approved documents, drug accountability 
records, site delegation lists and curriculum vitae, trial correspondence and a list of the patients’ 
names and addresses. 
The principal investigator must retain copies of all essential documents for the period specified 
by ICH GCP and by applicable regulatory requirements. 
The principal investigator will inform the Sponsor of the storage location of the essential 
documents and must contact the Sponsor for approval before disposing of any of these 
documents. 
It is the responsibility of the Sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. The Sponsor should be informed immediately by the 
investigator/institution of any change concerning archiving facilities. 
12.9 
End of trial 
For administrative and safety reporting purposes the end of the trial will be defined as 14 days 
after the last patient completes treatment in My-CRA Month 2.  This provides for a single and 
conservative definition. 
12.10 Publication Policy 
The Sponsor will prepare a written clinical trial report according to ICH guidelines to summarise 
the trial following completion of the analysis. 
Investigators may not submit trial information for publication without prior consultation and 
written approval from the Sponsor. However such approval should not be unreasonably withheld. 


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13 
 
ADMINISTRATIVE OBLIGATIONS 
13.1 
Source Data 
All relevant trial data will be recorded in the CRF. Where relevant data already exists on other 
source documents such as laboratory reports or ECGs, the information required will be 
transcribed into the CRF. All other data will be directly written into the CRF. 
13.2 
Monitoring 
Routine monitoring visits will be made by the monitors designated by the Sponsor to check 
compliance with the protocol, the completeness, accuracy and consistency of the data, and 
adherence to GCP.  
The principal investigator must ensure that CRFs are completed in a timely manner and must 
allow periodical access to CRFs, patient records, drug logs and all other trial-related documents 
and materials.  The frequency of monitoring visits will be determined by factors such as trial 
design and the site enrolment requirements.  For this trial, monitoring visits will usually occur a 
few weeks after a patient is recruited and completes My CRA-Month 2, at an individual site. 
The investigator will agree to provide the monitor direct access to the patients’ source data, 
which may exist in the form of hospital records, patient files and notes, and laboratory 
assessment reports and results.  
13.3 
Quality Control and Quality Assurance 
Appropriately qualified and trained staff will be involved in this trial. Staff at the investigational 
site will be instructed in the conduct of the trial according to this protocol.   
In order to check the compliance of the trial regarding GCP, audits may be carried out by a 
quality assurance representative.  The investigator will provide access to authorised persons 
during regulatory authority inspections or Sponsor audits. 
13.4 
Data Collection and Management 
A CRF will be completed for each patient who enters the trial. The CRFs will be printed and the 
original CRFs will be collected by the Sponsor or their delegate – a photocopy will be retained at 
the site.   
The CRFs should be completed legibly in English with a black ball-point pen.  Errors should be 
crossed by a single line but not obliterated, and the change initialled and dated by the 
investigator or designee.  The use of correction fluid or tape is not allowed. The investigator will 
sign and date at the indicated places in the CRF. This signature will indicate a thorough 
inspection of the data on the CRF has been made, and will certify the contents of the form. 
CRFs will be completed promptly and submitted to the monitor in person for checking and 
collection. When changes to CRF data are necessary following removal of the original CRF from 
the trial site these changes will be documented on data clarification/resolution forms which will 
be signed by the investigator. 
The data will be entered into a validated database.  TASK Applied Science Pty Ltd will be 
responsible for data processing, in accordance with the Sponsor or Sponsor’s delegated service 
provider’s data management procedures.  Database lock will occur once quality assurance 
procedures have been completed.  Nova will send results to other South Africa.  Patients 
information sheets will include details that cover data being sent outside of the UK, and the 
consent form will cover a request for consent to do so.  


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Data items from the CRF will be entered centrally into the trial database by Data Management 
using double data entry, with verification upon second entry. Concomitant medication entered 
onto the database will be coded using the WHO Drug Reference List. Coexisting diseases and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Laboratory samples will be processed and results sent to Data Management.  
13.6 
Adherence to the Protocol 
Protocol violations are any deviations from the procedures outlined in this document, for 
example, missed evaluations, incorrect timing of evaluations, non-compliance with IMP and 
intake of prohibited medications. It is the investigator’s responsibility to make all reasonable 
efforts to avoid protocol violations in order to avoid possible exclusion of the patient from the 
trial and/or analyses.  
All protocol violations will be reported immediately to the Sponsor and any action required, for 
example, discontinuation of the patient will be discussed.  Evaluability of the patient(s) 
concerned will be performed by the Sponsor prior to the statistical analysis.  
Any deviation from the protocol that has not been approved by The Sponsor and the IEC could 
result in a discontinuation from the trial of the site involved. 
13.7 
Trial or site discontinuation 
The Sponsor may temporarily or permanently discontinue the trial at a single site or at all sites 
for safety, ethical, compliance or other reasons. If this is necessary, The Sponsor will endeavour 
to provide advance notification to the site(s) involved.  If the site or trial is suspended or 
discontinued, the principal investigator will be responsible for promptly informing the IEC.  
Where required by local regulations, The Sponsor will be responsible for informing the IEC of 
trial or site discontinuation.  In such cases, all trial data and unused investigational medicinal 
product must be returned to The Sponsor. 
13.8 
PERSONNEL RESPONSIBILITIES 
The trial will be conducted in accordance with the protocol, Good Clinical Practice and 
applicable regulatory requirements. 
13.8.1 Investigator 
The investigator’s responsibilities shall include but not be limited to: 
 
(i) 
adhering to the conduct of the trial as described in this protocol 
 
(ii) 
ensuring the accuracy and legibility of the CRFs and their security 
(iii) 
immediately reporting any serious adverse events to the Sponsor and, if 
appropriate, the Ethics committee 
(iv) 
adhering to the guidelines described in the Declaration of Helsinki and ICH 
Guideline for Good Clinical Practice and local regulatory requirements. 
(v) 
informing the patient’s general practitioner that the patient is taking part in the 
trial, provided that the patient agrees to this contact.  A copy of the 
correspondence should be filed in the Investigator Site File. 
(vi) 
Provide expert research input and advice relating to trial design and execution. 
(vii) 
Be responsible for the review and sign-off of the final report. 
 
13.8.2 Clinical monitor  
The clinical monitor’s responsibilities shall include but not be limited to: 
 
(i) 
verifying protocol adherence 
 
(ii) 
verifying the data on the CRFs with information in the patient’s clinic notes and     
                        other source documents 


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(iii) 
ensuring the trial documents such as the CRFs, protocol and any correspondence 
are maintained in a secure area 
(iv) 
reporting and discussing any problems with the investigators and reporting them 
to the Sponsor. 
 
13.8.3 Sponsor 
As trial Sponsor’s responsibilities shall include but not be limited to: 
 
(i) 
providing the principal investigator with all the necessary trial  
 
 
 
            documents and trial supplies prior to trial initiation 
 
(ii) 
providing the investigator with updates on new developments regarding   
 
            the trial drug 
 
(iii) 
sending the principal investigator financial reimbursement during the  
 
 
            conduct of the trial according to a schedule agreed upon in the budget 
 


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14 
REFERENCES  
1. Gareth J. Veal, Julie Errington,  Sophie E. Rowbotham et al. Adaptive dosing approaches to the 
individualization of 13-cisretinoic acid (isotretinoin) treatment for children with high-risk 
Neuroblastoma. Clin Cancer Res. 2013 January 15; 19(2): 469–479. doi:10.1158/1078-
0432.CCR-12-2225 
2. Hewson QD1, Lovat PE, Corazzari M, Catterall JB, Redfern CP. The NF-kappaB pathway 
mediates fenretinide-induced apoptosis in SH-SY5Y neuroblastoma cells.  Apoptosis. 2005 
May;10(3):493-8. 
3. Reynolds CP, Schindler PF, Jones DM, Gentile JL, Proffitt RT, Einhorn PA. Comparison of 13-
cis-retinoic acid to trans-retinoic acid using human neuroblastoma cell lines. Prog Clin Biol Res 
1994;385:237–44. 
4. Veal GJ, Errington J, Redfern CPF, Pearson ADJ, Boddy AV. Influence of isomerisation on the 
growth inhibitory effects and cellular activity of 13-cis and all-trans retinoic acid in 
neuroblastoma cells. Biochem Pharmacol 2002;63:207-15. 
5. Khan AA, Villablanca JG, Reynolds CP, Avramis VI. Pharmacokinetic studies of 13-cis-retinoic 
acid in pediatric patients with neuroblastoma following bone marrow transplantation. Cancer 
Chemother Pharmacol 1996;39:34-41.  
6. Khan AA, Villablanca JG, Reynolds CP, Avramis VI. Pharmacokinetic studies of 13-cis-retinoic 
acid in pediatric patients with neuroblastoma following bone marrow transplantation. Cancer 
Chemother Pharmacol 1996;39:34-41.  
7. High Risk Neuroblastoma Study 1.7 of SIOP-Europe (SIOPEN), note this is the current protocol 
(dated as of approval of this My-13 CRA study protocol), when enrolment completes patients will 
be treated under the next version of this study protocol. 
8. Oral retinoids: pregnancy prevention—reminder of measures to minimise teratogenic risk MHRA 
25 
June 
2013. 
https://www.gov.uk/drug-safety-update/oral-retinoids-pregnancy-prevention-
reminder-of-measures-to-minimise-teratogenic-risk 
9. Declaration of Helsinki: http://www.wma.net/en/30publications/10policies/b3/ 
10. Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
Version 
4.0 
Published: 
May 
28, 
2009 
(v4.03: 
June 
14, 
2010) 
available 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Guidance documents: 
 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States, Official 
Journal of the European Communities, 1.5.2001; L 121/34-44. 
 
European Clinical Trials Directive, 2005/28/EC European Good Clinical Practice Directive and 
associated guidance. 
 
 
ICH Topic E 6. Guideline for Good Clinical Practice. Step 5, Consolidated Guideline from 01.05.1996. 
Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95). Jan.1997.  


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INTEGRATED ADDENDUM TO ICH E6(R1): 1 December 2016 EMA/CHMP/ICH/135/1995 
Committee for Human Medicinal Products.  Guideline for good clinical practice E6(R2)  
Step 5  
 
Statutory Instruments (UK Law): SI 2004 No. 1031, 2006 No 1928. The Medicines For Human Use 
(Clinical Trials) Regulations 2004 and associated amendments. 
 
EUROPEAN COMMISSION: Guidance Document: Detailed guidance on the request to the competent 
authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of 
substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01)  
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2010 c82 01/2010 c82 01 en.pdf 
 
EUROPEAN COMMISSION:  Guidance Document: Detailed guidance on the collection, verification and 
presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human 
use (‘CT-3’) (2011/C 172/01)  
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf 


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15  APPENDICES 
 
 
Appendix I 
 
Trial schedule 
 
Appendix II 
 
Co-Investigator Signature sheet 
 
Appendix III  
Protocol Amendments 
 
 
 
 
 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 44 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
APPENDIX I TRIAL SCHEDULE: EACH CYCLE 
Test 
Pre trial 
Day 1 
Day 14 
Day 15/16 
End of 
trial7 
(Day 29) 
 
 
 
 
 
 
Informed consent / assent1 
x 
 
 
 
 
Medical history 
x 
 
 
 
 
Concomitant medications 
x 
x 
x 
 
x 
Physical Examination 
x 
 
 
 
 
Pregnancy Test2 
x 
 
 
 
 
Check for central line in situ 
x 
x 
 
 
 
13-CRA morning dose 
 
x 
x 
 
 
Pharmacokinetic blood 
samples3 
 
x 
x 
x 
 
Vital signs for safety4 
  
x 
x 
 
 
Palatability5 
 
 
x 
 
 
Oro-pharyngeal tolerability6 
 
x 
x 
 
x 
Adverse events / serious 
adverse events7 
 
x 
x 
 
x 
1 
Parents/legal guardian will be asked to give informed consent to their child participating in the pharmacokinetic  
trial before 13-CRA is administered.  Patients over the age of 7 years will be asked to give their assent to participate in 
the pharmacokinetic trial if it is deemed appropriate. 
2 
Pregnancy test for females of childbearing age, not more than 7 days prior to starting treatment (each cycle). 
3 
Up to five pharmacokinetic blood samples will be taken. 
4 
Systolic and diastolic blood pressure, pulse and body temperature at baseline (in older patients this will be following 5 
mins rest in supine position). 
5 
Palatability assessment will be made at the 14 day visit.  This will be done using a face to face survey. 
6 
Assessed at baseline and during the trial and follow up  
7 
On discharge from site or withdrawal from trial (AEs followed for up to 14 days later, if in diary card or if reported to 
research staff. 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 45 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
APPENDIX II CO-INVESTIGATOR SIGNATURE SHEET 
INVESTIGATOR SIGNATURE SHEET 
 
The signature below constitutes approval of this protocol by the signatory and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol 
including all statements regarding confidentiality. 
 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. 
I will conduct the trial as outlined herein and in accordance with the ethical principles of the 
Declaration of Helsinki and ICH GCP guidelines. I will provide copies of the protocol and all 
pertinent information to all individuals responsible to me who assist in the conduct of this trial. I 
will discuss the material with them to ensure they are fully informed regarding the drug and the 
conduct of the trial. 
I will only use the informed consent form approved by the sponsor or its representative and will 
fulfill all responsibilities for submitting pertinent information to the Independent Ethics 
Committee (IEC) responsible for the trial. 
 
INVESTIGATOR 
 
NAME: (to be completed for each investigator) 
 
 
ADDRESS: (to be completed for each investigator) 
 
 
 
Signed: 
_________________________________________ 
 
Date:   
_________________________ 
 
 
  
 
 
 




CONFIDENTIAL                             Nova Laboratories Limited                                            Page 47 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
 
PROTOCOL AMENDMENT NUMBER 2 (Version 2.0 to Version 3.0):  
 
Reason for Amendment - 2: Administrative amendment 
 
Update to include requirements of ICH E6R2, quality management, risk-based approach and 
definition of critical data. 
 
A requirement to remove the requirement for patients to be high-risk Neuroblastoma, as some 
patients with intermediate risk may be eligible. 
 
Section 3.5 to clarify that oncology history may be diagnosis only and treatment only needs to 
include treatment in the last month. 
 
Section 4.6 clarification of food to be given with food and the removal of standardised meals 
 
Small administrative edits. 
 
Page 1:  
 
The following text is to be deleted: 
 
VERSION NUMBER: 
 
2.0 
DATE: 
 
9 June 2017 
The following text is to be added: 
 
VERSION NUMBER: 
 
3.0 
DATE: 
 
28 Sept 2017  
 
 
Page 19:  
 
The following text in italics is to be added: 
 
• 
Oncology history (diagnosis) and treatment (over the last month) to include concomitant 
medication for their indication (i.e. confirmation of eligibility for 13-CRA treatment and 
current treatment). 
 
Page 21:  
 
The following text is to be deleted: 
 
appropriate standardised meals/drinks to be provided to patients during the period following 
dosing on PK days 
 
The following text in italics is to be added: 
 
which foods such as yogurt or ice cream can be given with the medicine 


CONFIDENTIAL                             Nova Laboratories Limited                                            Page 48 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
Page 35:  
 
The following text in italics is to be added: 
The Sponsor has implemented a quality management system to manage quality throughout all 
stages of the trial process, using a risk-based approach.  A Study Management Plan will be 
developed and will include a risk analysis for identification, evaluation, control, communication, 
review and reporting of the risks to the safety and integrity of the patients and the scientific 
integrity of the trial.  This risk analysis will identify processes and data that are critical to ensure 
human subject protection and reliability of results, this risk assessment will be reviewed as 
appropriate during the study. 
 
Page 44:  
 
An error on the study schedule was corrected (medical history and concomitant medications to 
be collected at pre-trial visit) adverse events also added as to be collected on PK days). 
 
 
PROTOCOL AMENDMENT NUMBER 3 (Version 3.0 to Version 4.0):  
 
Reason for Amendment - 2: Administrative amendment, inconsistencies in blood sampling 
schedules 
 
Change in flow chart to remove pre-dosing blood sample as was intended, i.e. to reduce the 
number of samples taken from each child. 
 
Small administrative edits. 
 
Page 1:  
 
The following text is to be deleted: 
 
VERSION NUMBER: 
 
3.0 
DATE: 
 
28 Sept 2017 
The following text is to be added: 
 
VERSION NUMBER: 
 
4.0 
DATE: 
 
11 Oct 2017  
 
 
Page 12: 
The following Text will be deleted: 
A pre-dose blood sample will be taken (2ml) and then blood will be sampled post-dose at time 
points selected as follows: 
Page 12: 
The following Text will be added: 
Blood (2 ml) will be sampled post-dose at time points selected as follows: 
 




CONFIDENTIAL                             Nova Laboratories Limited                                            Page 50 of 50 
 
 
 
EudraCT No: 2016-005104-25  
 
Protocol Number: INV500                                       
VERSION 5.0 Dated: 08 Dec 2017 
 
 
1. 
Positive pregnancy test - pregnancy testing will be undertaken no more than seven days before treatment 
commences and routinely no more than seven days before each course of treatment in females of childbearing 
potential.  If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the 
pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or 
not treatment is continued. 
 
Page 21, Pregnancy prevention, Paragraph 1: 
The text in underlined italics will be added: 
For women of childbearing potential all conditions of the Pregnancy Prevention Programme 
should be met (8). Patients of childbearing potential, their partners and parents must understand 
and accept the need for effective contraception, be informed and understand the potential 
consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.  
Female patients of childbearing age must be provided with comprehensive information on 
pregnancy prevention and should be referred for contraceptive advice if appropriate. As part of 
the standard clinical care, female patients of childbearing potential will undergo a pregnancy test 
no more than seven days prior to the start of treatment and routinely no more than seven days 
before each course of treatment. Although the likelihood of pregnancy in patients receiving 13-
CRA is extremely low, if a positive pregnancy test does result during the trial, the next course of 
treatment will not be given until the pregnancy has been discussed with the treating clinician, and 
the patient will be withdrawn from the trial whether or not treatment is continued 
 
Page 23, Section 5 Selection of Patients; Section 5.1, Inclusion criteria 5: 
The text in underlined italics will be added: 
 
5. 
Negative pregnancy test for females of child-bearing potential no more than seven days before initiation of 
treatment, and sexually active patients and partners agreeing to undertake adequate contraceptive measures (see 
section 4.5). 
 
Page 11, Section 5 Selection of Patients; Section 5.2,  Criteria prior to starting each cycle of 
13-Cis-RA 5: 
The text in underlined italics will be added: 
 
5. Serum calcium ≥ 2.0 mmol/L to ≤ 2.9mmol/L. 
 
Page 11, Section 5 Selection of Patients; Section 5.2,  Withdrawal criteria 1: 
The text in underlined italics will be added: 
 
1. 
Positive pregnancy test - pregnancy testing will be undertaken no more than seven days before treatment 
commences and routinely no more than seven days before each course of treatment in females of childbearing 
potential.  If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the 
pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or 
not treatment is continued. 
 
Page 26, Investigational Medicinal product, Packaging, Test Drug Product: 
The following text is to be added: 
The medicinal product is photosensitive and should be protected from light and stored in the 
original carton at all times 
Shake the bottle vigorously for at least 30 seconds before use 
 
Page 44, Appendix 1 Pregnancy testing Footnote 2: 
The text in underlined italics will be added: 
2. Pregnancy test for females of childbearing age, not more than 7 days prior to starting treatment (each cycle). 
 

SAP_001.pdf: