Conditions: Sleep Disorders
Keywords: Sleep disturbance Circadian Prolong release melatonin Autism Spectrum Disorder Smith-Magenis Syndrome Angelman Syndrome tuberous sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 125
Healthy volunteers: no

Brief summary:
The purpose of this study is to establish the efficacy and safety of Circadin in children with neurodevelopmental disorders and to determine the dose, this randomized, placebo-controlled study is planned to evaluate the efficacy of a double-blind, 13 week treatment period with Circadin 2/5mg in improving maintenance of sleep, sleep latency and additional parameters in children with neurodevelopmental disabilities. The efficacy and safety of Circadin 2/5 mg will continue to be assessed during an open-label extension period of 13 weeks.

Detailed description:
This is a randomized placebo-controlled study in children diagnosed with autism spectrum disorders (ASDs) and neurodevelopmental disabilities caused by neurogenetic diseases.

Children who are found to be eligible for the study will follow a 4-week, basic sleep hygiene and behavioral intervention wash-out period, and will continue in a 2-week single-blind (SB) placebo run-in period. Then, they will be randomized in a 1:1 ratio to receive either Circadin® 2 mg or placebo for 3 weeks in a double-blind treatment period.

After 3 weeks of treatment, on the last day of Week 5 ±3 days (Visit 3), sleep variables will be assessed to determine if dose modification (an increase to 5 mg) is required. Children will then continue on 2 or 5 mg of Circadin® or placebo for an additional double-blind period of 10 weeks. This double-blind period will be followed by an open-label period of 13 weeks. At the end of the 13-week open-label period on the last day of Week 28 ±3 days (Visit 5), sleep variables will be assessed to determine if a potential additional dose modification (i.e., an increase either to 5 mg for patients who are still on 2 mg or an increase to 10 mg for patients who are on 5 mg) is necessary (If a dose increase is decided upon, the dose increase should be from 2 mg to 5 mg, or 5 mg to 10 mg). Children will continue at 2, 5, or 10 mg Circadin® in an open-label period for another 78 weeks of follow-up, which will include continuous safety monitoring and 2 efficacy assessment time points at Weeks 41 and 54. The study will end with a 2-week SB placebo run-out period.

Each patient will participate in the study until the end of the second open-label safety follow-up period, and 2 week run-out period. The study duration will be 112 weeks, including the 4-week wash-out period with sleep hygiene and behavioral intervention.

Arms:
arm 1: Active arm arm 2: Placebo arm

Interventions: intervention 1: Circadin 2/5/10 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Circadin 2/5/10 mg. Active arm intervention 2: Control arm

Protocol document:
Prot_002.pdf: 
Neurim Pharmaceuticals Ltd 
27 Habarzel St 
Tel-Aviv 69710 
Israel 
Page 1 
 
Version 6.0 
19 May 2015 Final, Amendment 5 
 
CLINICAL STUDY PROTOCOL 
 
 
A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO INVESTIGATE 
THE EFFICACY AND SAFETY OF CIRCADIN® TO ALLEVIATE SLEEP 
DISTURBANCES IN CHILDREN WITH NEURODEVELOPMENTAL 
DISABILITIES 
Protocol Number:  NEU_CH_7911 
Phase:  III 
EudraCT Number:  2013-001832-23 
Date of Original Protocol:  Final 01 July 2013 
Amendment 1:  Final 01 August 2013 
Amendment 2:  Final 19 November 2013 
Amendment 3:  Final 18 June 2014 
Amendment 4:  Final 29 January 2015 
Amendment 5:  Final 19 May 2015 
 
Study Director 
Tali Nir, DVM 
Vice President, Clinical and Regulatory Affairs 
Neurim Pharmaceuticals 
27 Habarzel St., Tel Aviv 69710 
Israel 
+97 237 6849 02 
 
Medical Monitor, EU 
Florin Floricel, MD 
Medical Director, Medical Affairs,  
PRA Health Sciences  
Gottlieb-Daimler-Strasse 10 
Manheim, Germany, 68165 
+44 179 2525 608 
 


Neurim Pharmaceuticals Ltd 
27 Habarzel St 
Tel-Aviv 69710 
Israel 
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Medical Monitor, US 
Patrick Keenan, MD 
Medical Director, Medical Affairs 
PRA Health Sciences  
4130 Park Lake Avenue Suite 400 
Raleigh, North Carolina 27612 
United States 
+1 866 326-5053 
 
Principal Investigator, EU 
Paul Gringras 
Professor, Paediatric Sleep and Neurodisability  
Paediatric Neurosciences 
St Thomas Hospital, Westminster Bridge Road, SE1 7EH 
United Kingdom 
+020 71884649 
 
Principal Investigator, US 
Robert L. Findling, MD, MBA  
Vice Chair, and Director of Child & Adolescent Psychiatry,  
Department of Psychiatry and Behavioral Sciences 
The Johns Hopkins Hospital, Bloomberg Children’s Center  
1800 Orleans Street, Suite 12344A, Baltimore, MD  
United States 
+1 410 614 3225 
 
 
 




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1 PROTOCOL SYNOPSIS 
Compound: 
Melatonin 
Protocol Number and 
Title: 
Protocol Number:  NEU_CH_7911 
A Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of 
Circadin® to Alleviate Sleep Disturbances in Children with Neurodevelopmental 
Disabilities 
Study Objectives: 
Primary Objective  
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep maintenance 
(total sleep time [TST]) as assessed by the Sleep and Nap Diary after 13 weeks of double-blind 
treatment.  
Secondary Objectives  
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep 
latency as derived from a Sleep and Nap Diary (Appendix 1) after 13 weeks of 
double-blind treatment 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on the duration 
of wake after sleep onset period as derived from a Sleep and Nap Diary after 13 weeks 
of double-blind treatment 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on number of 
awakenings as derived from a Sleep and Nap Diary after 13 weeks of double-blind 
treatment 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on the duration 
of the longest sleep period as derived from a Sleep and Nap Diary after 13 weeks of 
double-blind treatment 
• 
To assess the treatment effect of Circadin® 2/5 mg to that of placebo on children’s 
social functioning at home, in school, and community settings as assessed by the 
Children Global Assessment Scale (CGAS; Appendix 3) after 13 weeks of 
double-blind treatment 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on children’s 
behavior at home and in school as assessed by the Strength and Difficulties 
Questionnaire (SDQ; Appendix 4) after 13 weeks of double-blind treatment 
• 
To compare the number of dropouts between Circadin® 2/5 mg to that of placebo 
during the 13 weeks of double-blind treatment 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep 
parameters as measured by actigraphy after 13 weeks of double-blind treatment 
• 
To compare the safety and tolerability of Circadin® treatment to that of placebo and 
evaluate the safety and tolerability throughout the study including the run-out 
(withdrawal) period by using the adverse event (AE)-eliciting method Treatment 
Emergent Signs and Symptoms questionnaire (TESS; Appendix 5) 
• 
To assess vital signs and physical examination in Circadin® and placebo groups 
Exploratory Objectives 
• 
To evaluate the effect of Circadin® 2/5 mg on all sleep variables derived from the 
Sleep and Nap Diary after 3 weeks of double blind treatment (Week 15), and after 13, 
26, and 39 weeks of open label treatment (Weeks 28, 41, and 54) as compared to 
baseline (Week 2) 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep 
disturbance as assessed by Composite Sleep Disturbance Index (CSDI; Appendix 6) 
score after 3 and 13 weeks of double blind treatment (Weeks 5 and 15), after 13, 26, 


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39, and 91 weeks of open label treatment (Weeks 28, 41, 54, and 106, respectively), 
and at the end of study visit (Week 108) as compared to baseline (Week 2) 
• 
To assess the treatment effect of Circadin® 2/5 mg on children's social functioning at 
home, in school, and community settings as assessed by the CGAS (Appendix 3) after 
13 weeks (Week 28) of Circadin® open label treatment as compared to baseline 
(Week 2) 
• 
To assess the treatment effect of Circadin® 2/5 mg on children's behavior at home and 
in school as assessed by the SDQ (Appendix 4) after 13 weeks (Week 28) of Circadin® 
open label treatment as compared to baseline (Week 2)   
• 
To assess the level of caregiver’s daytime sleepiness (i.e., NOT the child’s) during the 
study using the Epworth Sleepiness Scale (ESS; Appendix 7; at Weeks 0, 2, 5, 15, 28, 
41, 54, 106 and 108)   
• 
To assess the level of caregiver’s quality of sleep at night (i.e., NOT the child’s) 
during the study using the Pittsburgh Sleep Quality Index (PSQI; Appendix 8) global 
score and components (at Weeks 0, 2, 5, 15, 28, 41, 54, 106 and 108) 
• 
To assess the level of caregiver’s well-being (i.e., NOT the child’s) during the study 
using the World Health Organization Well-Being Index (WHO-5; Appendix 9) 
well-being questionnaire (at Weeks 0, 2, 5, 15, 28, 41, 54, 106 and 108) 
• 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on children’s 
body mass index (BMI) and Z-score after 3 and 13 weeks of double-blind treatment, 
and to evaluate the effect of Circadin® 2/5/10 mg compared to baseline, at the end of 
the open-label period and at the end of placebo run-out period 
• 
To assess the treatment effect of Circadin® 2/5/10 mg on children’s pubertal status 
using the Tanner scale will be used in children ≥8 years of age.  For children ≤5 years 
of age, only height and head circumference will be used to stage children 
development.  Between the age of 5 and 8 the children’s physical development will be 
determined using the BMI (baseline through Week 108) 
• 
In children diagnosed with epilepsy, to compare the effect of Circadin® 2/5 mg to that 
of placebo on the number and severity of epilepsy seizures during double-blind 
treatment and to assess the effect of Circadin® 2/5/10 mg during the open-label period 
using seizure diaries.   
Study Design:   
This is a randomized placebo-controlled study in children diagnosed with autism spectrum 
disorders (ASDs) and neurodevelopmental disabilities caused by neurogenetic diseases.  
Children will have a documented history of these disorders, as confirmed or consistent with the 
International Classification of Diseases (ICD-10) or Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (Text Revision; DSM-5/4) criteria, having International 
Classification of Sleep Disorders (ICSD) criteria-based sleep disturbances modified to take into 
account the uniqueness of insomnia in the pediatric population at screening.   
The children will undergo 4 weeks of basic sleep hygiene and behavioral intervention, which 
will serve as a wash-out period from any hypnotics; a gradual withdrawal will take place during 
the first 2 weeks and a complete withdrawal of prohibited medications will take place during 
the last 2 weeks.   
Children who are still found to be eligible for the study after the 4-week, basic sleep hygiene 
and behavioral intervention wash-out period, will continue in a 2-week single-blind (SB) 
placebo run-in period.  In order to be eligible for the 2-week SB placebo run-in period, the child 
should not have responded to sleep hygiene and behavioral intervention during the first 4 weeks 
and therefore will not need to continue this therapy during the study.  Children with a 
documented history of sleep hygiene and behavioral intervention, who are still found eligible, 
will enter directly into the 2-week SB placebo run-in period.   
Children with a documented history of sleep hygiene and behavioral intervention who are 


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taking a prohibited medication will not require additional training and will undergo a 2 week 
wash-out period before Visit 1 (e.g., Weeks -2 through 0 to wash out melatonin or any other 
prohibited medications).  During these 2 weeks there is no need to complete the sleep and nap 
diary. 
After the 4-week sleep hygiene wash-out and 2-week SB placebo run-in periods, children who 
are still found eligible for study participation will be randomized in a 1:1 ratio to receive either 
Circadin® 2 mg or placebo for 3 weeks in a double blind treatment period.  After 3 weeks of 
treatment, on the last day of Week 5 ±3 days (Visit 3), sleep variables will be assessed to 
determine if dose modification (an increase to 5 mg) is required.  Children will then continue 
on 2 or 5 mg of Circadin® or placebo for an additional double-blind period of 10 weeks.  This 
double-blind period will be followed by an open-label period of 13 weeks.  At the end of the 
13-weekopen-label period on the last day of Week 28 ±3 days (Visit 5), sleep variables will be 
assessed to determine if a potential additional dose modification (i.e., an increase either to 5 mg 
for patients who are still on 2 mg or an increase to 10 mg for patients who are on 5 mg) is 
necessary (If a dose increase is decided upon, the dose increase should be from 2 mg to 5 mg, 
or from 5 mg to 10 mg).  Children will continue at 2, 5, or 10 mg Circadin® in an open-label 
period for another 78 weeks of follow-up, which will include continuous safety monitoring, and 
2 efficacy assessment time points at Weeks 41 and 54.  The study will end with a 2-week SB 
placebo run-out period.   
Each patient will participate in the study until the end of the second open-label safety follow-up 
period, and 2 week run-out period.  Study duration will be 112 weeks, including the 4-week 
wash-out period with sleep hygiene and behavioral intervention. 
Test Drugs/Study 
Medications: 
Test drug:   
Circadin® 1 mg minitablets will be used in this study.  These tablets are 3 mm in diameter and 
will allow flexibility of dosing for the required dose titrations from 2 mg to 5 mg or 10 mg.   
Reference drug:   
Placebo will be identical in appearance and formulation to active Circadin® minitablets, but will 
contain no active melatonin.   
Circadin® and placebo are to be administered orally, 1 portion of minitablets daily, taken 
postprandial at 0.5 to 1 hour before desired bedtime (bedtime should be age-appropriate 
bedtime).  The minitablets should be swallowed whole and should not be crushed or halved. 
Inclusion Criteria: 
To be eligible for study entry, all patients must satisfy all of the following criteria at screening:   
1. Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study 
drug  
2. Must have written informed consent provided by a legal guardian and assent (if 
needed)  
3. Must have a documented history of ASD according to or consistent with the ICD-10 or 
DSM-5/4 criteria, or neurodevelopmental disabilities caused by neurogenetic diseases 
(i.e., Smith-Magenis syndrome, Angelman syndrome, Bourneville’s disease [tuberous 
sclerosis]) as confirmed by case note review showing that diagnosis was reached 
through assessment by a community pediatrician or pediatric neurologist or other 
health care professionals experienced in the diagnosis who took into account early 
developmental history and school records.   
4. Must have current sleep problems including:  a minimum of 3 months of impaired 
sleep defined as ≤6 hours of continuous sleep AND/OR ≥0.5 hour sleep latency from 
light off in 3 out of 5 nights based on parent reports and patient medical history.  (The 
maintenance and latency problems do not necessarily have to be in the same 3 nights 
of the week.) 
5. May be on a stable dose of non-excluded medication for 3 months, including 
anti-epileptics, anti-depressants (selective serotonin reuptake inhibitor [SSRIs]), 


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stimulants, all mood changing drugs and β-blockers.  (Only morning administration of 
β-blockers is allowed since β-blockers at night have the potential to reduce 
endogenous melatonin levels and might cause disturbed sleep)   
6. The sleep disturbance is not due to the direct physiological effects of any concomitant 
medications such as SSRIs, stimulants, etc.   
After completing 4 weeks of sleep hygiene training (for those who need it) and 2 weeks of 
placebo run-in, patients will be eligible to continue the study if they comply with the following: 
• 
Continue to fulfill sleep problem criteria (see Inclusion Criterion 4) based on the 
completed Sleep and Nap Diary entered into the electronic case report form   
• 
Parents demonstrate compliance in Sleep and Nap Diary completion (5 out of 
7 nights).  Compliance means that in at least 5 out of 7 nights per week (total of 
2 weeks before each scheduled visit) the parents complete the diary pages with all 
mandatory questions (mandatory questions are marked with an asterisk [*] in 
Appendix 1).   
• 
Continue to fulfil all other eligibility criteria   
Exclusion Criteria: 
Children who meet any of the following criteria will be excluded from participating in the 
study:   
1. Have had treatment with any form of melatonin within 2 weeks prior to Visit 1  
2. Have a known allergy to melatonin or lactose  
3. Have a known moderate to severe sleep apnea   
4. Have an untreated medical/ineffectively treated/psychological condition that may be 
the etiology of sleep disturbances 
5. Did not respond to previous Circadin® therapy based on past medical history records 
in the last 2 years  
6. Are taking or have been taking prohibited medication within 2 weeks prior to Visit 1 
(Section 7.1)  
7. Are females of child-bearing potential that are not using contraceptives and/or 
breastfeeding and that are sexually active (Abstinence is an acceptable method of 
contraception.)  
8. Pregnant females 
9. Are currently participating in a clinical trial or have participated in a clinical trial 
involving medicinal product within the last 3 months prior to the study (this does not 
include patients who participated in the Phase I PK study who can be already included 
in the study)   
10. Children with known renal or hepatic insufficiency  
Number of Patients: 
Enough eligible male and female children of ages 2 to 17.5 years will be screened for the study 
to allow for 120 patients to then be randomized in a 1:1 ratio to receive Circadin® or placebo at 
Visit 2.  A minimum of 90 children are expected to complete the double-blind and first 
open-label period.  A minimum of 50 children are expected to complete the second open-label 
safety follow-up period. 
Study Duration: 
Each patient will participate in the study until the end of the second open-label safety follow-up 
period, and 2-week SB run-out period.  Altogether, the study duration will be 112 weeks 
including 4-week wash-out period with sleep hygiene and behavioral intervention. 
Study Endpoints: 
Primary Efficacy Endpoint 
The primary efficacy endpoint is TST time as assessed by a Sleep and Nap Diary after the 
13-week, double-blind treatment period.   
Secondary Efficacy Endpoints 


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• 
Sleep latency as assessed by a Sleep and Nap Diary after 13 weeks (Week 15) of 
double-blind treatment  
• 
Duration of wake after sleep onset from the Sleep and Nap Diary after 13 weeks 
(Week 15) of double-blind treatment  
• 
Number of awakenings from the Sleep and Nap Diary after 13 weeks (Week 15) of 
double-blind treatment  
• 
Longest sleep period from the Sleep and Nap Diary after 13 weeks (Week 15) of 
double-blind treatment 
• 
Social functioning at home, in school, and in community settings as assessed by the 
CGAS after 13 weeks (Week 15) of double-blind treatment   
• 
Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 15) of 
double-blind treatment 
• 
Number of dropouts during the 13-week (Week 15) double-blind treatment period 
• 
Assessment of sleep parameters by actigraphy after 13 weeks (Week 15) of 
double-blind treatment 
Exploratory Efficacy Endpoints 
• 
Sleep variables as assessed by the Sleep and Nap Diary at baseline (Week 2), after 
3 weeks of double blind treatment (Week 5), and after 13, 26, and 39 weeks of open 
label treatment (Weeks 28, 41, and 54)  
• 
Sleep disturbance as assessed by the CSDI score at baseline after 3 and 13 weeks of 
double-blind treatment (Weeks 5 and 15, respectively), after 13, 26, 39, and 91 weeks 
of open label treatment (Weeks 28, 41, 54, and 106, respectively), and at the end of 
study visit (Week 108) 
• 
Social functioning at home, in school, and in community settings as assessed by the 
CGAS after 13 weeks (Week 28)of open-label treatment  
• 
Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 28) of 
open-label treatment  
• 
Caregiver’s daytime sleepiness (i.e., NOT the child’s) during the study as assessed by 
the ESS (Weeks 0, 2, 5, 15, 28, 41, 54, 106 and 108) 
• 
Caregiver’s well-being (i.e., NOT the child’s) during the study as assessed by the 
WHO-5 questionnaire (Weeks 0, 2, 5 15, 28, 41, 54, 106 and 108) 
• 
Caregiver’s quality of sleep at night (i.e., NOT the child’s) during the study using the 
PSQI global score and components (at Weeks 0, 2, 5, 15, 28, 41, 54, 106 and 108) 
Safety Endpoints 
Safety Endpoints (Secondary) 
• 
Assessment of AEs throughout the study and upon study withdrawal using the TESS  
• 
Vital signs at each visit including the placebo run-out (withdrawal) period 
• 
Physical examination at each visit including the placebo run-out (withdrawal) period 
Safety Endpoints (Exploratory) 
• 
BMI and Z-score assessed during the study 
• 
Pubertal assessment using the Tanner scale during the study (The Tanner scale will be 
used to assess and stage physical development in children ≥8 years of age.  For 
children ≤5 years of age, only height and head circumference will be used to stage 
children development.  Between the age of 5 and 8, the children’s physical 
development will be determined using BMI.  
• 
In children diagnosed with epilepsy, the number and severity of epilepsy seizures 
assessed during the study using seizures diaries completed by the parents at the time of 
the seizures  


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Sample Size 
Estimation: 
To achieve 95% power at the 5% level for the primary objective (assuming a change of 
0.72 hour in the Circadin® arm and 0.27 hour in the placebo arm and a standard deviation (SD) 
of 0.69 in the Circadin® arm and 0.45 in the placebo arm), 45 patients are required per 
combined group.  Therefore, 90 patients in total are required to complete Visit 5.  These 
estimations are based on previous studies conducted with Circadin®. 
Statistical Methods: 
Primary Efficacy Analysis  
Total sleep time will be assessed by a Sleep and Nap Diary, and will be summarized after 
13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual change from 
baseline) for each treatment group using descriptive statistics (n, mean, SD, median, minimum 
and maximum).  For each treatment group for this outcome, the mean score at 13 weeks will be 
compared, adjusting for baseline, using linear regression model (Analysis of Covariance 
[ANCOVA]) to test the null hypothesis so that these adjusted mean scores are equal. 
Secondary Efficacy Analyses  
Sleep latency will be assessed by a Sleep and Nap Diary, and will be summarized after 
13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual change from 
baseline) for each treatment group using descriptive statistics (n, mean, SD, median, minimum, 
and maximum).  For each treatment group for this outcome, the mean score at 13 weeks will be 
compared, adjusting for baseline, using an ANCOVA model to test the null hypothesis so that 
these adjusted mean scores are equal. 
Duration of wake after sleep onset period will be assessed by a Sleep and Nap Diary, and will 
be summarized after 13 weeks (mean of the last 14 days before visit) of double-blind treatment 
(actual change from baseline) for each treatment group using descriptive statistics (n, mean, 
SD, median, minimum, and maximum).  For each treatment group for this outcome, the mean 
score at 13 weeks will be compared, adjusting for baseline, using an ANCOVA model to test 
the null hypothesis so that these adjusted mean scores are equal. 
The number of awakenings will be assessed by a Sleep and Nap Diary, and will be summarized 
after 13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual change 
from baseline) for each treatment group using descriptive statistics (n, mean, SD, median, 
minimum and maximum).  For each treatment group for this outcome, the mean score at 
13 weeks will be compared, adjusting for baseline, using an ANCOVA model to test the null 
hypothesis so that these adjusted mean scores are equal. 
The longest sleep episode will be assessed by a Sleep and Nap Diary, and will be summarized 
after 13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual change 
from baseline) for each treatment group using descriptive statistics (n, mean, SD, median, 
minimum and maximum).  For each treatment group for this outcome, the mean score at 
13 weeks will be compared, adjusting for baseline, using an ANCOVA model to test the null 
hypothesis so that these adjusted mean scores are equal.   
The CGAS score will be summarized at baseline and after 13 weeks of double-blind treatment 
(actual change from baseline) for each treatment group using descriptive statistics (n, mean, 
SD, median, minimum, and maximum).  For each treatment group for this outcome, the mean 
score at 13 weeks will be compared, adjusting for baseline, using an ANCOVA model to test 
the null hypothesis so that these adjusted mean scores are equal. 
The SDQ score will be summarized at baseline and after 13 weeks of double-blind treatment 
(actual change from baseline) for each treatment group using descriptive statistics (n, mean, 
SD, median, minimum, and maximum).  For each treatment group for this outcome, the mean 
score at 13 weeks will be compared, adjusting for baseline, using an ANCOVA model to test 
the null hypothesis so that these adjusted mean scores are equal. 
The number of dropouts will be compared between the treatment groups and analyzed using a 
dichotomized data analysis (chi-square test). 
Sleep parameters, as measured by actigraphy, will be summarized at baseline and after 


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13 weeks of double-blind treatment (actual change from baseline) for each treatment group 
using descriptive statistics (n, mean, SD, median, minimum, and maximum).  For each 
treatment group for this outcome, the mean score at each time point will be compared using an 
ANCOVA model to test the null hypothesis so that these mean scores are equal. 
For all primary and secondary analyses, a mixed-effect repeated-measures model (MMRM) 
will be fitted to assess any differences in treatment effects over time.  The base models will 
contain the specified outcome measure after baseline as the dependent variable, with 
independent variables in the form of the baseline score, the study visit (categorical variable) 
and treatment allocation.  A general covariance structure will be assumed.  The global treatment 
effect estimates will be reported, with 95% confidence intervals (CIs) and p-values.  Further 
analysis will include interaction between treatment and visit.  Interaction p-values will be 
reported with treatment effect estimates at each visit with 95% CIs and p-values.  
Exploratory Efficacy Analyses  
All sleep variables will be assessed by a Sleep and Nap Diary, and will be summarized at 
baseline and after 3 weeks of double-blind treatment (actual and change from baseline) for each 
treatment group using descriptive statistics (n, mean, SD, median, minimum, and maximum).  
For each treatment group for this outcome, the mean score at 3 weeks will be compared, 
adjusting for baseline, using an ANCOVA model to test the null hypothesis so that these 
adjusted mean scores are equal. 
Sleep disturbance will be assessed by CSDI score, and will be summarized at baseline, after 3 
and 13 weeks of double-blind treatment (actual and change from baseline) for each treatment 
group using descriptive statistics (n, mean, SD, median, minimum and maximum).  For each 
treatment group, for this outcome, the mean score (actual and change from baseline) at each 
time point will be compared, adjusting for baseline, using an ANCOVA model to test the null 
hypothesis so that these adjusted mean scores are equal.   
All sleep variables will be assessed by the CSDI and the Sleep and Nap Diary, and will be 
summarized at baseline and after 13, 26 and 39 weeks of Circadin® open-label treatment 
(Weeks 28, 41 and 54, actual change from baseline) for each treatment group using descriptive 
statistics (n, mean, SD, median, minimum, and maximum).  CSDI will be also summarized 
after 106 and 108 weeks of Circadin® open-label treatment. 
CGAS score will be summarized at baseline and after 13 weeks of Circadin® open-label 
treatment (Week 28; actual change from baseline) for each treatment group using descriptive 
statistics (n, mean, SD, median, minimum, and maximum). 
The SDQ score will be summarized at baseline and after 13 weeks of Circadin® open-label 
treatment (Week 28; actual change from baseline) for each treatment group using descriptive 
statistics (n, mean, SD, median, minimum and maximum). 
The ESS score for the parent and caregiver will be summarized at baseline and at the 5, 15, 28, 
41, 54, 106 and 108 week time points (actual change from baseline) using descriptive statistics 
(n, mean, SD, median, minimum, and maximum).  Note:  The ESS is to assess the sleepiness of 
the parent/caregiver and NOT the child.) 
The WHO-5 score (parent’s well-being assessment) will be summarized at baseline and at the 
5, 15, 28, 41, 54, 106 and 108 week time points (actual change from baseline) using descriptive 
statistics (n, mean, SD, median, minimum, and maximum).  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.) 
The PSQI global score and components (parent’s sleep variables) will be summarized at 
baseline and at the 5, 15, 28, 41, 54, 106 and 108 week time points (actual change from 
baseline) using descriptive statistics (n, mean, SD, median, minimum, and maximum).  Note:  
The PSQI is to assess the quality of sleep of the parent/caregiver and NOT the child.)  
For all exploratory analyses for the double-blind period, a MMRM will be fitted to assess any 
differences in treatment effects over time.  The base models will contain the specified outcome 
measure after baseline as the dependent variable, with independent variables in the form of the 


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baseline score, the study visit (categorical variable) and treatment allocation. 
 
Safety Analyses  
Secondary Safety Endpoints 
Descriptive statistics will be provided for AEs, changes in physical examinations and vital signs 
measurements.  The number of patients withdrawing during the treatment periods will be 
summarized by primary reason for withdrawal for each treatment group.   
Exploratory Safety Endpoints 
The changes in BMI and Z-score from baseline to the end of the study will be summarized 
using shift tables showing the number of children having values below, within and above 
Z-calculated normal at each treatment group separately.  The BMI and Z-scores are designed to 
take into account the amount of weight gain that would be expected due to normal growth in 
children and adolescents.  The BMI and Z-scores are categorized by age and gender 
standardized values (corresponding to a normal distribution with mean 0 and a SD of 1) of the 
actual weight measurements, based on the Growth Charts provided by the Centers for Disease 
Control. 
Tanner scores for pubertal assessment in children ≥8 years of age during the study will be 
analyzed using the web application (http://vps.stefvanbuuren.nl/puberty)20.  This tool calculates 
SD scores of individual observations of Tanner scores and additionally plots those scores in 
stage line diagram21.   
Descriptive statistics will be provided for head and height measurements and changes in head 
and height measurements from baseline to Week 108 in children ≤5 years of age.  
Descriptive statistics will also be provided for the number and severity of epilepsy seizures in 
children diagnosed with epilepsy, using the Epilepsy Seizures Diaries that are completed by 
parents at the time of the seizures and entered in the eCRF at a later time point by the site. 
 


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2 TABLE OF CONTENTS  
1 
PROTOCOL SYNOPSIS .......................................................................................................... 4 
2 
TABLE OF CONTENTS ........................................................................................................ 12 
DEFINITION OF TERMS.................................................................................................................. 18 
LIST OF ABBREVIATIONS ............................................................................................................. 19 
3 
INTRODUCTION.................................................................................................................... 20 
4 
OBJECTIVES OF THE STUDY ............................................................................................ 22 
5 
INVESTIGATIONAL PLAN ................................................................................................. 24 
5.1 
Overall study design .............................................................................................................. 24 
5.2 
Efficacy Assessments............................................................................................................. 25 
5.3 
Safety Assessments ................................................................................................................ 26 
6 
STUDY POPULATION AND SELECTION ........................................................................ 31 
6.1 
Inclusion Criteria ................................................................................................................... 31 
6.2 
Exclusion Criteria .................................................................................................................. 32 
6.3 
Withdrawal of Patients from Treatment ................................................................................ 32 
6.4 
Replacement of Patients ......................................................................................................... 33 
7 
TREATMENTS ADMINISTERED ....................................................................................... 33 
7.1 
Prohibited Medications .......................................................................................................... 34 
7.2 
Investigational Medicinal Product ......................................................................................... 34 
7.3 
Circadin® Administration ....................................................................................................... 35 
7.3.1 
Dose Modification ........................................................................................................ 35 
7.3.2 
Dose Reduction ............................................................................................................ 36 
7.4 
Blinding.................................................................................................................................. 36 
7.5 
Dose Selection Rationale ....................................................................................................... 37 
7.6 
Treatment Compliance ........................................................................................................... 37 
8 
CONDUCT OF STUDY AND STUDY ASSESSMENTS .................................................... 37 
8.1 
Screening Visit (Day 1 at -4 Weeks ±3 Days) ....................................................................... 39 
8.2 
Pre-Visit 1 .............................................................................................................................. 40 
8.3 
Visit 1 (Week 1 Day 1 ±3 Days) ............................................................................................ 40 
8.4 
Pre-Visit 2 Phone Call ........................................................................................................... 41 
8.5 
Visit 2 (Randomization/Baseline Visit; Last Day of Week 2 ±3 Days) ................................ 41 
8.6 
Pre-Visit 3 .............................................................................................................................. 42 
8.7 
Visit 3 (Possible Dose Modification; Last Day of Week 5 ±3 Days) .................................... 42 
8.8 
Pre-Vi sit 4 ............................................................................................................................. 43 
8.9 
Visit 4 (Last Day of Week 15 ±3 Days) ................................................................................ 43 


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8.10 
Pre-Visit 5 .............................................................................................................................. 45 
8.11 
Visit 5 (Last Day of Week 28 ±3 Days) ................................................................................ 45 
8.12 
Pre-Visit 6 .............................................................................................................................. 46 
8.13 
Visit 6 (Last Day of Week 41 ±7 Days) ................................................................................ 46 
8.14 
Pre-Visit 7 .............................................................................................................................. 47 
8.15 
Visit 7 (Last Day of Week 54 ±7 Days) ................................................................................ 47 
8.16 
Pre-Visit 8 .............................................................................................................................. 47 
8.17 
Visit 8 (Last Day of Week 106 ±7 Days) .............................................................................. 47 
8.18 
Pre-End of Study Visit ........................................................................................................... 48 
8.19 
End of Study Visit (Last Day of Week 108 ±3 Days) ........................................................... 48 
8.20 
Unscheduled Visit(s) .............................................................................................................. 49 
10 
CLINICAL PHARMACOLOGY ASSESSMENTS ............................................................. 51 
10.1 
Pharmacokinetic (PK) Assessments ...................................................................................... 51 
10.2 
Pharmacodynamic (PD) Assessments.................................................................................... 51 
10.3 
Biomarker and Exploratory Assessments .............................................................................. 51 
11 
SAFETY ASSESSMENTS ...................................................................................................... 51 
11.1 
Adverse Events ...................................................................................................................... 51 
11.1.1 
Definition of an Adverse Event .................................................................................... 51 
11.1.2 
Assessment of Severity ................................................................................................ 52 
11.1.3 
Assessment of Frequency ............................................................................................. 52 
11.1.4 
Assessment of Outcome ............................................................................................... 52 
11.1.5 
Assessment of Causality and Relatedness .................................................................... 53 
11.1.6 
Follow-up of Adverse Events ....................................................................................... 54 
11.2 
Serious Adverse Events ......................................................................................................... 54 
11.2.1 
Definition of a Serious Adverse Event ......................................................................... 54 
11.2.2 
Definition of an Unexpected Adverse Event................................................................ 55 
11.2.3 
Reporting of Serious Adverse Events .......................................................................... 55 
11.3 
Withdrawal Due to an Adverse Event ................................................................................... 55 
11.4 
Monitoring of Patients with AEs ........................................................................................... 56 
11.5 
PHYSICAL EXAMINATION AND VITAL SIGNS ........................................................... 56 
11.6 
Treatment of Overdose of Study Medication ......................................................................... 56 
11.7 
Pregnancy ............................................................................................................................... 57 
11.8 
Physical Examination and Vital Signs ................................................................................... 57 
11.9 
Other Safety Assessments ...................................................................................................... 57 
12 
DATA MANAGEMENT AND STATISTICAL ANALYSIS .............................................. 57 
12.1 
Data Management .................................................................................................................. 57 
12.2 
Statistical Analysis Plan ......................................................................................................... 58 
12.3 
General Considerations .......................................................................................................... 58 


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12.4 
Randomization ....................................................................................................................... 58 
12.5 
Analysis Sets .......................................................................................................................... 58 
12.6 
Sample Size ............................................................................................................................ 59 
12.7 
Study Population .................................................................................................................... 59 
12.7.1 
Patient Disposition ....................................................................................................... 59 
12.7.2 
Demographic and Baseline Characteristics .................................................................. 59 
12.8 
Study Endpoints and statisitcal methods................................................................................ 59 
12.8.1 
Efficacy Endpoints ....................................................................................................... 59 
12.8.2 
Safety Endpoints .......................................................................................................... 62 
12.8.3 
Exploratory Endpoints.................................................................................................. 62 
12.9 
Study Termination Criteria .................................................................................................... 62 
12.10 Data Safety Monitoring Board ............................................................................................... 63 
12.11 Handling of Dropouts/Missing Data ...................................................................................... 63 
12.12 Changes to the Planned Analysis ........................................................................................... 64 
13 
MONITORING PROCEDURES (QUALITY CONTROL AND QUALITY 
ASSURANCE) ...................................................................................................................................... 64 
13.1 
Routine Monitoring ................................................................................................................ 65 
13.2 
Inspections and Auditing Procedures ..................................................................................... 65 
13.3 
Protocol Amendments and Significant Protocol Deviations and Violations ......................... 66 
13.3.1 
Protocol Amendments .................................................................................................. 66 
13.3.2 
Protocol Deviations, Violations, and Exceptions ......................................................... 66 
13.4 
Information to Study Personnel ............................................................................................. 67 
13.5 
Record Keeping ..................................................................................................................... 67 
14 
STUDY MANAGEMENT AND MATERIALS .................................................................... 67 
14.1 
Electronic Case Report Forms ............................................................................................... 67 
14.2 
Data Collection ...................................................................................................................... 68 
14.3 
Source Documents Maintenance............................................................................................ 68 
14.4 
Record Maintenance .............................................................................................................. 69 
14.5 
Confidentiality ....................................................................................................................... 69 
15 
DRUG ACCOUNTABILITY .................................................................................................. 70 
16 
ETHICS AND INFORMED CONSENT ............................................................................... 71 
16.1 
ETHICS.................................................................................................................................. 71 
16.1.1 
Regulatory and Ethical Approvals ............................................................................... 71 
16.1.2 
Ethical Conduct of the Study ....................................................................................... 71 
16.2 
Patient Information and Informed Consent............................................................................ 71 


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17 
FINANCING AND INSURANCE .......................................................................................... 71 
18 
REPORTING AND PUBLICATION .................................................................................... 72 
19 
REFERENCES ......................................................................................................................... 73 
20 
APPENDICES .......................................................................................................................... 75 
 


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LIST OF APPENDICES 
Appendix 1:  Sleep and Nap Diary ........................................................................................................ 75 
Appendix 2:  Sleep and Nap Diary Take-Home Instructions for Parents .............................................. 78 
Appendix 3:  Children Global Assessment Scale and Rating Guidelines ............................................. 84 
Appendix 4:  Strength and Difficulties Questionnaires ......................................................................... 88 
Appendix 5:  Treatment Emergent Signs and Symptoms .................................................................... 103 
Appendix 6:  Composite Sleep Disturbance Index .............................................................................. 107 
Appendix 7:  Epworth Sleepiness Scale .............................................................................................. 109 
Appendix 8:  Pittsburgh Sleep Quality Index ...................................................................................... 111 
Appendix 9:  WHO-5 Well-being Index .............................................................................................. 114 
Appendix 10:  Epilepsy Seizures Diary ............................................................................................... 116 
Appendix 11:  Prohibited Medication List........................................................................................... 118 
 
 


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LIST OF IN-TEXT TABLES 
Table 5-1:  Study Treatment Schedule................................................................................................... 27 
Table 5-2:  Schedule of Study Assessments .......................................................................................... 28 
Table 8-1:  Summary of Questionnaires ................................................................................................ 39 


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DEFINITION OF TERMS 
Safety Analysis Set 
All patients randomized to treatment who take at 
least 1 dose of study medication. 
Full Analysis Set (FAS) 
All patients in the Safety Analysis Set who 
satisfy all major entry criteria and who have 
efficacy data for the primary parameter recorded 
for baseline and at least 1 post-baseline period 
assessment 
Per Protocol Set  
All patients in the FAS for whom there were no 
serious violations of the protocol  
 


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LIST OF ABBREVIATIONS 
AE 
adverse events 
ANCOVA 
analysis of covariance 
ASD 
Autism Spectrum Disorder 
BMI 
Body mass index 
CGAS 
Children Global Assessment Scale 
CSDI 
Composite Sleep Disturbance Index 
CSR 
clinical study report 
DSM-5/4 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (Text Revision) 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ESS 
Epworth Sleepiness Scale 
EU 
European Union  
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICD-10 
International Classification of Diseases 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICSD 
International Classification of Sleep Disorders 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product  
IR 
immediate-release 
IRB 
Institutional Review Board 
MMRM 
mixed-effect repeated measures model 
PI 
Principal Investigator 
PIP 
Pediatric Investigational Plan 
PR 
prolonged-release 
PSQI 
Pittsburgh Sleep Quality Index 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SB 
single blind 
SD 
standard deviation 
SDQ 
Strength and Difficulties Questionnaire 
SMS 
Smith-Magenis syndrome 
SSRI 
selective serotonin reuptake inhibitor 
TESS 
Treatment-Emergent Signs and Symptoms Questionnaire  
TST 
total sleep time 
WHO-5 
World Health Organization Well-Being Index 
 
 


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3 INTRODUCTION  
Sleep disturbance is 1 of the most common complaints in children with autism spectrum disorder 
(ASD), mental retardation or other developmental delays1-3.  High prevalence for moderate sleep 
disturbances in these children populations is associated with significant sleep problems and subsequent 
distress for the families of these children, which in many cases, lead to the decision to institutionalize 
the children4.  Specifically, a frequent cause of families giving up their care is discontinuous sleep with 
frequent awakenings throughout the night.  There is a growing body of evidence on abnormal 
melatonin secretion in children with neurodevelopmental disorders5, which prompted the use of 
melatonin to treat sleep disorders in these populations.  Several exploratory studies and case reports 
have led to strong consensus among researchers that exogenous melatonin is beneficial for treating 
chronic sleep disturbances of children who have neurodevelopmental and neuropsychiatric difficulties.  
Although in none of these studies significant adverse events (AEs) as a result of melatonin use have 
been reported, the safe, appropriate dosing (including amounts and timing), have not been established 
for children.  Moreover, in many cases, immediate-release (IR) melatonin preparations that are 
available as food supplements in the USA were used.  These formulations did not improve total sleep 
time (TST) and sleep maintenance, which are the most disturbing parameters for families6.  As 
melatonin has a very short half-life (40 minutes), prolonged-release (PR) formulations are sought to 
cover the night period, and should affect sleep maintenance. 
Circadin® is a 2 mg PR melatonin formulation that mimics the physiological secretion profile of 
melatonin and can offer more sustained blood levels of melatonin overnight.  Circadin® 2 mg is the 
first, fully developed melatonin pharmaceutical product and was approved for marketing in the 
European Union (EU) in 2007 for the treatment of primary insomnia in patients aged 55 years and 
older7.   
Several published studies performed in Canada8-10 and France8-14 have looked at the use of Circadin® to 
treat sleep wake cycle disturbances in children with neurodevelopmental disabilities.  The efficacy and 
safety of Circadin® was evaluated in 42 children with chronic sleep–wake cycle disorders10.  All 
42 patients had severe neurodevelopmental difficulties.  Initially, a randomized, double-blinded, 
cross-over design was used in 16 children, comparing the effectiveness of IR and PR Circadin®.  In the 
remainder of the patients, the PR melatonin was studied on a clinical basis.  The effectiveness of 
treatment was assessed by sleep charts and clinical follow-up.  Emphasis was placed on the judgment 
of the parents, who had guidance from the physicians.  The average final PR melatonin dose in the 
42 patients was 5.7 mg (2 to 12 mg).  The studies showed that the IR melatonin was most effective 
when there was only delayed sleep onset, but PR formulations were more useful for sleep maintenance.   
Data from 44 children with neurodevelopmental disabilities and treatment-resistant circadian rhythm 
sleep disorders who had participated in the placebo controlled, double-blind cross-over trial of 
PR-melatonin (not Circadin®) were reported in a prospective follow-up study9.  The follow-up study 
involved a structured telephone interview of caregivers every 3 months for up to 3.8 years.  Adverse 
reaction to melatonin therapy and development of tolerance were not evident.  Better sleep was 
associated with reported improvement in health, behavior, and learning.  At the end of the study, the 


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parental comments regarding the effectiveness of long-term melatonin therapy were highly positive.  
Parents whose children had sleep maintenance difficulties expressed a wish to have a commercially 
available PR-melatonin product which would promote sleep for 8 to 10 hours. 
Treatment with Circadin® was reported in children who presented with Smith-Magenis syndrome 
(SMS), mental retardation, encephalopathy, autism, Angelman syndrome, Rett syndrome, Bourneville 
syndrome, blindness, and delayed-sleep-phase syndrome12.  Patients aged 3 to 18 years were given 
Circadin® (4 to 6 mg/day) as a single evening dose over a treatment duration which ranged from 6 to 
72 months.  In the group of children for whom there were full reports by their parents (49 children) 
within 3 months, sleep latency with Circadin® decreased by 44.0% (p-value <0.001); sleep duration 
increased by 10.1% (p-value <0.001); and the number of midnight awakenings decreased by 75% 
(p-value <0.001) compared with baseline.  Additionally, sleep quality improved by 75% compared 
with baseline (2.1±0.34 vs. 1.2±0.4, respectively, p-value <0.001).  No serious adverse events (SAEs) 
or treatment related co-morbidities were reported.  Other studies using PR-melatonin15 (not Circadin®) 
indicated long-term effectiveness of PR-melatonin at a maximal dose of 4 mg in children 4 years or 
less and 6 mg over this age.  In children aged 2.6 to 9.6 years with autism without other coexistent 
pathologies, PR-melatonin was evaluated openly.  Treatment gains were maintained at 12 and 
24-month follow-ups.  It was concluded that PR melatonin may provide an effective and well-tolerated 
treatment for autistic children with chronic sleep disorders.   
In order to establish the efficacy and safety of Circadin® in children with neurodevelopmental disorders 
and to determine the dose, this randomized, placebo-controlled study is planned to evaluate the 
efficacy of a double-blind, 13-week treatment period with Circadin® 2/5 mg in improving maintenance 
of sleep, sleep latency and additional parameters in children with neurodevelopmental disabilities.  
The efficacy and safety of Circadin® 2/5 mg will continue to be assessed during an open-label 
extension period of 13 weeks.  Withdrawal effects will also be assessed during the 2-week single-blind 
(SB) placebo run-out period.  


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4 OBJECTIVES OF THE STUDY 
Primary Objective 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep maintenance (TST) as 
assessed by the Sleep and Nap Diary (Appendix 1) after 13 weeks of double-blind treatment. 
Secondary Objectives 
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep latency as 
derived from a Sleep and Nap Diary (Appendix 1) after 13 weeks of double-blind treatment 
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on the duration of wake 
after sleep onset period as derived from a Sleep and Nap Diary after 13 weeks of double-blind 
treatment 
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on number of 
awakenings as derived from a Sleep and Nap Diary after 13 weeks of double-blind treatment   
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on the duration of the 
longest sleep period as derived from a Sleep and Nap Diary after 13 weeks of double-blind 
treatment 
• To assess the treatment effect of Circadin® 2/5 mg to that of placebo on children’s social 
functioning at home, in school, and community settings as assessed by the Children Global 
Assessment Scale (CGAS; Appendix 3) after 13 weeks of double-blind treatment 
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on children’s behavior at 
home and in school as assessed by the Strength and Difficulties Questionnaire (SDQ; 
Appendix 4) after 13 weeks of double-blind treatment 
• To compare the number of dropouts between Circadin® 2/5 mg to that of placebo during the 
13 weeks of double-blind treatment 
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep parameters as 
measured by actigraphy after 13 weeks of double-blind treatment 
• To compare the safety and tolerability of Circadin® treatment to that of placebo and evaluate the 
safety and tolerability throughout the study including the run-out (withdrawal) period using AE 
eliciting method Treatment Emergent Signs and Symptoms questionnaire (TESS; Appendix 5) 
• To assess vital signs and physical examinations in Circadin® and placebo groups 
Exploratory Objectives 
• To evaluate the effect of Circadin® 2/5 mg on all sleep variables derived from the Sleep and Nap 
Diary after 3 weeks of double-blind treatment (Week 15), and after 13, 26, and 39 weeks of 
open-label treatment (Weeks 28, 41, and 54) as compared to baseline (Week 2) 


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• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep disturbance as 
assessed by Composite Sleep Disturbance Index (CSDI; Appendix 6) score after 3 and 
13 weeks of double-blind treatment (Weeks 5 and 15), after 13, 26, 39, and 91 weeks of 
open-label treatment (Weeks 28, 41, 54, and 106, respectively), and at the end of study visit 
(Week 108) as compared to baseline (Week 2) 
• To assess the treatment effect of Circadin® 2/5 mg on children’s social functioning at home, in 
school, and community settings as assessed by the CGAS (Appendix 3) after 13 weeks 
(Week 28) of Circadin® open-label treatment as compared to baseline (Week 2) 
• To assess the treatment effect of Circadin® 2/5 mg on children’s behavior at home and in school 
as assessed by the SDQ (Appendix 4) after 13 weeks (Week 28) of Circadin® open-label 
treatment as compared to baseline (Week 2)  
• To assess the level of caregiver’s daytime sleepiness (i.e., NOT the child’s sleepiness) during 
the study using the Epworth Sleepiness Scale (ESS; Appendix 7) at Weeks 0, 2, 5, 15, 28, 41, 
54, 106, and 108 
• To assess the level of caregiver’s quality of sleep (i.e., NOT the child’s quality of sleep) at night 
during the study using the Pittsburgh Sleep Quality Index (PSQI; Appendix 8) at Weeks 0, 2, 5, 
15, 28, 41, 54, 106, and 108 
• To assess the level of caregiver’s well-being (i.e., NOT the child’s well-being) during the study 
using the World Health Organization Well-Being Index (WHO-5) questionnaire (Appendix 9) 
at Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108 
• To compare the treatment effect of Circadin® 2/5 mg to that of placebo on children’s body mass 
index (BMI) and Z-score after 3 and 13 weeks of double-blind treatment, and to evaluate the 
effect of Circadin® 2/5/10 mg compared to baseline, at the end of the open-label period, and at 
the end of the placebo run-out period 
• To assess the treatment effect of Circadin® 2/5/10 mg on pubertal status the Tanner scale will be 
used in children ≥8 years of age.  For children ≤5 years of age, only height and head 
circumference will be used to stage children development.  Between the age of 5 and 8 the 
children’s physical development will be determined using the BMI (baseline through 
Week 108)  
• In children diagnosed with epilepsy, to compare the effect of Circadin® 2/5 mg to that of 
placebo on the number and severity of epilepsy seizures during double-blind treatment and to 
assess the effect of Circadin® 2/5/10 mg during the open-label period using seizure diaries  


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5 INVESTIGATIONAL PLAN  
5.1 
OVERALL STUDY DESIGN 
This is a randomized placebo-controlled study in children diagnosed with ASDs and 
neurodevelopmental disabilities caused by neurogenetic diseases.  Children will have a documented 
history of these disorders, as confirmed or consistent with the International Classification of Diseases 
(ICD-10) or Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision 
(DSM-5/4) criteria, having International Classification of Sleep Disorders (ICSD) criteria-based sleep 
disturbances modified to take into account the uniqueness of insomnia in the pediatric population at 
screening.   
The children will undergo 4 weeks of basic sleep hygiene and behavioral intervention, which will 
serve as a wash-out period from any hypnotics; a gradual withdrawal will take place during the first 
2 weeks and a complete withdrawal of prohibited medications will take place during the last 2 weeks.   
Children who are still found to be eligible for the study after the 4-week, basic sleep hygiene and 
behavioral intervention wash-out period, will continue in a 2-week SB placebo run-in period.  In order 
to be eligible for the 2-week SB placebo run-in period, the child should not have responded to sleep 
hygiene and behavioral intervention during the first 4 weeks and therefore will not need to continue 
this therapy during the study.  Children with a documented history of sleep hygiene and behavioral 
intervention, who are still found eligible, will enter directly into the 2-week SB placebo run-in period.   
Children with a documented history of sleep hygiene and behavioral intervention who are taking 
prohibited medications will not require additional training and will undergo a 2-week wash-out period 
before Visit 1 (e.g., Weeks -2 through 0 to wash out melatonin or any other prohibited medications).  
During these 2 weeks there is no need to complete the sleep and nap diary. 
After the 4-week sleep hygiene (for children who do not have a documented history of sleep hygiene 
and behavioral intervention) and 2-week SB placebo run-in period, children who are still found eligible 
for study participation will be randomized in a 1:1 ratio to receive either Circadin® 2 mg or placebo for 
3 weeks in a double-blind treatment period.  After 3 weeks of treatment, on the last day of Week 5 
±3 days (Visit 3), sleep variables will be assessed to determine if dose modification (an increase to 
5 mg) is required.  Children will then continue on 2 or 5 mg of Circadin® or placebo for an additional 
double-blind period of 10 weeks.  This double-blind period will be followed by an open-label period of 
13 weeks.  At the end of the 13-week open-label period on the last day of Week 28 ±3 days (Visit 5), 
sleep variables will be assessed to determine if a potential additional dose modification (i.e., an 
increase either to 5 mg for patients who are still on 2 mg or an increase to 10 mg for patients who are 
on 5 mg) is necessary.  Children will continue at 2, 5, or 10 mg Circadin® in an open-label period for 
another 78 weeks of follow-up, which will include continuous safety monitoring and 2 efficacy 
assessment time points at Weeks 41 and 54.  The study will end with a 2-week SB placebo run-out 
period.    


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Each patient will participate in the study until the end of the second open-label safety follow-up period, 
and 2-week SB placebo run-out period.  Study duration will be 112 weeks, including the 4-week 
wash-out period with sleep hygiene and behavioral intervention.   
Circadin® and placebo are to be administered orally, 1 portion of minitablets daily, taken postprandial 
0.5 to 1 hour before desired bedtime (bedtime should be defined as age-appropriate bedtime).  The 
minitablets should be swallowed whole and should not be crushed or halved.   
The study population will include male and female children 2 to 17.5 years of age with confirmed 
history of ASDs or neurodevelopmental disabilities caused by neurogenetic diseases.  At Visit 1, 
enough eligible male and female children, of ages 2 to 17.5 years, will be screened for the study to 
allow for 120 patients to then be randomized in a 1:1 ratio to receive Circadin® or placebo at Visit 2.  
A minimum of 90 children are expected to complete the double-blind and first open-label period.  A 
minimum of 50 children are expected to complete the second open-label safety follow-up period. 
5.2 
EFFICACY ASSESSMENTS  
Primary Efficacy Endpoint 
The primary efficacy parameter is TST time as assessed by a Sleep and Nap Diary after the 13-week, 
double-blind treatment period.   
Secondary Efficacy Endpoints 
• Sleep latency as assessed by a Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment  
• Duration of wake after sleep onset period from the Sleep and Nap Diary after 13 weeks 
(Week 15) of double-blind treatment 
• Number of awakenings from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
• Longest sleep period from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
• Social functioning at home, in school, and in community settings as assessed by the CGAS after 
13 weeks (Week 15) of double-blind treatment 
• Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 15) of 
double-blind treatment 
• Number of dropouts during the 13-week (Week 15) double-blind treatment period 
• Assessment of sleep parameters by actigraphy after 13 weeks (Week 15) of double-blind 
treatment  


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Exploratory Efficacy Endpoints 
• Sleep variables as assessed by the Sleep and Nap Diary at baseline (Week 2), after 3 weeks of 
double-blind treatment (Week 5), and after 13, 26, and 39 weeks of open-label treatment 
(Weeks 28, 41, and 54)  
• Sleep disturbance as assessed by the CSDI score at baseline after 3 and 13 weeks of 
double-blind treatment (Weeks 5 and 15, respectively), after 13, 26, 39, and 91 weeks of 
open-label treatment (Weeks 28, 41, 54, and 106, respectively), and at the end of study visit 
(Week 108) 
• Social functioning at home, in school, and in community settings as assessed by the CGAS after 
13 weeks (Week 28)of open-label treatment  
• Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 28) of open-label 
treatment  
• Caregiver’s daytime sleepiness (i.e., NOT the child’s sleepiness) during the study as assessed by 
the ESS (Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108) 
• Caregiver’s well-being (i.e., NOT the child’s well-being) during the study as assessed by the 
WHO-5 questionnaire (Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108) 
• Caregiver’s quality of sleep (i.e., NOT the child’s quality of sleep) at night during the study as 
assessed by the PSQI questionnaire (Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108) 
5.3 
SAFETY ASSESSMENTS 
Safety Endpoints (Secondary) 
• Assessment of AEs throughout the study after Visit 1 and upon study withdrawal using the 
TESS  
• Vital signs at each visit including the placebo run-out (withdrawal) period  
• Physical examination at each visit including the placebo run-out (withdrawal) period  
Safety Endpoints (Exploratory) 
• BMI and Z-score assessed during the study 
• Pubertal assessment using the Tanner scale during the study (The Tanner scale will be used to 
assess and stage physical development in children ≥8 years of age.  For children ≤5 years of 
age, only height and head circumference will be used to stage children development.  Between 
the age of 5 and 8, the children’s physical development will be determined using BMI.  
• In children diagnosed with epilepsy, the number and severity of epilepsy seizures assessed 
during the study using Epilepsy Seizures Diaries.   
 


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Table 5-1:  Study Treatment Schedule  
Period 
Wash-out 
Sleep 
Hygiene 
Run-in, 
Single-blind 
Double-blind 
Open-Label 
Run-out,  
Single-Blind 
Treat- 
ment 
No drug 
inter- 
vention1 
Placebo 
Circadin®  
2 mg or PBO 
Circadin®  
2 mg, 5 mg, 
or PBO 
Circadin®  
2 mg or 5 mg 
Circadin® 
2 mg, 5 mg, or 10 mg 
Placebo 
Week 
-4 to 0 
1 
2 
3 
5 
6 
15 
16 
28 
29 
41 
42 
54 
55 
106 
107 
108 
Visit3 
SCRN  
 
first day  
of  
Week -4, 
±3 days 
Visit 1 
 
first day 
of  
Week 1, 
±3 days 
Visit 2  
 
last day  
of  
Week 2, 
±3 days 
 
random- 
ization/ 
baseline 
visit 
 
Visit 32 
 
last day  
of  
Week 5, ±3 
days 
 
dose modi- 
fication 
 
Visit 4 
 
last day 
of 
Week 1
5, ±3 
days 
 
Visit 52  
 
last day  
of 
Week 28, 
±3 days  
 
dose 
modi- 
fication  
 
Visit 6 
 
last day 
of 
Week 4
1, ±7 
days 
 
Visit 7 
 
last day  
of 
Week 54, 
±7 days 
 
Visit 8 
 
last day  
of 
Week 10
6, ±7 
days 
 
End of 
Study  
last day  
of 
Week 108, 
±3 days 
 
SCRN = Screening; PBO = placebo  
* The visit should be carried out within ±3 days. 
** The visit should be carried out within ±7 days. 
1.  First 2 weeks are a gradual withdrawal and the last 2 weeks are a complete withdrawal of prohibited medications. 
2.  Data analysis (assessment of sleep variables) will be performed at the end of Week 5 (Visit 3) and Week 28 (Visit 5) to determine if a dose modification (i.e., an increase to 5 mg or 5/10 mg 
Circadin®, respectively) is required.   
3.  All visits, except screening and Visit 1 will occur on the last day of the week in which they occur, as indicated above. 
 


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Table 5-2:  Schedule of Study Assessments 
 
Wash-out Sleep 
Hygiene 
Run-in, 
Single-blind 
Double-blind  
Open-label 
Run-out, 
Single-Blind 
 
Screening 
–4 Weeks* 
Visit 1/ 
Week 0* 
Visit 2 
/Randomization/ 
Baseline Visit* 
Week 2 
Visit 3/ 
Week 5* 
Visit 4/ 
Week 15* 
Visit 5/ 
Week 281* 
Visit 6/ 
Week 41** 
Visit 7/ 
Week 54** 
Visit 8/ 
Week 106** 
End of Study 
Visit/  
Week 108* 
Screening 
procedures 
 
 
 
 
 
 
 
 
 
 
Explanation of 
Study 
X 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
Sleep problem 
verification 
X 
X 
X 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
Sleep hygiene 
training booklet 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Dose 
Modification 
 
 
 
X 
 
X 
 
 
 
 
Safety 
Assessments 
 
 
 
 
 
 
 
 
 
 
Compliance 
verification 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and 
height for BMI 
and Z-score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test2 
X 
 
X 
 
X 
 
 
 
 
X 


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Wash-out Sleep 
Hygiene 
Run-in, 
Single-blind 
Double-blind  
Open-label 
Run-out, 
Single-Blind 
 
Screening 
–4 Weeks* 
Visit 1/ 
Week 0* 
Visit 2 
/Randomization/ 
Baseline Visit* 
Week 2 
Visit 3/ 
Week 5* 
Visit 4/ 
Week 15* 
Visit 5/ 
Week 281* 
Visit 6/ 
Week 41** 
Visit 7/ 
Week 54** 
Visit 8/ 
Week 106** 
End of Study 
Visit/  
Week 108* 
Pubertal 
Assessment 
(Tanner) and 
Physical 
Development 3 
 
 
X 
 
X 
X 
 
 
X 
X  
Epilepsy Diary4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TESS5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
Assessments 
 
 
 
 
 
 
 
 
 
 
Sleep and Nap 
Diary6 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CSDI7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Actigraphy8 
 
X 
X8 
X 
X8 
 
 
 
 
 
CGAS5 
 
X 
X 
X 
X 
X 
 
 
 
 
SDQ7 
 
X 
X 
X 
X 
X 
 
 
 
 
ESS7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSQI7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO-57 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP Dispensing 
 
X 
X 
X 
X 
X 
X 
X9 
X 
 
 
 
 


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Footnotes for Table 5-2:   
*  The visit should be carried out within ±3 days. 
**  The visit should be carried out within ±7 days. 
1.  End of Phase I of the study  
2.  For female patients of childbearing potential, urine dipstick pregnancy tests will be administered.   
3.  The Tanner scale will be used to assess and stage physical development in children ≥8 years of age.  For children ≤5 years of age, only height and head circumference will 
be used to stage children development.  Between the age of 5 and 8 the children’s physical development will be determined using the BMI.  
4.  For patients with epilepsy and a history of seizures, the Epilepsy Seizures Diary is to be dispensed to the parent at each visit and completed only on the days that the 
patients has a seizure, which should include the date, time, duration and type of the seizure (Appendix 10).  The Epilepsy Seizures Diary is to be completed only by the 
patient’s parent/caregiver after each seizure and to be entered into the electronic case report form (eCRF) by the site at each study visit.   
5.  The TESS (Appendix 5) and CGAS (Appendix 9) must be administered and completed by the Investigator with the parent/caregiver’s input at the study visit indicated.   
6.  Sleep and Nap Diary is to be completed 14 nights before each scheduled visit (Appendix 1 and Appendix 2).  The parent will complete the questionnaire either directly into 
the eCRF or on the printed version.  If the printed version is used, at a later time point, the site coordinator will enter the questionnaire data into the eCRF.  At the screening 
visit, the Sleep and Nap Diary is dispensed.  The study coordinator/Investigator must provide guidance to the parents on how to complete the diary by reviewing the diary 
question by question and explaining the importance of completing all required data entry every morning, preferably within 2 to 3 hours after the patient wakes up.  It is critical 
that the study coordinator/Investigator provide a thorough review and explanation of the diary to the parents to ensure that the data retrieved is high quality and reliable.  A 
follow-up phone call to remind patients to begin filling out Sleep and Nap Diaries will be made every week before Visits 1 and 2, as well as every week during the study 
period up to Visit 7.  Between Visits 7 and Visit 8, the phone call will be made once a month.   
7.  CSDI (Appendix 6), SDQ (Appendix 8), ESS (Appendix 7), WHO-5 (Appendix 9), and PSQI (Appendix 8) are to be completed by the site coordinators/Investigators with 
the parents/caregiver, by posing the questions in the questionnaires and filling in the responses given by the parents/caregiver.  Note: The ESS, WHO-5, and PSQI are to 
assess sleepiness, quality of sleep, and well-being of the parent/caregiver’s and NOT the child.   
8.  Actigraphy (Actiwatches) is dispensed to patients at Visit 1 so that they can be worn for 14 days prior to Visit 2.  The device is to be delivered to the patient’s home no 
earlier than 3 weeks before Visit 4 to ensure the actigraphy maintains adequate battery strength.  Actiwatches are to be worn 14 nights before Visit 2 and Visit 4 and collected 
at Visit 2 and Visit 4.  The actigraphy should be worn by the patient from drug-intake at night until lights on in the morning.   
9.  The study site can choose to not dispense all investigational medicinal product (IMP) up to Visit 8 at once.  The site can send new IMP to patients in quarterly intervals 
(i.e., in periods of 3 month intervals).  
 
 


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6 STUDY POPULATION AND SELECTION 
The study population for this study will include patients with confirmed history of ASDs (pervasive 
developmental disorders) according to DSM-5/4 criteria or ICD-10 or neurodevelopmental disabilities 
caused by neurogenetic diseases (SMS, Angelman syndrome, Bourneville’s disease [tuberous 
sclerosis]).  Enough patients will be screened for the study to allow for 120 patients to be randomized 
in a 1:1 ratio to receive Circadin® or placebo at Visit 2.  Patients will be screened for the study after 
their legal guardians provide written, informed consent on their behalf (refer to Section 16.2 for further 
details).  In order to be randomized to treatment, patients must meet all inclusion criteria listed in 
Section 6.1 and none of the exclusion criteria listed in Section 6.2.   
6.1 
INCLUSION CRITERIA 
To be eligible for study entry, all patients must satisfy all of the following criteria at screening: 
• Must be children 2 to 17.5 years of age at Visit 2 who comply with taking the study drug. 
• Must have written informed consent provided by a legal guardian and assent (if needed). 
• Must have a documented history of ASD according to or consistent with the ICD-10 or 
DSM-5/4 criteria, or neurodevelopmental disabilities caused by neurogenetic diseases (SMS, 
Angelman syndrome, Bourneville’s disease [tuberous sclerosis]) as confirmed by case note 
review showing that diagnosis was reached through assessment by a community pediatrician or 
pediatric neurologist or other health care professionals experienced in the diagnosis who took 
into account early developmental history and school records.   
• Must have current sleep problems including:  a minimum of 3 months of impaired sleep defined 
as ≤6 hours of continuous sleep AND/OR ≥0.5 hour sleep latency from light off in 3 out of 
5 nights based on parent reports and patient medical history.  (The maintenance and latency 
problems do not necessarily have to be in the same 3 nights of the week.) 
• May be on a stable dose of non-excluded medication for 3 months, including anti-epileptics, 
anti-depressants (selective serotonin reuptake inhibitors [SSRIs]), stimulants, all mood 
changing drugs and β-blockers.  (Only morning administration of β-blockers is allowed since 
β-blockers at night have the potential to reduce endogenous melatonin levels and might cause 
disturbed sleep).   
• The sleep disturbance is not due to the direct physiological effects of any concomitant 
medications such as SSRIs, stimulants, etc.    
After completing 4 weeks of sleep hygiene training (for those who need it) and 2 weeks of placebo 
run-in,  patients will be eligible to continue the study if they comply with the following: 
• Continue to fulfil sleep problem criteria (see Inclusion Criterion 4) based on the completed 
Sleep and Nap Diary entered into the electronic case report form (eCRF)   


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• Parents demonstrate compliance in Sleep and Nap Diary completion (5 out of 7 nights).  
Compliance means that in at least 5 out of 7 nights per week  (total of 2 weeks before each 
scheduled visit) the parents complete the diary pages with all mandatory questions (mandatory 
questions are marked with an asterisk [*] in Appendix 1).   
• Continue to fulfil all other eligibility criteria  
6.2 
EXCLUSION CRITERIA 
Children who meet any of the following criteria will be excluded from participating in the study: 
• Have had treatment with any form of melatonin within 2 weeks prior to Visit 1  
• Have a known allergy to melatonin or lactose  
• Have a known moderate to severe sleep apnea 
• Have an untreated medical/ineffectively treated/psychological condition that may be the 
etiology of sleep disturbances 
• Did not respond to previous Circadin® therapy based on past medical history records in the last 
2 years  
• Are taking or have been taking prohibited medication within 2 weeks prior to Visit 1 
(Section 7.1)  
• Are females of child-bearing potential that are not using contraceptives and/or breastfeeding and 
that are sexually active (Abstinence is an acceptable method of contraception.)  
• Pregnant females 
• Are currently participating in a clinical trial or have participated in a clinical trial involving 
medicinal product within the last 3 months prior to the study (this does not include patients 
who participated in the Phase I PK study who can be already included in the study).   
• Children with known renal or hepatic insufficiency  
6.3 
WITHDRAWAL OF PATIENTS FROM TREATMENT 
Children must be withdrawn from the clinical study if any of the following reasons occur: 
• The parents or the patient withdraw their consent. 
• The Investigator considers, for safety reasons, it is in the best interests of the patient that the 
patient be withdrawn from the study. 
• A protocol violation or inter-current illnesses occurs, which, in the clinical judgment of the 
Investigator or after discussion with the Sponsor, may invalidate the study by interfering with 
the investigational medicinal product (IMP). 
• It is discovered that the patient has entered the study in violation of the protocol. 
• A significant protocol violation occurs during the study (e.g., a patient violates a major 
Inclusion/Exclusion criteria; Section 13.3.2).  


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• The randomization code is broken for that patient by any 1 of the staff at the clinical study site. 
• The patient has taken any prohibited medication listed in Section 7.1 (Appendix 11).   
• The patient is lost to follow-up. 
The date and reason for withdrawal should be noted in the Withdrawal Form in the eCRF.  A parent 
who withdraws consent will be asked by the Investigator to give a reason, but is not obligated to do so.  
A patient who withdraws from the clinical study should, if possible, be seen for a Withdrawal Visit 
scheduled as soon as possible and the end of study procedures should be carried out, as shown in 
Section 8.19, after the patient has withdrawn from the clinical study.  No new information will be 
collected from the patient except information collected in relation to the scheduled Follow-up Visit or 
needed for the follow-up of AEs or SAEs.   
If a patient is withdrawn from the study, no replacement will be considered.   
6.4 
REPLACEMENT OF PATIENTS 
Patients who have been screened but have not been previously randomized to this study may be 
rescreened for participation if they are eligible.   
7  TREATMENTS ADMINISTERED 
Children found eligible who do not have documented sleep hygiene training in their history will start a 
4-week sleep hygiene and behavioral intervention, which will serve as a wash-out period from any 
hypnotics with gradual withdrawal during the first 2 weeks and complete withdrawal during the last 
2 weeks.  Patients will then enter a 2-week SB placebo run-in period.  Enough eligible children will be 
screened for the study to allow for 120 patients to be randomized in a 1:1 ratio to receive Circadin® or 
placebo at the end of the 2-week SB placebo run-in period, whether they are children who underwent 
the sleep hygiene and behavioral intervention or not.   
Children with a documented history of sleep hygiene and behavioral intervention who are taking 
prohibited medications will not require additional training and will undergo a 2 week wash-out period 
before Visit 1 (e.g., Weeks 2 through 0 to wash out melatonin or any other prohibited medications).  
During these 2 weeks there is no need to complete the sleep and nap diary.    
Children with documented history of sleep hygiene and behavioral intervention, who are still found 
eligible, will enter directly into the 2-week SB placebo run-in period.  After the 2-week placebo run-in 
period, patients who are still found eligible will be randomized in a 1:1 ratio to receive either 
Circadin® 2 mg or matching placebo for 3 weeks.  At the end of the 3-week double-blind period, a 
decision on dose modification (i.e., an increase to 5 mg) will be made based on predefined criteria 
(Section 7.3.1).  The double-blind period will continue for another 10 weeks (total 13 weeks) after 
which Circadin® 2 or 5 mg will be given open-label for another 13 weeks of follow-up to evaluate 
maintenance of efficacy and safety.  At this time point (Week 28), data gathered from both the 
double-blind and open-label periods will be analyzed.  The study will continue with a second 
opportunity for dose modification according to the same criteria as before (an increase either to 5 mg 
for patients who are still on 2 mg or to 10 mg for patients who are on 5 mg) after which open-label 


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treatment will continue for an additional 78 weeks of follow-up to evaluate maintenance of efficacy 
and safety.  At the end of the Circadin® open-label period, patients will undergo a 2-week SB placebo 
run-out period to assess withdrawal effects.  A minimum of 90 children are expected to complete the 
double-blind and first open-label period.  A minimum of 50 children are expected to complete the 
second open-label safety follow-up period. 
7.1 
PROHIBITED MEDICATIONS 
The following medications are not permitted for use for the duration of the study and within 2 weeks 
prior to Visit 1.  If use of these medications is unavoidable for clinical reasons, then the patient will 
need to be withdrawn from the study: 
• Melatonin or melatonin agonists (other than the study treatment) 
• Excessive consumption of alcohol 
The full list of prohibited medications is given in Appendix 11.  This is a living list that will not cause 
any protocol amendment if needs to be amended.  
7.2 
INVESTIGATIONAL MEDICINAL PRODUCT 
Circadin® 
Generic name:   
Melatonin 
Trade name:  
Circadin® 
Chemical name: 
N-Acetyl-5-Methoxytryptamine 
Formulation:  
Amino-methacrylate co-polymer 
 
 
 
Calcium hydrogen phosphate 
 
 
 
Lactose 
 
 
 
Silicon dioxide 
 
 
 
Talcum 
 
 
 
Magnesium stearate 
The PR of melatonin is achieved primarily by the methacrylate polymer EUDRAGIT.  The calcium 
hydrogen phosphate serves as a filling and binding agent and lactose as a diluent and bulking agent.  
Talc and magnesium stearate serve as lubricants.  Circadin® 1 mg minitablets will be used in this study.  
These tablets are 3 mm in diameter and will allow flexibility of dosing for the required dose titrations 
from 2 mg to 5 mg or 10 mg. 
Study drug (IMP) will be stored in the medical center's local pharmacy or in the Investigator's office 
securely, separate from other drugs (IMP Handling Guidelines).  Study drug should not be exposed to 
direct sunlight or other sources of heat, and is to be kept at room temperature (<25°C).   


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Placebo 
Placebo will be identical in appearance and formulation to active Circadin® minitablets, but will 
contain no active melatonin.   
7.3 
CIRCADIN® ADMINISTRATION 
The dose will be titrated from 2 mg (2 minitablets) to 5 mg (5 minitablets – Visit 3) to 10 mg 
(10 minitablets – Visit 5), as instructed in Section 7.3.2. 
Circadin® and placebo are to be administered orally, 1 portion of minitablets daily, taken postprandial 
at 0.5 to 1 hour before desired bedtime (bedtime should be age-appropriate bedtime).  The minitablets 
should be swallowed whole and should not be crushed or halved.  Both Circadin® and placebo 
minitablets can be administered in foods such as orange juice, semi-skimmed milk, strawberry yogurt, 
and strawberry jam, to allow dosing of multiple minitablets to the children studied.  Melatonin was 
found to be compatible and stable for up to 6 hours in these specific common foods and liquids16. 
7.3.1 Dose Modification 
At the end of 3 weeks of double-blind treatment (Visit 3) and 13 weeks of open-label treatment 
(Visit 5), the Investigator will review the Sleep and Nap Diaries and the eCRF recommendation for 
dose increase and then make an assessment of treatment effect.  If the Investigator decides that a dose 
increase is necessary, the following criteria must be met before the increase can take place:   
• The patient has an absence of SAEs related to study drug.   
• The patient has an absence of daytime fatigue related to study drug. 
• The parents demonstrated compliance in Sleep and Nap Diary completion (5 out of 7 nights).  
Compliance means that in at least 5 out of 7 nights per week (total of 2 weeks before each 
scheduled visit) the parents completed the diary pages with all mandatory questions (i.e., those 
marked with an asterisk [*], Appendix 1).   
• The patient has received at least 5 of 7 doses in the current week based on Diary-reported data. 
AND 
• The patient had ≤6 hours of continuous sleep AND/OR ≥0.5 hours of sleep latency from light 
off in ≥3 out of 5 nights (i.e., in 3 nights or more a week, as a minimum of 5 diaries must be 
completed each week) in each of the 2 weeks prior to Visit 3 or Visit 5.  This will be derived 
from the Sleep and Nap Diary and calculated by the eCRF.   
OR 
• The patient had ≤6 hours of continuous sleep AND/OR ≥0.5 hours of sleep latency from light 
off only in ≤2 out of 5 nights (i.e., in 2 nights or less a week, as a minimum of 5 diaries must be 
completed each week) in each of the 2 weeks prior to Visit 3 or Visit 5, AND did NOT 
improve from Visit 2 by at least 1 hour as measured by either shortening of sleep latency or 
increase in sleep duration or both.  Change in sleep duration and sleep latency will be measured 


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by subtracting the Visit 2 mean duration and sleep latency values from the mean duration and 
the mean sleep latency values from all available nights 2 weeks prior to Visit 3 or Visit 5.  
Values will be derived from the Sleep and Nap Diary and calculated by the eCRF.  The eCRF 
will advise whether a dose increase is recommended or not.  
If any of the above criteria are not met, or if there is any doubt regarding a criterion, the current dose 
should be maintained.   
Allowed dose increases include 2 mg to 5 mg at Visit 3, and/or 2 mg to 5 mg or 5 mg to 10 mg at 
Visit 5.   
7.3.2 Dose Reduction 
At any time, a patient’s dose maybe reduced to 2 mg or 5 mg for reasons such as AEs that are 
considered related to the study drug, and/or specifically for the following reasons:   
• An unacceptable increase in daytime fatigue  
• An unacceptable behavioral change 
• If the patient ceases to respond to study drug (sleep improved and then deteriorated on higher 
dose) 
If a dose reduction is thought to be required following a scheduled telephone call, the Investigator 
should consult with the Principal Investigator (PI) or the Medical Monitor prior to a dose modification.  
If a dose reduction is agreed upon, an unscheduled visit should be arranged.  Dose modifications 
should be documented in the eCRF.   
If a dose is reduced for any reason, the Investigator may, at their discretion, restart the previous dosage 
at Visit 3 or Visit 5.   
7.4 
BLINDING 
The initial 2-week SB placebo run-in period of this study is designed as a SB period with the patients 
blinded as to what study drug they will receive.  All patients will receive placebo during the run-in 
period.  The run-in period will be followed by 13 weeks of double-blind treatment, where the 
Investigator and the patient will be blinded to treatment allocation.  Patients will be randomized using 
a 1:1 ratio to receive either Circadin® 2 mg (2 minitablets each containing 1 mg of Circadin®) or 
placebo (2 minitablets containing 1 mg of placebo).  The placebo will have the same appearance as 
Circadin®.  After 3 weeks of study, if dose modification is deemed necessary, patients will receive 
increased doses in the same manner (5 minitablets containing 1 mg of Circadin® or placebo).  The 
randomization scheme will be designed to ensure that patients requiring dose modification will 
continue receiving the same treatment (Circadin® or placebo). 
Except in an emergency, the blind should not be broken until all completed eCRFs are received by 
Data Management and the database is locked. 
All sites will receive unblinding envelopes to facilitate emergency unblinding if needed. 


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7.5 
DOSE SELECTION RATIONALE 
Several studies have tested the effect of melatonin on sleep efficiency and quality in children with 
autistic spectrum disorders, delayed sleep phase syndrome and other neurodevelopmental disabilities17.  
Children in these studies received melatonin dosages in the range of 2 to10 mg, with a 5 mg dose given 
in 2, randomized placebo-controlled studies18, 19.  Another study investigated the effect of Circadin® in 
doses of 4 to 6 mg in children with various neurodevelopmental disorders12.  Results of these studies 
indicated that the proposed Circadin® dosage regimen provided optimal effects with respect to 
efficacy, and there were no safety concerns for the dose proposed for use in this study.  A PR 
preparation, taken postprandial 0.5 to 1 hours before bedtime, will supply and sustain sufficient 
melatonin in the circulation during the whole sleep cycle.   
7.6 
TREATMENT COMPLIANCE 
Treatment compliance will be calculated at each study visit by counting returned minitablets and using 
the following formula, except for Visit 8, where treatment compliance will be determined according to 
the parents reporting on the amount of tablets the child has taken since Visit 7: 
Compliance (%) = 
Number of tablets dispensed – Number of tablets returned* –  
Number of tablets lost 
× 100 
 
Number of minitablets per day x Number of days since last visit 
* In case patients/parents forgot to bring in the unused IMP, the number of tablets returned is to be 
replaced by the number of tablets remaining in the IP pack, as reported by the patient.   
Any divergence from the accepted level of compliance (70% to 130% of expected consumption) is to 
be investigated by the Investigator and could lead to withdrawal of the patient from the study. 
Treatment compliance will be recorded in the patient’s eCRF by the Investigator. 
8 CONDUCT OF STUDY AND STUDY ASSESSMENTS 
This study will be conducted as outlined in the following sections and in accordance with the treatment 
schedule (Table 5-1) and the schedule of study assessments (Table 5-2).  The first study visit will 
occur at Week -4 and the final study visit will occur at the last day of Week 108.  Sleep will be 
measured by (1) Sleep and Nap Diaries 14 nights before each scheduled visit from Visit 1 (Week 0) up 
to and including Visit 7 (54 weeks) and (2) actigraphy 14 nights before Visits 2 and 4.  Phone calls to 
remind patients to begin filling out Sleep and Nap Diaries will be made every week before Visits 1 and 
2, as well as every week during the study period up to Visit 7.  Between Visits 7 and 8, a phone call 
will be made once a month. 
This is a randomized placebo-controlled study in children diagnosed with ASDs and 
neurodevelopmental disabilities caused by neurogenetic diseases.  Patients will start 4 weeks of basic 
sleep hygiene and behavioral intervention (wash-out period) followed by a 2-week SB placebo run-in 
period, and will then be randomized in a 1:1 ratio to receive either Circadin® 2 mg or matching 


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placebo for 13 weeks with a dose modification after the first 3 weeks.  Patients who have been 
screened but have not been previously randomized can be rescreened they are eligible.  This 
double-blind period will be followed by an open-label period of 13 weeks.  Data will be gathered at the 
end of the 13-week open-label period (Week 28), and analyzed; however, children will continue in the 
study for another 78 weeks of follow-up.  The study will end with a 2-week SB placebo run-out period.  
All together 10 visits are planned, including screening visit and end of study visit, and additional 
unscheduled visits may be necessary (Section 8.20).   
At each visit, study questionnaires and diaries will be dispensed and completed according to the 
schedule in Table 5-2, and as described in the sections below.  Questionnaires and diaries are to be 
completed as follows:  
• The Sleep and Nap Diary is to be completed only by the patient’s parent/caregiver during the 
14 nights before each scheduled visit, every morning 2 to 3 hours after the child awakens 
(Appendix 1 and Appendix 2).  The diary can be completed either directly in the eCRF or by 
using a paper version.  If the diary is completed on paper, the site coordinator will enter the 
questionnaire data into the eCRF during the visit.  The diaries prior to Visit 1 and Visit 2 must 
be entered in to the system at the respective visit in order to allow eligibility assessment to 
occur at Visit 1 and Visit 2.  Prior to Visit 1, diaries are required only for children who had 
undergone the 4-week sleep hygiene and behavioral intervention training period, to check 
whether they responded to the therapy.  Diaries prior to Visit 1 are not required for children 
with a documented history of sleep hygiene and behavioral intervention, as Visit 1 eligibility 
for these children is measured based on the parent’s report of their child’s sleep over the 
previous 3 months, which is reported at screening.  If the child doesn’t need the sleep hygiene 
but needs the 2-week wash-out period prior to Visit 1, the parent doesn’t need to complete the 
sleep diary either.  
• For patients with epilepsy and a history of seizures, the Epilepsy Seizures Diary is to be 
dispensed to the parents/caregivers at each visit and to be completed by the patient’s 
parent/caregiver only on the days that the patients has a seizure.  It should include the date, 
time, duration and type of the seizure (Appendix 10).  The Epilepsy Seizures Diary is to be 
completed only by the patient’s parent/caregiver after each seizure.  
• The questionnaires CSDI, SDQ, ESS, WHO-5, and PSQI are to be completed by the site 
coordinators/Investigators with the parents/caregiver, by posing the questions in the 
questionnaires and filling in the responses given by the parents/caregiver.  Note:  The ESS, 
WHO-5, and PSQI are to assess sleepiness, quality of sleep, and well-being of the 
parent/caregiver and NOT the child.   
• The TESS (Appendix 5) and CGAS (Appendix 3) must be administered and completed by the 
Investigator with the parent/caregiver’s input.   
The following table (Table 8-1) identifies to whom the questionnaire relates and who is responsible for 
completing the questionnaire.  


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Table 8-1:  Summary of Questionnaires  
Questionnaire 
Information 
relates to: 
Completed by: 
Sleep and Nap Diary 
Child 
Parent/caregiver 
Epilepsy Seizures Diary 
Child 
Parent/caregiver 
CSDI 
Child 
Site coordinators/Investigator with parent/caregiver’s input  
SDQ 
Child 
Site coordinators/Investigator with parent/caregiver’s input  
ESS 
Parent 
Site coordinators/Investigator with parent/caregiver’s input  
WHO-5 
Parent 
Site coordinators/Investigator with parent/caregiver’s input  
PSQI 
Parent 
Site coordinators/Investigator with parent/caregiver’s input  
CGAS 
Child 
Investigator with parent/caregiver’s input 
TESS 
Child 
Investigator with parent/caregiver’s input 
8.1 
SCREENING VISIT (DAY 1 AT -4 WEEKS ±3 DAYS) 
These items may be carried out by the Investigator or a qualified designee:    
• Explain the conduct of the study.  
• Provide the informed consent form (ICF) and information sheet to patients and legal guardians 
to read and sign.  
• Eligibility screening done by Investigator or a qualified designee:   
• Record detailed medical history. 
• Record of demographic data. 
• Verify sleep problem based on completed diaries.  
• Perform physical examination and measure vital signs. 
• Measure body weight and height for the BMI and Z-score calculations.   
• Review inclusion/exclusion criteria.  
• Administer urine dipstick pregnancy tests to females of child-bearing potential.  
• Explain sleep hygiene training and dispense training booklet.  
• Explain and dispense the Sleep and Nap Diary (to be completed during the 14 nights before 
Visit 1; Appendix 1).  The study coordinator/Investigator must provide guidance to the parents 
on how to complete the diary by reviewing the diary question by question and explaining the 
importance of completing all required data entry every morning, preferably within 2 to 3 hours 
after the patient woke up.  It is critical that the study coordinator/Investigator provide a 
thorough review and explanation of the diary to the parents to ensure that the data retrieved is 
high quality and reliable.  Please also refer to Appendix 2 (Sleep and Nap Diary Guidelines, 
Presentation and Take-Home Instructions for Parents). 


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• Explain and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure).  
• The visit should be carried out within ±3 days.  
During the screening period, if a parent does not complete the diary appropriately due to a 
misunderstanding, then with the Investigator’s approval, a patient can be re-screened.   
8.2 
PRE-VISIT 1   
A follow-up phone call to remind patients to begin filling out Sleep and Nap Diaries will be made 
every week before Visits 1 and 2, as well as every week during the study period up to Visit 7.  The site 
is to make a phone call at 2 weeks ahead of Visit 1 to remind patients to begin filling out Sleep and 
Nap Diaries.  If sleep hygiene was not required (i.e., the patient entered the study with history of 
documented sleep hygiene at Visit 1), no call will be needed, as Visit 1 will be the first visit and serve 
as the screening visit.   
8.3 
VISIT 1 (WEEK 1 DAY 1 ±3 DAYS)  
• Confirm eligibility. 
• Verify sleep problem based on completed diaries.  
• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.   
• Record medical history. 
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input.  At Visit 1 TESS information is used to assess patient medical history.  All symptoms 
that are at score of 1 of more should be recorded in the medical history as they will serve as the 
baseline for future AEs throughout the entire study.  
• Fill out CGAS (Appendix 3; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out SDQ (Appendix 4; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input). 
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill 
out 
WHO-5 
questionnaire 
(Appendix 9; 
to 
be 
completed 
by 
the 
site 
coordinators/Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.).  


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• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10); to be completed by the parent/caregiver after each seizure).  
• Collect and dispense Sleep and Nap Diary (Appendix 1) to be completed by the parent/caregiver 
during the 14 nights before Visit 2).  If the Sleep and Nap Diaries were completed on a paper 
version, then the diary data is to be entered into the eCRF.   
• Explain and dispense of study drug (IMP Handling Guidelines).   
• Explain the actigraphy procedure and dispense actigraphy (Actiwatches) and the take-home 
instructions.  The actiwatches should be worn by the patient from drug-intake at night until 
lights on in the morning).  Actigraphy (Actiwatches) are to be worn for 14 days prior Visit 2.   
• The visit should be carried out within ±3 days. 
8.4 
PRE-VISIT 2 PHONE CALL 
A phone call will be made every week before Visits 1 and 2 to remind patients to begin filling out 
Sleep and Nap Diaries and to have the patient wear the actigraphy (Actiwatch).   
8.5 
VISIT 2 (RANDOMIZATION/BASELINE VISIT; LAST DAY OF WEEK 2 ±3 DAYS) 
• Confirm eligibility; if a patient does not meet the eligibility criteria for randomization, as listed 
in Section 6.1, the patient will be withdrawn from study and end of study procedures will be 
carried out, as listed in Section 8.19.  Any end of study assessments performed should be 
entered on the visit at which the patient is deemed ineligible and the eCRF Study 
Completion/Withdrawal page should be completed, as described in Section 6.3.   
• Verify compliance.  
• Verify sleep problem based on completed diaries.  
• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  
• Record AEs.  
• Administer pregnancy test to females of child-bearing potential.   
• Assess pubertal status using the Tanner scale.  (The Tanner scale will be used to assess and 
stage physical development in children ≥8 years of age.  For children ≤5 years of age, only 
height and head circumference will be used to stage children development.  Between the age of 
5 and 8 the children’s physical development will be determined using the BMI.)   
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  


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• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out CGAS (Appendix 9; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out SDQ (Appendix 4; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill 
out 
WHO-5 
questionnaire 
(Appendix 9; 
to 
be 
completed 
by 
the 
site 
coordinators/Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Sleep and Nap Diary (Appendix 1; to be completed by the parent/caregiver 
during the 14 nights before Visit 3).  If the Sleep and Nap Diaries were completed on a paper 
version, then the diary data is to be entered into the eCRF.   
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Explain and dispense study drug (IMP Handling Guidelines).  
• Collect actigraphy (Actiwatches).  
• Perform randomization.  
• The visit should be carried out within ±3 days.  
8.6 
PRE-VISIT 3 
Phone calls should be made weekly.  In addition, on the phone call 2 weeks prior to Visit 3, parents are 
to be reminded to begin filling out the Sleep and Nap Diary.   
8.7 
VISIT 3 (POSSIBLE DOSE MODIFICATION; LAST DAY OF WEEK 5 ±3 DAYS) 
• Perform potential dose modification. 
• Verify compliance.  
• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  


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• Record AEs. 
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input). 
• Fill out CGAS (Appendix 9; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out SDQ (Appendix 4; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill 
out 
WHO-5 
questionnaire 
(Appendix 9; 
to 
be 
completed 
by 
the 
site 
coordinators/Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Sleep and Nap Diary (Appendix 1; to be completed by the parent/caregiver 
during the 14 nights before Visit 4).  If the Sleep and Nap Diaries were completed on a paper 
version, then the diary data is to be entered into the eCRF.  
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Explain the actigraphy procedure and provide take-home instructions for actigraphy 
(Actiwatches) to be worn for 14 days prior Visit 4.  The device is not provided at Visit 3, but is 
to be mailed or given to the patient at least 17 days, and no earlier than 3 weeks, before Visit 4 
to ensure the actigraphy maintains adequate battery strength.   
• Explain and dispense study drug (IMP Handling Guidelines).  
• The visit should be carried out within ±3 days.   
8.8 
PRE-VI SIT 4 
Phone calls should be made weekly.  The site should confirm with parents that the actigraphy device 
was received.  On the phone call 2 weeks prior to Visit 4, parents are to be reminded to begin filling 
out the Sleep and Nap Diary and to have patients wear the actigraphy (Actiwatch).  
8.9 
VISIT 4 (LAST DAY OF WEEK 15 ±3 DAYS) 
• Verify compliance.  


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• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  
• Record AEs. 
• Administer pregnancy test to females of child bearing potential.   
• Assess pubertal status using the Tanner scale (The Tanner scale will be used to assess and stage 
physical development in children ≥8 years of age.  For children ≤5 years of age, only height 
and head circumference will be used to stage children development.  Between the age of 5 and 
8 the children’s physical development will be determined using the BMI.)  
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out CGAS (Appendix 9; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out SDQ (Appendix 4; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill 
out 
WHO-5 
questionnaire 
(Appendix 9; 
to 
be 
completed 
by 
the 
site 
coordinators/Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Collect and dispense Sleep and Nap Diary (Appendix 1; to be completed by the parent/caregiver 
during the 14 nights before Visit 5).  If the Sleep and Nap Diaries were completed on a paper 
version, then the diary data is to be entered into the eCRF. 
• Explain and dispense study drug (IMP Handling Guidelines).  
• Collect actigraphy (Actiwatches). 
• The visit should be carried out within ±3 days.  


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8.10 PRE-VISIT 5 
Phone calls should be made weekly.  In addition, on the phone call 2 weeks prior to Visit 5, parents are 
to be reminded to begin filling out the Sleep and Nap Diary. 
8.11 VISIT 5 (LAST DAY OF WEEK 28 ±3 DAYS) 
• Perform potential dose modification  
• Verify compliance.  
• Measure vital signs.  
• Perform physical examination.  
• Measure body weight and height for the BMI and Z-score calculations.   
• Record AEs.  
• Assess pubertal status using the Tanner scale (The Tanner scale will be used to assess and stage 
physical development in children ≥8 years of age.  For children ≤5 years of age, only height 
and head circumference will be used to stage children development.  Between the age of 5 and 
8 the children’s physical development will be determined using the BMI.)  
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out CGAS (Appendix 9; to be completed by the Investigator with the parent/caregiver’s 
input)  
• Fill out SDQ (Appendix 4; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill 
out 
WHO-5 
questionnaire 
(Appendix 9; 
to 
be 
completed 
by 
the 
site 
coordinators/Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Sleep and Nap Diary (Appendix 1; to be completed by the parent/caregiver 
during the 14 nights before Visit 6).  If the Sleep and Nap Diaries were completed on a paper 
version, then the diary data is to be entered into the eCRF. 


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• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Explain and dispense study medication (IMP Handling Guidelines).  
• The visit should be carried out within ±3 days.  
8.12 PRE-VISIT 6  
Phone calls should be made weekly.  In addition, on the phone call 2 weeks prior to Visit 6, parents are 
to be reminded to begin filling out the Sleep and Nap Diary and to have patients wear the actigraphy 
(Actiwatch).   
8.13 VISIT 6 (LAST DAY OF WEEK 41 ±7 DAYS) 
• Verify compliance.  
• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  
• Record AEs. 
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill 
out 
WHO-5 
questionnaire 
(Appendix 9; 
to 
be 
completed 
by 
the 
site 
coordinators/Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the 
quality of sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Sleep and Nap Diary (Appendix 1; to be completed by the parent/caregiver 
during the 14 nights before Visit 7).  If the Sleep and Nap Diaries were completed on a paper 
version, then the diary data is to be entered into the eCRF.  
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Explain and dispense study drug (IMP Handling Guidelines). 
• The visit should be carried out within ±7 days.  


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8.14 PRE-VISIT 7 
Phone calls should be made weekly.  In addition, on the phone call 2 weeks prior to Visit 7, parents are 
to be reminded to begin filling out the Sleep and Nap Diary.   
8.15 VISIT 7 (LAST DAY OF WEEK 54 ±7 DAYS) 
• Verify compliance.  
• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  
• Record AEs. 
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill out WHO-5 questionnaire (Appendix 9; to be completed by the site coordinators/ 
Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the quality of 
sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Collect the Sleep and Nap Diary (Appendix 1; to be completed by the parent/caregiver during 
the 14 nights before Visit 8).  If the Sleep and Nap Diaries were completed on a paper version, 
then the diary data is to be entered into the eCRF.   
• Explain and dispense study drug (IMP Handling Guidelines).  
• The visit should be carried out within ±7 days.  
8.16 PRE-VISIT 8  
Make follow-up phone call once a month until Visit 8. 
8.17 VISIT 8 (LAST DAY OF WEEK 106 ±7 DAYS) 
• Verify compliance.  


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• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  
• Record AEs.  
• Assess pubertal status using the Tanner scale (The Tanner scale will be used to assess and stage 
physical development in children ≥8 years of age.  For children ≤5 years of age, only height 
and head circumference will be used to stage children development.  Between the age of 5 and 
8 the children’s physical development will be determined using the BMI.)  
• Fill out TESS (Appendix 5; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input). 
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill out WHO-5 questionnaire (Appendix 9; to be completed by the site coordinators/ 
Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the quality of 
sleep of the parent/caregiver and NOT the child.).  
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect and dispense Epilepsy Seizures Diaries for patients diagnosed with epilepsy 
(Appendix 10; to be completed by the parent/caregiver after each seizure). 
• Explain and dispense study medication (placebo run-out) (IMP Handling Guidelines).  
• The visit should be carried out within ±7 days. 
8.18 PRE-END OF STUDY VISIT 
Make follow-up phone call 1 week before the end of study visit to ensure that patients are taking study 
treatment and to schedule an end of study visit.   
8.19 END OF STUDY VISIT (LAST DAY OF WEEK 108 ±3 DAYS)  
• Verify compliance.  
• Measure vital signs. 
• Perform physical examination. 
• Measure body weight and height for the BMI and Z-score calculations.  
• Record AEs.  


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• Assess pubertal status using the Tanner scale (The Tanner scale will be used to assess and stage 
physical development in children ≥8 years of age.  For children ≤5 years of age, only height 
and head circumference will be used to stage children development.  Between the age of 5 and 
8 the children’s physical development will be determined using the BMI.)  
• Administer pregnancy test to females of child bearing potential.   
• Fill out TESS (Appendix 5; to be completed by the Investigator with the parent/caregiver’s 
input).  
• Fill out CSDI (Appendix 6; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input).  
• Fill out ESS (Appendix 7; to be completed by the site coordinators/Investigator with the 
parent/caregiver’s input.  Note:  The ESS is to assess sleepiness of the parent/caregiver and 
NOT the child.). 
• Fill out WHO-5 questionnaire (Appendix 9; to be completed by the site coordinators/ 
Investigator with the parent/caregiver’s input.  Note:  The WHO-5 is to assess the quality of 
sleep of the parent/caregiver and NOT the child.). 
• Fill out PSQI questionnaire (Appendix 8; to be completed by the site coordinators/Investigator 
with the parent/caregiver’s input.  Note:  The PSQI is to assess the well-being of the 
parent/caregiver and NOT the child.). 
• Collect Epilepsy Seizures Diaries for patients diagnosed with epilepsy (Appendix 10 to be 
completed by the parent/caregiver after each seizure). 
• The visit should be carried out within ±3 days.  
8.20 UNSCHEDULED VISIT(S) 
At any point during the study, the Investigator could call the patient in for an unscheduled visit if the 
Investigator was concerned about safety issues; the unscheduled visit page in the eCRF should be 
completed if such a visit takes place.   


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9 EFFICACY ASSESSMENTS 
Primary Efficacy Endpoint 
The primary efficacy endpoint is TST time as assessed by a Sleep and Nap Diary after the 13-week, 
double-blind treatment period.   
Secondary Efficacy Endpoints 
• Sleep latency as assessed by a Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
• Duration of wake after sleep onset period from the Sleep and Nap Diary after 13 weeks 
(Week 15) of double-blind treatment 
• Number of awakenings from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
• Longest sleep period from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
• Social functioning at home, in school, and in community settings as assessed by the CGAS after 
13 weeks (Week 15) of double-blind treatment.   
• Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 15) of 
double-blind treatment 
• Number of dropouts during the 13 weeks (Week 15) of double-blind treatment period. 
• Assessment of sleep parameters by actigraphy after 13 weeks (Week 15) of double-blind 
treatment  
Exploratory Efficacy Endpoints 
• Sleep variables as assessed by the Sleep and Nap Diary at baseline (Week 2), after 3 weeks of 
double-blind treatment (Week 5), and after 13, 26, and 39 weeks of open-label treatment 
(Weeks 28, 41, and 54)  
• Sleep disturbance as assessed by the CSDI score at baseline after 3 and 13 weeks of 
double-blind treatment (Weeks 5 and 15, respectively), after 13, 26, 39, and 91 weeks of 
open-label treatment (Weeks 28, 41, 54, and 106, respectively), and at the end of study visit 
(Week 108) 
• Social functioning at home, in school, and in community settings as assessed by the CGAS after 
13 weeks (Week 28) of open-label treatment   
• Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 28) of open-label 
treatment  
• Caregiver’s daytime sleepiness (i.e., NOT the child’s) during the study as assessed by the ESS 
(Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108) 


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• Caregiver’s well-being (i.e., NOT the child’s) during the study as assessed by the WHO-5 
questionnaire (Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108) 
• Caregiver’s quality of sleep at night (i.e., NOT the child’s) during the study as assessed by the 
PSQI questionnaire (Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108) 
10 CLINICAL PHARMACOLOGY ASSESSMENTS 
10.1 PHARMACOKINETIC (PK) ASSESSMENTS 
Not applicable. 
10.2 PHARMACODYNAMIC (PD) ASSESSMENTS 
Not applicable. 
10.3 BIOMARKER AND EXPLORATORY ASSESSMENTS 
Not applicable. 
11 SAFETY ASSESSMENTS 
11.1 ADVERSE EVENTS 
It is the responsibility of the Investigator to document all AEs that occur during the study.  Adverse 
events should be elicited using the TESS (Appendix 5).   
11.1.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient who 
is administered a pharmaceutical product during participation in an investigational study, which may 
or may not have a causal relationship with this treatment.   
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding or 
physical examination), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.   
An AE includes any noxious, pathological or unintended change in anatomical, physiological or 
metabolic functions as indicated by physical signs, symptoms and/or laboratory changes whether 
associated with the study drug and whether or not considered drug related.  This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction or the 
significant worsening of the indication under investigation that is not recorded elsewhere in the eCRF 
under specific efficacy assessments.  Anticipated day-to-day fluctuations of pre-existing conditions, 
including the disease under study, which do not represent a clinically significant exacerbation or 
worsening, need not be considered AEs. 
Patient entry into the study is defined as the time at which informed consent is obtained (this must be 
before any protocol-specific diagnostic procedures or interventions).  All AEs on this study subsequent 
to Visit 1 must be reported regardless of whether or not they are considered related to study drug.  Any 


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AEs experienced subsequent to signing of the informed consent/assent will be recorded as a medical 
history item. 
At Visit 1, the TESS questionnaire (Appendix 5) is completed and the information is used to assess 
medical history.  All symptoms that are score of 1 or more should be recorded in the medical history as 
it will serve us throughout the study as a baseline to see if a symptom was worsen or not.  At Visit 2 
and all subsequent visits thereafter, the TESS questionnaire is used to report all treatment-emergent 
signs and symptoms that may have occurred since Visit 1.  As instructed in Appendix 5, a given sign 
and symptom is to be reported as a corresponding AE if a score of 1 or above is selected, and if the 
sign or symptom is a new symptom or if there is an increase in severity of an existing symptom from 
the first visit (i.e., Visit 1).  If a specific symptom has the same score or lower from Visit 1 AEs should 
not be reported. 
Adverse events are also to be reported on the appropriate page of the patient’s eCRF.  
11.1.2 Assessment of Severity 
Each AE will be assigned a category as follows: 
Mild:   
Not sufficiently intense to result in discontinuation of the study drug.  Symptomatic 
treatment may have been given. 
Moderate: 
Sufficiently intense to result in discontinuation of the study drug.  Symptomatic 
treatment may have been given.   
Severe: 
 More intense than moderate; moreover the AE interferes significantly with ability to do 
work or usual activity. 
A change in the severity of an AE will require it to be recorded as a separate event. 
11.1.3 Assessment of Frequency 
Frequency should be assessed using the following categories: 
• Unique 
• Intermittent 
• Continued 
11.1.4 Assessment of Outcome 
Outcome should be assessed using the following categories: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Fatal 


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• Unknown  
11.1.5 Assessment of Causality and Relatedness 
Every effort should be made by the Investigator to explain each AE and assess its relationship, if any, 
to study drug.  Even if the Investigator feels there is no relationship to the study drug, all adverse 
experiences MUST be recorded in the eCRF.  The Investigator is requested to assess the relationship 
of any clinical adverse experiences to treatment using the following definitions: 
Causality should be assessed using the following categories: 
• Not related:  those AEs which are clearly and incontrovertibly due to extraneous causes 
(concurrent drugs, environment etc.) and do not meet the criteria for drug relationship listed 
under Unlikely, Possible, Probable or Related. 
• Unlikely to be related:  an adverse experience may be considered unlikely if it includes at least 
the first 2 features: 
o It does not follow a reasonable temporal sequence from administration of the drug  
o It could readily have been produced by the patient's clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient  
o It does not follow a known pattern to the suspected drug  
o It does not reappear or worsen when the drug is re-administered  
• Possibly related:  an adverse experience may be considered possible if it includes at least the 
first 2 features:   
o It follows a reasonable temporal sequence from administration of the drug 
o It could readily have been produced by the patient's clinical state, environment or toxic 
factors, or other modes of therapy administered to the patient 
o It follows a known response pattern to the suspected drug 
• Probably related:  an adverse experience may be considered probable if it includes at least the 
first 3 features:   
o It follows a reasonable temporal sequence from administration of the drug. 
o It could not be reasonably explained by the known characteristics of the patient's clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
patient 
o It disappears or decreased on cessation or reduction in dose.  There are exceptions when 
an AE does not disappear upon discontinuation of the drug (e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.). 
o It follows a known pattern of response to the suspected drug. 


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• Definitely related:   
An adverse experience may be considered related if it includes all of the 
following features: 
o It follows a reasonable temporal sequence from administration of the drug. 
o It could not be reasonably explained by the known characteristics of the patient's clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
patient. 
o It disappears or decreased on cessation or reduction in dose.  There are exceptions when 
an AE does not disappear upon discontinuation of the drug.  For example:  bone 
marrow depression, fixed drug eruptions, tardive dyskinesia, etc. 
o It follows a known pattern of response to the suspected drug. 
o It reappears or worsens if the drug is re-administered. 
11.1.6 Follow-up of Adverse Events 
All Investigators should follow-up with patients who experience AEs until the event is resolved or 
until, in the opinion of the Investigator, the event is stabilized or determined to be chronic.  Details of 
AE resolution must be documented in the eCRF. 
11.2 SERIOUS ADVERSE EVENTS 
11.2.1 Definition of a Serious Adverse Event 
An SAE is defined as any event which is: 
• Fatal 
• Life threatening: 
o An AE is life threatening if the patient is at immediate risk of death from the event as it 
occurs (i.e., it does not include a reaction that might have caused death if it had 
occurred in a more serious form). 
• Disabling or incapacitating : 
o An AE is incapacitating or disabling if it results in a substantial and/or permanent 
disruption of the patient’s ability to carry out normal life functions. 
• Results in hospitalization or prolongs a hospital stay: 
o Complications occurring during hospitalization are considered AEs and are SAEs if they 
cause prolongation of the current hospitalization.  Hospitalization for elective treatment 
of a pre-existing non-worsening condition is not considered an AE.  The details of such 
hospitalizations must be recorded on the medical history/physical examination page of 
the eCRF. 
In addition, medical and scientific judgment is required to decide if prompt notification is required in 
other situations (i.e., any event which the Investigator regards as serious that does not strictly meet the 


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criteria above but may jeopardize the patient or required intervention to prevent 1 of the outcomes 
listed above, or which would suggest any significant hazard, contraindication, side effect or precaution 
that may be associated with the use of the study drug. 
11.2.2 Definition of an Unexpected Adverse Event 
An unexpected AE, is defined as 1 that has not been reported as expected in this protocol or the 
Investigator’s Brochure, either from previous clinical studies or the pre-clinical studies. 
11.2.3 Reporting of Serious Adverse Events 
Any SAE must be reported by the Investigator if it occurs during the study or within 30 days of 
receiving study drug, whether or not the SAE is related to the study drug.  A SAE report consists of the 
SAE form, the AE form and the concomitant medication form.  A copy of these forms must be faxed 
by the Investigator for the attention of the study Safety Officer within 24 hours following knowledge 
of the SAE. 
The Investigator should not wait to receive additional information to fully document the event before 
notification of a SAE, though additional information may be requested.  Where applicable, information 
from relevant laboratory results, hospital case records and autopsy reports should be obtained. 
Instances of death, congenital abnormality or an event that is of such clinical concern as to influence 
the overall assessment of safety, if brought to the attention of the Investigator at any time after 
cessation of study medication and linked by the Investigator to this study should be reported to the 
study monitor immediately.   
Serious adverse events should be reported to: 
Tali Nir, DVM  
Vice President Clinical and Regulatory Affairs 
Neurim Pharmaceuticals Ltd. 
Tel:  +972-3-7684902  
Fax:  +972-3-6494568 
talin@neurim.com 
www.neurim.com 
Please also send a copy to PharSafer:  
drugsafety@pharsafer.com 
 
11.3 WITHDRAWAL DUE TO AN ADVERSE EVENT 
Any patient who experiences an AE may be withdrawn from the study drug at any time at the 
discretion of the Investigator.  If a patient is withdrawn wholly or in part because of an AE, both the 
AEs page and termination page of the eCRF will be completed at that time.  As described in 
Section 6.3, a patient who withdraws from the clinical study is required to be seen for a Withdrawal 
Visit scheduled as soon as possible after the patient has withdrawn, and end-of-study procedures are to 


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be carried out as shown in Section 8.19.  The patient will be monitored until the event has resolved or 
stabilized, until a determination of a cause unrelated to the study drug or study procedure is made, or 
until the patient is referred to the care of a local health care professional.  The Investigator must inform 
the medical monitor as soon as possible of all patients who are being considered for withdrawal due to 
AEs.  Additional reports must be provided when requested.   
If a patient is withdrawn from the study drug for multiple reasons that include AEs, the termination 
page of the eCRF should indicate that the withdrawal was related to an AE. 
11.4 MONITORING OF PATIENTS WITH AES 
Each patient must be carefully monitored for AEs.  Assessments must be made of the seriousness, 
intensity and relationship to the administration of the study treatment.  After the initial AE/SAE report 
the Investigator is required to follow-up proactively each patient and provide further information to 
PRA Health Sciences on the patient’s condition.  During the study all AE/SAEs should be followed up 
to resolution unless the event is considered by the Investigator to be unlikely to resolve due to the 
patient’s underlying condition, or the patient is lost to follow-up.   
11.5 PHYSICAL EXAMINATION AND VITAL SIGNS 
Vital signs and physical examination will be assessed at screening each visit including the placebo run-
out (withdrawal) period.  Physical examination findings at screening will be classified using standard 
categories as listed on the Medical History eCRFs.  Any physical examination finding that is judged by 
the Investigator as a clinically significant change (worsening) compared to a baseline value (Visit 2) 
will be considered an AE, recorded on the adverse event eCRF, and monitored as described in 
Section 11.4.   
A complete physical examination will include examination of body systems (including, but not limited 
to, general appearance, skin, neck, eyes, ears, nose, throat, breasts, lungs, heart, abdomen, back, lymph 
nodes, extremities, and nervous system).   
The Tanner scale will be used to assess and stage physical development in children ≥8 years of age.  
For children ≤5 years of age, only height and head circumference will be used to stage children 
development.  Between the age of 5 and 8 the children’s physical development will be determined 
using the BMI.   
11.6 TREATMENT OF OVERDOSE OF STUDY MEDICATION 
There is no experience of overdosing with Circadin®.  No specific treatment for overdosing is known.  
Administration of daily doses of up to 300 mg of melatonin without causing clinically significant 
adverse reactions have been reported in the literature.  
If overdose occurs, drowsiness is to be expected.  Clearance of the active substance is expected within 
12 hours after ingestion.  Treatment given to a patient in case of overdosing should be symptomatic 
and supportive.   


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Any overdose, with or without associated AEs, in a clinical study must be reported to PRA Health 
Sciences.  All reports of overdoses must be filed in the Study Center File.  Any AEs associated with 
the overdose should be reported on relevant AE/SAE sections in the eCRF.   
11.7 PREGNANCY 
Pregnancy will not be considered an AE or SAE.  If pregnancy does occur during the study, a 
pregnancy notification form will be completed, and the patient will discontinue study medication and 
the Investigator will remove the patient from the study.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, normal birth or congenital abnormality) must be followed up and 
documented even if the patient was discontinued from the study.  All reports of congenital 
abnormalities/birth defects are SAEs.  Spontaneous miscarriages should also be reported and handled 
as SAEs (Section 11.2.3).  Elective abortions without complications should not be handled as AEs.  
All outcomes of pregnancy must be reported to PRA Health Sciences.   
11.8 PHYSICAL EXAMINATION AND VITAL SIGNS 
Vital signs and physical examination will be assessed at each visit including the placebo run-out 
(withdrawal) period. 
11.9 OTHER SAFETY ASSESSMENTS 
BMI and Z-score calculations will be assessed at each visit including the placebo run-out (withdrawal) 
period. 
In children diagnosed with epilepsy the number and severity of epilepsy seizures during the study will 
be completed by the parents throughout the study in Epilepsy Seizures Diaries.   
12 DATA MANAGEMENT AND STATISTICAL ANALYSIS  
12.1 DATA MANAGEMENT 
An eCRF will be used for the current study and a data management plan will be prepared.   
The site will be supplied with the following data collection tools:  a web browser address for an 
Electronic Data Capture (EDC) system database that has been fully validated and conforms to 21 CFR 
Part 11 and the Guidance for Industry on Computerized Systems Used in Clinical Trials requirements.  
The EDC system database will be maintained by Datatrial.   
Trained site staff will enter the data required by the protocol into the eCRFs from source documents 
(e.g., medical records and study-specific data capture forms as needed) into the EDC system.  All 
information on the eCRFs must be traceable to these source documents.  Data recorded directly on the 
eCRFs will be defined before study start.  The eCRFs will be completed for all patients randomized to 
study treatment.  The eCRFs for patients who are randomized but not treated will be completed with 
all data collected at the time of patient study discontinuation.  Screen failures should also be entered 
into the eCRF.  Clinical Research Associates will review the eCRFs entered by investigational staff for 
completeness and accuracy.   


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Automatic validation programs check for data discrepancies in the eCRFs resulting in electronic 
queries generated for resolution by the investigational site.  Designated site staff is required to respond 
to queries and make any necessary changes to the data.  After database lock, the Investigator will 
receive the patient data on a CD for archiving at the investigational site.   
All treatment-emergent AEs (events occurring from the first dose of study medication through the last 
study evaluation) will be recorded in the EDC system.  AEs will be coded using the MedDRA 
dictionary (version 16.1) and concomitant medications will be coded using a standard dictionary (e.g., 
WHODrug, dated March 2013).   
The process of randomization and allocating randomized treatments using the eCRF is described in the 
eCRF completion guidelines and the IMP Handling Guidelines.   
When the database has been declared to be complete and accurate, the database will be locked.  Any 
changes to the database after that time can only be made by written agreement between Neurim and 
the PRA Health Sciences project team. 
12.2 STATISTICAL ANALYSIS PLAN 
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the study database.  
The SAP will provide a detailed description of the statistical methods and expand on the details 
provided in the protocol.  Additional analyses may be added.  Tables, listing and figures shells will 
also be provided.   
12.3 GENERAL CONSIDERATIONS 
Results of primary, secondary and selected exploratory efficacy analyses will be summarized at the 
end of the first open-label period (Week 28; Visit 5), and will be submitted in the form of a clinical 
study report (CSR) to the regulatory authorities for evaluation of approval of the study drug for use in 
the investigated population.  At the completion of the study (at the end of the second open-label safety 
follow-up period [Week 108]), another final CSR will be submitted to regulatory authorities.  This 
report will include all the remaining results and analyses (this is in compliance with the final Pediatric 
Committee opinion on Neurim Pharmaceuticals (1991) Pediatric Investigational Plan [PIP] for the 
study drug, Circadin® (IMP), deferring the completion of the safety follow-up part of the study - EM 
EA-000440- PIP02 -11).   
12.4 RANDOMIZATION 
At Visit 1, enough eligible male and female children, of ages 2 to 17.5 years, will be screened for the 
study to allow for 120 patients to then be randomized in a 1:1 ratio to receive Circadin® or placebo at 
Visit 2.  A minimum of 90 children are expected to complete the double-blind and first open-label 
period.  A minimum of 50 children are expected to complete the second open-label safety follow-up 
period.  The process of randomization and allocating randomized treatments using the eCRF is 
described in the eCRF completion guidelines and the IMP Handling Guidelines.   
12.5 ANALYSIS SETS 
Full Analysis Set 


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Efficacy analyses will be performed on the Full Analysis Set (FAS), and will include all patients in the 
Safety Analysis Set who satisfy all major entry criteria (Inclusion Criteria 1-5, Section 6.1) and who 
have efficacy data for the primary endpoint recorded for baseline and at least 1 post-baseline period 
assessment. 
Per Protocol Set 
The Per Protocol Set is a subset of the FAS, which excludes all patients for whom there were no 
serious violations of the protocol.   
Safety Analysis Set 
Safety analyses will be performed on the Safety Analysis Set, which includes all patients randomized 
to treatment who take at least 1 dose of study medication. 
12.6 SAMPLE SIZE  
Statistical analysis will be performed on the combined group of patients.  To achieve 95% power at the 
5% level for the primary objective (assuming a change of 0.72 hour in the Circadin® arm and 0.27 hour 
in the placebo arm and a standard deviation (SD) of 0.69 in the Circadin® arm and 0.45 in the placebo 
arm), 45 patients are required per combined group.  Therefore, 90 patients in total are required to 
complete Visit 5.  These estimations are based on previous studies conducted with Circadin®.   
12.7 STUDY POPULATION 
The set of enrolled patients (see Section 12.5) will be used for all study population summaries unless 
otherwise noted.  Summaries will be presented for all patients.   
12.7.1 Patient Disposition 
A summary of patient disposition will include all patients enrolled.  Data from patients who are 
enrolled, patients enrolled but not treated, patients in the FAS, patients who complete the study, and 
patients who withdraw from the study will be summarized using descriptive statistics.  Data from 
patients who were enrolled but not treated will be listed, with the reason why the patient was not 
treated.  Data from patients who were withdrawn from the study will also be summarized by reason for 
withdrawal using descriptive statistics.  The denominator for calculating percentages will be the set of 
enrolled patients.   
12.7.2 Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics taken at screening, consisting of medical history, 
physical examination findings, vital signs, and BMI and Z-score will be summarized using descriptive 
statistics.  For continuous variables, descriptive statistics (n, mean, SD, SE, median, minimum, and 
maximum) will be provided.  For categorical variables, patient counts and percentages will be 
provided.  Categories for missing data will be presented if necessary. 
12.8 STUDY ENDPOINTS AND STATISITCAL METHODS 
12.8.1 Efficacy Endpoints  


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Primary 
Total sleep time will be assessed by a Sleep and Nap Diary, and will be summarized after 13 weeks 
(mean of the last 14 days before visit) of double-blind treatment (actual change from baseline) for each 
treatment group using descriptive statistics (n, mean, SD, median, minimum and maximum).  For each 
treatment group for this outcome, the mean score at 13 weeks will be compared, adjusting for baseline, 
using linear regression model (Analysis of Covariance [ANCOVA]) to test the null hypothesis so that 
these adjusted mean scores are equal. 
Secondary 
Sleep latency will be assessed by a Sleep and Nap Diary, and will be summarized after 13 weeks 
(mean of the last 14 days before visit) of double-blind treatment (actual change from baseline) for each 
treatment group using descriptive statistics (n, mean, SD, median, minimum, and maximum).  For each 
treatment group for this outcome, the mean score at 13 weeks will be compared, adjusting for baseline, 
using an ANCOVA model to test the null hypothesis so that these adjusted mean scores are equal.   
Duration of wake after sleep onset period will be assessed by a Sleep and Nap Diary, and will be 
summarized after 13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual 
change from baseline) for each treatment group using descriptive statistics (n, mean, SD, median, 
minimum, and maximum).  For each treatment group for this outcome, the mean score at 13 weeks 
will be compared, adjusting for baseline, using an ANCOVA model to test the null hypothesis so that 
these adjusted mean scores are equal. 
The number of awakenings will be assessed by a Sleep and Nap Diary, and will be summarized after 
13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual change from 
baseline) for each treatment group using descriptive statistics (n, mean, SD, median, minimum, and 
maximum).  For each treatment group for this outcome, the mean score at 13 weeks will be compared, 
adjusting for baseline, using an ANCOVA model to test the null hypothesis so that these adjusted 
mean scores are equal. 
The longest sleep episode will be assessed by a Sleep and Nap Diary, and will be summarized after 
13 weeks (mean of the last 14 days before visit) of double-blind treatment (actual change from 
baseline) for each treatment group using descriptive statistics (n, mean, SD, median, minimum, and 
maximum).  For each treatment group for this outcome, the mean score at 13 weeks will be compared, 
adjusting for baseline, using an ANCOVA model to test the null hypothesis so that these adjusted 
mean scores are equal.   
The CGAS score will be summarized at baseline and after 13 weeks of double-blind treatment (actual 
change from baseline) for each treatment group using descriptive statistics (n, mean, SD, median, 
minimum, and maximum).  For each treatment group for this outcome, the mean score at 13 weeks 
will be compared, adjusting for baseline, using an ANCOVA model to test the null hypothesis so that 
these adjusted mean scores are equal. 
The SDQ score will be summarized at baseline and after 13 weeks of double-blind treatment (actual 
change from baseline) for each treatment group using descriptive statistics (n, mean, SD, median, 


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minimum, and maximum).  For each treatment group for this outcome, the mean score at 13 weeks 
will be compared, adjusting for baseline, using an ANCOVA model to test the null hypothesis so that 
these adjusted mean scores are equal. 
The number of dropouts will be compared between the treatment groups and analyzed using a 
dichotomized data analysis (chi-square test). 
Sleep parameters, as measured by actigraphy, will be summarized at baseline and after 13 weeks of 
double-blind treatment (actual change from baseline) for each treatment group using descriptive 
statistics (n, mean, SD, median, minimum, and maximum).  For each treatment group for this outcome, 
the mean score at each time point will be compared using an ANCOVA model to test the null 
hypothesis so that these mean scores are equal. 
For all primary and secondary analyses, a mixed-effect repeated-measures model (MMRM) will be 
fitted to assess any differences in treatment effects over time.  The base models will contain the 
specified outcome measure after baseline as the dependent variable, with independent variables in the 
form of the baseline score, the study visit (categorical variable) and treatment allocation.  A general 
covariance structure will be assumed.  The global treatment effect estimates will be reported, with 
95% CIs and p-values.  Further analysis will include interaction between treatment and visit.  
Interaction p-values will be reported with treatment effect estimates at each visit with 95% CI and 
p-values. 
Exploratory  
Sleep variables and sleep disturbance will be assessed by the Sleep and Nap Diary and the CSDI, 
respectively, at baseline (Week 2) and after 3 and 13 weeks of double-blind treatment (Weeks 5 and 
15, respectively) by presenting actual and change from baseline for each treatment group using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  For this outcome, the mean 
score at 3 weeks will be compared between treatment groups, adjusting for baseline, and by using an 
ANCOVA model to test the null hypothesis so that these adjusted mean scores are equal.  
The CSDI and Sleep and Nap Diary variables will also be summarized after 13, 26, and 39 weeks of 
open-label treatment (Weeks 28, 41, and 54) by presenting actual values and change from baseline for 
each treatment group using descriptive statistics (n, mean, SD, median, minimum, and maximum).  
CSDI will be also summarized after 91 weeks of open-label treatment and at the end of study visit 
(Week 108) using descriptive statistics (n, mean, SD, median, minimum, and maximum).   
The CGAS and SDQ scores will be summarized at baseline (Week 2), after 3 and 13 weeks of 
double-blind treatment (Weeks 5 and 15, respectively), and after 13 weeks of open-label treatment 
(Week 28) by presenting actual values and change from baseline for each treatment group using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  
The ESS, PSQI and WHO-5 scores (for the parent/caregiver) will be summarized at baseline (Week 2), 
after 3 and 13 weeks of double-blind treatment (Weeks 5 and 15, respectively), after 13, 26, 39, and 91 
weeks of open-label treatment (Weeks 28, 41, 54, and 106, respectively), and at the end of study visit 


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(Week 108) by presenting actual values and change from baseline using descriptive statistics (n, mean, 
SD, median, minimum, and maximum).  
For all exploratory analyses for the double-blind period, a MMRM will be fitted to assess any 
differences in treatment effects over time.  The base models will contain the specified outcome 
measure after baseline as the dependent variable, with independent variables in the form of the 
baseline score, the study visit (categorical variable) and treatment allocation. 
12.8.2 Safety Endpoints 
Descriptive statistics will be provided for AEs, changes in physical examinations and vital signs 
measurements.  The number of patients withdrawing during the treatment periods will be summarized 
by primary reason for withdrawal for each treatment group.   
12.8.3 Exploratory Endpoints 
The changes in BMI and Z-score from baseline to the end of the study will be summarized using shift 
tables showing the number of children below, within and above z calculated normal at each treatment 
group, separately. The BMI and Z-scores are designed to take into account the amount of weight gain 
that would be expected due to normal growth in children and adolescents.  The BMI and Z-scores are 
categorized by age and gender standardized values (corresponding to a normal distribution with mean 
0 and a SD of 1) of the actual weight measurements, based on the Growth Charts provided by the 
Centers for Disease Control.   
Tanner scores for pubertal assessment in children ≥8 years of age during the study will be analyzed 
using the web application (http://vps.stefvanbuuren.nl/puberty)20.  This tool calculates SD scores of 
individual observations of Tanner scores and additionally plots those scores in stage line diagram21. 
Descriptive statistics will be provided for head and height measurements and changes in head and 
height measurements from baseline to Week 108 in children ≤5 years of age.   
Descriptive statistics will also be provided for the number and severity of epilepsy seizures in children 
diagnosed with epilepsy, using the Epilepsy Seizures Diaries that are completed by parents at the time 
of the seizures and entered in the eCRF at a later time point by the site.  
12.9 STUDY TERMINATION CRITERIA 
Neurim Pharmaceuticals (1991) Ltd reserves the right to discontinue the study at any time.  
The reasons will be discussed with the Investigator and Data Safety Monitoring Board (DSMB).  
A study site may also be discontinued by Neurim Pharmaceuticals (1991) Ltd for significant deviations 
from the protocol or due to insurmountable difficulties experienced in running the study at that center.   
The study may be terminated before the planned number of patients has been achieved for the 
following reasons: 
• Safety and tolerability issues with study IMP which have come to light since study started. 
• Slow patient recruitment 
• Global recruitment target achieved 


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• Sponsors decision 
• Investigator’s decision 
• Force Majeure 
Specifically, the study may be terminated prematurely at any time that emergent data indicate that the 
potential benefit of participation is outweighed by observed risks.  Additionally the Sponsor may 
terminate the study if information emerges which demonstrates that the study will not meet its primary 
objective or progress is unsatisfactory. 
A written statement fully documenting the reasons for premature termination will be provided to the 
responsible Ethics Committees (ECs) and Regulatory Authorities within the timelines required by 
local regulations. 
12.10 DATA SAFETY MONITORING BOARD 
A DSMB will be involved in the management of this study.  The DSMB will monitor safety data 
generated by the study at regular intervals for the duration of the study.  Their role is to protect the 
interests of patients in the study and those to be entered, by review of accumulating safety and 
tolerability data generated in this study.  The data provided to the DSMB will not be considered ‘clean’ 
until the database is locked.  Data will be provided to the DSMB by an independent Biostatistician 
who is not assigned to the project. 
Further details regarding the DSMB will be provided in the DSMB charter.  The DSMB charter will 
define the primary responsibilities of the DSMB, guide its activities, its relationship with other trial 
components, its membership and the purpose and timing of its meetings.  It will provide the 
procedures for ensuring confidentiality, formal communication and outline of the content of the reports 
that will be provided by the DSMB. 
12.11 HANDLING OF DROPOUTS/MISSING DATA  
Missing data will not be replaced for both primary and secondary criteria.  The following will be 
applied concerning start and end dates: 
• If the day is unknown and the month and the year are known, it will be replaced by 01 in case of 
a start date or by the last day of the month in case of an end date. 
• If the day and the month are unknown, they will be replaced by 01/01 in case of a start date or 
31/12 in case of an end date. 
• If the day, the month and the year are unknown, the date will be considered as missing. 
For start and end dates of AEs, there is an exception from the above mentioned rules: 
• If the day is unknown and the month and the year are the same as the first treatment intake 
known, it will be replaced by the date of first treatment intake. 
• If the day and the month are unknown and the year is the same as the first treatment intake 
known, it will be replaced by the date of first treatment intake. 


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At least 3 documented attempts must be made to contact any patient lost to follow-up at any 1 time 
point prior to the last scheduled contact (clinic visit or telephone contact).  One of these documented 
attempts must include a written communication sent to the patient’s last known address via a courier or 
mail (with acknowledgement of receipt request) asking that they return any unused IMP and return to 
the clinic/site for final safety evaluations. 
Sleep and Nap Diaries should not be amended by site personnel, with exception of the following 
situations:   
• Dates presented with inconsistent formatting can be edited for consistency.  
• Missing or incorrect dates in a sequence can be corrected (e.g., the dates Dec 2014 to Jan 2014 
could be corrected to Dec 2014 to Jan 2015)  
• Time entered using the 12-hour format can be revised to the 24-hour format.   
• Hours can be converted to minutes and vice versa, as needed.   
• If at any visit the site determines that parents were not compliant in completing the Sleep and 
Nap Diaries (i.e., mandatory questions in the diaries were not correctly completed for at least 
5 out of 7 nights per week (total of 2 weeks before each scheduled visit), it will be at the 
discretion of the Investigator to determine whether the patient will be excluded from study as a 
result of lack of compliance (Section 6.1).  At Visits 1 and 2, this criterion is required to be met 
for patients to be eligible to continue on study and is considered a major entry criterion.  As 
well, at Visit 3 and Visit 5, if parents were not compliant in completing the Sleep and Nap 
Diaries the Investigator cannot increase a patient’s dose if so desired by the Investigator 
(Section 7.3.1).  If parents were not compliant in completing the Sleep and Nap Diaries at 
Visits 3 and 5, this is to be considered a significant violation (Section 13.3.2) and reported in 
the eCRF.  If a patient visit is delayed the parents are required to continue with completing 
diaries until the next visit.  Compliance will be judged on the diaries completed in the 2 weeks 
prior to the newly scheduled visit.  
The study coordinator should follow-up with parents during the phone calls to ensure diaries are 
completed in a timely manner and to make all attempts to prevent missing data and/or inconsistent data 
entry, according to the instructions in the Sleep and Nap Diary Guidelines.   
12.12 CHANGES TO THE PLANNED ANALYSIS 
Not applicable. 
13 MONITORING PROCEDURES (QUALITY CONTROL AND QUALITY 
ASSURANCE) 
The Sponsor has ethical, legal, and scientific obligations to conduct this study in accordance with 
established research principles and ICH GCP guidelines, and according to applicable SOPs, the 
protocol, and other written instructions and regulatory guidelines.  As such, in order to fulfil these 
obligations and to maintain current of study progress, the Sponsor's monitors or representatives will 


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visit the investigative sites during study conduct, in addition to maintaining telephone and written 
communication.  On-site visits, telephone calls, and regular inspection of the eCRFs will be conducted 
in order to assess patient enrolment, compliance with protocol procedures, completeness and accuracy 
of data entered on the eCRFs, verification of eCRF data against original source documents, and 
occurrence of AEs.  The Investigator must provide the monitor with full access to all source and study 
documents. 
13.1 ROUTINE MONITORING 
The study monitors will contact each Investigator and visit the study center at regular intervals 
throughout the study.  Sponsor assigned monitors will conduct regular site visits to the investigational 
facilities for the purpose of monitoring various aspects of the study.  The Investigator must agree to 
Sponsor-authorized personnel having direct access to the clinical (or associated) files and clinical 
study supplies (dispensing and storage areas) for all study patients considered for study entry for the 
purpose of verifying entries made in the eCRF, and assist with their activities, if requested.  The site 
must complete the eCRFs in a timely manner and on an ongoing basis to allow regular review by the 
study monitor.  The study monitor will indicate verification by electronically applying source 
document verification flags to the eCRF and will ensure that all required electronic signatures are 
implemented accordingly at the end of study.  Adequate time and space for monitoring visits should be 
made available by the Investigator.   
Whenever a patient name is revealed on a document that is to be collected for the Sponsor the name 
must be blacked out permanently by the site personnel, and annotated with the patient number as 
identification.   
As part of the supervision of study progress, other Sponsor personnel may, on request, accompany the 
study monitor on visits to the study center.  Each Investigator and assisting staff must agree to 
cooperate with the study monitor to resolve any problems, errors, or possible misunderstandings 
concerning the findings detected in the course of these monitoring visits. 
13.2 INSPECTIONS AND AUDITING PROCEDURES 
This study will be subject to audit by the Sponsor or their representatives.  The audits will be 
undertaken to check compliance with the requirements of Good Clinical Practice (GCP) and the ICH 
Guidelines and will include a minimum of: 
• In-house study file audit 
• Audit of computer database quality control 
• Audit of clinical report quality control 
The Sponsor or its representative may conduct audits at the investigative sites including, but not 
limited to patient notes, study documentation and facilities, laboratories used for the study drug supply, 
presence of required documents, and the informed consent process and comparison of eCRFs with 
source documents.  All medical records (progress notes) must be available for audit.  The Investigator 
agrees to participate with audits conducted at a convenient time in a reasonable manner. 


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Government regulatory authorities may also inspect the Investigator during or after the study.  The 
Investigator or designee should contact the Sponsor/CRO immediately if this occurs.  He/she must 
cooperate fully with regulatory authorities or other audits conducted at a convenient time in a 
reasonable manner. 
The purpose of an audit is to assess whether ethics, regulatory and quality requirements are fulfilled. 
13.3 PROTOCOL AMENDMENTS AND SIGNIFICANT PROTOCOL DEVIATIONS AND 
VIOLATIONS  
13.3.1 Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics Committee (IEC) or 
other regulatory authorities, except when necessary to eliminate immediate safety concerns to the 
patients or when the change involves only logistics or administration.  The PI and the Sponsor will 
sign the protocol amendment.   
13.3.2 Protocol Deviations, Violations, and Exceptions 
A protocol deviation is nonadherence to protocol-specific study procedures or schedules that does not 
involve inclusion/exclusion criteria, primary objective variable criteria, and/or GCP guidelines.  
Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e., nonadherence on the part of 
the patient, the Investigator, or the Sponsor to protocol-specific inclusion/exclusion criteria, primary 
objective variable criteria, and/or GCP guidelines.  Protocol violations will be identified and recorded, 
by study site personnel, on the eCRF. 
In this study, significant protocol violations will be defined as those that affect the assessment of safety 
or efficacy.  The significant protocol violations will be agreed prior to database lock and will be 
categorised as follows: 
• Patient’s overall treatment compliance for the study is less than 70% or greater than 130% 
throughout the study   
• Patient fails to meet any inclusion criteria or meets any exclusion criteria 
• Any issues related to Sleep and Nap Diary completion 
• Patient takes a prohibited medication during the study 
• Wrong IMP kit dispensed 
• Patient has an insufficient wash-out of prohibited medications prior to beginning the 2-week SB 
placebo run-in period of the study  
• Other, defined as any deviation that causes the Investigator to withdraw the patient from the 
study for the reason “protocol violation”, “protocol deviation” or “protocol non-compliance” 
on the study completion/withdrawal page of the eCRF 


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As a matter of policy, the Sponsor will not grant exceptions to protocol-specific entry criteria to allow 
patients to enter a study.  If under extraordinary circumstances such action is considered ethically, 
medically, and scientifically justified for a particular patient, prior approval from the Sponsor and the 
responsible Institutional Review Board (IRB)/IEC, in accordance with the SOP, is required before the 
patient will be allowed to enter the study.  If investigative site personnel learn that a patient who did 
not meet protocol eligibility criteria was entered in a study (a protocol violation), they must 
immediately inform the Sponsor.  Such patients will be discontinued from the study, except in a rare 
instance following review and written approval by the Sponsor and the responsible IRB/IEC, 
according to the applicable SOP.   
13.4 INFORMATION TO STUDY PERSONNEL 
Each Investigator is responsible for giving information about the study to all staff members involved in 
the study or in any element of patient management, both before starting the practical performance of 
the study and during the course of the study (e.g., when new staff become involved).  Each 
Investigator must assure that all study staff members are qualified by education, experience, and 
training to perform their specific responsibilities.  These study staff members must be listed on the site 
authorization form, which includes a clear description of each staff member’s responsibilities.  This list 
must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including each 
Investigator, and for ensuring their compliance with the protocol.  Additional information will be made 
available during the study when new staff become involved in the study and as otherwise agreed upon 
with either the Investigator or the study monitor. 
13.5 RECORD KEEPING 
After completion of the study, all documents and data relating to the study will be kept by the 
Investigator in a secure study file.  This file will be available for inspection by the Sponsor and/or their 
representatives.  Essential documents must be retained for 2 years after the final marketing approval in 
an ICH region or at least 2 years have elapsed since the discontinuation of clinical development of the 
IMP.  The Investigator must contact the Sponsor before destroying any trial-related documentation.  In 
addition, all patients’ medical records and other source documentation will be kept for the maximum 
time permitted by the hospital, institution or medical practice. 
14 STUDY MANAGEMENT AND MATERIALS 
14.1 ELECTRONIC CASE REPORT FORMS 
An eCRF will be used to store and transmit patient information.  The file structure and format for the 
eCRF will be provided by the Sponsor or their representative and should be handled in accordance 
with the instructions provided. 
It is preferred that the Sleep and Nap diary be entered directly into the eCRF but dairies are permitted 
to be completed on a paper diary as well.  If the diary is entered directly to the eCRF by the parent, 
then the eCRF serves as the source data.  If the diary is completed on paper and later entered into the 


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eCRF by the site, then the paper version serves as the source data.  No amendment can be made to the 
parent-reported data except in cases indicated in Section 12.11 (missing data). 
The eCRF must be reviewed and electronically signed, and dated by the Investigator. 
Access to the eCRF will be strictly password protected and limited to personnel directly participating 
in the study.  Data should be entered into the eCRF completely by examining personnel or the study 
coordinator.  The eCRF must be completed as soon as possible after any patient evaluation or 
communication.  If data are to be changed due to erroneous input or other reason, an electronic audit 
trail will track these changes.  The eCRFs and computers that store them must be accessible to study 
monitors and other regulatory auditors.   
14.2 DATA COLLECTION 
During each study visit, a physician participating in the study will maintain progress notes, in ink, in 
the patient’s medical records to document all significant observations.  At a minimum, these notes will 
contain: 
The date of the visit and the corresponding day or visit in the study schedule (e.g., screening, Day 1, 
Day 28, etc.) 
• General condition and status remarks by the patient, including any significant medical findings.  
The severity, frequency, duration, and resolution of any reported AE, and the Investigator's 
assessment as to whether or not the reported AE is study drug-related 
• Changes in concomitant medications or dosages 
• A general reference to the procedures completed 
• The signature or initials of all physicians making an entry in the medical record (progress notes) 
In addition, any contact with the patient via telephone or other means that provides significant clinical 
information and record of any scheduled phone call will also be documented in the medical record 
(progress notes), as described above.   
Information from the medical records (progress notes) and other source documents will be promptly 
transcribed to the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes), eCRF, and other source documents will 
be initialled and dated on the day the change is made by the Investigator or designee.  If the reason for 
the change is not apparent, a brief explanation for the change will be written adjacent to the change. 
14.3 SOURCE DOCUMENTS MAINTENANCE 
Source documents contain the results of original observations and activities of a clinical investigation.  
Source documents include, but are not limited to, medical records (progress notes), computer printouts, 
screening logs and recorded data from automated instruments.   
Source documents from this study will be maintained by the Investigator and made available for 
inspection by authorized persons with the exception of the Sleep and Nap Diary.  As described above, 


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if the Sleep and Nap Diary is entered directly to the eCRF by the parent, then the eCRF serves as the 
source data.  If the diary is completed on paper and later entered in to the eCRF by the site, then the 
paper version serves as the source data.   
The original signed informed consent for each patient shall be filed with records kept by the 
Investigator and a copy shall be given to the patient. 
14.4 RECORD MAINTENANCE 
All data derived from the study will remain the property of Neurim. 
Records must be retained in accordance with the current ICH Guidelines on GCP.  All essential study 
documents including records of patients, source documents, eCRFs and study drug (IMP) inventory 
must be kept on file. 
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the conduct 
of this study and the distribution of IMP, including eCRFs, consent forms, and medical inventory 
records, must be retained by the PI for 2 years after marketing application approval.  If no application 
is filed, these records must be kept 2 years after the investigation is discontinued and the US FDA and 
the applicable national and local health authorities are notified.  The Sponsor or their representative 
will notify the PI of these events. 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational products.  However, essential documents may be retained for a 
longer period if required by the applicable regulatory requirements or by agreement with the Sponsor.  
The Sponsor is responsible for informing the Investigator when these documents need no longer be 
retained. 
The Investigator will not dispose of any records relevant to this study without written permission from 
the Sponsor, and will provide the Sponsor the opportunity to collect such records.  The Investigator 
shall take responsibility for maintaining adequate and accurate hard copy source documents of all 
observations and data generated during this study.  Such documentation is subject to inspection by the 
Sponsor, its representatives and regulatory authorities. 
If an Investigator moves, withdraws from an investigation or retires the responsibility for maintaining 
the records may be transferred to another person who will accept responsibility.  Notice of transfer 
must be made to and agreed by the Sponsor. 
14.5 CONFIDENTIALITY 
All information obtained during the conduct of the study with respect to the patient’s state of health 
will be regarded as confidential.  For disclosure of any such information, an agreement will be 
obtained in writing.   
The Investigator must ensure that each patient’s anonymity is maintained.  On eCRFs and other 
documents submitted to the Sponsor or the CRO, patients must not be identified by name.  Instead, 


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patients will only be known by their initials and by the unique patient number allocated to them in 
order to ensure confidentiality on all study documentation.  Patients will retain this unique number 
throughout the study.  The Investigator will keep a separate log of these codes. 
In order to comply with government regulatory guidelines and to ensure patient safety, it may be 
necessary for the Sponsor and its representative, the CRO personnel, the local research review board, 
or the US FDA to review patients’ medical records as they relate to this study.  Only the patient’s 
unique number on the eCRFs will identify him/her, but their full names may be made known to a drug 
regulatory authority or other authorized government or health care officials, if necessary, and to 
personnel designated by the Sponsor. 
Documents that are not for submission to the Sponsor or the CRO (e.g., consent forms) will be 
maintained by the Investigator in strict confidence, except to the extent necessary to allow monitoring 
by the Sponsor and the CRO, and auditing by regulatory authorities.  No documents identifying 
patients by name will leave the investigative site and patient identity will remain confidential in all 
publications related to the study. 
15 DRUG ACCOUNTABILITY 
Investigators will be provided with sufficient amounts of the IMP to carry out this protocol for the 
agreed number of patients.  The Investigator or designee will acknowledge receipt of the IMP 
documenting shipment content and condition.  Accurate records of all IMP dispensed, used, returned 
and/or destroyed must be maintained.  Sites are responsible for ordering sufficient amounts of IMP to 
manage their IMP stock.   
The Investigator or his/her designee (as documented in by the Investigator in the applicable study 
delegation log) will dispense the IMP only to patients included in the study following the procedures 
set out in the protocol.  Each patient will be given only the IMP carrying his/her treatment assignment.  
All dispensing will be documented on the eCRFs and/or other IMP record.  The Investigator is 
responsible for assuring the retrieval of all study supplies from patients. 
No IMP stock or returned inventory from a Neurim sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the Sponsor.  If such a transfer is 
authorized by the Sponsor, all applicable local, state and national laws must be adhered to for transfer. 


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16 ETHICS AND INFORMED CONSENT 
16.1 ETHICS 
16.1.1 Regulatory and Ethical Approvals  
The regulatory permission to perform the study will be obtained in accordance with applicable 
regulatory requirements.  The EC or IRB will approve this protocol, the patient information sheet, the 
ICF and their updates.  The regulatory and ethical approvals must be available before a patient is 
exposed to any study-related procedure, including screening tests to determine eligibility for the study. 
16.1.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the ethical principles stated in the current Declaration 
of Helsinki, as revised in Seoul in 2008 as well as ICH, GCP, European Commission Directive, and 
Code of Federal Regulations, including relevant Sponsor or Designee’s Standard Operating 
Procedures.   
16.2 PATIENT INFORMATION AND INFORMED CONSENT 
It is the responsibility of the Investigator to obtain written informed consent from all study patients 
prior to any study-related procedures including screening assessments.  All consent documentation 
must be in accordance with applicable regulations and GCP.  Written consent will be obtained from 
each patient’s legal guardian/guardians after an appropriate explanation of the aims, methods, 
anticipated benefits, potential hazards, and any other aspect of the study which is relevant to his/her 
decision to participate.  The consent form will be signed and dated by the patient’s legal guardian 
before the patient is exposed to any study-related procedure, including screening tests for eligibility.  
Each patient's legal guardian will authorise in writing that his/her custodian's source records may be 
reviewed by a monitor, an auditor or a regulatory inspector, in accordance with applicable regulatory 
requirements. 
A written assent will be obtained from the patient provided the young patient has a sufficient 
understanding and intelligence to understand what is proposed. 
A patient legal guardian/guardians or a young patient who has the sufficient understanding can 
withdraw consent/assent at any time during the study, without obligation or prejudice.  This will not 
affect the future care and treatment of the patient. 
Patient Information Sheets and Consent Forms, versions must be approved by an EC prior to 
consenting a patient. 
17 FINANCING AND INSURANCE 
The Investigator is required to disclose any financial arrangements during the study and for 1 year 
after, whereby the value of the compensation for conducting the study could be influenced by the 
outcome of the study.  The following information is collected:  any research, compensation in the form 
of equipment, retainer for ongoing consultation or honoraria; any proprietary interest in the IMP; any 
significant equity interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2 (b) (1998). 


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In consideration of participation in the study, the Sponsor pays the Investigator or nominated payee the 
sums set out in the payment schedule attached to the Investigator Agreement. 
The Sponsor responsible for this study is: 
Neurim Pharmaceuticals  
27 Habarzel St. 
Tel Aviv, 69710, Israel 
The Sponsor will provide appropriate Insurance cover for this study. 
18 REPORTING AND PUBLICATION 
Neurim Pharmaceuticals Ltd. (1991) has the ownership of all data and results collected during this 
study.  In consequence, Neurim Pharmaceutical Ltd. reserves the right to use the data from the present 
study, either in the form of eCRFs (or copies of these), or in the form of a CSR (with or without 
comments and with or without analysis) in order to submit them to the Health Authorities of any 
country.  Furthermore, in the event that the clinical research leads to patentable results, the Investigator 
(or entity acting on his behalf following local requirements) shall refrain from filing patent(s) 
application which will be filed by Neurim Pharmaceuticals Ltd. or any other entity delegated by 
Neurim Pharmaceuticals Ltd.  
 


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Smith-Magenis syndrome. J Med Genet - wwwjmedgenetcom. 2003; 40: 74-8. 
15. 
Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An Open-Label Study of Controlled-Release 
Melatonin in Treatment of Sleep Disorders in Children with Autism. J Autism Dev Disord. 2006. 
16. 
Shah T, Apy, TSE., Gill, H., Wong, ICK., Sutcliffe, A., Gringras, P., Appleton, R., Tuleu, C. 
Administration of melatonin mixed with soft food and liquids for children with neurodevelopmental 
difficulties. Developmental Medicine & Child Neurology. 2008; 50: : 845–9. 
17. 
Miano S, Ferri R. Epidemiology and management of insomnia in children with autistic spectrum 
disorders. Paediatr Drugs. 2010; 12(2): 75-84. 
18. 
Garstang J, Wallis M. Randomized controlled trial of melatonin for children with autistic 
spectrum disorders and sleep problems. Child Care Health Dev. 2006; 32(5): 585-9. 
19. 
Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, et al. A randomized, 
placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and 
impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008; 
44(1): 57-64. 
20. 
van Buuren S, Ooms JC. Stage line diagram: an age-conditional reference diagram for tracking 
development. Stat Med. 2009; 28(11): 1569-79. 


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21. 
van Geijlswijk IM, Mol RH, Egberts TC, Smits MG. Evaluation of sleep, puberty and mental 
health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset 
insomnia. Psychopharmacology (Berl). 2011; in press. 
 
 
 


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20 APPENDICES 
Appendix 1:  Sleep and Nap Diary  
This is to be completed by the parent/caregiver daily at home, preferably 2-3 hours after the child 
wakes up.    
Site: 
Subject number:  
NEU_CH_7911 - Sleep and Nap Diary 
For all questions below please try to give the exact times and durations however if you do not remember the exact times 
please give your best estimation 
Date of diary (morning after medication administration) 
 
Questionnaire completed by 
○ 
Mother 
○ 
Father 
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Did the child take his/her medicine last night? 
○ 
Yes 
○ 
No 
○ 
Unknown 
If yes, when? (24 hr clock) 
 
Comments 
 
Sleep last night and feeling this morning: 
 
* What time did the child go to bed last night? (24 hr clock) 
 
* How long did it take the child to fall asleep (minutes)? 
 
* How many times did the child wake up in the night? 
 
* For each wake period please try to provide the exact times and 
duration awake 
 
Wake period number 
 
Wake time (24 hr clock) 
 
Waking duration in minutes 
 
Wake period number 
 
Wake time (24 hr clock) 
 


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Site: 
Subject number:  
NEU_CH_7911 - Sleep and Nap Diary 
Waking duration in minutes  
 
Wake period number 
 
Wake time (24 hr clock) 
 
Waking duration in minutes 
 
* How long did the child stay awake during the night (minutes)? 
 
* How many hours of actual sleep did the child get that night 
(hours:minutes)?  
(This may be different than the number of hours he/she spent in 
bed) 
 
* What time did the child wake up? (24 hr clock) 
 
What time did the child get out of bed? (24 hr clock) 
 
Can you describe the child's sleep quality last night as one of the 
following: 
○ 
Very bad 
○ 
Bad 
○ 
Fair 
○ 
Good 
○ 
Very good 
○ 
Unknown 
Can you describe the child's feeling now as one of the following: 
○ 
Very alert 
○ 
Alert 
○ 
Quite alert 
○ 
Tired 
○ 
Very tired 
○ 
Unknown 
Can you describe the child's feeling when he/she woke up for 
the day as one of the following: 
○ 
Very refreshed 
○ 
Refreshed 
○ 
Somewhat refreshed 
○ 
Fatigued 
○ 
Very fatigued 
○ 
Unknown 
The child's daily naps yesterday: 
 
How many naps did the child have (naps are defined as any sleep 
 


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Site: 
Subject number:  
NEU_CH_7911 - Sleep and Nap Diary 
in periods outside his/her normal bedtime)?  
Please record the duration of each nap on a new row below  
 
Nap number 
 
Nap start time (24 hr clock) 
 
Nap duration in minutes 
 
Nap number 
 
Nap start time (24 hr clock) 
 
Nap duration in minutes 
 
Nap number 
 
Nap start time (24 hr clock) 
 
Nap duration in minutes 
 
Final version: 2014-06-09 (1.000.003.000) 
CONFIDENTIAL  
Neurim Pharmaceuticals Ltd. 


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Appendix 2:  Sleep and Nap Diary Take-Home Instructions for Parents  
 
The Diary has to be completed for 14 days prior to each visit in the first year of participation. The 
diary should be completed every morning preferably 2-3 hours after the child went out of bed. 
 
    What time did the child go to bed? 
 
    This is the moment that bedtime routines are over (lights off). From this 
moment onwards, no further reading or parent interaction should happen and 
the child is expected to attempt to sleep. Use 24 hour clock (i.e. 21:35) to 
record times. 
    When all bedtime routines are over (lights off), the event marker button on the 
Actiwatch is to be pushed. Ensure the time entered in the diary for the child going 
to bed is the same as the one appearing on the Actiwatch screen. 
    If Actiwatch was not pushed, in error, at the correct moment, please use the 
actual time the child went to bed (the time bedtime routines were over) for 
the Diary 
    Do not change the initial time entered in the diary if the child has difficulties 
falling asleep i.e. calls you into the bedroom or leaves the bedroom to find you. 
 
    How long did it take your child to fall asleep? 
 
    This is the duration in minutes from first attempt to fall asleep (bedtime routines 
are over, lights off) to final sleep. 
 
    Times and durations of wakes up during the night. 
 
    Enter the accurate times and durations. Do not round times up or down. For times 
use 
24 hours clock i.e. 01:35 – 02:45. Durations should be entered in minutes, i.e. 
70 minutes. 
 
    In case you do not remember exact times and durations please give your 
best estimation. 
 
    How many hours of actual sleep did the child get that night? – 
 
    Please use hours:minutes for example six and a half hours should be entered as 6:30 
 
    What time did the child wake up? 
 
    This is the time your child finally woke up and did not fall asleep anymore (lights on). 
This may be different from the time the child got out of bed. Use 24 hour clock (i.e. 
07:35) to record times. 
 
    The time of wake up (lights on) should be marked also by pushing the event 
marker button on the Actiwatch – use the time that appears on the Actiwatch 
for the diary. 
 
    Example responses to the questions of the Sleep Nap diary are provided in the table 
–on the next page. 
 


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Electronic Sleep and Nap Diary Completion Guidelines 
You will be given a unique username and password and the URL (web address) to allow 
access to the 
Sleep and Nap Diary at the site. The diary will be displayed in your local language. 
 
The login screen will ask you to enter your username and password. Please note 
these are case sensitive. Then select ‘Login’. 
 
 
 
When you first log into the system, you will be asked to change your password. Enter 
the current password you were given by the site and create a new password for your 
account that you will remember. 
 
 
 
If you forget your password at any time, please contact your site and they will be able to 
reset this for you. 
 
For security reasons, after 60 days you will be asked again to change your password. The 
“Change 
Expired Password” screen will appear as it did the first time you logged into the system. 
 
When you login, you will see your child’s screening number and the Sleep and Nap 
Diaries that you enter beneath it. 
 


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To create a new Diary, click on the ‘+’ sign and confirm that you would like to create a 
new repeat. 
 
 
 
This will create repeat (1) of the page. You should create a new repeat for every day that 
you complete the Sleep and Nap Diary, for 14 days prior to each visit. 
 
When you create a new repeat, this will open the page where you will enter the 
information required into the Sleep and Nap Diary. 
 
Each diary should be completed in the morning for the previous 
night’s sleep. 
 
Validation prompts are present on the page to ensure that the data is 
entered logically. 
 
If the data entered is inconsistent you will be prompted to update the data, in some cases 
a comment can be entered to explain why the data entered is inconsistent. The prompt 
below requires data to be updated. 
 
 
 
The page can only be saved when questions with a red star next to them have been 
answered. 
 
 
 
When you have entered the data onto the page, select ‘Submit’ from the buttons at the 
bottom right of the screen. This will save the page and take you to a ‘Browse’ view of the 
page. 
 


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If you were unable to answer any of the questions with a red star, you can select ‘Submit as 
incomplete’. Please note that incomplete diaries might affect suitability to continue in the 
study. 
 
 
 
Once you have entered your Sleep and Nap Diary, you can logout using the logout button at 
the top right of the page. 
 
 
 
Once you have completed entry, the pages will be locked to prevent further editing. If you have 
made an error and would like to amend any of your diary data after you have saved it, you should 
contact your site who can unlock the page for you to edit or amend the data on your behalf. 


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Actiwatch Guidelines for the Parents 
 
 
General introduction 
 
Actiwatch is a device that will monitor the activity level of your child. It enables your study 
doctor to determine sleep and activity patterns. It should be worn all night. It should be 
considered no more intrusive than a wristwatch. The Actiwatch should not be removed except as 
instructed below. 
 
    Try to acclimate the child to wearing the watch by introducing plastic bracelets and toy 
watches 
 
    The non-dominant wrist is preferred, the same wrist should always be used every night 
 
    Place the Actiwatch on the subject’s wrist and fasten it in such a way as to be slightly snug, 
but comfortable 
    The Actiwatch should be worn for 14 nights before visit 2 and visit 4 
 
    Remember: keep the Actiwatch in a safe place during the day 
 
    Actiwatches are considered water resistant (not water proof). However, please try to 
avoid showering, bathing, washing the device 
 
    Please stop using the Actiwatch and contact your study doctor in case: 
     skin reddening or inflammation appears 
    the device becomes damaged 
 
What to do at night 
 
    Place the Actiwatch 30 minutes before bedtime 
 
    The Actiwatches display will change when it is put on the wrist. 
 
    After bedtime routine (lights off), press the Marker Button on the Actiwatch - 
Immediately record this time on the sleep diary as time the child went to bed. 
 
    Do not press the marker button again during the night. Even if the child requires 
additional assistance (calls you again, comes to your room etc.) there is no need to 
press the marker button again. 
    Pressing the event Marker Button will not turn on/off the device but rather mark the 
time of going to sleep/ waking up in the morning. 
 
What to do in the morning 
 
    In the morning press the marker button as soon as the child awakens for the day (lights on). 
Record this time in the diary as time of wake up. 
 
    Remove the Actiwatch 30 minutes after the child wakes up in the morning 
 
 


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Appendix 3:  Children Global Assessment Scale and Rating Guidelines  
This is to be completed by the Investigator with the parent/caregiver’s input.   
Site: 
Subject number:  
NEU_CH_7911 - Children Global Assessment Scale 
(CGAS) 
Was the Children Global Assessment Scale performed? 
○ 
Yes 
○ 
No 
Date of assessment 
 
Questionnaire completed by 
○ 
Mother 
○ 
Father 
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Enter the overall score based on the below scale: 
 
100 - 91: Doing very well 
90 - 81: Doing well 
80 - 71: Doing alright, some minor impairment 
70 - 61: Some problems, in one area only 
60 - 51: Some noticeable problems, in more than one area 
50 - 41: Obvious problems, moderate impairment in most areas or 
severe in one area 
40 - 31: Serious problems, major impairment in several areas and 
unable to function in one area 
30 - 21: Severe problems, unable to function in almost all situations 
20 - 11: Very severely impaired, so impaired that considerable 
supervision is required for safety 
10 - 1: Extremely impaired, so impaired that constant supervision is 
required for safety 
 
Overall Score 
 
 
Final version: 2014-06-19 (1.000.003.000)  
CONFIDENTIAL  
Neurim Pharmaceuticals Ltd. 
 
 
 


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CGAS Rating Guide 
The coding guidance notes and vignettes are provided to assist in the process of rating the clinical 
severity of all the young people who have been admitted to your service. The vignettes provided were 
originally developed for the 'Children and Young Persons In-patient Evaluation (CHYPIE) Study. 
CODING THE CGAS 
Code the CGAS on the basis of your patient's worst level of emotional and behavioural functioning in 
the past three months by selecting the lowest level which describes his/her functioning on a 
hypothetical continuum of health-illness.  The scores can range from 1, which is the very worst, to 
100, which is the very best.  Use intermediary levels (e.g., 35, 58, 62). 
 
Rate actual functioning regardless of treatment or prognosis.  
Do not count functional physical impairments unless they are clearly related to emotional functioning, 
(i.e., functional handicap due to cerebra/palsy or blindness would not be coded, but difficulty as a 
consequence of soiling would be). (Note that the HoNOSCA coding differs here - cf area A6.) 
 
It will be helpful to take into account how your patient functions in four major areas: 
1. At home with family 
2. At school 
3. With friends 
4. During leisure time 
The overall score will represent an overall rating from these four areas.  
Locating the score 
1. Locate a decile based on the descriptions that follow. 
2. Consider the appropriate decile in thirds and locate the functioning in the upper middle or lower 
third of the decile. 
3. Choose a score within that third as the overall score. 
 
 


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CHILDREN'S GLOBAL ASSESSMENT SCALE 
David Shaffer, M.D., Madelyn S. Gould, Ph.D., Hector Bird, M.D., Prudence Fisher, B.A Adaptation 
of the Adult Global Assessment Scale (Robert L. Spitzer, M.D., Nathan Gibbon, M.S.W., Jean Endicott, 
Ph.D.) 
The examples of behaviour provided are only illustrative and are not required for a particular rating. 
Specified time period: 1 month 
100-91  
DOING VERY WELL 
Superior functioning in all areas (at home, at school and with peers), involved in a range of activities 
and his many interests (e.g., has hobbies or participates in extracurricular activities or belongs to an 
organised group such as Scouts, etc.).  Likeable, confident, everyday worries never get out of hand. 
Doing well in school. No symptoms.  
90-81  DOING WELL 
Good functioning 'in all areas.  Secure in family, school, and with peers.  There may be transient 
difficulties and "everyday" worries that occasionally get out of hand (e.g., mild anxiety associated with 
an important exam, occasionally "blow-ups" with siblings, parents or peers). 
80-71  DOING ALL RIGHT - minor impairment 
No more than slight impairment in functioning at home, at school, or with peers. Some disturbance of 
behaviour or emotional distress may be present in response to life stresses (e.g., parental separations, 
deaths, birth of a sibling) but these are brief and interference with functioning is transient, such 
children are only minimally disturbing to others and are not considered deviant by those who know 
them. 
70-61  SOME PROBLEMS - in one area only 
Some difficulty in a single area, but generally functioning pretty well, (e.g., sporadic or isolated 
antisocial acts, such as occasionally playing hooky, petty theft; consistent minor difficulties with 
school work, mood changes of brief duration, fears and anxieties which do not lead to gross avoidance 
behaviour; self-doubts).  Has some meaningful interpersonal relationships.  Most people who do not 
know the child well would not consider him/her deviant but those who do know him/her well might 
express concern.  
60-51  SOME NOTICEABLE PROBLEMS - in more than one area 
Variable functioning with sporadic difficulties or symptoms in several but not all social areas.  
Disturbance would be apparent to those who encounter the child in a dysfunctional setting or time but 
not to those who see the child in other settings.  
50-41  OBVIOUS PROBLEMS- moderate impairment in most areas or severe in one area. 


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Moderate degree of interference in functioning in most social areas or severe impairment functioning 
in one area, such as might result from, for example, suicidal preoccupations and ruminations, school 
refusal and other forms of anxiety, obsessive rituals, major conversion symptoms, frequent anxiety 
attacks, frequent episodes of aggressive or other antisocial behaviour with some preservation of 
meaningful social relationships. 
40 1 SERIOUS PROBLEMS - major impairment in several areas and unable to function in one 
area 
Major impairment in functioning in several areas and unable to function in one of these areas (i.e., 
disturbed at home, at school, with peers, or in the society at large [e.g., persistent aggression without 
clear instigation; markedly withdrawn and isolated behaviour due to either mood or though 
disturbance, suicidal attempts with clear lethal intent]).  Such children are likely to require special 
schooling and/or hospitalisation or withdrawal from school (but this is not a sufficient criterion for 
inclusion in this category). 
30-21  SEVERE PROBLEMS - unable to function in almost all situations. 
Unable to function in almost all areas (e.g., stays at home, in ward or in bed all day without taking part 
in social activities) OR severe impairment in reality testing OR serious impairment in communication 
(e.g., sometimes incoherent or inappropriate).  
20-11  VERY SEVERELY IMPAIRED - considerable supervision is required for safety. 
Needs considerable supervision to prevent hurting others or self (e.g., frequently violent, repeated 
suicide attempts OR to maintain personal hygiene) OR gross impairment in all forms of 
communication (e.g., severe abnormalities in verbal and gestural communication, marked social 
aloofness, stupor, etc.).  
10-1  EXTREMELY IMPAIRED - constant supervision is required for safety. 
Needs constant supervision (24-hour care) due to severely aggressive or self-destructive behaviour or 
gross impairment in reality testing, communication, cognition, affect, or personal hygiene. 
 
 


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Appendix 4:  Strength and Difficulties Questionnaires  
This is to be completed by the site coordinator/Investigator with the parent/caregiver’s input.   
Age 2 – 4  
Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 2 – 4 
Was the Strengths and Difficulties Questionnaire performed? 
○ 
Yes 
○ 
No 
Age range 
○ 
Age 2 - 4 years (use if 4 years) 
Date of birth 
 
Gender 
○ 
Male 
○ 
Female 
Questionnaire completed by 
○ 
Mother  
○ 
Father  
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Date of assessment 
 
 
Considerate of other people's feelings 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Restless, overactive, cannot stay still for long 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often complains of headaches, stomach-aches or sickness 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Shares readily with other children, for example toys, treats, pencils 
○ 
Not true 
○ 
Somewhat true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 2 – 4 
○ 
Certainly true 
Often loses temper 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Rather solitary, prefers to play alone 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Generally well behaved, usually does what adults request 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Many worries or often seems worried 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Helpful if someone is hurt, upset or feeling ill 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Constantly fidgeting or squirming 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Has at least one good friend 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often fights with other children or bullies them 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often unhappy, depressed or tearful 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 2 – 4 
Generally liked by other children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Easily distracted, concentration wanders 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Nervous or clingy in new situations, easily loses confidence 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Kind to younger children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often argumentative with adults 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Picked on or bullied by other children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often offers to help others (parents, teachers, other children) 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Can stop and think things out before acting 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Can be spiteful to others 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Gets along better with adults than with other children 
○ 
Not true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 2 – 4 
○ 
Somewhat true 
○ 
Certainly true 
Many fears, easily scared 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Good attention span, sees tasks through to the end 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Total difficulties score (calculated) 
 
 
Do you have any other comments or concerns? 
○ 
Yes 
○ 
No 
If yes, please provide details: 
 
 
 
Overall, do you think that that your child has difficulties in one or 
more of the following areas: emotions, concentration, behavior or 
being able to get on with other people? 
○ 
No 
○ 
Yes – minor difficulties  
○ 
Yes – definite difficulties  
○ 
Yes – severe difficulties  
If you have answered yes, please answer the following questions 
about these difficulties: 
 
How long have these difficulties been present? 
○ 
Less than 1 month  
○ 
1-5 months 
○ 
6-12 months   
○ 
Over a year  
Do the difficulties upset or distress your child? 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Do the difficulties interfere with your child's everyday life in the  


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 2 – 4 
following areas? 
Home life 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Friendships 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Learning 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Leisure activities 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Do the difficulties put a burden on you or the family as a whole? 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Impact score (calculated) 
 
© Robert Goodman, 2005 
 
 


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Age 4 – 10  
Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 4 - 10 
Was the Strengths and Difficulties Questionnaire performed? 
○ 
Yes 
○ 
No 
Age range 
○ 
Age 4 - 10 years  
Date of birth 
 
Gender 
○ 
Male 
○ 
Female 
Questionnaire completed by 
○ 
Mother  
○ 
Father  
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Date of assessment 
 
 
Considerate of other people's feelings 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Restless, overactive, cannot stay still for long 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often complains of headaches, stomach-aches or sickness 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Shares readily with other children, for example toys, treats, pencils 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often loses temper 
○ 
Not true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 4 - 10 
○ 
Somewhat true 
○ 
Certainly true 
Rather solitary, prefers to play alone 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Generally well behaved, usually does what adults request 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Many worries or often seems worried 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Helpful if someone is hurt, upset or feeling ill 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Constantly fidgeting or squirming 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Has at least one good friend 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often fights with other children or bullies them 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often unhappy, depressed or tearful 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Generally liked by other children 
○ 
Not true 
○ 
Somewhat true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 4 - 10 
○ 
Certainly true 
Easily distracted, concentration wanders 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Nervous or clingy in new situations, easily loses confidence 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Kind to younger children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often lies or cheats 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Picked on or bullied by other children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often offers to help others (parents, teachers, other children) 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Thinks things out before acting 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Steals from home, school or elsewhere 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Gets along better with adults than with other children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 4 - 10 
Many fears, easily scared 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Good attention span, sees chores or homework through to the end 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Total difficulties score (calculated) 
 
 
Do you have any other comments or concerns? 
○ 
Yes 
○ 
No 
If yes, please provide details: 
 
 
 
Overall, do you think that that your child has difficulties in one or 
more of the following areas: emotions, concentration, behavior 
or being able to get on with other people? 
○ 
No 
○ 
Yes – minor difficulties  
○ 
Yes – definite difficulties  
○ 
Yes – severe difficulties 
If you have answered yes, please answer the following questions 
about these difficulties: 
 
How long have these difficulties been present? 
○ 
Less than 1 month  
○ 
1-5 months 
○ 
6-12 months   
○ 
Over a year  
Do the difficulties upset or distress your child? 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Do the difficulties interfere with your child's everyday life in the 
following areas? 
 
Home life 
○ 
Not at all  
○ 
Only a little  


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Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 4 - 10 
○ 
Quite a lot  
○ 
A great deal 
Friendships 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Classroom learning 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Leisure activities 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Do the difficulties put a burden on you or the family as a whole? 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Impact score (calculated) 
 
© Robert Goodman, 2005 
 
 


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Age 11 – 17  
Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 11 - 17 
Was the Strengths and Difficulties Questionnaire performed? 
○ 
Yes 
○ 
No 
Age range 
○ 
Age 11 - 17 years 
Date of birth 
 
Gender 
○ 
Male 
○ 
Female 
Questionnaire completed by 
○ 
Mother  
○ 
Father  
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Date of assessment 
 
 
Considerate of other people's feelings 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Restless, overactive, cannot stay still for long 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often complains of headaches, stomach-aches or sickness 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Shares readily with other youth, for example CD's, games, food 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often loses temper 
○ 
Not true 


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Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 11 - 17 
○ 
Somewhat true 
○ 
Certainly true 
Would rather be alone than with other youth 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Generally well behaved, usually does what adults request 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Many worries or often seems worried 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Helpful if someone is hurt, upset or feeling ill 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Constantly fidgeting or squirming 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Has at least one good friend 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often fights with other children or bullies them 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often unhappy, depressed or tearful 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Generally liked by other youth 
○ 
Not true 
○ 
Somewhat true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 11 - 17 
○ 
Certainly true 
Easily distracted, concentration wanders 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Nervous in new situations, easily loses confidence 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Kind to younger children 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often lies or cheats 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Picked on or bullied by other youth 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Often offers to help others (parents, teachers, other children) 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Thinks things out before acting 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Steals from home, school or elsewhere 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Gets along better with adults than with other youth 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 11 - 17 
Many fears, easily scared 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Good attention span, sees chores or homework through to the end 
○ 
Not true 
○ 
Somewhat true 
○ 
Certainly true 
Total difficulties score (calculated) 
 
 
Do you have any other comments or concerns? 
○ 
Yes 
○ 
No 
If yes, please provide details: 
 
 
 
Overall, do you think that that your child has difficulties in one or 
more of the following areas: emotions, concentration, behavior 
or being able to get on with other people? 
○ 
No 
○ 
Yes – minor difficulties  
○ 
Yes – definite difficulties  
○ 
Yes – severe difficulties 
If you have answered yes, please answer the following questions 
about these difficulties: 
 
How long have these difficulties been present? 
○ 
Less than 1 month  
○ 
1-5 months 
○ 
6-12 months   
○ 
Over a year  
Do the difficulties upset or distress your child? 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Do the difficulties interfere with your child's everyday life in the 
following areas? 
 
Home life 
○ 
Not at all  
○ 
Only a little  


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Site: 
Subject number:  
Visit number:  
NEU_CH_7911 - Strength and Difficulties Questionnaire – Blank 
CRF - Age 11 - 17 
○ 
Quite a lot  
○ 
A great deal 
Friendships 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Classroom learning 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Leisure activities 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Do the difficulties put a burden on you or the family as a whole? 
○ 
Not at all  
○ 
Only a little  
○ 
Quite a lot  
○ 
A great deal 
Impact score (calculated) 
 
© Robert Goodman, 2005 
 
 
 


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Appendix 5:  Treatment Emergent Signs and Symptoms  
This is to be completed by Investigator with the parent/caregiver’s input.   
Site: 
Subject number:  
NEU_CH_7911 - Treatment Emergent Signs and 
Symptoms (TESS) 
Was a Treatment Emergent Signs and Symptoms assessment 
performed? 
○ 
Yes 
○ 
No 
Date of assessment 
 
Select a response for the symptoms and sensations: 
If a score of 1 or above is selected please record a corresponding Adverse Event (only if this is a new symptom or if there is an increase in 
severity of an existing symptom from the first visit) 
1. Somnolence 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
2. Fatigue 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
3. Increased excitability/activity 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
4. Dizziness 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
5. Hangover feelings 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
6. Mood swings 
○ 
0 - No Symptoms 


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Subject number:  
NEU_CH_7911 - Treatment Emergent Signs and 
Symptoms (TESS) 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
7. Tremor 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
8. Seizures 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
9. Headache 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
10. Nausea and/or vomiting 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
11. Rash 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
12. Hypothermia 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
13. Coughing / breathlessness 
○ 
0 - No Symptoms 
○ 
1 - Mild 


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Site: 
Subject number:  
NEU_CH_7911 - Treatment Emergent Signs and 
Symptoms (TESS) 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
14. Other adverse effects not listed 
○ 
Yes 
○ 
No 
Please specify other adverse effects below: 
Adverse effect 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
Response 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
Please specify other adverse effects below: 
Adverse effect 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
Response 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
Please specify other adverse effects below: 
Adverse effect 
○ 
0 - No Symptoms 
○ 
1 - Mild 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
Response 
○ 
0 - No Symptoms 
○ 
1 - Mild 


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Site: 
Subject number:  
NEU_CH_7911 - Treatment Emergent Signs and 
Symptoms (TESS) 
○ 
2 - Moderate 
○ 
3 – Severe 
○ 
Not Done 
Final version: 2014-06-19 (1.000.004.000)  
CONFIDENTIAL  
Neurim Pharmaceuticals Ltd. 
 
 


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Appendix 6:  Composite Sleep Disturbance Index  
This is to be completed by the site coordinator/Investigator with the parent/caregiver’s input.    
Site: 
Subject number:  
NEU_CH_7911 - Composite Sleep Disturbance Index 
(CSDI) 
Was a Composite Sleep Disturbance questionnaire assessment 
performed? 
○ 
Yes 
○ 
No 
Date of assessment 
 
Questionnaire completed by 
○ 
Mother 
○ 
Father 
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Child's sleep habits since last month or visit 
 
How often does your child have problems settling at bed time? 
○ 
Less than once a week 
○ 
1 or 2 nights a week 
○ 
3 or more nights a week 
How long does it take them to settle to sleep? 
○ 
Few minutes 
○ 
Up to 30 minutes 
○ 
More than 30 minutes 
How often does your child wake in the night? 
○ 
Less than once a week 
○ 
1 or 2 nights a week 
○ 
3 or more nights a week 
How long does it usually take to resettle him/her? 
○ 
Few minutes 
○ 
Up to 30 minutes 
○ 
More than 30 minutes 
How often does your child wake before 5am in the morning and 
remain awake? 
○ 
Less than once a week 
○ 
1 or 2 nights a week 
○ 
3 or more nights a week 


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Site: 
Subject number:  
NEU_CH_7911 - Composite Sleep Disturbance Index 
(CSDI) 
How often does your child insist on sleeping with someone else for 
most/all of the night? 
○ 
Less than once a week 
○ 
1 or 2 nights a week 
○ 
3 or more nights a week 
How satisfied are you with your child's current sleep pattern? 
○Completely satisfied 
○Mostly satisfied, although some aspects still cause problems 
○Neither satisfied nor dissatisfied 
○Mostly dissatisfied, although some aspects are OK 
○Completely dissatisfied 
Total sleep problem subscale score (calculated) 
 
Final version: 2014-03-07 (1.000.002.000) 
CONFIDENTIAL  
Neurim Pharmaceuticals Ltd. 
 
 


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Appendix 7:  Epworth Sleepiness Scale  
This is to be completed by the site coordinator/Investigator with the parent/caregiver’s input.  Note:  
The ESS is to assess sleepiness of the parent/caregiver and NOT the child.  
Site: 
Subject number:  
NEU_CH_7911 - Epworth Sleepiness Scale (ESS) 
Was the Epworth Sleepiness Scale questionnaire completed? 
○ 
Yes 
○ 
No 
Date of assessment 
 
Questionnaire completed by 
○ 
Mother 
○ 
Father 
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Likelihood of dozing or falling asleep: 
 
Sitting and reading 
○ 
Would never doze 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
Watching TV 
○ 
Would never doze 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
Sitting, inactive in a public place (e.g., a theatre or a meeting) 
○ 
Would never doze 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
As a passenger in a car for an hour without a break 
○ 
Would never doze 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
Lying down to rest in the afternoon when circumstances permit 
○ 
Would never doze 


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Site: 
Subject number:  
NEU_CH_7911 - Epworth Sleepiness Scale (ESS) 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
Sitting and talking to someone 
○ 
Would never doze 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
Sitting quietly after a lunch without alcohol 
○ 
Would never doze 
○ 
Slight chance of dozing 
○ 
Moderate chance of dozing 
○ 
High chance of dozing 
In a car, while stopped for a few minutes in the traffic 
 
Total (calculated) 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5 (PubMed 
abstract). ESS © MW Johns 1990-1997. Used under license. ESS contact information and permission to use: MAPI Research Trust, Lyon, 
France. E-mail: PROinformation@mapi-trust.org  – Internet: www.mapi-trust.org. 
 
 
 


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Appendix 8:  Pittsburgh Sleep Quality Index  
This is to be completed by the site coordinator/Investigator with the parent/caregiver’s input.  Note:  
The PSQI is to assess the well-being of the parent/caregiver and NOT the child.   
Site: 
Subject number:  
NEU_CH_7911 - Pittsburgh Sleep Quality Index (PSQI)  
Was the Pittsburgh Sleep Quality Index questionnaire completed? 
○ 
Yes 
○ 
No 
Date of assessment 
 
Time of questionnaire 
 
Questionnaire completed by 
○ 
Mother 
○ 
Father 
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
1. During the past two weeks, what time have you usually gone to 
bed at night? 
 
2. During the past two weeks, how long (in minutes) has it usually 
taken you to fall asleep each night? 
 
3. During the past two weeks, what time have you usually gotten up 
in the morning? 
 
4. During the past two weeks, how many hours of actual sleep did 
you get at night? (This may be different than the number of hours 
you spent in bed) 
 
5. During the past two weeks how often have you had trouble 
sleeping because you… 
 
a. cannot get to sleep within 30 minutes 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
b. wake up in the middle of the night or early morning 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 


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Subject number:  
NEU_CH_7911 - Pittsburgh Sleep Quality Index (PSQI)  
c. have to get up to use the bathroom 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
d. cannot breath comfortably 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
e. cough or snore loudly 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
f. feel too cold 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
g. feel too hot 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
h. had bad dreams 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
i. have pain 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
j. other reason(s), please describe 
 
k. how often during the past two weeks have you have had trouble 
sleeping because of this? 
○ 
Not during the past two weeks 


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Subject number:  
NEU_CH_7911 - Pittsburgh Sleep Quality Index (PSQI)  
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
6. During the past two weeks, how would you rate your sleep quality 
overall? 
○ 
Very good 
○ 
Fairly good 
○ 
Fairly bad 
○ 
Very bad 
7. During the past two weeks, how often have you taken medicine to 
help you sleep (prescribed or "over the counter")? 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
8. During the past two weeks, how often have you had trouble 
staying awake while driving eating meals, or engaging in social 
activity? 
○ 
Not during the past two weeks 
○ 
Less than once a week 
○ 
Once or twice a week 
○ 
Three or more times a week 
9. During the past two weeks, how much of a problem has it been for 
you to keep up enough enthusiasm to get things done? 
○ 
No problem at all 
○ 
Only a very slight problem 
○ 
Somewhat of a problem 
○ 
A very big problem 
Scoring 
 
Component 1 Score (calculated) 
 
Component 2 Score (calculated) 
 
Component 3 Score (calculated) 
 
Component 4 Score (calculated) 
 
Component 5 Score (calculated) 
 
Component 6 Score (calculated) 
 
Component 7 Score (calculated) 
 
Global PSQI Score (calculated) 
 
Final version: 2014-03-07 (1.000.002.000) 
CONFIDENTIAL  
Neurim Pharmaceuticals Ltd. 
 


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Appendix 9:  WHO-5 Well-being Index  
This is to be completed by the site coordinator/Investigator with the parent/caregiver’s input.  Note:  
The WHO-5 is to assess the quality of sleep of the parent/caregiver and NOT the child. 
Site: 
Subject number:  
NEU_CH_7911 - WH0-5 Well-being Index 
Was the WH0-5 Wellbeing Index questionnaire completed 
○ 
Yes 
○ 
No 
Date of assessment 
 
Questionnaire completed by 
○ 
Mother 
○ 
Father 
○ 
Guardian 
○ 
Caregiver 
○ 
Other 
If completed by other, please specify 
 
Over the last two weeks 
 
1.  I have felt cheerful and in good spirits 
○ 
All of the time 
○ 
Most of the time 
○ 
More than half of the time  
○ 
Less than half of the time  
○ 
Some of the time 
○ 
At no time 
2.  I have felt calm and relaxed 
○ 
All of the time 
○ 
Most of the time 
○ 
More than half of the time  
○ 
Less than half of the time  
○ 
Some of the time 
○ 
At no time 


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Version 6.0  
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Site: 
Subject number:  
NEU_CH_7911 - WH0-5 Well-being Index 
3.  I have felt active and vigorous 
○ 
All of the time 
○ 
Most of the time 
○ 
More than half of the time  
○ 
Less than half of the time  
○ 
Some of the time 
○ 
At no time 
4.  I woke up feeling fresh and rested 
○ 
All of the time 
○ 
Most of the time 
○ 
More than half of the time  
○ 
Less than half of the time  
○ 
Some of the time 
○ 
At no time 
5.  My daily life has been filled with things that interest me 
○ 
All of the time 
○ 
Most of the time 
○ 
More than half of the time  
○ 
Less than half of the time  
○ 
Some of the time 
○ 
At no time 
Total Score (calculated) 
 
 
 
Scoring the WHO-5 Well-being Index: 
 
The raw score is calculated by totalling the figures of the five 
answers. 
 
All of the time = 5 
 
Most of the time = 4 
 
More than half of the time = 3 
 
Less than half of the time = 2 
 
Some of the time = 1 
 
At no time = 0 
 
 
 


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Appendix 10:  Epilepsy Seizures Diary 
This is to be completed only by the patient’s parent/caregiver after each seizure. 
Site: 
Subject number:  
NEU_CH_7911 - Epileptic Seizure Diary  
Did the child have any seizures since the last visit? 
○ 
Yes 
○ 
No 
If yes, please provide details for all seizures 
Date of seizure 
 
Day or Night 
○ 
Day 
○ 
Night 
Duration of seizure (minutes) 
 
Seizure type 
○ 
G1 - absence seizure 
○ 
G2 - myoclonic seizure 
○ 
G3 - atonic seizure 
○ 
G4 - tonic seizure 
○ 
G5 - clonic seizure 
○ 
G6 - tonic-clonic convulsion 
○ 
G7 - other with unconsciousness 
○ 
F1 - aura 
○ 
F2 - other with consciousness retained 
Was emergency medication given? 
○ 
Yes 
○ 
No 
If yes, please provide details for all seizures 
Date of seizure 
 
Day or Night 
○ 
Day 
○ 
Night 
Duration of seizure (minutes) 
 
Seizure type 
○ 
G1 - absence seizure 
○ 
G2 - myoclonic seizure 
○ 
G3 - atonic seizure 
○ 
G4 - tonic seizure 
○ 
G5 - clonic seizure 


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Site: 
Subject number:  
NEU_CH_7911 - Epileptic Seizure Diary  
○ 
G6 - tonic-clonic convulsion 
○ 
G7 - other with unconsciousness 
○ 
F1 - aura 
○ 
F2 - other with consciousness retained 
Was emergency medication given? 
○ 
Yes 
○ 
No 
If yes, please provide details for all seizures 
 
Date of seizure 
 
Day or Night 
○ 
Day 
○ 
Night 
Duration of seizure (minutes) 
 
Seizure type 
○ 
G1 - absence seizure 
○ 
G2 - myoclonic seizure 
○ 
G3 - atonic seizure 
○ 
G4 - tonic seizure 
○ 
G5 - clonic seizure 
○ 
G6 - tonic-clonic convulsion 
○ 
G7 - other with unconsciousness 
○ 
F1 - aura 
○ 
F2 - other with consciousness retained 
Was emergency medication given? 
○ 
Yes 
○ 
No 
Final version: 2014-03-07 (1.000.002.000) 
CONFIDENTIAL  
Neurim Pharmaceuticals Ltd. 
 
 


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Appendix 11:  Prohibited Medication List  
Active compound Trade name 
Class 
Reason for Exclusion 
Agomelatine 
Valdoxan 
Melitor 
Thymanax 
Melatonin agonist 
Major depressive disorder 
Ramelteon 
Rozerem 
Melatonin agonist 
Anxiolytic,myorelaxant, 
and amnesic 
Zopiclone 
Imovane 
Zopiclone 
Nocturno 
Nocturno S.L. 
Z-Drugs 
Hypnotic 
Zaleplon 
Sonata 
Starnoc 
Z-Drugs 
Sedative/hypnotic 
Zolpidem 
Zodorm 
Stilnox 
Z-Drugs 
Hypnotic 
Eszopiclone 
Lunesta 
Z-Drugs 
Sedative/hypnotic 
Brotizolam 
Bondormin 
Brotizolam 
Benzodiazepine 
Hypnotic 
Clonazepam* 
Clonex 
Rivotril 
Klonopin 
Benzodiazepine 
Hypnotic 
Diazepam 
Assival 
Diaz Valium 
Stesolid 
Benzodiazepine 
Hypnotic 
Flunitrazepam 
Hypnodorm 
Benzodiazepine 
Hypnotic 
Lorazepam 
Lorivan 
Ativan 
Benzodiazepine 
Hypnotic 
Lormetazepam 
Loramet 
Noctamid 
Benzodiazepine 
Sedative/hypnotic 
Nitrazepam 
Numbon 
Benzodiazepine 
Sedative 
Oxazepam 
Vaben 
Alepam 
Medopam 
Alopam Sobril 
Oxascand 
Benzodiazepine 
Sedative/hypnotic 
Midazolam 
Dormicum 
Hypnovel 
Versed 
Benzodiazepine 
Hypnotic 
Trialzolam 
Trialzolam 
Benzodiazepine 
Hypnotic 
Temazepam 
Restoril 
Normison 
Benzodiazepine 
Hypnotic 
Oxazepam 
Vaben 
Benzodiazepine 
Hypnotic 
Loprazolam 
Dormonoct 
Havlane Sonin 
Somnovit 
Benzodiazepine 
derivative 
Sedative 
Estazolam 
ProSom 
Eurodin 
Benzodiazepine 
derivative 
Sedative 
Triprolidine 
hydrochloride 
Anti-histamine 
Sedative/hypnotic 
Diphenhydramine 
hydrochloride 
Anti-histamine 
Sedative/hypnotic 
Chlorpheniramine 
maleate 
Anti-histamine 
Sedative/hypnotic 


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Dexchlorpheniramine 
maleate 
Anti-histamine 
Sedative/hypnotic 
Diphenhydramine 
Anti-histamine 
Sedative 
Promethazine 
Phenergan 
Promethegan 
Romergan 
Farganesse 
Lergigan 
Anti-histamine 
Sedative 
Doxylamine 
Unisom 
Anti-histamine 
Sedative 
Niaprazine 
Nopron 
Phenylpiperazine class 
Sedative/hypnotic 
Clomethiazole 
Thiamine- vitamin B1 like 
Sedative/hypnotic 
Phenobarbital 
Phenobarbital 
Phenobarbitone 
Philinet 
Philinal 
Pacetal 
Barbiturate 
Sedative 
Chloral hydrate 
Sedative/hypnotic 
Triclofos 
Sedative 
Alimemazine  
Nedeltran, Panectyl, 
Repeltin, Therafene, 
Theraligene, Theralen, 
Theralene, Vallergan, 
Vanectyl, and Temaril  
Antipruritic   
Sedative/hypnotic 
Valerian 
 
Herbal 
Fluvoxamine 
Luvox 
Antidepressant 
Interact with endogenous 
melatonin  and increases 
melatonin levels by inhibiting 
its metabolism 
* If a child receives a single dose of Clonazepam to treat seizures he should not be withdrawn from the study but a 
deviation should be recorded.  

SAP_003.pdf: 
 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 1 of 61 
 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Neurim Pharmaceuticals Ltd 
27 Habarzel St, Tel-Aviv 69710, Israel 
 
Investigational Product: Circadin® 
Protocol: NEU_CH_7911 
Phase: III 
 
A Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of Circadin® to Alleviate 
Sleep Disturbances in Children with Neurodevelopmental Disabilities 
 
Version: Final 3.0 
Date: 10OCT2016 
 
 


 
Protocol NEU_CH_7911/ P0315 
 
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Statistical Analysis Plan 
 
10OCT2016 
 
Page 2 of 61 
 
CONFIDENTIAL 
APPROVAL SIGNATURES 
Protocol: NEU_CH_7911 
Protocol Title: A Randomized, Placebo-controlled Study to Investigate the Efficacy and Safety of Circadin® 
to Alleviate Sleep Disturbances in Children with Neurodevelopmental Disabilities 
Author: 
Signature 
 
Date 
 
Barbara Collins 
Senior Statistician 
Datatrial Reviewer: 
Signature 
 
Date 
 
John Breddy 
Consultant Statistician 
Sponsor Reviewer: 
Signature 
 
Date 
 
Dr. Tali Nir 
VP Clinical and Regulatory Affairs, Neurim Pharmaceuticals 
Sponsor Reviewer: 
Signature 
 
Date 
 
Prof. Nava Zisapel 
CSO, Neurim Pharmaceuticals 
 


 
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Statistical Analysis Plan 
 
10OCT2016 
 
Page 3 of 61 
 
CONFIDENTIAL 
Contents 
1 
Version Control .......................................................................................................................................... 7 
2 
Study Rationale .......................................................................................................................................... 7 
3 
Objectives .................................................................................................................................................. 8 
3.1 
Primary Objective .............................................................................................................................. 8 
3.2 
Secondary Objectives ........................................................................................................................ 8 
3.3 
Exploratory Objective ........................................................................................................................ 9 
4 
Endpoints ................................................................................................................................................. 10 
4.1 
Primary Endpoint ............................................................................................................................. 10 
4.2 
Secondary Endpoints ....................................................................................................................... 10 
4.3 
Exploratory Endpoints ..................................................................................................................... 11 
5 
Study Design ............................................................................................................................................ 12 
6 
Statistical Considerations ........................................................................................................................ 13 
6.1 
Sample Size ...................................................................................................................................... 13 
6.2 
Randomization ................................................................................................................................. 13 
7 
Protocol Deviations ................................................................................................................................. 13 
8 
Analysis Populations ................................................................................................................................ 14 
8.1 
All Enrolled Set................................................................................................................................. 14 
8.2 
All Randomized Set .......................................................................................................................... 14 
8.3 
Safety Set ......................................................................................................................................... 14 
8.4 
Full Analysis Set ............................................................................................................................... 14 
8.5 
Per Protocol Set ............................................................................................................................... 14 
9 
Data Reporting Conventions ................................................................................................................... 15 
9.1 
Descriptive Statistics ........................................................................................................................ 15 
9.2 
Reporting of Phases ......................................................................................................................... 15 
9.3 
Baseline Derivation .......................................................................................................................... 15 
9.4 
Missing Dates ................................................................................................................................... 15 
10 Subject Disposition, and Demographic and Baseline Characteristics ..................................................... 16 
10.1 
Subject Disposition .......................................................................................................................... 16 
10.2 
Demographic and Baseline Characteristics ..................................................................................... 16 
10.3 
Neurodevelopmental Disability ....................................................................................................... 17 
10.4 
Melatonin Use ................................................................................................................................. 17 


 
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10.5 
Medical History ................................................................................................................................ 17 
10.6 
Prior and Concomitant Medications................................................................................................ 17 
11 Efficacy ..................................................................................................................................................... 18 
11.1 
Primary Efficacy Variable ................................................................................................................. 18 
11.1.1 
Total Sleep Time (TST) ............................................................................................................. 18 
11.2 
Secondary Efficacy Variables ........................................................................................................... 19 
11.2.1 
Sleep and Nap Diary ................................................................................................................ 19 
11.2.1.1 Sleep Latency ........................................................................................................................... 19 
11.2.1.2 Duration of Wake .................................................................................................................... 20 
11.2.1.3 Number of Awakenings ........................................................................................................... 20 
11.2.1.4 Longest Sleep Period ............................................................................................................... 20 
11.2.1.5 Total Time in Bed ..................................................................................................................... 20 
11.2.2 
CSDI .......................................................................................................................................... 20 
11.2.3 
CGAS ........................................................................................................................................ 21 
11.2.4 
SDQ .......................................................................................................................................... 21 
11.2.5 
Number of Dropouts................................................................................................................ 21 
11.2.6 
Actigraphy ................................................................................................................................ 21 
11.3 
Exploratory Efficacy Variables ......................................................................................................... 22 
11.3.1 
Sleep and Nap Diary by Visit .................................................................................................... 22 
11.3.2 
Sleep Disturbance by Visit ....................................................................................................... 23 
11.3.3 
CGAS by Visit ............................................................................................................................ 23 
11.3.4 
SDQ by Visit ............................................................................................................................. 23 
11.3.5 
ESS ........................................................................................................................................... 23 
11.3.6 
PSQI.......................................................................................................................................... 23 
11.3.7 
WHO-5 Well-being Index ......................................................................................................... 23 
11.3.8 
Actigraphy by Visit ................................................................................................................... 23 
11.4 
Other Efficacy Variables .................................................................................................................. 23 
11.4.1.1 Quality of Sleep........................................................................................................................ 23 
11.4.1.2 Current Alertness ..................................................................................................................... 24 
11.4.1.3 Feeling on Awakening .............................................................................................................. 24 
11.4.1.4 Number of Naps....................................................................................................................... 24 
11.4.1.5 Duration of Naps...................................................................................................................... 24 


 
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11.4.2 
CSDI .......................................................................................................................................... 24 
11.5 
Missing Efficacy Data ....................................................................................................................... 25 
11.5.1 
Multiple Imputation ................................................................................................................ 25 
11.5.2 
Baseline Observation Carried Forward .................................................................................... 27 
11.6 
Subgroup Analysis............................................................................................................................ 27 
11.6.1 
Inclusion of Additional Factors in MMRM Analysis ................................................................. 27 
11.6.2 
SND Summaries by Final Dose ................................................................................................. 28 
11.7 
Agreement between Sleep and Nap Diary and Actigraphy ............................................................. 28 
11.8 
Correlation between Sleep and Nap Diary and Actigraphy versus Daytime Endpoints .................. 29 
12 Safety ....................................................................................................................................................... 29 
12.1 
Treatment Exposure ........................................................................................................................ 30 
12.2 
Treatment Emergent Signs and Symptoms ..................................................................................... 30 
12.3 
Adverse Events ................................................................................................................................ 30 
12.4 
Vital Signs......................................................................................................................................... 31 
12.5 
BMI and Z-scores ............................................................................................................................. 31 
12.6 
Tanner Assessment of Pubertal Development ................................................................................ 32 
12.7 
Epilepsy ............................................................................................................................................ 33 
12.8 
Other Data ....................................................................................................................................... 33 
12.8.1 
Pregnancy Test ........................................................................................................................ 33 
12.8.2 
Physical Examination ............................................................................................................... 33 
12.8.3 
Visit Dates ................................................................................................................................ 33 
13 Interim Analysis ....................................................................................................................................... 33 
14 Changes to Planned Methodology .......................................................................................................... 34 
15 References ............................................................................................................................................... 34 
16 Tables, Figures and Listings ..................................................................................................................... 34 
16.1 
List of Tables .................................................................................................................................... 35 
16.2 
List of Figures ................................................................................................................................... 46 
16.3 
List of Listings................................................................................................................................... 48 
Appendices ...................................................................................................................................................... 50 
Appendix A - SAS Program to generate SDQ Scores .................................................................................... 50 
Appendix B – SAS Program to generate BMI percentiles and Z scores ....................................................... 58 
 


 
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Abbreviations 
Abbreviation 
Meaning 
AE 
adverse events 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
CGAS 
Children Global Assessment Scale 
CI 
Confidence Interval 
CSDI 
Composite Sleep Disturbance Index 
CSR 
clinical study report 
eCRF 
electronic case report form 
ESS 
Epworth Sleepiness Scale 
FAS 
Full Analysis Set 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effect repeated measures model 
PP 
Per Protocol 
PSQI 
Pittsburgh Sleep Quality Index 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SB 
single blind 
SD 
standard deviation 
SDQ 
Strength and Difficulties Questionnaire 
SND 
Sleep and Nap Diary (Sleep Log) 
TESS 
Treatment-Emergent Signs and Symptoms Questionnaire 
TST 
total sleep time 
WHO 
World Health Organization 
WHO-5 
World Health Organization Well-Being Index 
 
 


 
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CONFIDENTIAL 
1 
Version Control 
This Statistical Analysis Plan (SAP) is based on the protocol version 6.0 Amendment 5 dated 19th May 2015 
and case report form, (CRF) dated 18th March 2015. 
All results will be summarized at the end of the first open-label period (Week 28; Visit 5), and will be 
submitted in the form of a clinical study report (CSR) to the regulatory authorities for evaluation of approval 
of the study drug for use in the investigated population. This will constitute the final analysis of data up to 
that point and no statistical adjustment of significance tests is required. 
The data from the second open-label period will be summarized on the completion of the study and reported 
as an appendix to the CSR. 
2 
Study Rationale 
Prolonged release melatonin (PRM) may be the response to the unmet need in the field of insomnia in the 
paediatric population and, specifically, in children with neurodevelopmental disorders, as currently there is 
no approved drug that is proven to be both effective and safe for this population and thus there is no 
approved drug indicated for insomnia in the paediatric population.  
The optimal profile of a hypnotic is:  
(a) high oral bioavailability;  
(b) short elimination half-life;  
(c) rapid onset of action;  
(d) once-nightly dosing;  
(e) low risk for dependence, abuse, tolerance, withdrawal, and rebound, without daytime residual 
effects.  
These agents should also carry favourable side-effect profiles, and show no significant reductions in REM and 
NREM sleep stages and SWS.  
PRM fulfils all these pharmacokinetic and pharmacodynamic properties. Importantly, PRM has been found 
to be effective in primary insomnia patients >55 with no impairment of morning alertness and memory, lack 
of withdrawal and rebound effects and no tolerance in primary insomnia patients aged 18-80 in the long-
term.  In particular, PRM 4-6 mg demonstrated a safe and effective therapy in the long-term for the treatment 
of sleep disorders in children with neurodevelopmental disorders.  
In a recent publication it was found that children with autism that suffer from sleep disturbances, have 
decreased melatonin levels as compared to age match controls, as indicated by urine levels of the primary 
melatonin metabolite, 6-sulfatoxymelatonin (6-SMT). The relationship between 6-SMT levels and sleep 
architecture in children with ASD was investigated. Some publications indicate  that higher urinary 6-SMT 
excretion rates were associated with increased N3 sleep, decreased N2 sleep, and decreased daytime 
sleepiness. Indeed, another therapeutic benefit of PRM, although not tested in paediatric population is its 
lack of effect on sleep architecture and improved morning alertness and vigilance. This is opposed to other 
sleep medication like benzodiazepines or benzodiazepine-like drugs that are known to affect sleep 
architecture specifically by reducing SWS and REM. Indeed a recent study comparing PRM, temazepam and 
zolpidem, demonstrated that the effects of PRM on the nocturnal sleep EEG (NREM and REM sleep) were 


 
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CONFIDENTIAL 
minor and were different from those of temazepam and zolpidem; this is likely due to the different 
mechanisms of action of the medications [Arbon 2015]. 
In addition to this favourable profile of PRM meeting the desired hypnotic profile, using PRM also addresses 
the physiological background of insomnia in children with neurodevelopmental disorders and not only the 
symptom.  In children with neurodevelopmental disorders specifically ASD and SMS there may be low 
endogenous melatonin secretion caused by inadequate regulation and metabolism of melatonin, 
contributing to impairment in both the initiation of sleep and sleep maintenance. Hence, melatonin 
substitution therapy is proposed to be effective for insomnia in children with impaired endogenous 
melatonin levels. 
Details of references may be found in the Protocol. 
3 
Objectives 
To compare and evaluate safety, tolerability and efficacy of Circadin® 2/5 mg (prolonged release mini-tablet 
age appropriate oral solid dosage form) to that of placebo after 13 weeks of double blind treatment period 
as detailed below: 
3.1 Primary Objective 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on total sleep time (TST) as 
assessed by the Sleep and Nap Diary after 13 weeks of double-blind treatment. 
3.2 Secondary Objectives 
The secondary objectives of the study are: 
 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep latency as derived 
from a Sleep and Nap Diary after 13 weeks of double-blind treatment 
 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on the duration of wake after 
sleep onset period as derived from a Sleep and Nap Diary after 13 weeks of double-blind treatment 
 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on number of awakenings 
as derived from a Sleep and Nap Diary after 13 weeks of double-blind treatment 
 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on the duration of the longest 
sleep period as derived from a Sleep and Nap Diary after 13 weeks of double-blind treatment 
 
Sub-analysis to evaluate the impact of shortening latency time versus increasing sleep time after 
sleep onset on the primary endpoint  - TST. 
 
To assess the treatment effect of Circadin® 2/5 mg to that of placebo on sleep disturbance as 
assessed by Composite Sleep Disturbance Index (CSDI) after 13 weeks of double-blind treatment 
 
To assess the treatment effect of Circadin® 2/5 mg to that of placebo on children’s social functioning 
at home, in school, and community settings as assessed by the Children Global Assessment Scale 
(CGAS) after 13 weeks of double-blind treatment 


 
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 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on children’s behavior at 
home and in school as assessed by the Strength and Difficulties Questionnaire (SDQ) after 13 weeks 
of double-blind treatment 
 
To compare the number of dropouts between Circadin® 2/5 mg to that of placebo during the 13 
weeks of double-blind treatment 
 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep parameters as 
measured by actigraphy after 13 weeks of double-blind treatment 
 
To compare the safety and tolerability of Circadin® treatment to that of placebo and evaluate the 
safety and tolerability throughout the study including the run-out (withdrawal) period using AE 
eliciting method Treatment Emergent Signs and Symptoms questionnaire (TESS) 
 
To assess vital signs and physical examinations in Circadin® and placebo groups 
 
3.3 Exploratory Objective 
The exploratory objectives of the study are: 
 
To evaluate the effect of Circadin® 2/5 mg on all sleep variables derived from the Sleep and Nap Diary 
after 3 weeks of double-blind treatment (Week 5), and after 13, 26, and 39 weeks of open-label 
treatment (Weeks 28, 41, and 54) as compared to baseline (Week 2) 
 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on sleep disturbance as 
assessed  by CSDI score after 3 weeks of double-blind treatment (Week 5), after 13, 26, 39, and 91 
weeks of open-label treatment (Weeks 28, 41, 54, and 106, respectively), and at the end of study 
visit (Week 108) as compared to baseline (Week 2) 
 
To assess the treatment effect of Circadin® 2/5 mg on children’s social functioning at home, in school, 
and community settings as assessed by the CGAS after 13 weeks (Week 28) of Circadin® open-label 
treatment as compared to baseline (Week 2) 
 
To assess the treatment effect of Circadin® 2/5 mg on children’s behavior at home and in school as 
assessed by the SDQ after 13 weeks (Week 28) of Circadin® open-label treatment as compared to 
baseline (Week 2) 
 
To assess the level of caregiver’s daytime sleepiness (i.e., NOT the child’s sleepiness) during the study 
using the Epworth Sleepiness Scale (ESS) at Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 108 
 
To assess the level of caregiver’s quality of sleep (i.e., NOT the child’s quality of sleep) at night during 
the study using the Pittsburgh Sleep Quality Index (PSQI) at Weeks 0, 2, 5, 15, 28, 41, 54, 106, and 
108 
 
To assess the level of caregiver’s well-being (i.e., NOT the child’s well-being) during the study using 
the World Health Organization Well-Being Index (WHO-5) questionnaire at Weeks 0, 2, 5, 15, 28, 41, 
54, 106, and 108 
 
To determine the proportion of children using a maximum of 2 or 5 mg in the Circadin® and placebo 
groups 


 
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 
To compare the treatment effect of Circadin® 2/5 mg to that of placebo on children’s body mass 
index (BMI) and Z-score after 3 and 13 weeks of double-blind treatment, and to evaluate the effect 
of Circadin® 2/5/10 mg compared to baseline, at the end of the open-label period, and at the end of 
the placebo run-out period 
 
To assess the treatment effect of Circadin® 2/5/10 mg on pubertal status using the Tanner scale in 
children ≥8 years of age. For children ≤5 years of age, only height and head circumference will be 
used to stage children development. Between the age of 5 and 8 the children’s physical development 
will be determined using the BMI (baseline through Week 108) 
 
In children diagnosed with epilepsy, to compare the effect of Circadin® 2/5 mg to that of placebo on 
the number and severity of epilepsy seizures during double-blind treatment and to assess the effect 
of Circadin® 2/5/10 mg during the open-label period using seizure diaries 
4 
Endpoints 
4.1 Primary Endpoint 
 
The primary efficacy parameter is TST time as assessed by a Sleep and Nap Diary after the 13-week, 
double-blind treatment period. 
4.2 Secondary Endpoints 
 
Sleep latency as assessed by a Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
 
Duration of wake after sleep onset period from the Sleep and Nap Diary after 13 weeks (Week 15) of 
double-blind treatment 
 
Number of awakenings from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
 
Longest sleep period from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind 
treatment 
 
Total time in bed from the Sleep and Nap Diary after 13 weeks (Week 15) of double-blind treatment 
 
Sleep disturbance as assessed by CSDI after 13 weeks (Week 15) of double-blind treatment 
 
Social functioning at home, in school, and in community settings as assessed by the CGAS after 13 
weeks (Week 15) of double-blind treatment 
 
Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 15) of double-blind 
treatment 
 
Number of dropouts during the 13-week (Week 15) double-blind treatment period 
 
TST time as assessed by actigraphy after the 13-week, double-blind treatment period. 
 
Sleep latency as assessed by actigraphy after 13 weeks (Week 15) of double-blind treatment 


 
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 
Duration of wake after sleep onset period as assessed by actigraphy after 13 weeks (Week 15) of 
double-blind treatment 
 
Number of awakenings as assessed by actigraphy after 13 weeks (Week 15) of double-blind 
treatment 
 
Longest sleep period as assessed by actigraphy after 13 weeks (Week 15) of double-blind treatment 
 
Sleep efficiency as assessed by actigraphy after 13 weeks (Week 15) of double-blind treatment 
 
Assessment of AEs throughout the study and upon study withdrawal using the TESS 
 
Vital signs at each visit including the placebo run-out (withdrawal) period 
 
Physical examination at each visit including the placebo run-out (withdrawal) period 
4.3 Exploratory Endpoints 
 
Sleep variables as assessed by the Sleep and Nap Diary at baseline (Week 2), after 3 weeks of double 
blind treatment (Week 5), and after 13, 26, and 39 weeks of open-label treatment (Weeks 28, 41, 
and 54) 
 
Sleep disturbance as assessed by the CSDI score at baseline after 3 weeks of double-blind treatment 
(Week 5), after 13, 26, 39, and 91 weeks of open-label treatment (Weeks 28, 41, 54, and 106, 
respectively), and at the end of study visit (Week 108) 
 
Social functioning at home, in school, and in community settings as assessed by the CGAS after 13 
weeks (Week 28) of open-label treatment 
 
Behavior at home and in school as assessed by the SDQ after 13 weeks (Week 28) of open-label 
treatment 
 
Caregiver’s daytime sleepiness (i.e., NOT the child’s) during the study as assessed by the ESS (Weeks 
0, 2, 5, 15, 28, 41, 54, 106 and 108) 
 
Caregiver’s well-being (i.e., NOT the child’s) during the study as assessed by the WHO-5 questionnaire 
(Weeks 0, 2, 5 15, 28, 41, 54, 106 and 108) 
 
Caregiver’s quality of sleep at night (i.e., NOT the child’s) during the study using the PSQI global score 
and components (at Weeks 0, 2, 5, 15, 28, 41, 54, 106 and 108) 
 
Dosage received by visit and maximum dosage received overall 
 
BMI and Z-score assessed during the study 
 
Pubertal assessment using the Tanner scale during the study. The Tanner scale will be used to assess 
and stage physical development in children ≥8 years of age. For children ≤5 years of age, only height 
and head circumference will be used to stage children development. Between the age of 5 and 8, the 
children’s physical development will be determined using BMI. 
 
In children diagnosed with epilepsy, the number and severity of epilepsy seizures assessed during 
the study using seizures diaries completed by the parents at the time of the seizures 


 
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5 
Study Design 
This is a randomized placebo-controlled study in children diagnosed with Autism Spectrum Disorders and 
neurodevelopmental disabilities caused by neurogenetic diseases. Children will have a documented history 
of these disorders, as confirmed or consistent with the International Classification of Diseases (ICD-10) or 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5/4) criteria, having 
International Classification of Sleep Disorders (ICSD) criteria-based sleep disturbances modified to take into 
account the uniqueness of insomnia in the pediatric population at screening. 
The children will undergo 4 weeks of basic sleep hygiene and behavioral intervention, which will serve as a 
wash-out period from any hypnotics; a gradual withdrawal will take place during the first 2 weeks and a 
complete withdrawal of prohibited medications will take place during the last 2 weeks. 
Children who are still found to be eligible for the study after the 4-week, basic sleep hygiene and behavioral 
intervention wash-out period, will continue in a 2-week single blind (SB) placebo run-in period. In order to 
be eligible for the 2-week SB placebo run-in period, the child should not have responded to sleep hygiene 
and behavioral intervention during the first 4 weeks and therefore will not need to continue this therapy 
during the study. Children with a documented history of sleep hygiene and behavioral intervention, who are 
still found eligible, will enter directly into the 2-week SB placebo run-in period. 
Children with a documented history of sleep hygiene and behavioral intervention who are taking prohibited 
medications will not require additional training and will undergo a 2-week wash-out period before Visit 1 
(e.g., Weeks -2 through 0 to wash out melatonin or any other prohibited medications). During these 2 weeks 
there is no need to complete the sleep and nap diary. 
After the 4-week sleep hygiene (for children who do not have a documented history of sleep hygiene and 
behavioral intervention) and 2-week SB placebo run-in period, children who are still found eligible for study 
participation will be randomized in a 1:1 ratio to receive either Circadin® 2 mg or placebo for 3 weeks in a 
double-blind treatment period. After 3 weeks of treatment, on the last day of Week 5 ±3 days (Visit 3), sleep 
variables will be assessed to determine if dose modification (an increase to 5 mg) is required. Children will 
then continue on 2 or 5 mg of Circadin® or placebo for an additional double-blind period of 10 weeks. This 
double-blind period will be followed by an open-label period of 13 weeks. At the end of the 13-week open-
label period on the last day of Week 28 ±3 days (Visit 5), sleep variables will be assessed to determine if a 
potential additional dose modification (i.e., an increase either to 5 mg for subjects who are still on 2 mg or 
an increase to 10 mg for subjects who are on 5 mg) is necessary. Children will continue at 2, 5, or 10 mg 
Circadin® in an open-label period for another 78 weeks of follow-up, which will include continuous safety 
monitoring and two efficacy assessment time points at Weeks 41 and 54. The study will end with a 2-week 
SB placebo run-out period. 


 
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6 
Statistical Considerations 
6.1 Sample Size 
To achieve 95% power at the 5% level for the primary objective (assuming a change of 0.72 hour in the 
Circadin® arm and 0.27 hour in the placebo arm and a standard deviation (SD) of 0.69 in the Circadin® arm 
and 0.45 in the placebo arm), 45 subjects are required per combined group. Therefore, 90 subjects in total 
are required to complete Visit 5. These estimations are based on previous studies conducted with Circadin®. 
6.2 Randomization 
At Visit 1, enough eligible male and female children, of ages 2 to 17.5 years, will be screened for the study to 
allow for 120 subjects to then be randomized in a 1:1 ratio to receive Circadin® or placebo at Visit 2. A 
minimum of 90 children are expected to complete the double-blind and first open-label period (up to Week 
28). A minimum of 50 children are expected to complete the second open-label safety follow-up period. 
7 
Protocol Deviations 
Major protocol deviations are defined as those deviations from the study protocol that may have the ability 
to impact the efficacy results. As such, subjects with major deviations occurring up to the end of the double-
blind phase will be excluded from the per-protocol (PP) population (as defined in Section 8.5). 
Major protocol deviations include (but are not limited to): 
 
Deviation from inclusion/exclusion criteria 
 
Withdrawal criteria met during the study but subject was not withdrawn  
 
Prohibited concomitant medications  
 
Substantial deviations from the dosing schedule (Subjects received at least 5 of 7 doses in the week 
prior to the scheduled visit and treatment compliance is within the range >60%) 
 
Substantial deviations in the completion of the sleep and nap diary (Subjects must have completed 
the diary at least 3 out of 7 nights per week over the two weeks prior to the scheduled visit and have 
a valid mean TST value at Visit 4) 
 
Where possible, major deviations will be programmatically verified by Datatrial. Listings of concomitant 
medications in Excel format will be provided to the sponsor by Datatrial for review to identify prohibited 
medications prior to unblinding. 
Major protocol deviations occurring up to the end of the first open-label phase will be identified during a 
Blinded Data Review Meeting (BDRM) prior to database lock and unblinding. 
The purpose of the BDRM will be two-fold; It will be used to review and confirm the data identified as protocol 
deviations as detailed above. It will also be used to review the Sleep and Nap diary and confirm that the data 
is correct and/or identify implausible values and document any changes that are made to the source data. 
Blinded SAS listings of the Sleep and Nap diary data including derivation of mean TST will be provided by 


 
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Datatrial in advance of the BDRM to aid this review. Any changes to the source data may require a further 
review of the protocol deviations. 
8 
Analysis Populations 
8.1 All Enrolled Set 
The All Enrolled Set will include all subjects who have given written informed consent. This set will be used 
for subject disposition and demographic characteristic summaries, and disposition, eligibility and 
demographic listings. 
8.2 All Randomized Set 
The All Randomized Set will include the subjects from the All Enrolled Subset who have been randomized. 
Subjects will be classified according to randomized treatment.  This set will be used for demographic 
characteristic, and baseline characteristic summaries, and all listings excluding disposition, eligibility and 
demographic listings.  
Furthermore, the All Randomized Set will be used for the sensitivity analyses of missing efficacy data as 
detailed in Section 11.4. 
8.3 Safety Set 
Safety analyses will be performed on the Safety Analysis Set, which includes all subjects randomized to 
treatment who take at least one dose of study medication. Subjects will be classified according to actual 
treatment received. This analysis set will be used for all safety analyses. 
8.4 Full Analysis Set 
Efficacy analyses will be performed on the Full Analysis Subset (FAS), and will include all subjects in the Safety 
Analysis Set who satisfy all major entry criteria (Inclusion Criteria 1-5) and who have a valid mean TST result 
recorded for baseline and at least one post-baseline period assessment during the double blind phase. 
Subjects will be classified according to randomized treatment.  This analysis set will be used for all efficacy 
analyses. 
8.5 Per Protocol Set 
The Per Protocol (PP) Set is a subset of the FAS, which excludes all subjects for whom there were major 
violations of the protocol as detailed in Section 7. Subjects will be classified according to randomized 
treatment.  This analysis subset will be used for sensitivity analyses of the primary endpoint and select 
secondary endpoints. 


 
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9 
Data Reporting Conventions 
9.1 Descriptive Statistics 
Unless otherwise stated, all continuous parameters will be summarized using standard summary statistics as 
appropriate (n, mean, standard deviation, minimum, median and maximum). In presentations of summary 
statistics, the minimum and maximum will be displayed to the same number of decimal places as the variable 
being summarized was recorded to. The mean and median will be displayed to one extra decimal place; the 
standard deviation (SD) will be displayed to two extra decimal places. 
Categorical variables (e.g., gender) will summarized using frequency counts and percentages.  Unless 
otherwise stated, these presentations will consist of the number of subjects in a particular category and the 
percentage of the total number of subjects.  Percentages will be presented to one decimal place. 
Unless otherwise noted, all analyses will be conducted using the validated statistical software Statistical 
Analysis System (SAS) version 9.3. 
9.2 Reporting of Phases 
Unless otherwise specified, tables will be reported separately for the Double Blind and Open Label phases. 
Tables reporting the Double Blind phase will be presented by treatment group.  
In addition, baseline demographic and history tables will include an Overall column. 
Tables reporting data from the Open Label phases will be presented by the original Double Blind treatment 
group and will also include an ‘All Circadin’ group. Unless otherwise specified, the two Open Label phases will 
be reported in the same table. For the main analysis, the Open Label tables will only include data for Visit 5. 
On completion of the study, the open label tables will be re-run to include all data up to the end of the study. 
9.3 Baseline Derivation 
For all efficacy and safety variables, the baseline value will be calculated as the last recorded value prior to 
the start of randomized treatment.   
9.4 Missing Dates 
For partial date of births, where the day and month are missing, they will be replaced with 30/06. 
The following will be applied to start and end dates for baseline histories, concomitant medications and 
adverse events where required for calculation of durations and assignment to phases. No imputed values will 
appear in the listings. 
• If the day is unknown and the month and the year are known, it will be replaced by 01 in the case of a start 
date or by the last day of the month in the case of an end date. 


 
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• If the day and the month are unknown, they will be replaced by 01/01 in the case of a start date or 31/12 
in the case of an end date.  
• If the day, the month and the year are unknown, the date will be considered as missing. 
For start and end dates of AEs, there is an exception from the above mentioned rules: 
• If the day is unknown and the month and the year are the same as the first treatment intake known, it will 
be replaced by the date of first treatment intake. 
• If the day and the month are unknown and the year is the same as the first treatment intake known, it will 
be replaced by the date of first treatment intake. 
10 Subject Disposition, and Demographic and Baseline Characteristics 
10.1 Subject Disposition 
Study completion and discontinuation details, eligibility, treatment allocation, population assignment, and 
protocol deviations will be listed. 
The number of subjects screened, randomized, receiving and completing double-blind treatment and the 
primary reasons for any study treatment discontinuations in the double-blind phase will be tabulated. A 
subject is considered to have completed the double-blind phase if they have attended Visit 4 without having 
discontinued the study. 
The number of subjects starting and completing each of the open-label phases and the primary reasons for 
discontinuation in each of the open-label phases will be tabulated. A subject is considered to have started 
the first (second) open-label phase if they have been supplied with study treatment at Visit 4 (Visit 5). They 
are considered to have completed the first (second) open-label phase if they have attended Visit 5 (Visit 8) 
without having discontinued the study. 
The number and percentage of subjects in each analysis population will be tabulated. The number and 
percentage of subjects in each center and in each geographic region (US and Europe) will be tabulated. 
10.2 Demographic and Baseline Characteristics 
Demographic parameters will include date of birth, age, sex, race, ethnicity and screening body weight, 
height and BMI. 
Age will be derived from the birth date and screening date as using the following SAS code: 
Age=floor ((intck('month',birth,screen) - (day(screen) < day(birth))) / 12) 
Body weight and height will be measured at Screening. Body mass index (BMI) at screening will be 
programmatically calculated in the eCRF. 


 
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Demographics will be listed and tabulated using descriptive statistics. 
The following baseline characteristics will also be tabulated: 
- 
ADHD (Yes, No; identified from the medical history) 
- 
Epilepsy (Yes, No)  
- 
Prior Anti-Epileptic Treatment (ATC code N03) 
- 
Prior Anti-Depressant Treatment (selective serotonin reuptake inhibitor [SSRIs] ATC code N06AB)  
- 
Prior Beta-Blockers  Use (ATC code C07) 
- 
Prior Stimulant Use (ATC code N06B) 
- 
Prior ADHD Treatment (Ritalin ATC code N06BA04) 
- 
Prior Clonidine Use (ATC code C02AC01) 
10.3 Neurodevelopmental Disability 
Details of the diagnosis of neurodevelopmental disability will be listed and tabulated. The time since first 
diagnosis of neurodevelopmental disability (in months) will be calculated from date of informed consent and 
summarized descriptively. 
10.4 Melatonin Use 
Details of melatonin use will be listed and tabulated. 
10.5 Medical History 
Details of medical history will be listed including condition, start and stop dates. Partial dates may be 
recorded in the electronic data capture system and no imputations will be made for missing or partial dates 
in the listing. 
Medical histories will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version 18 or higher. A summary of medical histories and number of subjects with a medical history will be 
presented by System Organ Class and Preferred Term.  
10.6 Prior and Concomitant Medications 
Concomitant medications recorded during the study will be coded using World Health Organization (WHO)-
Drug. Details of concomitant medication will be listed. 
Concomitant medications will be summarized according to whether they were being taken pre-study (prior 
medications) and/or during the study (concomitant medication). Prior medications are any that were being 
taken prior to the first dose of study medication (medication stop date prior to the first dose of study 
medication). Concomitant medications are any that were being taken on or after the first dose of study 
medication. If the start and stop dates of the concomitant medications do not clearly define the period during 
which a medication was taken, it will be assumed to be a concomitant medication. 


 
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Concomitant medications will be assigned to the phase they were taken: Double-Blind, first Open-Label, 
second Open-Label. If a concomitant medication starts or is ongoing between Visit 2 and Visit 4, it will be 
assigned to the Double-Blind phase. If a concomitant medication starts or is ongoing between Visit 4 + 1 day 
and Visit 5, it will be assigned to the first Open-Label phase. If a concomitant medication starts or is ongoing 
between Visit 5 + 1 day and Visit 8, it will be assigned to the second Open-Label phase. If the start and stop 
dates of the concomitant medications do not clearly define the phase during which a medication was taken, 
it will be assumed to be taken across all phases. 
Prior and concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) level 2 
term and preferred term. 
Details of non-pharmacological concomitant measures will be listed. 
11 Efficacy 
Subjects will be classified and summarized by randomized treatment.  For all efficacy assessments, the 
baseline values will be calculated as the last recorded value prior to the start of randomized treatment.  
Change from baseline values will be calculated as the assessment score minus the baseline value.  For 
questionnaires the change from baseline values will be calculated for each item and total/subscale score as 
applicable.  
All summaries and analyses will be performed on the FAS set. The primary efficacy endpoint and select 
secondary efficacy endpoints will also be analyzed on the PP set. Analyses looking at the impact missing data 
on the primary efficacy endpoint will also be performed on the All Randomized set. 
11.1 Primary Efficacy Variable 
11.1.1 Total Sleep Time (TST) 
TST will be assessed by a Sleep and Nap Diary.  
Daily TST will be calculated programmatically as follows: 
the time the child woke up in the morning minus  
the time the child went to bed minus 
the time taken to fall asleep minus 
the total duration of any night awakenings  
If the time the child went to bed and the time they woke up in the morning are the same, the TST will be set 
to 0. 
The number of daily diaries with data recorded and the number of daily diaries with a valid mean TST will be 
tabulated by scheduled visit. 
For each subject the mean TST will then be calculated as the mean of the last 14 days prior to each 
scheduled visit. A subject will be required to have a minimum of 3 nightly TST values per week (6 nights in 
total) in order to have a valid mean TST after baseline. A subject will be required to have a minimum of 6 


 
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nightly TST values across the 2 weeks in order to have a valid mean TST at baseline. The mean TST and 
change from baseline in mean TST will be summarized by scheduled visit using descriptive statistics. The 
change from baseline in mean TST will be plotted over time. Empirical cumulative distribution functions by 
treatment group will be plotted for change from baseline in mean TST at Visit 4 (Week 15). 
The change from baseline in mean TST will be analyzed using a mixed-effects model for repeated-measures 
(MMRM). The model will contain the TST at Visit 3 (Week 5) and Visit 4 (Week 15) as the dependent variable, 
with fixed effects for visit, the mean baseline TST, randomized treatment and the mean baseline TST and 
randomised treatment both nested within visit. Visit-to-visit repeated measures will assume a general 
(unstructured) covariance structure. Standard errors and degrees of freedom for significance tests will be 
derived using the Kenward-Roger method [1].   
From this model, the adjusted mean change from baseline (and standard error) in TST after 13 weeks of 
treatment for each treatment group will be calculated and the associated 95% confidence intervals (CI) for 
the change presented. Furthermore, the estimated difference (and standard error) between treatments will 
be estimated, the associated 95% CI presented and the null hypothesis that these means are equal will be 
tested.  
Example SAS code for this analysis is given below: 
proc mixed data=tst method=reml; 
  class subjid trtp avisitn; 
  model chg=trtp avisitn base trtp(avisitn) base(avisitn)/ddfm=kr; 
  repeated avisitn/subject=subjid type=un; 
  lsmeans trtp(avisitn)/diff cl om; 
  ods output lsmeans=lsm(where=(avisitn=4)) diffs=diff(where=(avisitn=4)); 
run; 
 
In addition, the effect size will be calculated based on Cohen’s d (mean difference between groups/pooled 
standard deviation) where the mean difference is adjusted for other model factors using MMRM and the 
pooled standard deviation is evaluated using the model standard errors as follows:  
 
sdpool=√(((secirc*secirc*(ncirc-1)*ncirc)+(seplac*seplac*(nplac-1)*nplac))/(ncirc+nplac-2)).  
 
where ncirc and nplac are the number of subjects with a measurement at Visit 4 (Week 15) and secirc and seplac 
are the standard errors of the adjusted means in the Circadin and Placebo groups respectively.  
11.2 Secondary Efficacy Variables 
11.2.1 Sleep and Nap Diary 
11.2.1.1 Sleep Latency 
Sleep latency as assessed by a Sleep and Nap Diary will be calculated as the mean of the last 14 days prior to 
each scheduled visit. If the time the child went to bed and the time they woke up in the morning are the 
same, the sleep latency for that night will be set to 360 minutes. Mean sleep latency and the change from 
baseline in mean sleep latency will be summarized by scheduled visit using descriptive statistics. The change 
from baseline in sleep latency will be plotted over time. The change from baseline in mean sleep latency at 
13 weeks will be analysed as detailed above for TST. 


 
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11.2.1.2 Duration of Wake 
Duration of wake after sleep onset period as assessed by a Sleep and Nap Diary will be calculated as the mean 
of the last 14 days prior to each scheduled visit. Mean duration of wake and the change from baseline in 
mean duration of wake will be summarized by scheduled visit using descriptive statistics. The change from 
baseline in duration of wake will be plotted over time. The change from baseline in mean duration of wake 
at 13 weeks will be analysed as detailed above for TST. 
11.2.1.3 Number of Awakenings 
The number of awakenings as assessed by a Sleep and Nap Diary will be calculated as the mean of the last 14 
days prior to each scheduled visit.  The mean number of awakenings and change from baseline in the mean 
number of awakenings will be summarized by scheduled visit using descriptive statistics. The change from 
baseline in number of awakenings will be plotted over time. The change from baseline in the mean number 
of awakenings at 13 weeks will be analysed as detailed above for TST. 
11.2.1.4 Longest Sleep Period 
The longest sleep period as assessed by a Sleep and Nap Diary will be calculated as the mean of the last 14 
days prior to each scheduled visit.  The mean longest sleep period and the change from baseline in the mean 
longest sleep period will be summarized by scheduled visit using descriptive statistics. The change from 
baseline in longest sleep period will be plotted over time. The change from baseline in the mean longest sleep 
period at 13 weeks will be analysed as detailed above for TST. 
11.2.1.5 Total Time in Bed 
In order to evaluate the impact of shortening latency time versus increasing sleep time after sleep onset on 
the primary endpoint, TST, a new parameter will be further analysed by removing sleep latency from the TST 
calculation. This will be referred to as the total time in bed.  
That is, total time in bed is defined as follows: 
the time the child woke up in the morning  minus  
the time the child went to bed minus 
the total duration of any night awakenings 
The total time in bed as assessed by a Sleep and Nap Diary will be calculated as the mean of the last 14 days 
prior to each scheduled visit.  
The mean total time in bed and the change from baseline in the mean total time in bed will be summarized 
by scheduled visit using descriptive statistics. The change from baseline in total time in bed will be plotted 
over time. The change from baseline in the mean total time in bed at 13 weeks will be analysed as detailed 
above for TST. 
11.2.2 CSDI 
Sleep disturbance as assessed by the CSDI and change from baseline will be summarized by scheduled visit 
for each treatment group using descriptive statistics for the total score. The change from baseline in the total 
CSDI score at 13 weeks will be analysed as detailed above for TST. 


 
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11.2.3 CGAS 
The CGAS score and change from baseline will be summarized by scheduled visit for each treatment group 
using descriptive statistics. The change from baseline in CGAS score at 13 weeks will be analysed as detailed 
above for TST. 
11.2.4 SDQ 
The SDQ consists of 25 items which are divided into 5 subscales:  
1) emotional symptoms (5 items) 
2) conduct problems (5 items)  
3) hyperactivity/inattention (5 items) 
 
4) peer relationship problems (5 items)  
5) prosocial behaviour (5 items). 
Subscales 1 to 4 added together generate a total difficulties score (20 items).  An impact score will also be 
calculated as part of the SDQ. 
The 
following 
website 
provides 
SAS 
syntax 
to 
enable 
scoring 
of 
the 
5 
subscales: 
http://www.sdqinfo.com/c2.html. (Appendix A) 
The total difficulties score, impact score and the subscale total scores and corresponding changes from 
baseline will be summarized by scheduled visit for each treatment group using descriptive statistics. The 
change from baseline in the scores at 13 weeks will also be analysed as detailed above for TST. 
11.2.5 Number of Dropouts 
The proportion of subjects dropping out in the double-blind phase will be compared between the treatment 
groups using a chi-square test with continuity correction. 
Example SAS code for this analysis is given below: 
proc freq data=drop; 
  table drop*trtp/chisq; 
  ods output chisq=chi(where=(statistic='Continuity Adj. Chi-Square')); 
run; 
11.2.6 Actigraphy 
Sleep parameters (Total Sleep Time, Sleep Latency, Duration of Wake and Number of Awakenings, Longest 
Sleep Period and Sleep Efficiency) as measured by actigraphy will be calculated as the mean of the last 14 
days prior to each scheduled visit. The sleep parameters and corresponding changes from baseline will be 
summarized by scheduled visit using descriptive statistics. The sleep parameters at 13 weeks will be analysed 
as detailed above for TST.  


 
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11.3 Exploratory Efficacy Variables 
11.3.1 Sleep and Nap Diary by Visit 
The change from baseline at 3 weeks of double-blind treatment is analysed in the same model as the change 
from baseline at 13 weeks. From that model, the adjusted mean change from baseline (and standard error) 
in TST after 3 weeks of treatment for each treatment group will be calculated and the associated 95% CI for 
the change presented. Furthermore, the estimated difference (and standard error) between treatments will 
be estimated, the associated 95% confidence interval presented and the null hypothesis that these means 
are equal will be tested. 
For the TST during open-label treatment the estimated change from baseline (and standard error) will be 
calculated and associated 95% CI for the change will be presented for each visit. A paired t-test will be 
performed comparing the mean TST at visit to the baseline mean. 
Example SAS code for this analysis is given below: 
proc means data=tst mean stderr lclm uclm probt; 
  var chg; 
run; 
These analyses will be repeated for the other sleep variables derived from the Sleep and Nap diary. 
A subject is defined as a TST responder if the mean change from baseline in TST is 45 minutes or greater 
(increase in TST) over the 14 days prior to each scheduled visit. A subject is defined as a sleep latency 
responder if the mean change from baseline in sleep latency is 15 minutes or greater (reduction in SL) over 
the 14 days prior to each scheduled visit. Frequency tables of TST response and sleep latency response will 
be presented by scheduled visit.  
For Visits 3 and 4, the TST response rate and sleep latency response rate will be analysed using logistic 
regression. Subjects without a mean TST (or mean sleep latency) at a visit will be taken to be non-responders 
in this analysis. The model will include terms for treatment and mean baseline value of TST and sleep latency 
respectively. From the model the estimated odds of responding will be calculated, as will estimated odds 
ratios, associated 95% CI and p-values for testing the null hypothesis of the odds ratio being 1. 
Example SAS code for this analysis is given below: 
proc genmod data=resp; 
  class trtp; 
  model resp=trtp base/link=logit dist=bin; 
  lsmeans trtp/diff cl om exp; 
run; 
The responder analysis will be repeated on all non-missing data. That is, subjects without a mean TST (or 
mean sleep latency) at a visit will not be included in the analysis. 
The time to going to bed will be categorized to the following time slots: < 18:00, 18:00 - < 19:00, 19:00 - 
<20:00, 20:00 - < 21:00, 21:00 - < 22:00, 22:00 - < 23:00, 23:00 - < 00:00, >= 00:00.  


 
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The shift in time to going to bed will be tabulated by scheduled visit for the most frequently occurring time 
slot over the 14 days at each visit. Where the daily time to going to bed is equally distributed across the time 
slots, the latest occurring time slot will be selected for inclusion in the shift table. 
11.3.2 Sleep Disturbance by Visit 
For the sleep disturbance as assessed by the CSDI, the total CSDI score after 3 weeks of double blind 
treatment and during open-label treatment will be analysed as for TST. 
11.3.3 CGAS by Visit 
The CGAS score after 3 weeks of double blind treatment and 13 weeks of open-label treatment will be 
analysed as detailed above for TST. 
11.3.4 SDQ by Visit 
The SDQ score for total difficulties score, impact score and the subscale total scores after 3 weeks of double 
blind treatment and 13 weeks of open-label treatment will be analysed as detailed above for TST. 
11.3.5 ESS 
Caregiver sleepiness as assessed by the ESS total score and the change from baseline in ESS total score will 
be summarized by scheduled visit using descriptive statistics. The ESS total score after 3 weeks and 13 weeks 
of double blind treatment and during open-label treatment will be analysed as detailed above for TST. 
11.3.6 PSQI 
The global PSQI score and corresponding component scores and changes from baseline will be summarized 
by scheduled visit using descriptive statistics. The global PSQI score after 3 weeks and 13 weeks of double 
blind treatment and during open-label treatment will be analysed as detailed above for TST. 
11.3.7 WHO-5 Well-being Index 
WHO-5 Well-being Index total score and change from baseline in the total score will be summarized by 
scheduled visit using descriptive statistics. The Well-being Index total score after 3 weeks and 13 weeks of 
double blind treatment and during open-label treatment will be analysed as detailed above for TST. 
11.3.8 Actigraphy by Visit 
The shift in time to going to bed will be tabulated by scheduled visit. The categories used will be as detailed 
for Sleep and Nap Diary Time to bed. 
The number and percentage of subjects defined as a responder according to actigraphy will be tabulated for 
the run-in period. A responder is defined as > 6 hours of continuous sleep and < 0.5 hour sleep latency from 
light off in 3 out of 5 nights.  
11.4 Other Efficacy Variables 
11.4.1.1 Quality of Sleep 
The quality of sleep as assessed by a Sleep and Nap Diary will be calculated as the mean of the last 14 days 
prior to each scheduled visit. Quality of sleep will be scored as follows: 


 
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Very bad = 1; bad = 2; fair = 3; good = 4; very good = 5; unknown = not scored. 
The mean quality of sleep and change from baseline in the mean quality of sleep during the day will be 
summarized by scheduled visit using descriptive statistics. The change from baseline in the mean quality of 
sleep at 13 weeks will be analysed as detailed above for TST. 
11.4.1.2 Current Alertness 
The current alertness as assessed by a Sleep and Nap Diary will be calculated as the mean of the last 14 days 
prior to each scheduled visit. Current alertness will be scored as follows: 
Very tired = 1; tired = 2; quite alert = 3; alert = 4; very alert = 5; unknown = not scored. 
The mean current alertness and change from baseline in the mean current alertness during the day will be 
summarized by scheduled visit using descriptive statistics. The change from baseline in the mean current 
alertness at 13 weeks will be analysed as detailed above for TST. 
11.4.1.3 Feeling on Awakening 
The child’s feeling on awakening as assessed by a Sleep and Nap Diary will be calculated as the mean of the 
last 14 days prior to each scheduled visit. Feeling on awakening will be scored as follows: 
Very fatigued = 1; fatigued = 2; somewhat refreshed = 3; refreshed = 4; very refreshed = 5; unknown = not 
scored. 
The mean feeling on awakening and change from baseline in the mean feeling on awakening during the day 
will be summarized by scheduled visit using descriptive statistics. The change from baseline in the mean 
feeling on awakening at 13 weeks will be analysed as detailed above for TST. 
11.4.1.4 Number of Naps 
The number of naps during the day as assessed by a Sleep and Nap Diary will be calculated as the mean of 
the last 14 days prior to each scheduled visit.  The mean number of naps during the day and change from 
baseline in the mean number of naps during the day will be summarized by scheduled visit using descriptive 
statistics. The change from baseline in the mean number of naps at 13 weeks will be analysed as detailed 
above for TST. 
11.4.1.5 Duration of Naps 
The duration of naps during the day as assessed by a Sleep and Nap Diary will be calculated as the mean of 
the last 14 days prior to each scheduled visit.  The mean duration of naps during the day and change from 
baseline in the mean duration of naps during the day will be summarized by scheduled visit using descriptive 
statistics. The change from baseline in the mean duration of naps at 13 weeks will be analysed as detailed 
above for TST. 
11.4.2 CSDI 
Sleep disturbance as assessed by the CSDI and change from baseline will also be summarized by scheduled 
visit for each treatment group using descriptive statistics, for each of the individual questions. The change 


 
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from baseline in the total CSDI score at 13 weeks for of the individual questions, will be analysed as detailed 
above for TST. 
Individual questions will be scored as follows: 
Questions 1, 3, 5 and 6 - 3 or more nights a week = 2; 1 or 2 nights a week = 1; less than once a week = 0; 
Questions 2 and 4 - More than 30 minutes = 2; up to 30 minutes = 1; few minutes = 0; 
Question 7 - Completely dissatisfied = 1; mostly dissatisfied = 2; neither satisfied nor dissatisfied = 3; mostly 
satisfied = 4; completely satisfied = 5. 
11.5 Missing Efficacy Data 
11.5.1 Multiple Imputation 
For the primary efficacy variable and the secondary efficacy variables collected using the Sleep and Nap Diary, 
an analysis will be undertaken to assess the effect of missing data arising on the estimated treatment effects. 
This will be done using a pattern mixture model where missing data from subjects who are withdrawn is 
imputed with observations imitating the placebo response [2]. 
Specifically, using the absolute values for baseline, Week 5 and Week 15, a monotone multiply imputed (1000 
imputations) dataset will be initially created. Using this dataset the remaining missing data will then be 
imputed (1 imputation) using an imputation model based on sequential regression methodology. Starting at 
Week 5, values for subjects that have missing data will be imputed based on all placebo-treated subjects 
having a value at that visit. The effect of this is to mimic the expected response as if the withdrawn subjects 
had been treated with placebo from the point of withdrawal. Next, at Week 15, values for subjects that have 
missing data will be imputed based on all placebo-treated subjects having a value at that visit. The change 
from baseline to Week 15 will then be calculated. 
These imputed datasets will be analysed separately using ANCOVA with randomised treatment as a factor 
and baseline as a covariate. The individual results will then be combined using the method of Rubin [3]. The 
adjusted mean change from baseline (and standard error) in TST after 13 weeks of treatment for each 
treatment group, the estimated difference (and standard error) between treatments, the associated 95% CI 
presented and the p-value for the test of null hypothesis that these means are equal will be presented.   
Example SAS code for this analysis is given below: 
* Create monotone dataset; 
proc mi data=tst out=mi_mono nimpute=1000 seed=5635245; 
  by trtp; 
  var week_0 week_3 week_13; 
  mcmc impute=monotone; 
run; 
 
* Pattern mixture model with placebo-based imputation; 
* Impute week 3; 
data mi_imp1 mi_rest1; 
  set mi_mono; 


 
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  if trtp='Circadin' and lastwk>=3 then output mi_rest1; 
  else output mi_imp1; 
run; 
 
proc mi data=mi_imp1 out=mi_reg_imp1 nimpute=1 seed=8254340; 
  class gender disease; 
  var week_0 week_3; 
  monotone regression; 
  by _imputation_; 
run; 
 
data midata_2; 
  set mi_rest1 mi_reg_imp1; 
  by _imputation_; 
run; 
 
* Impute week 13; 
data mi_imp2 mi_rest2; 
  set midata_2; 
  if trtp='Circadine' and lastwk=13 then output mi_rest2; 
  else output mi_imp2; 
run; 
 
proc mi data=mi_imp2 out=mi_reg_imp2 nimpute=1 seed=1066436; 
  class gender disease; 
  var week_0 week_3 week_13; 
  monotone regression; 
  by _imputation_; 
run; 
 
data tst_mi; 
  set mi_rest2 mi_reg_imp2; 
  by _imputation_; 
  chg=week_13-week_0; 
  base=week_0; 
run; 
 
* Perform analysis; 
proc mixed data=tst_mi; 
  class trtp gender disease; 
  model chg=trtp base; 
  lsmeans trtp/cl diff; 
  by _imputation_; 
  ods output Diffs=est LSMeans=lsm; 
run; 
 
* Combine estimates of adjusted means from each imputation; 
proc sort data=lsm; 
  by trtp; 
run; 
 
proc mianalyze data=lsm; 
  by trtp; 
  modeleffects estimate; 
  stderr stderr; 
  ods output ParameterEstimates=milsm; 
run; 


 
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* Combine estimates of treatment difference from each imputation; 
proc mianalyze data=est; 
  modeleffects estimate; 
  stderr stderr; 
  ods output ParameterEstimates=midiff; 
run; 
11.5.2 Baseline Observation Carried Forward 
In addition to using the MI method, the effect of missing data will also be assessed using the Baseline 
Observation Carried Forward (BOCF) method. For the primary efficacy variable and the secondary efficacy 
variables collected using the Sleep and Nap Diary, the analysis will be repeated to assess the effect of missing 
data arising on the estimated treatment effects by imputing the missing values with the subject’s baseline 
observation. The analysis will be done using the substantive (ANCOVA) model used in the MI approach. 
11.6 Subgroup Analysis  
11.6.1 Inclusion of Additional Factors in MMRM Analysis 
The effect of treatment in subgroups of interest will be assessed by repeating the analysis of the primary 
efficacy variable by including the following factors in the model, one at a time.  
- 
Geographic region (US v Europe) 
- 
Center 
- 
Age (2-<6 yrs, 6-<12 yrs, >-12 yrs) 
- 
Gender 
- 
ADHD (Yes, No; identified from the medical history) 
- 
Austim Type 
- 
Epilepsy (Yes, No) 
- 
Prior Anti-Epileptic Treatment 
- 
Prior Anti-Depressant Treatment 
- 
Prior Beta-Blockers Use 
- 
Prior Stimulant Use  
- 
Prior ADHD Treatment  
- 
Prior Clonidine Use 
From this model, within each subgroup, the adjusted mean change from baseline (and standard error) in TST 
after 13 weeks of treatment for each treatment group will be calculated and the associated 95% CI for the 
change presented. Furthermore for each subgroup, the estimated difference (and standard error) between 
treatments will be estimated, the associated 95% CI presented and the null hypothesis that these means are 
equal will be tested. 
Example SAS code for this analysis is given below: 
proc mixed data=tst method=reml; 
  class subjid trtp avisitn geog; 
  model chg=trtp avisitn base geog trtp*geog trtp(avisitn) base(avisitn) 
geog(avisitn) trtp*geog(avisitn)/ddfm=kr; 
  repeated avisitn/subject=subjid type=un; 


 
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  lsmeans trtp*geog(avisitn)/diff cl om; 
  ods output lsmeans=lsm(where=(avisitn=4)) diffs=diff(where=(avisitn=4 and 
geog=_geog)); 
run; 
The above analysis will be repeated for CSDI, CGAS and Total SDQ at 13 weeks incorporating the following 
factors into the model: 
- 
ADHD (Yes, No) 
- 
Epilepsy (Yes, No) 
- 
Prior ADHD Treatment 
- 
Prior Clonidine Use 
11.6.2 SND Summaries by Final Dose 
The summary tables for the SND parameters will be presented separately for the double blind and open label 
phases by the final dose that the subject received at the end of each phase respectively. 
11.7 Agreement between Sleep and Nap Diary and Actigraphy  
An analysis will be performed to assess the agreement of the following sleep parameters collected via the 
Sleep and Nap Diary and actigraphy: 
- 
Total Sleep Time 
- 
Sleep Latency 
- 
Duration of Wake 
- 
Number of Awakenings 
- 
Longest Sleep Duration 
- 
Total Time in Bed 
- 
Number of Responders at baseline, Visit 2 (defined as > 6 hours of continuous sleep and < 0.5 hour 
sleep latency from light off in 3 out of 5 nights.) 
The analysis will use data from Visits 2 and 4. Agreement will be assessed using the methods described by 
Bland and Altman ([4], [5]). Bland and Altman plots (plotting the difference in the measurements from the 
two sources versus the average of the measurements from the two sources) will be produced and the 95% 
limits of agreement calculated. 
Example SAS code for the calculation of the limits of agreement is given below: 
proc mixed data=agree method=type1; 
  class subjid; 
  model diff=/solution ddfm=sat; 
  random subjid; 
  ods output CovParms=covparms; 
run; 
 
proc means data=agree noprint; 
  var diff; 
  output out=meandiff mean=meandiff; 
run; 


 
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data loa; 
  merge meandiff covparms(where=(covparm='SUBJID') rename=(estimate=between)) 
covparms(where=(covparm='Residual') rename=(estimate=within)); 
  std=sqrt(within+between); 
  upper_loa=meandiff+(1.96*std); 
  lower_loa=meandiff-(1.96*std); 
run; 
For number of responders, a 2 x 2 table will be presented tabulating responders according to the sleep and 
nap diary against responders according to actigraphy. Agreement between the sleep and nap diary and 
actigraphy responders will be summarised using Cohen’s kappa statistic. The hypothesis that Cohen’s kappa 
differs from 0 will be tested. A 95% confidence interval for Cohen’s kappa will also be presented. 
11.8 Correlation between Sleep and Nap Diary and Actigraphy versus Daytime Endpoints 
Scatterplots will be presented for selected sleep parameters collected via the Sleep and Nap Diary and 
actigraphy against CSDI, CGAS and SDQ Total score as follows: 
- 
SND TST versus CSDI 
- 
SND TST versus CGAS 
- 
SND TST versus SDQ Total Score 
- 
SND Sleep Latency versus CSDI 
- 
SND Sleep Latency versus CGAS 
- 
SND Sleep Latency versus SDQ Total Score 
- 
SND WASO versus CSDI 
- 
SND WASO versus CGAS 
- 
SND WASO versus SDQ Total Score 
- 
Actigraphy TST versus CSDI 
- 
Actigraphy TST versus CGAS 
- 
Actigraphy TST versus SDQ Total Score 
- 
Actigraphy Sleep Latency versus CSDI 
- 
Actigraphy Sleep Latency versus CGAS 
- 
Actigraphy Sleep Latency versus SDQ Total Score 
- 
Actigraphy WASO versus CSDI 
- 
Actigraphy WASO versus CGAS 
- 
Actigraphy WASO versus SDQ Total Score 
Spearman’s rank correlations will be calculated and presented on the scatterplot for each correlation. In 
addition, the null hypothesis of zero correlation will be tested.  
12 Safety 
Subjects will be classified and summarized by actual treatment. 
Safety will be assessed using TESS, AEs, vital signs, BMI and physical development data.  


 
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12.1 Treatment Exposure 
Details of study drug compliance, dose modifications and dose increases will be listed. 
The time on treatment will be listed and summarized descriptively. 
Time on treatment (days) in DB Phase = Last dose date of DB phase – first dose date of DB phase +1  
Time on treatment (days) in OL Phase = Last dose date of OL phase – first dose date of OL phase +1  
Time on active treatment (days) = Last dose date of active treatment – first dose date of active treatment +1  
The number of subjects having a decrease in dose or an increase in dose will be tabulated by visit. % 
compliance will be summarized descriptively. 
The dosage achieved (2/5/10mg) will be tabulated by scheduled visit and the maximum dose achieved will 
also be tabulated. 
12.2 Treatment Emergent Signs and Symptoms 
TESS are recorded throughout the study.  At Visit 1, the TESS questionnaire is completed and the information 
is used to assess medical history. All symptoms that are score of 1 or more will be recorded in the medical 
history. At Visit 2 and all subsequent visits thereafter, the TESS questionnaire will be used to report all 
treatment-emergent signs and symptoms that may have occurred since Visit 1. A given sign and symptom 
will be reported as a corresponding AE if the sign or symptom is a new symptom or if there is an increase in 
severity of an existing symptom from the first visit (i.e., Visit 1). If a specific symptom has the same score or 
lower from Visit 1, AEs will not be reported. 
A frequency table of TESS results will be presented by sign/symptom and scheduled visit for the thirteen 
hypothecated events. 
12.3 Adverse Events 
AEs will be coded according to MedDRA® version 18.0 or higher. 
An overall AE summary will be presented for the following pre-defined subsets of events:  
 Any TEAEs  
 Any TEAEs considered related to treatment 
 Any TEAEs leading to study drug discontinuation 
 Any SAEs  
 Any deaths 
 Any SAEs considered related to treatment 
 Any SAEs leading to study drug discontinuation 
 
Listings by subject will be presented for the following subsets: 
 Any TEAEs 


 
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 Any SAEs  
All TEAEs will be summarized and grouped by MedDRA® System Organ Class (SOC) and specific AE preferred 
term (PT). Results will be displayed in order of decreasing frequency by SOC and PT.  
Summaries will also be produced of SAEs, treatment related AEs and TEAEs leading to study drug 
discontinuation by SOC and PT terms. In addition, a summary will be provided by severity (mild, moderate, 
severe). 
For all summary tables, both number of events and number of subjects will be tabulated. For subjects, 
percentages will be calculated from the total number of subjects per treatment group. Related to treatment 
is defined as any adverse events considered either “possibly”, “probably” or “definitely” related to study 
drug. 
Tables will be presented for the double blind and open-label phases separately. 
In addition a cumulative summary will also be presented for all subjects on active treatment for all TEAEs, 
SAEs and TESAEs leading to discontinuation of study drug grouped by SOC and PT terms occurring in either 
the double blind or open-label phase. 
For the purposes of the interim analysis reporting, an AE cut-off point will be defined as any AE starting on 
or before Visit 5. 
12.4 Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, oral 
temperature (°C)  
The result, change from baseline and % change from baseline for all vital sign parameters will be listed and 
summarized descriptively by scheduled visit. 
12.5 BMI and Z-scores 
Weight, height and BMI will be recorded throughout the study. 
The result, change from baseline and % change from baseline for weight, height and BMI will be listed and 
summarized descriptively by scheduled visit. Descriptive statistics will also be presented for the following age 
groups: 2 to ≤5 years, > 5 to < 8 years and ≥8 years. 
The BMI percentiles and Z-scores are designed to take into account the amount of weight gain that would be 
expected due to normal growth in children and adolescents. The BMI percentiles and Z-scores are categorized 
by age and gender standardized values (corresponding to a normal distribution with mean 0 and a SD of 1) 
of the actual weight measurements, based on the Growth Charts provided by the Centers for Disease Control 
(CDC). 
A SAS program and reference data can be downloaded from the following webpage: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. (Appendix B) 


 
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The program will calculate the percentiles and z-scores (standard deviations) for a child’s sex and age for 
BMI, weight, height, and head circumference based on the CDC growth charts.  The reference data contains 
the L, M, and S parameters needed to generate the percentiles and z-scores. 
An input file should be setup containing AGEMOS (age in months), SEX (coded as 1 for boys and 2 for girls) 
and BMI.  An output file will be generated containing BMIPCT (BMI percentile) and BMIZ (BMI Z-Score). 
The BMI percentiles will be used to categorize the subject’s weight as follows: 
Weight Status Category 
Percentile Range 
Underweight 
Less than the 5th percentile 
Normal or Healthy Weight 
5th percentile to less than the 85th percentile 
Overweight 
85th to less than the 95th percentile 
Obese 
Equal to or greater than the 95th percentile 
 
A shift table will be presented for the change in weight status category from baseline to end of double-blind 
treatment, to the end of the first open-label phase and to the end of study.  
The Z-score and change from baseline will be listed and summarized descriptively by scheduled visit. 
BMI and Z-score after 3 weeks and 13 weeks of double blind treatment and during open-label treatment will 
be analysed as for TST. 
12.6 Tanner Assessment of Pubertal Development 
The Tanner scale will be used to assess and stage physical development in subjects ≥8 years of age. For 
subjects ≤5 years of age, only height and head circumference will be used to stage development. Between 
the age of 5 and 8 the subjects’ physical development will be determined using the BMI. 
Two measures are collected for males (genital development (5 stages G1–G5) and pubic hair (6 stages PH1–
PH6)) and females (breast development (5 stages B1–B5), pubic hair (6 stages PH1–PH6)) respectively. 
Tanner scores for pubertal assessment in subjects ≥8 years of age during the study will be analyzed using the 
web application (http://vps.stefvanbuuren.nl/puberty). The Tanner scores for each measure will be uploaded 
to the website as a .csv file. The file will contain the subject’s sex and age in months to two decimal places. 
An example file is available to ensure the correct format for uploading the file to the site. This tool will 
calculate SD scores of individual observations of Tanner scores for each assessment. 
Results from the Tanner assessment will be tabulated for each measure by scheduled visit. 
For subjects ≥8 years of age the SD score and change from baseline in the SD score for each pubertal 
assessment will be listed and summarized descriptively by scheduled visit.  
The result, change from baseline and % change from baseline for head circumference will be listed and 
summarized descriptively by scheduled visit. Descriptive statistics will also be presented for the following age 
group: 2 to ≤5 years, > 5 to < 8 years and ≥8 years. 


 
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12.7 Epilepsy 
Number and type of epilepsy seizures in children diagnosed with epilepsy will be tabulated, using the Epilepsy 
Seizures Diaries that are completed by parents at the time of the seizures. For the number of epilepsy 
seizures, percentages will be based on the number of children diagnosed with epilepsy. 
The median number of epilepsy seizures will be summarized by scheduled visit and across all visits. At each 
visit Wilcoxon rank-sum test will be performed to compare the number of seizures occurring between the 
two groups. 
Example SAS code for this analysis is given below: 
proc NPAR1WAY data=epil wilcoxon; 
 
class trtp; 
 
var numepil; 
 
exact wilcoxon; 
run; 
12.8 Other Data 
12.8.1 Pregnancy Test 
All subjects will be tested for pregnancy by urine dipstick at Screening, Week 2, Week 15 and Week 108.  
Details of pregnancy test results will be listed. 
12.8.2 Physical Examination 
Physical examination will be assessed at screening each visit including the placebo run-out (withdrawal) 
period. Physical examination findings at screening will be classified using standard categories as listed on the 
Medical History eCRFs. Any physical examination finding that is judged by the Investigator as a clinically 
significant change (worsening) compared to a baseline value (Visit 2) will be considered an AE and recorded 
on the adverse event eCRF. The date of the physical examination will be listed. 
12.8.3 Visit Dates 
Visit dates will be listed. 
13 Interim Analysis 
All results will be summarized at the end of the first open-label period (Week 28; Visit 5), and will be 
submitted in the form of a clinical study report (CSR) to the regulatory authorities for evaluation of approval 
of the study drug for use in the investigated population. This will constitute the final analysis of data up to 
that point and no statistical adjustment of significance tests is required. 
The data from the second open-label period will be summarized on the completion of the study and reported 
as an appendix to the CSR. 


 
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14 Changes to Planned Methodology 
The analysis of total CSDI score at 13 weeks has been moved from an exploratory endpoint to a secondary 
endpoint to reflect the greater importance being placed on this endpoint at the present time. 
15 References 
[1] Kenward, M. G. and Roger, J. H. (1997), Small Sample Inference for Fixed Effects from Restricted Maximum 
Likelihood, Biometrics, 53, 983–997 
[2] Ratitch, B. and O’Kelly, M. (2011), Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures, in Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS Users Group), SP04, Nashville. 
[3] Rubin, D. B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & Sons. 
[4] Bland, J.M., Altman, D.G. (1986). Statistical methods for assessing agreement between two methods of 
clinical measurement, Lancet, i: 307-310. 
[5] Bland, J.M., Altman, D.G. (2007). Agreement between methods of measurement with multiple 
observations per individual, J. Biopharmaceutical Statistics, 17: 571-582. 
16 Tables, Figures and Listings 
Tables and listings will be presented landscape. A font size of 8 and a font of courier new will be used 
throughout for tables and listings. Tables and listings will be provided as a bookmarked pdf. Figures will be 
provided as individual files. 
The subject population being utilized in the table will be indicated in the table title. Page numbers and dates 
of production will be included in an appropriate place at the bottom of the output.  Listings which support 
the table will also be detailed in an appropriate place at the bottom of the output. 
Tables will only be generated where there is sufficient data to warrant the inclusion of the table. 
 


 
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16.1 List of Tables 
 
Table Number 
Table Title 
Population 
Table 14.1.1.1 
Patient Disposition: Double Blind Phase 
All Enrolled Set 
Table 14.1.1.2 
Patient Disposition: First Open Label Phase 
All Enrolled Set 
Table 14.1.1.3 
Patient Disposition: Second Open Label Phase 
All Enrolled Set 
Table 14.1.2.1 
Demographic Characteristics  
All Enrolled Set 
Table 14.1.2.2 
Demographic Characteristics 
All Randomized Set 
Table 14.1.3 
Baseline Characteristics 
All Randomized Set 
Table 14.1.4 
Diagnosis of Neurodevelopmental Disability 
All Randomized Set 
Table 14.1.5 
Melatonin Use 
All Randomized Set 
Table 14.1.6 
Medical History 
All Randomized Set 
Table 14.1.7 
Prior Medications 
All Randomized Set 
Table 14.1.8 
Concomitant Medications - Double Blind Phase 
All Randomized Set 
Table 14.1.9 
Concomitant Medications - First Open Label Phase 
All Randomized Set 
Table 14.1.10 
Concomitant Medications - Second Open Label Phase 
All Randomized Set 
Table 14.2.1.1 
Number of Sleep and Nap Diaries with Data Recorded 
FAS Set 
Table 14.2.1.2 
Number of Sleep and Nap Diaries with a Valid TST 
FAS Set 
Table 14.2.1.3 
SND Total Sleep Time and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.4 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.5 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.1.6 
SND Sleep Latency and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.7 
SND Sleep Latency Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.8 
SND Sleep Latency Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 


 
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Page 36 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.1.9 
SND Duration of Wake and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.10 
SND Duration of Wake Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.11 
SND Duration of Wake Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.1.12 
SND Number of Awakenings and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.13 
SND Number of Awakenings Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.14 
SND Number of Awakenings Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.1.15 
SND Longest Sleep Period and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.16 
SND Longest Sleep Period Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.17 
SND Longest Sleep Period Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.1.18 
SND Total Time in Bed and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.19 
SND Total Time in Bed Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.20 
SND Total Time in Bed Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.1.21 
SND Quality of Sleep and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.22 
SND Quality of Sleep Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.23 
SND Current Alertness and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.24 
SND Current Alertness Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.25 
SND Feeling on Awakening and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.26 
SND Feeling on Awakening Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.27 
SND Number of Naps and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.28 
SND Number of Naps Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.1.29 
SND Duration of Naps and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.1.30 
SND Duration of Naps Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.1 
CSDI Sleep Disturbance Total Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.2 
CSDI Sleep Disturbance Total Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.3 
CSDI Sleep Disturbance Total Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.2.4 
CSDI Sleep Disturbance Problems Settling and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 37 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.2.5 
CSDI Sleep Disturbance Problems Settling Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.6 
CSDI Sleep Disturbance Time to Settle and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.7 
CSDI Sleep Disturbance Time to Settle Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.8 
CSDI Sleep Disturbance Night Awakening and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.9 
CSDI Sleep Disturbance Night Awakening Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.10 
CSDI Sleep Disturbance Time to Resettle and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.11 
CSDI Sleep Disturbance Time to Resettle Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.12 
CSDI Sleep Disturbance Awakening Before 5am and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.13 
CSDI Sleep Disturbance Awakening Before 5am Change from Baseline at 13 Weeks Double Blind – MMRM 
Analysis 
FAS Set 
Table 14.2.2.14 
CSDI Sleep Disturbance Co-Sleeping and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.15 
CSDI Sleep Disturbance Co-Sleeping Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.2.16 
CSDI Sleep Disturbance Satisfaction and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.2.17 
CSDI Sleep Disturbance Satisfaction Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.3.1 
CGAS Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.3.2 
CGAS Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.3.3 
CGAS Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.4.1 
SDQ Total Difficulties Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.2 
SDQ Total Difficulties Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.4.3 
SDQ Total Difficulties Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
Per Protocol Set 
Table 14.2.4.4 
SDQ Impact Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.5 
SDQ Impact Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.4.6 
SDQ Subscale Emotional Symptoms Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.7 
SDQ Subscale Emotional Symptoms Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.4.8 
SDQ Subscale Conduct Problem Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.9 
SDQ Subscale Conduct Problem Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 38 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.4.10 
SDQ Subscale Hyperactivity/Inattention Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.11 
SDQ Subscale Hyperactivity/Inattention Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.4.12 
SDQ Subscale Peer Relationship Problem Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.13 
SDQ Subscale Peer Relationship Problem Score Change from Baseline at 13 Weeks Double Blind – MMRM 
Analysis 
FAS Set 
Table 14.2.4.14 
SDQ Subscale Prosocial Behaviour Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.4.15 
SDQ Subscale Prosocial Behaviour Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.5.1 
Actigraphy Total Sleep Time and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.5.2 
Actigraphy Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.5.3 
Actigraphy Sleep Latency and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.5.4 
Actigraphy Sleep Latency Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.5.5 
Actigraphy Duration of Wake and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.5.6 
Actigraphy Duration of Wake Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.5.7 
Actigraphy Number of Awakenings and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.5.8 
Actigraphy Number of Awakenings Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.5.9 
Actigraphy Longest Sleep Period and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.5.10 
Actigraphy Longest Sleep Period Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.5.11 
Actigraphy Sleep Efficiency and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.5.12 
Actigraphy Sleep Efficiency Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.6.1 
SND Total Sleep Time Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.6.2 
SND Total Sleep Time and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.6.3 
SND Total Sleep Time Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.6.4 
SND Sleep Latency Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.6.5 
SND Sleep Latency and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.6.6 
SND Sleep Latency Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.6.7 
SND Duration of Wake Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 39 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.6.8 
SND Duration of Wake and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.6.9 
SND Duration of Wake Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.6.10 
SND Number of Awakenings Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.6.11 
SND Number of Awakenings and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.6.12 
SND Number of Awakenings Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.6.13 
SND Longest Sleep Period Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.6.14 
SND Longest Sleep Period and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.6.15 
SND Longest Sleep Period Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.6.16 
SND Total Time in Bed Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.6.17 
SND Total Time in Bed and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.6.18 
SND Total Time in Bed Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.6.19 
SND TST Response – Logistic Regression  
FAS Set 
Table 14.2.6.20 
SND Sleep Latency Response – Logistic Regression  
FAS Set 
Table 14.2.6.21 
SND TST Response – Logistic Regression (Non-Missing Data) 
FAS Set 
Table 14.2.6.22 
SND Sleep Latency Response – Logistic Regression (Non-Missing Data) 
FAS Set 
Table 14.2.6.23 
SND Shift in Time to Bed by Scheduled Visit 
FAS Set 
Table 14.2.7.1 
CSDI Sleep Disturbance Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.7.2 
CSDI Sleep Disturbance and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.7.2 
CSDI Sleep Disturbance Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.8.1 
CGAS Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.8.2 
CGAS Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.8.2 
CGAS Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.1 
SDQ Total Difficulties Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.9.2 
SDQ Total Difficulties Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.3 
SDQ Total Difficulties Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.4 
SDQ Impact Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 40 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.9.5 
SDQ Impact Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.6 
SDQ Impact Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.7 
SDQ Subscale Emotional Symptoms Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.9.8 
SDQ Subscale Emotional Symptoms Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.9 
SDQ Subscale Emotional Symptoms Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.10 
SDQ Subscale Conduct Problem Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.9.11 
SDQ Subscale Conduct Problem Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.12 
SDQ Subscale Conduct Problem Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.13 
SDQ Subscale Hyperactivity/Inattention Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.9.14 
SDQ Subscale Hyperactivity/Inattention Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.15 
SDQ Subscale Hyperactivity/Inattention Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.16 
SDQ Subscale Peer Relationship Problem Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.9.17 
SDQ Subscale Peer Relationship Problem Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.18 
SDQ Subscale Peer Relationship Problem Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.9.19 
SDQ Subscale Prosocial Behaviour Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.9.20 
SDQ Subscale Prosocial Behaviour Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.9.21 
SDQ Subscale Prosocial Behaviour Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.10.1 
ESS Caregiver Sleepiness Score and Change from Baseline – Double Blind -  Descriptive Statistics 
FAS Set 
Table 14.2.10.2 
ESS Caregiver Sleepiness Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.10.3 
ESS Caregiver Sleepiness Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.10.4 
ESS Caregiver Sleepiness Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.10.5 
ESS Caregiver Sleepiness Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.11.1 
PSQI Global Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.11.2 
PSQI Global Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.11.3 
PSQI Global Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.11.4 
PSQI Global Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 41 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.11.5 
PSQI Global Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.11.6 
PSQI Component Scores and Change from Baseline – Descriptive Statistics 
FAS Set 
Table 14.2.12.1 
WHO-5 Well-Being Index Score and Change from Baseline – Double Blind - Descriptive Statistics 
FAS Set 
Table 14.2.12.2 
WHO-5 Well-Being Index Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.12.3 
WHO-5 Well-Being Index Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.2.12.4 
WHO-5 Well-Being Index Score and Change from Baseline – Open Label - Descriptive Statistics 
FAS Set 
Table 14.2.12.5 
WHO-5 Well-Being Index Score Change from Baseline Analysis During the Open Label Phase 
FAS Set 
Table 14.2.13.1 
Actigraphy Shift in Time to Bed by Scheduled Visit 
FAS Set 
Table 14.2.13.2 
Number of Responders as per Actigraphy during the Run-In Period 
All Enrolled Set 
Table 14.2.14.1 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MI Analysis 
All Randomized Set 
Table 14.2.14.2 
SND Sleep Latency Change from Baseline at 13 Weeks Double Blind – MI Analysis 
All Randomized Set 
Table 14.2.14.3 
SND Duration of Wake Change from Baseline at 13 Weeks Double Blind – MI Analysis 
All Randomized Set 
Table 14.2.14.4 
SND Number of Awakenings Change from Baseline at 13 Weeks Double Blind – MI Analysis 
All Randomized Set 
Table 14.2.14.5 
SND Longest Sleep Duration Change from Baseline at 13 Weeks Double Blind – MI Analysis 
All Randomized Set 
Table 14.2.14.6 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – BOCF Analysis 
All Randomized Set 
Table 14.2.14.7 
SND Sleep Latency Change from Baseline at 13 Weeks Double Blind – BOCF Analysis 
All Randomized Set 
Table 14.2.14.8 
SND Duration of Wake Change from Baseline at 13 Weeks Double Blind – BOCF Analysis 
All Randomized Set 
Table 14.2.14.9 
SND Number of Awakenings Change from Baseline at 13 Weeks Double Blind – BOCF Analysis 
All Randomized Set 
Table 14.2.14.10 
SND Longest Sleep Duration Change from Baseline at 13 Weeks Double Blind – BOCF Analysis 
All Randomized Set 
Table 14.2.14.11 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Geographic 
Region as a Factor 
FAS Set 
Table 14.2.14.12 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Center as a 
Factor 
FAS Set 
Table 14.2.14.13 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Age as a 
Factor 
FAS Set 
Table 14.2.14.14 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Gender as a 
Factor 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 42 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.14.15 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including ADHD as a 
Factor 
FAS Set 
Table 14.2.14.16 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Autism Type 
as a Factor 
FAS Set 
Table 14.2.14.17 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Epilepsy as a 
Factor 
FAS Set 
Table 14.2.14.18 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior Anti-
Epileptic Treatment as a Factor 
FAS Set 
Table 14.2.14.19 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior Anti-
Depressant Treatment as a Factor 
FAS Set 
Table 14.2.14.20 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior Beta-
Blocker Use as a Factor 
FAS Set 
Table 14.2.14.21 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior ADHD 
Treatment as a Factor 
FAS Set 
Table 14.2.14.22 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior Clonidine 
Use as a Factor 
FAS Set 
Table 14.2.15.1 
CSDI Sleep Disturbance Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including ADHD as a 
Factor 
FAS Set 
Table 14.2.15.2 
CSDI Sleep Disturbance Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Epilepsy as a 
Factor 
FAS Set 
Table 14.2.15.3 
CSDI Sleep Disturbance Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior ADHD 
Treatment as a Factor 
FAS Set 
Table 14.2.15.4 
CSDI Sleep Disturbance Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior 
Clonidine Use as a Factor 
FAS Set 
Table 14.2.16.1 
CGAS Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including ADHD as a Factor 
FAS Set 
Table 14.2.16.2 
CGAS Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Epilepsy as a Factor 
FAS Set 
Table 14.2.16.3 
CGAS Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior ADHD Treatment 
as a Factor 
FAS Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 43 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.2.16.4 
CGAS Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior Clonidine Use as a 
Factor 
FAS Set 
Table 14.2.17.1 
SDQ Total Difficulties Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including ADHD as 
a Factor 
FAS Set 
Table 14.2.17.2 
SDQ Total Difficulties Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Epilepsy 
as a Factor 
FAS Set 
Table 14.2.17.3 
SDQ Total Difficulties Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior 
ADHD Treatment as a Factor 
FAS Set 
Table 14.2.17.4 
SDQ Total Difficulties Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis including Prior 
Clonidine Use as a Factor 
FAS Set 
Table 14.2.18.1 
SND Total Sleep Time and Change from Baseline – Double Blind - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.2 
SND Sleep Latency and Change from Baseline – Double Blind - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.3 
SND Duration of Wake and Change from Baseline – Double Blind - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.4 
SND Number of Awakenings and Change from Baseline – Double Blind - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.5 
SND Longest Sleep Period and Change from Baseline – Double Blind - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.6 
SND Total Sleep Time and Change from Baseline – Open Label - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.7 
SND Sleep Latency and Change from Baseline – Open Label - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.8 
SND Duration of Wake and Change from Baseline – Open Label - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.9 
SND Number of Awakenings and Change from Baseline – Open Label - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.18.10 
SND Longest Sleep Period and Change from Baseline – Open Label - Descriptive Statistics by Final Dose 
FAS Set 
Table 14.2.19 
Summary of Level of Agreement between Sleep and Nap Diary and Actigraphy Assessment of Responder 
FAS Set 
Table 14.3.1.1 
Summary of Study Drug Exposure 
Safety Set 
Table 14.3.1.2 
Summary of Study Drug Modifications 
Safety Set 
Table 14.3.1.3 
% Compliance by Scheduled Visit 
Safety Set 
Table 14.3.1.4 
Dosage Achieved by Scheduled Visit 
Safety Set 
Table 14.3.1.5 
Number of Dropouts -Chi-Square Test 
Safety Set 
Table 14.3.2.1 
Summary of TESS by Scheduled Visit 
Safety Set 


 
Protocol NEU_CH_7911/ P0315 
 
Version: Final 3.0 
Statistical Analysis Plan 
 
10OCT2016 
 
Page 44 of 61 
 
CONFIDENTIAL 
Table Number 
Table Title 
Population 
Table 14.3.2.2 
Overall Adverse Event Summary: Double Blind Phase 
Safety Set 
Table 14.3.2.3 
Overall Adverse Event Summary: Open Label Phase 
Safety Set 
Table 14.3.2.4 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term: Double Blind Phase 
Safety Set 
Table 14.3.2.5 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term: Open Label Phase 
Safety Set 
Table 14.3.2.6 
Serious Adverse Events by System Organ Class and Preferred Term: Double Blind Phase 
Safety Set 
Table 14.3.2.7 
Serious Adverse Events by System Organ Class and Preferred Term: Open Label Phase 
Safety Set 
Table 14.3.2.8 
Treatment Related Adverse Events by System Organ Class and Preferred Term: Double Blind Phase 
Safety Set 
Table 14.3.2.9 
Treatment Related Adverse Events by System Organ Class and Preferred Term: Open Label Phase 
Safety Set 
Table 14.3.2.10 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term and Severity: Double Blind Phase 
Safety Set 
Table 14.3.2.11 
Treatment Emergent Adverse Events by System Organ Class, Preferred Term and Severity: Open Label Phase 
Safety Set 
Table 14.3.2.12 
Treatment Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ Class and Preferred 
Term: Double Blind Phase 
Safety Set 
Table 14.3.2.13 
Treatment Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ Class and Preferred 
Term: Open Label Phase 
Safety Set 
Table 14.3.2.14 
Treatment Emergent Adverse Events on Active Treatment by System Organ Class and Preferred Term:  
Cumulative 
Safety Set 
Table 14.3.2.15 
Serious Adverse Events on Active Treatment by System Organ Class and Preferred Term:  Cumulative 
Safety Set 
Table 14.3.2.16 
Treatment Emergent Adverse Events Study Drug Discontinuation on Active Treatment by System Organ Class and 
Preferred Term:  Cumulative 
Safety Set 
Table 14.3.3 
Vital Sign Parameters and Change from Baseline – Descriptive Statistics 
Safety Set 
Table 14.3.4.1 
Weight and Change from Baseline – Descriptive Statistics 
Safety Set 
Table 14.3.4.2 
Weight and Change from Baseline by Age Group – Descriptive Statistics 
Safety Set 
Table 14.3.4.3 
Height and Change from Baseline – Descriptive Statistics 
Safety Set 
Table 14.3.4.4 
Height and Change from Baseline by Age Group – Descriptive Statistics 
Safety Set 
Table 14.3.5.1 
BMI and Change from Baseline – Descriptive Statistics 
Safety Set 
Table 14.3.5.2 
BMI and Change from Baseline by Age Group – Descriptive Statistics 
Safety Set 
Table 14.3.5.3 
Shift Table of Change in BMI Weight Status 
Safety Set 


 
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Table Number 
Table Title 
Population 
Table 14.3.5.4 
BMI Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.3.5.5 
BMI Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.3.5.6 
BMI Change from Baseline Analysis During the Open Label Phase and Run-Out Period 
FAS Set 
Table 14.3.5.7 
BMI Z-Score and Change from Baseline – Descriptive Statistics 
Safety Set 
Table 14.3.5.8 
BMI Z-Score Change from Baseline at 3 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.3.5.9 
BMI Z-Score Change from Baseline at 13 Weeks Double Blind – MMRM Analysis 
FAS Set 
Table 14.3.5.10 
BMI Z-Score Change from Baseline Analysis During the Open Label Phase and Run-Out Period 
FAS Set 
Table 14.3.6.1 
Summary of Tanner Assessment of Pubertal Development - Staging of Pubic  Hair Growth 
Safety Set 
Table 14.3.6.2 
Summary of Tanner Assessment of Pubertal Development - Staging of Breast Development 
Safety Set 
Table 14.3.6.3 
Summary of Tanner Assessment of Pubertal Development - Staging of Genitalia Development 
Safety Set 
Table 14.3.6.4 
SD Score and Change from Baseline - Pubic  Hair Growth – Descriptive Statistics 
Safety Set 
Table 14.3.6.5 
SD Score and Change from Baseline - Breast Development – Descriptive Statistics 
Safety Set 
Table 14.3.6.6 
SD Score and Change from Baseline - Genitalia Development – Descriptive Statistics 
Safety Set 
Table 14.3.7.1 
Head Circumference and Change from Baseline – Descriptive Statistics 
Safety Set 
Table 14.3.7.2 
Head Circumference and Change from Baseline by Age Group – Descriptive Statistics 
Safety Set 
Table 14.3.8.1 
Number of Epilepsy Seizures in Children Diagnosed with Epilepsy - Categorical Summary 
Safety Set 
Table 14.3.8.2 
Number of Epilepsy Seizures in Children Diagnosed with Epilepsy - Wilcoxon Rank-Sum Test 
Safety Set 
Table 14.3.8.3 
Type of Epilepsy Seizures in Children Diagnosed with Epilepsy 
Safety Set 
 
 
 


 
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16.2 List of Figures 
Figure Number 
Figure Title 
Population 
Figure 14.2.1.1 
Change from Baseline in Mean TST over Time 
FAS Set 
Figure 14.2.1.2 
Change from Baseline in Mean Sleep Latency over Time 
FAS Set 
Figure 14.2.1.3 
Change from Baseline in Mean Duration of Wake over Time 
FAS Set 
Figure 14.2.1.4 
Change from Baseline in Mean Number of Awakenings over Time 
FAS Set 
Figure 14.2.1.5 
Change from Baseline in Mean Longest Sleep Duration over Time 
FAS Set 
Figure 14.2.1.6 
SND Total Sleep Time Change from Baseline at 13 Weeks Double Blind - Empirical Cumulative 
Distribution Plot  
FAS Set 
Figure 14.2.1.7 
SND Sleep Latency Change from Baseline at 13 Weeks Double Blind - Empirical Cumulative 
Distribution Plot 
FAS Set 
Figure 14.2.1.8 
SND Duration of Wake Change from Baseline at 13 Weeks Double Blind - Empirical Cumulative 
Distribution Plot 
FAS Set 
Figure 14.2.1.9 
SND Number of Awakenings Change from Baseline at 13 Weeks Double Blind - Empirical 
Cumulative Distribution Plot 
FAS Set 
Figure 14.2.1.10 
SND Longest Sleep Duration Change from Baseline at 13 Weeks Double Blind - Empirical 
Cumulative Distribution Plot 
FAS Set 
Figure 14.2.2.1 
Total Sleep Time, Sleep and Nap Diary against Actigraphy – Bland and Altman Plots 
FAS Set 
Figure 14.2.2.2 
Sleep Latency, Sleep and Nap Diary against Actigraphy –  Bland and Altman Plots 
FAS Set 
Figure 14.2.2.3 
Duration of Wake, Sleep and Nap Diary against Actigraphy –  Bland and Altman Plots 
FAS Set 
Figure 14.2.2.4 
Number of Awakenings, Sleep and Nap Diary against Actigraphy –  Bland and Altman Plots 
FAS Set 


 
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Figure 14.2.2.5 
Longest Sleep Duration, Sleep and Nap Diary against Actigraphy –  Bland and Altman Plots 
FAS Set 
Figure 14.2.3.1 
Scatterplot of SND TST versus CSDI 
FAS Set 
Figure 14.2.3.2 
Scatterplot of SND TST versus CGAS 
FAS Set 
Figure 14.2.3.3 
Scatterplot of SND TST versus SDQ Total Score 
FAS Set 
Figure 14.2.3.4 
Scatterplot of SND Sleep Latency versus CSDI 
FAS Set 
Figure 14.2.3.5 
Scatterplot of SND Sleep Latency versus CGAS 
FAS Set 
Figure 14.2.3.6 
Scatterplot of SND Sleep Latency versus SDQ Total Score 
FAS Set 
Figure 14.2.3.7 
Scatterplot of SND WASO versus CSDI 
FAS Set 
Figure 14.2.3.8 
Scatterplot of SND WASO versus CGAS 
FAS Set 
Figure 14.2.3.9 
Scatterplot of SND WASO versus SDQ Total Score 
FAS Set 
Figure 14.2.4.1 
Scatterplot of Actigraphy TST versus CSDI 
FAS Set 
Figure 14.2.4.2 
Scatterplot of Actigraphy TST versus CGAS 
FAS Set 
Figure 14.2.4.3 
Scatterplot of Actigraphy TST versus SDQ Total Score 
FAS Set 
Figure 14.2.4.4 
Scatterplot of Actigraphy Sleep Latency versus CSDI 
FAS Set 
Figure 14.2.4.5 
Scatterplot of Actigraphy Sleep Latency versus CGAS 
FAS Set 
Figure 14.2.4.6 
Scatterplot of Actigraphy Sleep Latency versus SDQ Total Score 
FAS Set 
Figure 14.2.4.7 
Scatterplot of Actigraphy WASO versus CSDI 
FAS Set 
Figure 14.2.4.8 
Scatterplot of Actigraphy WASO versus CGAS 
FAS Set 
Figure 14.2.4.9 
Scatterplot of Actigraphy WASO versus SDQ Total Score 
FAS Set 


 
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16.3 List of Listings 
Listings will be sorted by treatment and subject number. 
Listing Number 
Listing Title 
Population 
Listing 16.2.1.1 
Patient Disposition 
All Enrolled Set  
Listing 16.2.1.2 
Informed Consent and Protocol Version 
All Enrolled Set 
Listing 16.2.1.3 
Eligibility 
All Enrolled Set 
Listing 16.2.1.4 
Inclusion and Exclusion Criteria 
All Enrolled Set 
Listing 16.2.2 
Protocol Deviations 
All Randomized Set 
Listing 16.2.3 
Subset Allocation 
All Enrolled Set 
Listing 16.2.4.1 
Demography 
All Enrolled Set 
Listing 16.2.4.2 
Diagnosis of Neurodevelopmental Disability 
All Randomized Set 
Listing 16.2.4.3 
Melatonin Use 
All Randomized Set 
Listing 16.2.4.4 
Medical History 
All Randomized Set 
Listing 16.2.4.5 
Prior and Concomitant Medications 
All Randomized Set 
Listing 16.2.4.6 
Non-Pharmacological Concomitant Measures 
All Randomized Set 
Listing 16.2.5.1 
Study Drug Administration - IMP Compliance 
All Randomized Set 
Listing 16.2.5.2 
Study Drug Administration - Dose Modification 
All Randomized Set 
Listing 16.2.5.3 
Study Drug Administration - Dose Increase (Visit 3 and Visit 5 only) 
All Randomized Set 
Listing 16.2.5.4 
Study Drug Administration - Overall Summary 
All Randomized Set 
Listing 16.2.6.1 
Sleep and Nap Diary 
All Randomized Set 
Listing 16.2.6.2 
Sleep and Nap Diary - Naps 
All Randomized Set 
Listing 16.2.6.3 
Sleep and Nap Diary - Daily Values 
All Randomized Set 
Listing 16.2.6.4 
Sleep Parameters - Sleep and Nap Diary and Actigraphy 
All Randomized Set 
  


 
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Listing Number 
Listing Title 
Population 
Listing 16.2.6.5 
Composite Sleep Disturbance Index 
All Randomized Set 
Listing 16.2.6.6 
Children Global Assessment Scale 
All Randomized Set 
Listing 16.2.6.7 
Strength and Difficulties Questionnaire 
All Randomized Set 
Listing 16.2.6.8 
Strength and Difficulties Questionnaire -Scores 
All Randomized Set 
Listing 16.2.6.9 
Actigraphy 
All Randomized Set 
Listing 16.2.6.10 
Pittsburgh Sleep Quality Index 
All Randomized Set 
Listing 16.2.6.11 
Epworth Sleepiness Scale 
All Randomized Set 
Listing 16.2.6.12 
WHO-5 Well-being Index 
All Randomized Set 
Listing 16.2.7.1 
Treatment Emergent Signs and Symptoms 
All Randomized Set 
Listing 16.2.7.2 
Adverse Events 
All Randomized Set 
Listing 16.2.7.3 
Serious Adverse Events 
All Randomized Set 
Listing 16.2.8 
Serum and Urine Pregnancy Test 
All Randomized Set 
Listing 16.2.9 
Vital Signs 
All Randomized Set 
Listing 16.2.10 
BMI and Z-scores 
All Randomized Set 
Listing 16.2.11 
Tanner Assessment of Pubertal Development 
All Randomized Set 
Listing 16.2.12 
Physical Examination  
All Randomized Set 
Listing 16.2.13 
Epileptic Seizure Diary 
All Randomized Set 
Listing 16.2.14 
Visit Dates 
All Randomized Set 


 
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Appendices 
Appendix A - SAS Program to generate SDQ Scores 
The scoring algorithm is based on the 25 variables plus impact items for each questionnaire. The algorithm 
expects to find these variables with specific names: the first letter of each variable name is 'p' for the 
parent SDQ, 's' for the self-report SDQ and 't' for the teacher SDQ. After this first letter, the variable names 
are as follows: 
consid 
= Item 1 : considerate 
restles 
= Item 2 : restless 
somatic = Item 3 : somatic symptoms 
shares 
= Item 4 : shares readily 
tantrum = Item 5 : tempers 
loner 
= Item 6 : solitary 
obeys 
= Item 7 : obedient 
worries 
= Item 8 : worries 
caring 
= Item 9 : helpful if someone hurt 
fidgety 
= Item 10 : fidgety 
friend 
= Item 11 : has good friend 
fights 
= Item 12 : fights or bullies 
unhappy = Item 13 : unhappy 
popular = Item 14 : generally liked 
distrac 
= Item 15 : easily distracted 
clingy 
= Item 16 : nervous in new situations 
kind 
= Item 17 : kind to younger children 


 
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lies 
= Item 18 : lies or cheats [for the SDQ for 2-4 year olds, replace 'lies' with 'argues'] 
bullied 
= Item 19 : picked on or bullied 
helpout = Item 20 : often volunteers 
reflect 
= Item 21 : thinks before acting 
steals 
= Item 22 : steals [for the SDQ for 2-4 year olds, replace 'steals' with 'spite'] 
oldbest 
= Item 23 : better with adults than with children 
afraid 
= Item 24 : many fears 
attends 
= Item 25 : good attention 
ebddiff 
= Impact question: oveall difficulties in at least one area 
distres 
= Impact question: upset or distressed 
imphome = Impact question: interferes with home life 
impfrie 
= Impact question: interferes with friendships 
impclas 
= Impact question: interferes with learning 
impleis 
= Impact question: interferes with leisure 
For each of these items, if the first response category (not true, no, not at all) has been selected, this is 
coded as zero, the next response category (somewhat true, yes-minor, just a little) is coded as one and so 
on. 
For each informant, the algorithm generates six scores. The first letter of each derived variable is 'p' for 
parent-based scores, 's' for self-report-based scores and 't' for teacher-based scores. After this first letter, 
the names of the scores are as follows: 
emotion = emotional symptoms 
conduct = conduct problems 
hyper 
= hyperactivity/inattention 
peer 
= peer problems 


 
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prosoc = prosocial 
ebdtot = total difficulties 
impact = impact 
 
if pconsid ge 0 then ppr1=1; 
else ppr1=0; 
if pshares ge 0 then ppr2=1; 
else ppr2=0; 
if pcaring ge 0 then ppr3=1; 
else ppr3=0; 
if pkind ge 0 then ppr4=1; 
else ppr4=0; 
if phelpout ge 0 then ppr5=1; 
else ppr5=0; 
pprotot=sum(pconsid,pshares,pcaring,pkind,phelpout); 
pprono=ppr1+ppr2+ppr3+ppr4+ppr5; 
pprosoc=round(pprotot*5/pprono,1); 
if pprono lt 3 then pprosoc=.; 
if ploner ge 0 then ppeer1=1; 
else ppeer1=0; 
if pfriend ge 0 then ppeer2=1; 
else ppeer2=0; 
if ppopular ge 0 then ppeer3=1; 
else ppeer3=0; 
if pbullied ge 0 then ppeer4=1; 
else ppeer4=0; 
if poldbest ge 0 then ppeer5=1; 
else ppeer5=0; 
pfrienx=2-pfriend; 
ppopulax=2-ppopular; 
ppeertot=sum(ploner,pfrienx,ppopulax,pbullied,poldbest); 
ppeerno=ppeer1+ppeer2+ppeer3+ppeer4+ppeer5; 
ppeer=round(ppeertot*5/ppeerno,1); 
if ppeerno lt 3 then ppeer=.; 
if prestles ge 0 then pha1=1; 
else pha1=0; 
if pfidgety ge 0 then pha2=1; 
else pha2=0; 
if pdistrac ge 0 then pha3=1; 
else pha3=0; 
if preflect ge 0 then pha4=1; 
else pha4=0; 
if pattends ge 0 then pha5=1; 
else pha5=0; 
preflecx=2-preflect; 


 
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pattendx=2-pattends; 
phatot=sum(prestles,pfidgety,pdistrac,preflecx,pattendx); 
phano=pha1+pha2+pha3+pha4+pha5; 
phyper=round(phatot*5/phano,1); 
if phano lt 3 then phyper=.; 
if psomatic ge 0 then pem1=1; 
else pem1=0; 
if pworries ge 0 then pem2=1; 
else pem2=0; 
if punhappy ge 0 then pem3=1; 
else pem3=0; 
if pclingy ge 0 then pem4=1; 
else pem4=0; 
if pafraid ge 0 then pem5=1; 
else pem5=0; 
pemtot=sum(psomatic,pworries,punhappy,pclingy,pafraid); 
pemno=pem1+pem2+pem3+pem4+pem5; 
pemotion=round(pemtot*5/pemno,1); 
if pemno lt 3 then pemotion=.; 
if ptantrum ge 0 then pco1=1; 
else pco1=0; 
if pobeys ge 0 then pco2=1; 
else pco2=0; 
if pfights ge 0 then pco3=1; 
else pco3=0; 
if plies ge 0 then pco4=1; 
else pco4=0; 
if psteals ge 0 then pco5=1; 
else pco5=0; 
pobeyx=2-pobeys; 
pcotot=sum(ptantrum,pobeyx,pfights,plies,psteals); 
pcono=pco1+pco2+pco3+pco4+pco5; 
pconduct=round(pcotot*5/pcono,1); 
if pcono lt 3 then pconduct=.; 
pebdtot=pemotion+pconduct+phyper+ppeer; 
pdistrez=pdistres-1 ; 
if pdistres=0 then pdistrez=0; 
pimphomz=pimphome-1 ; 
if pimphome=0 then pimphomz=0; 
pimpfriz=pimpfrie-1 ; 
if pimpfrie=0 then pimpfriz=0; 
pimpclaz=pimpclas-1 ; 
if pimpclas=0 then pimpclaz=0; 
pimpleiz=pimpleis-1 ; 
if pimpleis=0 then pimpleiz=0; 
pimpact=sum(pdistrez,pimphomz,pimpfriz,pimpclaz,pimpleiz); 
if pimpact lt 0 and pebddiff=0 then pimpact=0; 
drop ppr1 ppr2 ppr3 ppr4 ppr5 pprotot pprono 
ppeer1 ppeer2 ppeer3 ppeer4 ppeer5 pfrienx ppopulax ppeertot ppeerno 
pha1 pha2 pha3 pha4 pha5 preflecx pattendx phatot phano 


 
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pem1 pem2 pem3 pem4 pem5 pemtot pemno 
pco1 pco2 pco3 pco4 pco5 sobeyx pcotot pcono; 
 
if sconsid ge 0 then spr1=1; 
else spr1=0; 
if sshares ge 0 then spr2=1; 
else spr2=0; 
if scaring ge 0 then spr3=1; 
else spr3=0; 
if skind ge 0 then spr4=1; 
else spr4=0; 
if shelpout ge 0 then spr5=1; 
else spr5=0; 
sprotot=sum(sconsid,sshares,scaring,skind,shelpout); 
sprono=spr1+spr2+spr3+spr4+spr5; 
sprosoc=round(sprotot*5/sprono,1); 
if sprono lt 3 then sprosoc=.; 
if sloner ge 0 then speer1=1; 
else speer1=0; 
if sfriend ge 0 then speer2=1; 
else speer2=0; 
if spopular ge 0 then speer3=1; 
else speer3=0; 
if sbullied ge 0 then speer4=1; 
else speer4=0; 
if soldbest ge 0 then speer5=1; 
else speer5=0; 
sfrienx=2-sfriend; 
spopulax=2-spopular; 
speertot=sum(sloner,sfrienx,spopulax,sbullied,soldbest); 
speerno=speer1+speer2+speer3+speer4+speer5; 
speer=round(speertot*5/speerno,1); 
if speerno lt 3 then speer=.; 
if srestles ge 0 then sha1=1; 
else sha1=0; 
if sfidgety ge 0 then sha2=1; 
else sha2=0; 
if sdistrac ge 0 then sha3=1; 
else sha3=0; 
if sreflect ge 0 then sha4=1; 
else sha4=0; 
if sattends ge 0 then sha5=1; 
else sha5=0; 
sreflecx=2-sreflect; 
sattendx=2-sattends; 
shatot=sum(srestles,sfidgety,sdistrac,sreflecx,sattendx); 
shano=sha1+sha2+sha3+sha4+sha5; 
shyper=round(shatot*5/shano,1); 
if shano lt 3 then shyper=.; 
if ssomatic ge 0 then sem1=1; 


 
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else sem1=0; 
if sworries ge 0 then sem2=1; 
else sem2=0; 
if sunhappy ge 0 then sem3=1; 
else sem3=0; 
if sclingy ge 0 then sem4=1; 
else sem4=0; 
if safraid ge 0 then sem5=1; 
else sem5=0; 
semtot=sum(ssomatic,sworries,sunhappy,sclingy,safraid); 
semno=sem1+sem2+sem3+sem4+sem5; 
semotion=round(semtot*5/semno,1); 
if semno lt 3 then semotion=.; 
if stantrum ge 0 then sco1=1; 
else sco1=0; 
if sobeys ge 0 then sco2=1; 
else sco2=0; 
if sfights ge 0 then sco3=1; 
else sco3=0; 
if slies ge 0 then sco4=1; 
else sco4=0; 
if ssteals ge 0 then sco5=1; 
else sco5=0; 
sobeyx=2-sobeys; 
scotot=sum(stantrum,sobeyx,sfights,slies,ssteals); 
scono=sco1+sco2+sco3+sco4+sco5; 
sconduct=round(scotot*5/scono,1); 
if scono lt 3 then sconduct=.; 
sebdtot=semotion+sconduct+shyper+speer; 
sdistrez=sdistres-1 ; 
if sdistres=0 then sdistrez=0; 
simphomz=simphome-1 ; 
if simphome=0 then simphomz=0; 
simpfriz=simpfrie-1 ; 
if simpfrie=0 then simpfriz=0; 
simpclaz=simpclas-1 ; 
if simpclas=0 then simpclaz=0; 
simpleiz=simpleis-1 ; 
if simpleis=0 then simpleiz=0; 
simpact=sum(sdistrez,simphomz,simpfriz,simpclaz,simpleiz); 
if simpact lt 0 and sebddiff=0 then simpact=0; 
drop spr1 spr2 spr3 spr4 spr5 sprotot sprono 
speer1 speer2 speer3 speer4 speer5 sfrienx spopulax speertot speerno 
sha1 sha2 sha3 sha4 sha5 sreflecx sattendx shatot shano 
sem1 sem2 sem3 sem4 sem5 semtot semno 
sco1 sco2 sco3 sco4 sco5 sobeyx scotot scono; 
 
if tconsid ge 0 then tpr1=1; 
else tpr1=0; 
if tshares ge 0 then tpr2=1; 


 
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else tpr2=0; 
if tcaring ge 0 then tpr3=1; 
else tpr3=0; 
if tkind ge 0 then tpr4=1; 
else tpr4=0; 
if thelpout ge 0 then tpr5=1; 
else tpr5=0; 
tprotot=sum(tconsid,tshares,tcaring,tkind,thelpout); 
tprono=tpr1+tpr2+tpr3+tpr4+tpr5; 
tprosoc=round(tprotot*5/tprono,1); 
if tprono lt 3 then tprosoc=.; 
if tloner ge 0 then tpeer1=1; 
else tpeer1=0; 
if tfriend ge 0 then tpeer2=1; 
else tpeer2=0; 
if tpopular ge 0 then tpeer3=1; 
else tpeer3=0; 
if tbullied ge 0 then tpeer4=1; 
else tpeer4=0; 
if toldbest ge 0 then tpeer5=1; 
else tpeer5=0; 
tfrienx=2-tfriend; 
tpopulax=2-tpopular; 
tpeertot=sum(tloner,tfrienx,tpopulax,tbullied,toldbest); 
tpeerno=tpeer1+tpeer2+tpeer3+tpeer4+tpeer5; 
tpeer=round(tpeertot*5/tpeerno,1); 
if tpeerno lt 3 then tpeer=.; 
if trestles ge 0 then tha1=1; 
else tha1=0; 
if tfidgety ge 0 then tha2=1; 
else tha2=0; 
if tdistrac ge 0 then tha3=1; 
else tha3=0; 
if treflect ge 0 then tha4=1; 
else tha4=0; 
if tattends ge 0 then tha5=1; 
else tha5=0; 
treflecx=2-treflect; 
tattendx=2-tattends; 
thatot=sum(trestles,tfidgety,tdistrac,treflecx,tattendx); 
thano=tha1+tha2+tha3+tha4+tha5; 
thyper=round(thatot*5/thano,1); 
if thano lt 3 then thyper=.; 
if tsomatic ge 0 then tem1=1; 
else tem1=0; 
if tworries ge 0 then tem2=1; 
else tem2=0; 
if tunhappy ge 0 then tem3=1; 
else tem3=0; 
if tclingy ge 0 then tem4=1; 


 
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else tem4=0; 
if tafraid ge 0 then tem5=1; 
else tem5=0; 
temtot=sum(tsomatic,tworries,tunhappy,tclingy,tafraid); 
temno=tem1+tem2+tem3+tem4+tem5; 
temotion=round(temtot*5/temno,1); 
if temno lt 3 then temotion=.; 
if ttantrum ge 0 then tco1=1; 
else tco1=0; 
if tobeys ge 0 then tco2=1; 
else tco2=0; 
if tfights ge 0 then tco3=1; 
else tco3=0; 
if tlies ge 0 then tco4=1; 
else tco4=0; 
if tsteals ge 0 then tco5=1; 
else tco5=0; 
tobeyx=2-tobeys; 
tcotot=sum(ttantrum,tobeyx,tfights,tlies,tsteals); 
tcono=tco1+tco2+tco3+tco4+tco5; 
tconduct=round(tcotot*5/tcono,1); 
if tcono lt 3 then tconduct=.; 
tebdtot=temotion+tconduct+thyper+tpeer; 
tdistrez=tdistres-1 ; 
if tdistres=0 then tdistrez=0; 
timpfriz=timpfrie-1 ; 
if timpfrie=0 then timpfriz=0; 
timpclaz=timpclas-1 ; 
if timpclas=0 then timpclaz=0; 
timpact=sum(tdistrez,timpfriz,timpclaz); 
if timpact lt 0 and tebddiff=0 then timpact=0; 
drop tpr1 tpr2 tpr3 tpr4 tpr5 tprotot tprono 
tpeer1 tpeer2 tpeer3 tpeer4 tpeer5 tfrienx tpopulax tpeertot tpeerno 
tha1 tha2 tha3 tha4 tha5 treflecx tattendx thatot thano 
tem1 tem2 tem3 tem4 tem5 temtot temno 
tco1 tco2 tco3 tco4 tco5 tobeyx tcotot tcono tdistrez timpfriz timpclaz; 
 
 


 
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Appendix B – SAS Program to generate BMI percentiles and Z scores 
 
************************************************************* 
* This sas program calculates CDC percentiles and z-scores based on  
* the 2000 cdc growth charts 
* (http://www.cdc.gov/growthcharts/cdc_charts.htm.  
* The reference population is children examined in NCHS studies  
* from 1963-65 to 1988-94.  
 
* Biologically implausible values - based on the 1995 WHO cutpoints - are 
flagged,  
* but these values are not necessarily incorrect.  Please see the information  
* on 'Extreme or biologically implausible values' on the web page. 
 
* Unless you have a very good reason to alter this file (and this is unlikely), 
* please do NOT make changes.  This file is meant to be called with a %include 
* statement from your SAS program.   
 
* Program was revised in April 2015 to fix problems with labels and formats 
**************************************************************; 
 
**********************************************; 
*********  macros for calculations ***********; 
**********************************************; 
 
%macro _zscore(var,l, m, s, z, p, f);  
 
if &var >0 then do;   
 
 
if abs(&L) ge 0.01 then &z=((&var / &M)**&L-1)/(&L * &S); 
 
 
  else if .z < abs(&L) < 0.01 then &z=log(&var / &M)/ &S;   
 
 
&p=probnorm(&z)*100; 
 
 
 
 
sdl=((&M - &M*(1 - 2 * &L * &S)**(1 / &L)) / 2);  
 
 
sdh=((&M * (1 + 2 * &L * &S)**(1 / &L) - &M) / 2); 
 
 
 
if &var lt &M then &f= (&var - &M) / sdl; else &f= (&var 
- &M) / sdh;  
 
end;  
%mend _zscore; 
 
%macro _cuts(var,out,l,u); 
 
if &L <= &var <= &u then &out=0;  
 
 
else if &var> &u then &out=1; else if .< &var < &L then &out= -1;  
%mend _cuts; 
 
************ End of Macros ************; 
 
data _orig _mydata _old; set mydata; _id=_n_; length agemos 8 sex 3;  
 
* length and stand_ht are used later in deciding to use  
    * wt-for-stature or wt-for-len reference; 
  if (. < agemos < 24) then do; length=height; end;  
 
if agemos>=24 then stand_ht=height; 
 
  if agemos lt 240 then output _mydata; else output _old;  
  output _orig; 
 
 
  
data _cinage _cinlen _cinht; set _mydata;  
if agemos ge 0 and agemos lt 0.5 then _agecat=0; 


 
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    else _agecat=int(agemos+0.5)-0.5; 
if bmi < 0 & ( weight>0 & height >0 & agemos >=24) then 
bmi=weight/(height/100)**2; 
output _cinage; 
 
if length > . then do; 
    if length >= 45 then _htcat=int(length+0.5)-0.5; 
        if 45 <= length < 45.5 then _htcat=45; 
        output _cinlen;  
 
end; 
if stand_ht > . then do; 
    if stand_ht ge 77.5 then _htcat=int(stand_ht+0.5)-0.5; 
        else if 77<= stand_ht < 77.5 then _htcat=77; 
        output _cinht; 
    end; 
 
 
***********************************************************************; 
*** begin the for-age calcs - note that this calls up the refdir libname; 
data crefage; set refdir.CDCref_d; where denom='age';  
 
*contains all merged LMS data - use 'denom' variable; 
 
length sex 3;  
    proc sort; by sex _agecat;  
proc sort data=_cinage; by sex _agecat; 
 
 
data finfage; merge _cinage (in=a) crefage (in=b); by sex _agecat;  if a; 
    ageint = _agemos2-_agemos1; dage=agemos- _agemos1; 
 
 
array l0  _llg  _mlg  _slg  _lht  _mht  _sht  _lwt  _mwt  _swt _lhc  _mhc  _shc   
 
_lbmi  _mbmi  _sbmi; 
array l1 _llg1 _mlg1 _slg1 _lht1 _mht1 _sht1 _lwt1 _mwt1 _swt1 _lhc1 _mhc1 _shc1  
 
_lbmi1 _mbmi1 _sbmi1; 
array l2 _llg2 _mlg2 _slg2 _lht2 _mht2 _sht2 _lwt2 _mwt2 _swt2 _lhc2 _mhc2 _shc2  
 
_lbmi2 _mbmi2 _sbmi2; 
do over l0; l0= l1 + (dage * (l2 - l1)) / ageint; end; 
 
if agemos < 24 then _mbmi=.; *theres a valid value for 23.5 months! ; 
 
%_zscore(length, _llg, _mlg, _slg, lgz, lgpct, _Flenz);  
 
%_cuts(_flenz, _bivlg, -5, 3); 
%_zscore(stand_ht, _lht, _mht, _sht, stz, stpct, _Fstatz);  
 
%_cuts(_fstatz, _bivst, -5, 3); 
%_zscore(weight, _lwt, _mwt, _swt, waz, wapct, _Fwaz);  
 
%_cuts(_fwaz, _bivwt, -5, 5); 
%_zscore(headcir, _lhc, _mhc, _shc, headcz, headcpct, _Fheadcz);  
 
%_cuts(_fheadcz, _bivhc, -5, 5); 
%_zscore(bmi, _lbmi, _mbmi, _sbmi, bmiz, bmipct, _Fbmiz);  
 
%_cuts(_fbmiz, _bivbmi, -4, 5); 
 
bmi95 = _mbmi * ((1 + _lbmi*_sbmi*probit(0.95))**(1/_lbmi));     
 
bmipct95=100 * (bmi/bmi95);   
 
**% of 95th percentile: m * ((1+l*s*z)^(1/l)); 
 
drop _llg1 _mlg1 _slg1 _lht1 _mht1 _sht1 _lwt1 _mwt1 _swt1 _lhc1 _mhc1 _shc1  
 
_lbmi1 _mbmi1 _sbmi1 _llg2 _mlg2 _slg2 _lht2 _mht2 _sht2 _lwt2 _mwt2 
_swt2  
 
_lhc2 _mhc2 _shc2 _lbmi2 _mbmi2 _sbmi2 _lwht1  _mwht1  _swht1  _lwht2  
 
_mwht2  _swht2  _lwlg1  _mwlg1  _swlg1 _lwlg2  _mwlg2  _swlg2; 
 


 
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******************************************; 
*** begin for-length and for-stand_ht calcs; 
*****************************************; 
 
*** begin for-length calcs, birth to 36 mos; 
proc sort data=_cinlen; by sex _htcat; 
data creflg; set refdir.CDCref_d (keep=denom sex _lg1--_swlg2);   
 
where denom='length'; _htcat=_lg1;  
length sex 3;  
    proc sort data=creflg; by sex _htcat;  
 
data finflg; merge _cinlen (in=a) creflg; by sex _htcat; 
    if a & (43 < length <104);  
    lenint = _lg2- _lg1; dlen=length - _lg1; 
array l  _lwl  _mwl  _swl;  
array l1  _lwlg1  _mwlg1  _swlg1;  
array l2  _lwlg2  _mwlg2  _swlg2; 
do over l; l = l1 + (dlen * (l2 - l1)) / lenint; end; 
 
%_zscore(weight, _lwl, _mwl, _swl, wlz, wlpct, _Fwlz);  
 
%_cuts(_Fwlz,_bivwlg, -4, 5);  
keep _id sex _agecat agemos weight _Fwlz _bivwlg wlz wlpct; 
 
*** begin for-stand_ht calcs, zwtstat.xls; 
proc sort data=_cinht; by sex _htcat; 
data crefht; set refdir.CDCref_d  
 
(keep=denom sex _ht1 _ht2 _lwht1 _lwht2 _mwht1 _mwht2 _swht1 _swht2);  
 
where denom='height';  _htcat=_ht1;  length sex 3;  
 
proc sort data=crefht; by sex _htcat;  
 
data finfht; merge _cinht (in=a) crefht; by sex _htcat; 
    if a & (77 < height <122); 
    htint = _ht2- _ht1; dht=height - _ht1;  
array l   _lwh     _mwh   _swh;  
array l1  _lwht1  _mwht1  _swht1;  
array l2  _lwht2  _mwht2  _swht2; 
do over l; l = l1 + (dht * (l2 - l1)) / htint; end; 
 
%_zscore(weight, _lwh, _mwh, _swh, wstz, wstpct, _Fwstz);    
 
%_cuts(_Fwstz,_bivwst,-4,5); 
keep _id sex _agecat agemos weight _Fwstz _bivwst wstz wstpct; 
 
*** combine the for-age, for-length, and for-height calcs; 
proc sort data=finflg; by _id; proc sort data=finfht; by _id; 
data lenht; merge finflg finfht; by _id;  
 
 
 
proc sort data=finfage; by _id;  
data _outdata; **define height vars as max of standing height and lenth vars; 
  merge finfage lenht; by _id;  
 
 
    array a stz  stpct _bivst _fstatz wstz wstpct _bivwst _fwstz ; 
    array b lgz  lgpct _bivlg _flenz  wlz  wlpct  _bivwlg _fwlz; 
    array c haz  hapct _bivht _Fhaz   whz  whpct  _bivwh _Fwhz; 
 
do over c; if agemos ge 24 then c=a; else c=b; end; 
 
 
/* do over c; c=max(a,b); */ 
 


 
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if .z < weight< 0.01 then do; waz=.; wapct=.; bmiz=.; bmipct=.; whz=.; 
whpct=.; end; 
 
if .z < height< 0.01 then do; haz=.; hapct=.; bmiz=.; bmipct=.; whz=.; 
whpct=.; end; 
 
if .z < headcir< 0.01 then do; headcz=.; headcpct=.; end; 
 
 
 
min= min(of _bivht _bivwt _bivbmi _bivac _bivhc _bivssf _bivtsf _bivwh); 
 
 
if min>=0 then _bivlow=0; else if min= -1 then _bivlow=1; 
 
max= max(of _bivht _bivwt _bivbmi _bivac _bivhc _bivssf _bivtsf _bivwh); 
 
 
if max=0 or max= -1 then _bivhigh=0; else if max= 1 then 
_bivhigh=1; 
 
 
data _outdata; set _outdata; 
keep _Fbmiz _Fhaz _Fheadcz _Flenz _Fstatz _Fwaz _Fwhz _fwstz _Fwlz _bivbmi 
_bivhc  
 
_bivhigh _bivht _bivlg _bivlow _bivst _bivwh _bivwlg _bivwst _bivwt 
agemos bmi bmipct  
 
bmipct95 bmiz height haz stz lgz headcir headcpct headcz _id lgpct sex 
stpct wapct  
 
waz whpct whz hapct wstz wstpct _fstatz; 
 
 data _outdata; set _outdata _old; ** combine with older, excluded people; 
 
label waz='weight-for-age Z'  wapct='weight-for-age percentile' 
_fwaz='modified weight-for-age Z'  
 
 
 
 _bivwt='BIV weight-for-age' 
 
 
haz='height-for-age Z'  hapct='height-for-age percentile'  
_bivht='BIV height-for-age'   
 
 
 
_fhaz='modified height-for-age Z'  
 
 
bmiz='BMI-for-age Z'  bmipct='BMI-for-age percentile' 
_fbmiz='modified BMI-for-age Z'   
 
 
 
_bivbmi='BIV BMI-for-age' bmipct95='% of 95th BMI 
percentile'  
 
 
whz='weight-for-height Z' whpct='weight-for-height percentile'  
 
_bivwh='BIV weight-for-height'   
 
 
 
_fwhz='modified weight-for-height Z'  
 
 
headcz='head_circ-for-age Z' headcpct='head_circ-for age perc'  
 
_Fheadcz='modified head_circ Z'   
 
 
 
_bivhc='BIV head_circ'   
 
 
 
 
_bivlow='any low BIV'  _bivhigh='any high BIV';  
 
proc sort data= _outdata; by _id; proc sort data=_orig; by _id; 
 
data _cdcdata; update _outdata _orig; by _id;   
 
* variables in _orig dataset will overwrite any changes that were made; 
 
drop _id stz stpct _bivst _fstatz wstz wstpct _fwstz  lgz  lgpct _bivlg 
_flenz  _fwlz  
 
 
 
length stand_ht _bivwst _bivwlg;