Improving Sleep of Children With Neurodevelopmental Disorders: A Prospective, Randomised Controlled Trial Using Pulsed Current Stimulation Versus Melatonin
Phase: NA
Conditions: Insomnia, Neurodevelopmental Disorders
Sponsor: KK Women's and Children's Hospital

 
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CLINICAL TRIAL PROTOCOL 
 
PROTOCOL TITLE: 
Improving sleep of children with neurodevelopmental disorders: A Prospective Randomised Controlled 
Trial using Transcranial Pulsed Current Stimulation versus Melatonin    
 
 
PROTOCOL VERSION:  
4 
PROTOCOL DATE:  
05/12/2023 
 
PRINCIPAL INVESTIGATOR:  
Dr Ng Zhi Min  
Senior Consultant  
KK Women’s and Children’s Hospital  
 
 
CO-INVESTIGATORS: 
Dr Tan Yi Hua    
Consultant  
KK Women’s and Children’s Hospital  
 
Dr Christopher Ho      
Consultant  
KK Women’s and Children’s Hospital  
 
Dr Yeo Tong Hong     
Senior Consultant  
KK Women’s and Children’s Hospital  
 
Dr Wong Chui Mae     
Senior Consultant  
KK Women’s and Children’s Hospital  
 
Dr Teo Jia Hui 
Associate Consultant 
KK Women’s and Children’s Hospital  
 
Dr Sharon Low  
Senior Consultant  
KK Women’s and Children’s Hospital  
 
Dr Koh Pui San  
 

 
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Staff Registrar 
KK Women’s and Children’s Hospital  
 
Tan Ling Ying 
Senior Staff Nurse  
KK Women’s and Children’s Hospital  
 
Lim Guo Yong  
Pharmacist     
KK Women’s and Children’s Hospital  
 
 
 
 
 

 
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Table of Contents 
1 
BACKGROUND AND RATIONALE .................................................................................................................... 6 
1.1 
GENERAL INTRODUCTION .......................................................................................................................................................... 6 
1.2 
RATIONALE AND JUSTIFICATION FOR THE STUDY .................................................................................................................. 6 
1.2.1 
RATIONALE FOR THE STUDY PURPOSE ..................................................................................................................................... 7 
1.2.2 
RATIONALE FOR DOSES SELECTED ........................................................................................................................................... 7 
1.2.3 
RATIONALE FOR STUDY POPULATION ...................................................................................................................................... 7 
1.2.4 
RATIONALE FOR STUDY DESIGN ............................................................................................................................................... 7 
2 
HYPOTHESIS AND OBJECTIVES ....................................................................................................................... 8 
2.1 
HYPOTHESIS ................................................................................................................................................................................... 8 
2.2 
PRIMARY OBJECTIVES .................................................................................................................................................................. 8 
2.3 
SECONDARY OBJECTIVES ............................................................................................................................................................ 8 
2.4 
POTENTIAL RISKS AND BENEFITS: ............................................................................................................................................. 8 
2.4.1 
POTENTIAL RISKS ......................................................................................................................................................................... 8 
2.4.2 
POTENTIAL BENEFITS .................................................................................................................................................................. 8 
3 
STUDY POPULATION .......................................................................................................................................... 8 
3.1 
LIST THE NUMBER AND NATURE OF SUBJECTS TO BE ENROLLED ...................................................................................... 8 
3.2 
CRITERIA FOR RECRUITMENT AND RECRUITMENT PROCESS ................................................................................................ 8 
3.3 
INCLUSION CRITERIA ................................................................................................................................................................... 9 
3.4 
EXCLUSION CRITERIA .................................................................................................................................................................. 9 
3.5 
SUBJECT REPLACEMENT .............................................................................................................................................................. 9 
4 
STUDY DESIGN ................................................................................................................................................... 10 
4.1 
RANDOMISATION AND BLINDING .......................................................................................................................................... 10 
4.2 
CONTRACEPTION AND PREGNANCY TESTING ..................................................................................................................... 10 
4.3 
STUDY VISITS AND PROCEDURES ............................................................................................................................................ 11 
4.3.1 
SCREENING VISITS AND PROCEDURES ................................................................................................................................... 11 
4.3.2 
STUDY VISITS AND PROCEDURES ............................................................................................................................................ 11 
4.3.3 
FINAL STUDY VISIT: .................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
4.3.4 
POST STUDY FOLLOW UP AND PROCEDURES ......................................................... ERROR! BOOKMARK NOT DEFINED. 
4.4 
DISCONTINUATION/WITHDRAWAL ....................................................................................................................................... 12 
4.4.1 
DISCONTINUATION CRITERIA ................................................................................................................................................. 12 
4.4.2 
DISCONTINUATION VISIT AND PROCEDURES ....................................................................................................................... 12 
5 
TRIAL MATERIALS ............................................................................................................................................. 13 
5.1 
TRIAL PRODUCT (S) .................................................................................................................................................................... 13 
5.2 
STORAGE AND DRUG ACCOUNTABILITY ................................................................ ERROR! BOOKMARK NOT DEFINED. 
6 
TREATMENT ....................................................................................................................................................... 13 
6.1 
RATIONALE FOR SELECTION OF DOSE .................................................................................................................................. 13 
6.2 
STUDY DRUG FORMULATIONS ................................................................................. ERROR! BOOKMARK NOT DEFINED. 
6.3 
STUDY DRUG ADMINISTRATION ............................................................................................................................................. 13 
6.4 
SPECIFIC RESTRICTIONS / REQUIREMENTS ........................................................................................................................... 13 
6.5 
BLINDING .................................................................................................................................................................................... 13 
6.6 
CONCOMITANT THERAPY ......................................................................................................................................................... 13 
7 
SAFETY MEASUREMENTS ................................................................................................................................ 14 
7.1 
DEFINITIONS .............................................................................................................................................................................. 14 
7.2 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO CIRB ................................ 14 
7.3 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) ..................................................................................................................................................................................... 14 
7.4 
SAFETY MONITORING PLAN .................................................................................................................................................... 14 

 
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7.5 
COMPLAINT HANDLING ........................................................................................................................................................... 15 
8 
DATA ANALYSIS .................................................................................................................................................. 15 
8.1 
DATA QUALITY ASSURANCE .................................................................................................................................................... 15 
8.2 
DATA ENTRY AND STORAGE ................................................................................................................................................... 15 
9 
SAMPLE SIZE AND STATISTICAL METHODS .............................................................................................. 15 
9.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................................................................... 15 
9.2 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................................. 15 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................................................... 15 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................................... 16 
12 
ETHICAL CONSIDERATIONS .......................................................................................................................... 16 
12.1 
INFORMED CONSENT ................................................................................................................................................................ 16 
12.2 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ....................................................................................................... 16 
13 
PUBLICATIONS ................................................................................................................................................... 16 
14 
RETENTION OF TRIAL DOCUMENTS .......................................................................................................... 17 
15 
FUNDING AND INSURANCE ........................................................................................................................... 17 
REFERENCES ................................................................................................. ERROR! BOOKMARK NOT DEFINED. 

 
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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title:  
Improving sleep of children with neurodevelopmental disorders: A Prospective Randomised Controlled 
Trial using Transcranial Pulsed Current Stimulation versus Melatonin    
 
Protocol Version: 4 
 
 
Protocol Date: 5/12/2023 
 
 
Industrial Partner: Ascenzion 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described trial in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for 
Good Clinical Practice (GCP). 
 
  
 
 
Principal Investigator Name:  ______NG ZHI MIN ____________ 
                                                            
 
Principal Investigator Signature:  _______________________________________ 
                                                            
 
Date:  __________________________________________ 
                                                            
 
 
 
 
 
 
 

 
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1 
BACKGROUND AND RATIONALE 
 
Children with neurodevelopmental disorders such as cerebral palsy (CP) and autistic spectrum disorder 
(ASD) are found to have poor sleep.i,ii,iii,iv Poor sleep in children with these long-term 
neurodevelopmental conditions may lead to worsening spasticity, increased caregiver burden and poorer 
quality of life.v,vi  
 
Use of Melatonin and other pharmacological sleep aids, treatment of obstructive sleep apnoea and 
application of sleep systems are some of the conventional ways to treat sleep problems in these children. 
In recent years, non-invasive brain stimulation such as transcranial electrical stimulation (TES) has 
emerged as a potential modality treatment to improve sleep in adult patients with major depressive 
disorders, bipolar disorders, migraine and Parkinson’s disease.vii,viii,ix,x TES involves the application of mild 
electrical current by placing electrodes on the scalp, resulting in the modulation of membrane potentials 
of the neurons in the underlying brain cortex.xi TES of frontal brain regions where sleep slow oscillations 
originate, has been found to enhance spontaneous slow oscillatory EEG activity which induces 
sleepiness, ameliorating sleep quality and extending sleep duration.xii,xiii,xiv TES may be delivered in the 
form of transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) 
or transcranial pulsed current stimulation (tPCS). tPCS has increasingly gained attention as a novel safe 
and cost-effective treatment modality for spasticity in children with CP and for improvement of gait in 
adults with Parkinson’s Disease.xv,xvi This mode of therapy could serve as a potential alternative for 
pharmacotherapy in treatment of insomnia in children with neurodevelopmental disorders.xvii,xviii 
However, most studies on sleep intervention used subjective sleep questionnaires and the use of any 
form of TES to improve sleep has not been studied in children. Thus, we aim to objectively evaluate 
whether tPCS can improve sleep in children with neurodevelopmental disorders, as compared to 
Melatonin.  
 
1.1 General Introduction 
 
tPCS is a form of TES that delivers unidirectional pulsed currents at a predetermined frequency to the 
brain cortex, as opposed to the direct current provided by tDCS. (refer Figure A device) It has been 
demonstrated that tPCS increases endogenously generated brain oscillations in a frequency-specific 
manner and facilitates interhemispheric connectivity.xix,xx,xxi,xxii In recent studies, tPCS has shown to 
improve spasticity in children with CP and improve gait and balance in adults with Parkinson’s 
Disease.xv,xvii  It has been postulated that tPCS may also be used to treat sleep difficulties by modulating 
dysfunctional inter-hemispheric coordination within the brain’s default mode network and visual 
pathway, thought to be the core predisposing factors in the aetiology of primary insomnia.xxiii  
 
 
1.2 Rationale and Justification for the Study 
 
Sleep disturbance is a common problem in children with neurodevelopmental disorder. Poor sleep leads 
to worsening spasticity and behaviour and can also affect learning and daytime engagement in school and 
with family members. Many families seek effective and safe interventions to improve sleep of their 
children with neurodevelopmental disorder. Use of Melatonin is a safe treatment option but some 
children may require more sedating pharmacological options to sleep and these medications are not 
without side effects if on long-term use. A safe and non-invasive intervention that can improve sleep in 
children with neurodevelopmental disorder is needed.  
 

 
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1.2.1 
Rationale for the Study Purpose 
 
Considering the clinical need to improve sleep in children with neurodevelopmental disorder and the 
high safety profile of non-invasive TES in childrenxxiv,xxv,xxvi and the potential benefit of high frequency 
transcranial pulsed current stimulation applied at the cerebellum to modulate sleep-cycles, we aim to 
study the effectiveness in improving sleep in children with neurodevelopmental disorder.  
 
1.2.2 
Rationale for Doses Selected 
 
tPCS has been shown to reach subcortical brain targets like the hippocampus from surface application 
on the cortex, to the extent that the hippocampus is associated with deep sleep and is sensitive to 400Hz 
current stimulation in the inducement of LTP, there is a possibility that 400Hz tPCS may modulate sleep 
stages via influencing plasticity of the hippocampal formation.xxvii,xxviii 
 
The cerebellum displays various sorts of rhythmic activities that covers high-frequency oscillations, thus 
artificial resonance similar to intrinstic rhythms (400hz is within the high frequency category) may entrain 
intrinsic oscillations of the cerebellum based on resonance theory.xxix,xxx,xxxi,xxxii Preliminary studies have 
shown that the tDCS in the prefronto-cerebellar area improves sleep quality in euthymic bipolar 
patients.x The human cerebellum is easily accessible to non-invasive stimulation such as TES due to its 
anatomical location, and less painful compared to stimulating the prefrontal brain regions , making it 
more tolerable in children.xxxiii 
 
The low intensity current delivered by tPCS is between 1mA to 2mA, about 800-1000 times weaker than 
conventional electroconvulsive therapy used in treating neuropsychiatry diseases. The working 
mechanism of tPCS has been suggested to involve the induction of static and dynamic current 
components to modulate transmembrane neuronal potentials, which can influence the “excitability-
inhibitory balance” of cortical brain areas and regulate homeostasis in complex internal systems.xix 
 
Based on safety recommendations of TES in children, current intensities of ~1mA are often used, but 
trials up to 2 mA without serious adverse effects have been reported.xxxiv 
 
High frequency 400Hz, cerebello-cerebral tPCS at 1mA, 30mins per day over 12 weeks, has been 
tested in a study on 63 children with Cerebral Palsy, age 2 to 12 years old, to improve gross motor 
functions and spasticity, with no adverse event reported.xv 
 
 
1.2.3 
Rationale for Study Population 
 
Preliminary studies have shown that tPCS was effective in improving spasticity in children with cerebral 
palsy while tDCS was effective in improving behaviour in children with ASD.xv,xxxv,xxxvi This study will 
focus on effectiveness in sleep in this group of population. 
  
1.2.4 
Rationale for Study Design 
 
The unique Two-Period, Four-Sequence (Balaam’s) design is used in this crossover trial in which each 
subject serves as his or her own control. Therefore the estimated treatment differences tend to have less 
variability than that observed in a parallel design. Smaller variability leads to a smaller sample size. Also, 
the repeated- measurements feature of a crossover design eliminates the need for a lengthy run-in or 
baseline period. Moreover, Balaam’s design is a hybrid of a crossover design and a parallel design, 
whereby the estimated treatment difference is unbiased even in the presence of unequal carryover 

 
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effects.xxxvii 
 
HYPOTHESIS AND OBJECTIVES 
 
1.3 Hypothesis 
 
tPCS is effective in improving total sleep time in children with neurodevelopmental disorder.  
 
1.4 Primary Objectives 
 
The primary objective is to assess the effectiveness of tPCS in improving total sleep time by 20% in 
children with neurodevelopmental disorder, compared with using Melatonin.  
 
1.5 Secondary Objectives 
 
The secondary objective is to evaluate improvement in other objective sleep measures such as sleep 
onset latency, sleep efficiency, and wake after sleep onset based on actigraphy; and subjective sleep 
measures such as sleep initiation, sleep maintenance, sleep quality and change in behaviour based on 
questionnaires in children with neurodevelopmental disorder.   
 
We also hypothesise that objective improvement in sleep quality will correlate with a decreased score in 
Sleep Disturbance Scale in Children questionnaire.  
 
1.6 Potential Risks and Benefits:  
 
1.6.1 
Potential Risks 
 
tPCS may cause discomfort or tingling sensation to some people. Some people may have skin redness 
due to allergic reaction to electrode. Few people may complain of headache post stimulation. Otherwise, 
there is minimal risk in tPCS if there are no contraindication. 
 
1.6.2 
Potential Benefits 
 
Use of tPCS is potentially an effective intervention for children with neurodevelopmental disorder that 
can improve spasticity, motor function and sleep.  
 
2 
STUDY POPULATION 
 
2.1 List Number and Nature of Subjects to be enrolled 
 
Based on a two-sided paired t-test at 80% power and 5% one-sided alpha with 20% drop-out rate, a 
sample size of 40 is required to detect 20% improvement in primary end-point (total sleep time), 
assuming 15% standard deviation.  
 
2.2 Criteria for Recruitment and Recruitment Process 
 
The eligible participants will be recruited from the families who receive services and/or medical follow-
up at KKH. Information of the study and Consent Form will be provided to the families who show 
interest in the study.  
 

 
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2.3 Inclusion Criteria 
 
• Aged 4-16 
• Neurodevelopmental disorder including cerebral palsy, autistic spectrum disorder, neurogenetic 
syndrome.   
• Patients whose pre-intervention sleep questionnaire total score more than 46 and/or  pre-
intervention sleep questionnaire T-score more than 70 in any sleep domain 
• Children agree to tPCS as per procedure and consent to the study, including need to shave hair at 
the site of stimulation at the occiput (refer Figure B)  
• Parents/carers agree to bring children to KKH for tPCS as per visit schedule and procedure 
• Medical practitioner’s approval  
 
Figure A: tPCS device 
Figure B: Electrodes on occiput 
 
 
 
 
2.4 On Exclusion Criteria 
 
History of uncontrolled epileptic disorders and seizures, brain tumours or trauma and mental diseases, 
substance abuse or dependence, use of benzodiazepines, neuroleptic, serotonin or dopaminergic 
drugs, presence of metal/ electronic implant in brain/ body eg. shunt, cochlear implant, pacemaker or 
defibrillator, known untreated obstructive sleep apnoea or other sleep disorder, and current involvement 
in other tDCS or rTMS trials. Patients with history of drug allergy to Melatonin will also be excluded.  
 
2.5 Subject Replacement 
 
Drop-out definition: Any participant who reports significant adverse effects, are unable tolerate the 
session, or withdraw from the study will be considered drop-out.   
Subjects who drop out will not be replaced.  
 
 
 
 
 
 
 
 
 
 
 
 

 
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3 
STUDY DESIGN  
 
Figure C: Study Design  
 
                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At baseline (week 0), all patients will do a one-week sleep actigraphy and complete SDSC questionnaire. 
At week 1, patients will be randomised to one of the 4 treatment regimen that is determined by the first 
period of the sequence they are assigned to. Re-evaluation with sleep actigraphy and SDSC questionnaire 
will be done at week 4, 6 and 10.  At week 7, the patients will cross over to the treatment for the second 
period of the sequence they are assigned to. Over the 10-week period, sleep diary will also be completed 
daily.  
 
10 patients will receive dose-appropriate Melatonin over 8 weeks (Group A), 10 patients will receive 40 
sessions of home-based tPCS over 8 weeks (Group D), 10 patients will receive 4 weeks of Melatonin 
then cross over to receive 4 weeks of 20 sessions of home-based tPCS (Group B) and 10 patients will 
receive 4 weeks of 20 sessions of home-based tPCS then cross over to receive Melatonin over 4 weeks 
(Group C).  
 
There will be a washout period of 2 weeks (week 5 and 6) between cross over. Those on a Melatonin 
group cross over will also go through the same washout period.  
 
3.1 Randomisation and Blinding 
 
Randomisation will be conducted for the patients in a 1:1 ratio to two treatment groups in two sequence 
periods.  
 
Randomisation will be carried out by one study team member uninvolved in the final data analysis. The 
study member reporting the actigraphy, and the study member performing data analysis will be blinded.  
 
3.2 Contraception and Pregnancy Testing 
 
Not applicable.  
Group C:10 
10 
* 
Melatonin 
tPCS 
Melatonin 
Melatonin 
tPCS 
tPCS 
tPCS 
Melatonin 
Baseline 
investigation 
Week 0 
1 
4 
6 
5 
7 
Group A:10 
Group B:10 
Group D:10 

 
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3.3 Study Visits and Procedures 
 
Visit to KKH 
Visit 1 
 
Visit 2 
Visit 3 
 
Visit 4 
Timeline 
Week 0 
Week 1-4 
Week 4 
Week 6 
Week 7-10 
Week 10 
Procedure 
Baseline 
assessment 
First 
sequence 
Intervention 
Period 
Post-first 
sequence 
assessment 
Pre-second 
sequence 
assessment  
Second 
sequence 
Intervention 
Period  
Post-
second 
sequence 
assessment 
Informed 
Consent1 
X 
 
 
 
 
 
Questionnaires2 
X 
 
X 
X 
 
X 
Actigraphy3 
X 
 
X 
X 
 
X 
tPCS4 
or 
Melatonin5 
 
X  
 
 
X 
 
 
1Informed Consent will be taken at screening visit, i.e. on the same day as when they are identified as a 
potential participant. Randomisation will be performed after consent taking is completed.  
2Sleep questionnaires 
2.1 Sleep disturbance scale for children (SDSC) and Aberrant Behavior Checklist (ABC)  
2.2 WHO International Classification of Functioning, Disability and Health, Children & Youth version 
(ICF-CY) sleep ratings   
3Actigraphy. Participants will collect the Actiwatch and wear it for 1 week at home for whole night 
actigraphic data at start of the sequence period (Week 0 and Week 6) and at the end of the sequence 
period (Week 4 and Week 10). Patients will return the Actiwatch at the end of the study. 
4Transcranial Pulsed Current Stimulation (tPCS) – for intervention arm. 45min/ session of tPCS will be 
performed at home, supervised by a trained personnel, Monday to Friday for 20 sessions over 4 weeks in 
each sequence period. Participants will be asked to fill out the compliance/ adverse event log daily.  
5In the control group, participants will be given Melatonin over 4 weeks in each sequence period. They 
will be asked to fill out the compliance/ adverse event log daily.  
 
3.3.1 
Screening Visits and Procedures 
 
All KKH patients who are attending outpatient clinics for neurology service and/ or Physiotherapy and 
will be screened accordingly to the inclusion and exclusion criteria as stated in the preceding sections 3.2 
to 3.4 by the doctors in the clinic. Consent will be taken by anyone from the study team.  
 
3.3.2 
Study Visits and Procedures 
 
Baseline 
Prior to commencement of intervention, the patient will undergo: 
I. 
Actigraphy  
Actigraphy is a method used to study sleep-wake patterns and circadian rhythms by assessing 
movement, most commonly of the wrist.xxxviii We will be collecting whole night actigraphic data 
using Actiwatch (Actiwatch 2, Respironics, USA), worn on the nondominant wrist or ankle – 7 
days before intervention commences and in the last week of intervention/control. The four sleep 
statistics include total sleep time [TST (min)], sleep onset latency [SOL or period of time between 
bedtime and sleep start (min)], sleep efficiency [percentage of time in bed actually spent sleeping 
(%)], and wake after sleep onset (WASO) [the time in a sleep interval scored as wake (min)].  
 
II. 
Sleep disturbance scale for children (SDSC) questionnaire  

 
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The SDSC is a 26-item questionnaire that evaluates sleep disturbances including sleep CR 
initiation/maintenance, breathing, arousal, transitions, daytime sleepiness and sweating in 
children. xxxix 
 
III. 
Aberrant Behaviour Checklist (ABC)  
The ABC is a behavior rating scale for the assessment of treatment effect. It consists of 
five factors including (i) Irritability, Agitation, Crying; (ii) Lethargy, Social withdrawal; 
(iii) Stereotypic behaviour; (iv) Hyperactivity, Non-compliance; and (v) Inappropriate 
Speech. This will only be used for participants with autistic spectrum disorder. 
 
IV. 
ICF-CY sleep ratings  
Using the WHO International Classification of Functioning, Disability and Health, Children & 
Youth version (ICF-CY) in the domain of Body Structure/ Function, sleep is evaluated in four 
aspects: amount of sleep (B1340), onset of sleep (B1341), maintenance of sleep (B1342) and 
quality of sleep (B1343).17 Levels of ICF-CY impairment was graded according to frequency, 
intrusiveness or severity: from 0 (no impairment/ difficulty) to 4 (complete/ constant 
impairment/ difficulty/ intensity totally disruptive).18 
 
V. 
EQ5D  
Quality of life measures will be collected and compared between groups. 
 
 
 
Intervention 
Throughout the intervention period of 6 weeks, patients from the intervention arm will be receiving 
tPCS, 0.7-1mA for 45 min/ day Monday to Friday (non-public holiday) over 4 weeks in each sequence 
period. Any adverse event will be recorded in the adverse event log.  
 
Post-intervention 
Intervention group: Participants will wear the Actiwatch for 7 nights-actigraphic data in the last week of 
sequence period. Sleep questionnaires will be completed on the last day of the sequence period. 
 
Control group: Participants will take Melatonin daily at bedtime for 4 weeks and wear the Actiwatch for 
7 nights-actigraphic data in the last week of each sequence period. Sleep questionnaires will be completed 
on the last day of the sequence period.  
 
 
3.4  Discontinuation/Withdrawal 
 
3.4.1 
Discontinuation Criteria 
 
Study intervention will be discontinued if subject is unable to tolerate the tPCS or Melatonin.  
3.4.2 
Discontinuation Visit and Procedures 
 
Subjects may withdraw voluntarily from participation in the study at any time. If withdrawal occurs, 
subjects will still be asked to complete a questionnaire to study the reason for withdrawal. Actigraphy will 
be done (if any) to the point of withdrawal from participation in the study.  
 
 

 
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4 
TRIAL MATERIALS 
 
4.1 Trial Product (s) 
 
HSA CRM notification  
The tPCS is an electrical and neuromuscular stimulator classified as a general medical device. Clinical 
Research Material Notification from Health Science Authority Singapore has been obtained.   
 
Refer Annex B for picture of device.  
Technical Information of the tPCS (AscenZ-IV Multi-channel Pulsed Current Stimulator; Yiqi 
Biotechnology Co. Ltd., China): 
- 
Intensity: 0.7-1mA 
- 
Waveform: Monophasic square wave  
- 
Pulse width: 140µs 
- 
Frequency: 400Hz 
- 
Electrode materials: self-adhesive silica gel patch 
- 
Electrode size: 5*5cm  
 
 
5 
TREATMENT 
 
5.1 Rationale for Selection of Dose of Intervention 
 
1) Based on safety recommendations of TES in children, reduced (~1 mA) current intensities are often 
used, but trials up to 2 mA without serious adverse effects are reported [42].  
2) A study period of 20 sessions of 45 minutes duration is based on manufacturer's clinical experience, 
unpublished data. 
 
5.2 Intervention settings  
 
The intervention is the tPCS and it will be administered by trained personnel of the industrial partner. .    
 
5.3 Intervention Administration 
 
45min/ session of tPCS will be performed at home, supervised by a trained personnel, Monday to Friday 
for 20 sessions over 4 weeks in each sequence period.  
 
5.4 Specific Restrictions / Requirements  
 
Nil as long as exclusion criteria is not met.  
5.5 Blinding 
 
Blinding is not done to the patients. Only the study member reporting the actigraphy, and the study 
member performing data analysis will be blinded.  
 
5.6 Concomitant therapy 
 
Subjects can continue regular standard care.  

 
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6 
SAFETY MEASUREMENTS 
 
6.1 Definitions 
 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect 
 
6.2 Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to CIRB  
 
Only related SAEs (definitely/ probably/ possibly) will be reported to CIRB. Related means there 
is a reasonable possibility that the event may have been caused by participation in the clinical trial.  
Please refer to the CIRB website for more information on Reporting Requirement and Timeline 
for Serious Adverse Events.  
 
The investigator is responsible for informing CIRB after first knowledge that the case qualifies for 
reporting. Follow-up information will be actively sought and submitted as it becomes available.  
 
Related AEs will not be reported to CIRB.  However, the investigator is responsible to keep 
record of such AEs cases at the Study Site File. 
 
6.3 Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to the Health Science 
Authority (HSA) 
 
All SAEs that are unexpected and related to the study drug will be reported to HSA. Please refer 
to the HSA website for more information on Safety Reporting Requirements for Clinical Trials.  
 
6.4 Safety Monitoring Plan 
 
All data will be entered into a secure password-protected document in the desktop. Access to the data 
will only be open to the study investigators. Hardcopy of the data forms will be stored in a locked 
cupboard in the department. 
 
All adverse events of tPCS in all participants will also be logged and safety of tPCS will be monitored by 
the principal investigator.   
 

 
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6.5 Complaint Handling  
 
If there is any complaint of the tPCS, the Principal Investigator will be informed immediately to rectify 
the issue. If the subject is unable to tolerate the tPCS, the study will be discontinued.  
 
 
7 
DATA ANALYSIS 
 
7.1 Data Quality Assurance 
 
The Principal Investigator will ensure accuracy of the data entered. Identifiable patient data will be 
anonymised. Access to the data will only be open to the investigators in the team. 
 
7.2 Data Entry and Storage 
 
All data will be entered into a secure password-protected document in the desktop. Access to the data 
will only be open to the study investigators. The Principal Investigator will ensure accuracy of the data 
entered. Hardcopy of the data forms will be stored in a locked cupboard in the department. 
 
 
8 
SAMPLE SIZE AND STATISTICAL METHODS 
 
8.1 Determination of Sample Size  
 
In an inequality test on data from the Balaam’s crossover design, a sample size of 32 achieves 83% 
power at a 5% significance level when the absolute difference between the two treatment means is 0.2 
and the within-subject standard deviation is 0.15. To account for 20% drop-out rate, a sample size of 40 
(10 in each arm) is required.  
 
8.2 Statistical and Analytical Plans 
 
The SPSS® 25.0 software (IBM, Armonk, New York, United States) will be used, with statistical 
significance defined as a p-value of <0.05. Independent t-tests will be conducted to compare differences 
in outcomes between the two treatment groups; Wilcoxon signed-rank test will be used to compare 
continuous variables at start and end of treatment. Average of actigraphic measurements were used to 
compare effects of treatment on sleep parameters. One-way Repeated Measure ANOVA will be 
conducted to assess changes in outcomes and patient scores within the group across the timepoints. 
Non-parametric testing will also be conducted to observe for significant differences in patient outcomes 
within the groups at each timepoint.   
 
 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator(s)/institution(s) will permit study-related monitoring, audits and/or IRB review and 
regulatory inspection(s), providing direct access to source data/document. 
 
 

 
Version <No. 4>, Dated <05/12/2023> 
Page 16 of 21 
10 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
The principal investigator will ensure adherence with the protocol and accuracy in relation to data entry. 
Quality of the data will be ensured and monitored every month during the study period.   
 
The investigator will maintain essential study documents (protocol and amendments, source 
documentation, relevant correspondence, and all other supporting documentation) in a confidential 
manner as required by the approving ethics committee. 
 
 
11 
ETHICAL CONSIDERATIONS 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with the Good Clinical Practice and the applicable 
regulatory requirements. 
 
This final Clinical Trial Protocol, including the final version of the Participant Information Sheet 
and Consent Form, must be approved in writing by the Centralised Institutional Review Board 
(CIRB) and regulatory approval from Health Sciences Authority (HSA), prior to enrolment of any 
patient into the study. 
 
The principal investigator is responsible for informing the CIRB and HSA of any amendments to 
the protocol or other study-related documents, as per local requirement. 
 
11.1 Informed Consent 
 
In obtaining and documenting informed consent, the investigator will comply with the GCP 
guidelines and to the ethical principles that have their origin in the Declaration of Helsinki. 
Potential participant will be identified by therapist or doctor in KKH/and if inclusion criteria met, 
consent will be signed in the presence of a witness. Consent taking will take place in the clinic 
room or rehab outpatient room. The study investigator will sign the consent and make sure that 
study information is correctly given to the study participant. 
 
If the child has some but not full understanding of the Participant Information Sheet & Consent 
Form (attached to Section P6), (aged 6 and above), the simplified version (i.e. Child/ Participant 
Assent Form) will be used. If the child aged 13 and above, has sufficient understanding of the 
Participant Information Sheet & Consent Form, he will sign it with the parent co-signing in the 
legal guardian section. 
 
11.2 Confidentiality of Data and Patient Records 
 
All data will be entered into a secure password-protected document in the desktop. Identifiable patient 
data will be anonymised. Access to the data will only be open to the study investigators. Hardcopy of the 
data forms will be stored in a locked cupboard in the department. 
 
 
12 
PUBLICATIONS 
 
Following approval by CIRB, the study will be registered on ClinicalTrials.Gov by the Principal 
Investigator. Study results will be published in peer-reviewed scientific literature regardless of the trial’s 

 
Version <No. 4>, Dated <05/12/2023> 
Page 17 of 21 
outcome. The CONSORT 2010 Statement will be adhered to in publication of study findings to ensure 
that international standards of authorship and publication are met.  
 
 
13 
RETENTION OF TRIAL DOCUMENTS 
 
When the study is completed, the research data will be kept in a secure password-protected document in 
the desktop at the department. All the documents will be retained for at least 7 years after completion of 
the research study. 
 
14 
FUNDING and INSURANCE 
 
FUNDING AND RESOURCES  
In cash:  
Item 
Total 
Actigraphy ($2600 x 2) 
$5,600 
Travel allowance  
40 subjects x $50  
$2,000 
Melatonin ($25 for 70s) x 72 
bottles  
$1,800 
Research Coordinator (0.1 FTE 
x 2 years)  
$12,000  
IRB application  
$800 
Presentation 
at 
overseas 
conference 
$3,200 
Total 
$25,000 
 
In-kind contributions:  
KKH will supply the manpower for recruitment of study subjects and carrying out objective assessments 
and questionnaires for the study subjects.  
Ascenzion will supply up to 8 tPCS units and the manpower for carrying out the tPCS for the 
participants during the study period. 
 
 
 
 

 
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Page 19 of 21 
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