Effectiveness of E-based Cognitive Behavioral Therapy for Insomnia on Improving Mental Health in Chinese Youths With Insomnia: a Large-scale Randomized Control Trial
Phase: NA
Conditions: Insomnia
Sponsor: Chinese University of Hong Kong

Protocol version 5. 08/12/2022. NCT04069247 
 
1
Trial Protocol 
Project Title: Effectiveness of e-based cognitive behavioral therapy for insomnia on 
improving mental health in Chinese youths with insomnia: a large-scale randomized 
control trial 
 
Introduction 
Depression in Youth 
Youth is a sensitive and critical period of development marked by considerable changes 
in biological, cognitive, psychological and social functioning. It is also a vulnerable 
transitional stage often linked to the emergence of mental health problems. In particular, 
major depressive disorder (MDD) is among the most common psychiatric disorders in the 
youth population, and has become the leading cause of disability adjusted life-years 
(DALYs) for females aged 20-24 year.1 Two large epidemiological surveys reported that 
depressive symptoms were present in 13.8%- 21.0% of college students, and a recent 
meta-analysis showed that the prevalence estimate of depression or depressive symptoms 
among medical students is 27.2%.2-4 Youth depression is associated with substantial 
psychosocial and functional impairments (e.g. poor school achievement, impaired social 
skills, interpersonal difficulties, substance abuse) and an elevated risk of suicidal 
behaviour and completed suicide.5, 6 In addition, youth depression has been found to 
predict recurrent depression in adulthood and be associated with long-term functional 
impairment.7, 8 Although the treatments for youth depression, such as cognitive-
behavioral therapy and interpersonal approaches, have been widely investigated with 
substantial progress, non-response to treatment, residual symptoms and 
relapses/recurrence were commonly reported (e.g. up to 50% of the treated adolescent 
cases experienced a recurrence).9 Moreover, young people are often reluctant to initiate 
help seeking face-to-face for mental health problems, because of the fear of stigma and a 
preference of self-reliance.10 Thus, youth depression is often left untreated. According to 
national surveys conducted in America, only 24% of college students with depression 
were under appropriate treatment.11 In view of its high prevalence, persistence, 
deleterious long-term impacts and treatment challenges, there is an imperative need to 
develop and implement an effective prevention programme for depression, especially 
during early developmental stage, from a public health perspective. 
 
Insomnia as a Target for Prevention of Depression – Rationale, Empirical Basis & 
Research Gaps  
Interplay between insomnia and depression  
Targeting insomnia may become a promising intervention to prevent depression among 
youth, as Insomnia and depression are highly comorbid conditions, with increasing 
evidence suggesting their intricate, bidirectional relationship. In particular, insomnia and 
depression often co-occur, with 35-47% of individuals with insomnia having clinically 
significant depression and 60-84% of people with MDD experiencing comorbid insomnia 
symptoms.12 Rather than a symptom of depression, insomnia is an independent problem 
which commonly precedes the development of depression,13 and has been found to 
increase the risk of developing incident new depression,14, 15 lead to poorer treatment 
response,16 increase the susceptibility of having recurrence,17 and represent an 
independent risk factor for suicidal ideation and behaviour.18-20 This growing body of 

Protocol version 5. 08/12/2022. NCT04069247 
 
2
evidence emphasise the unique, independent role of insomnia in the course of MDD, and 
interventions which directly target insomnia are most likely to improve depression 
outcomes, or may even prevent depression. 
The mechanisms underlying the comorbidity of depression and insomnia have provided 
clues for further validating the preventive effect of insomnia treatments on depression. In 
biological domain, the most widely adopted theory is hyperarousal theory.21, 22 Evidence 
has clearly shown that stress-activated hypothalamic–pituitary–adrenal (HPA) axis 
hyperactivity exists in both depressed and insomniac patients. 23-25 Moreover, arousal 
responses of HPA axis is associated with slow wave sleep deficit and sleep continuity 
disruption in both depression and insomnia.26-28 In psychological domain, maladaptive 
cognitions and behaviors, such as worry, ruminations, vulnerability to stress and poor 
problem solving skills, are implicated in the association between depression and 
insomnia.22, 29 Additionally, a temporal relationship between depression and insomnia 
also favours the idea that effective treatment of insomnia would lower the risk of 
depression. As mentioned above, the occurrence of insomnia commonly precedes 
depression in most cases, and several longitudinal studies have demonstrated that 
previous insomnia was related to subsequent onset of depression.30-33 A meta-analytic 
review revealed that insomniac patients without depression at baseline have a twofold 
risk to develop depression.15 These evidences further indicated that insomnia could play a 
causal role in the onset of depression.26 
 
Cognitive behavioral therapy for insomnia  
Cognitive behavioral therapy for insomnia (CBT-I) is a multi-component, non-
pharmacologic intervention that targets behavioral, cognitive and physiological 
perpetuating factors of insomnia. There is a strong evidence base to support the short-
term and long-term efficacy of CBT-I for chronic primary insomnia in adults.34, 35 A meta-
analysis has validated the comparable treatment efficacy between CBT-I and 
pharmacotherapy during short-term treatment,36 and CBT-I is more effective than 
pharmacotherapy in long-term treatment.37 Additionally, CBT-I can benefit youth other 
than adults. A recent systematic review showed that CBT-I had large effects on various 
sleep variables and medium effects on mental health among college students, whereas 
other psychological interventions such as sleep hygiene and relaxation showed small to 
medium effects for sleep variables.38 Moreover, the preliminary results from our ongoing 
research showed that CBT-I significantly improved insomnia symptoms in adolescent 
patients with insomnia (Trial registration: clinicaltrials.gov Identifier: NCT03522701) 
and could prevent incident acute insomnia in the high-risk adolescents who genetically 
predisposed to insomnia and presented with subclinical insomnia symptoms (Funded by 
General Research Fund, Ref. CUHK 4012-PPR-11). 
 
Apart from its direct effects on sleep improvements, CBT-I can also be effective in 
reducing depressive severity. In line with the findings in previous studies [36, 61-63], our 
research team has validated the effectiveness of CBT-I for improving both depressive and 
insomnia symptoms in patients suffering insomnia and depression (Funded by Health and 
Medical Research Fund, Ref. 10110341). In a randomized trial which compared 
treatment effects of CBT-I and CBT for depression (CBT-D) in patients with comorbid 
MDD and insomnia, CBT-I was more effective than CBT-D in reducing insomnia 

Protocol version 5. 08/12/2022. NCT04069247 
 
3
severity, and equally effective in reducing depressive severity [64], indicating the 
importance of applying insomnia treatment for patients with both insomnia and 
depression. 
 
Digital approach to treatment of insomnia for preventing depression in youth 
While face-to-face CBT-I has shown promise in management of insomnia and psychiatric 
conditions such as depression, several barriers to implementation remain in clinical 
practice. Firstly, face-to-face CBT-I appears to be time-consuming for therapists in 
practice.39 Moreover, there are not enough therapists qualify for offering CBT-I.40, 41 
Thus, it is important to develop alternative delivery modalities of CBT-I which have 
comparable efficacy of standard face-to-face CBT-I and can improve its feasibility. Two 
major variants of CBT-I that may address barriers impacting CBT delivery are internet-
delivered CBT-I (e-CBT-I) and group CBT-I. A recent meta-analysis revealed that e-CBT-
I and face-to-face CBT-I had comparable effects on insomnia and other sleep-related 
symptoms,42 and meta-analysis of group CBT-I showed that group CBT-I is also an 
effective treatment for insomnia, as it has large effect sizes for sleep onset latency, sleep 
efficiency, and wake after sleep onset.43 As for youth with insomnia, a series of studies 
conducted by a research team in University of Amsterdam showed that both e-CBT-I and 
group CBT-I were well accepted and highly feasible with low dropout rates.44, 45 Further, 
two treatment modalities were effective for youth with insomnia and no significant 
differences were found between these two formats. However, this research team found 
that e-CBT-I was more cost effective than group CBT-I in treating youth insomnia.46 
Moreover, internet has the capacity to reach a large group of young people given their 
increased accessibility and frequent use of web and smartphone technology,47, 48 and is 
important in their daily lives.49 Therefore, e-CBT-I may be a preferable alternative for 
youth with insomnia. 
 
Currently, researchers have done considerable work to investigate whether e-CBT-I could 
be effective in improving psychological well-being for adults. To our knowledge, to date 
there is two randomised controlled trial (RCT) to particularly test whether indicated 
preventive intervention for insomnia could prevent depression in adults.50, 51 Christensen 
et al. and Cheng et al. both showed promising results of e-CBT-I in alleviating depressive 
symptoms in their study, and the effects persisted at 1-year follow-up and 18-month 
follow-up, respectively. However, Christensen et al. found that emergence of MDD was 
low in targeted sample and did not conduct clinical assessment at 18-month follow-up. 
By using self-report scale instead of clinical assessment, Cheng et al. found that in those 
with minimal to no depression at baseline, the incidence of moderate to severe depression 
at 1-year follow-up in the dCBT-I condition was less than half that in the control 
condition. Another study further demonstrated that the effects of e-CBT-I on improving 
psychological health were mediated by a reduction of insomnia symptoms.52  
 
Despite these findings, there are some issues of current studies that need to be addressed 
in the future. As the existing data on e-CBT-I mostly came from the studies based on the 
adult samples, little is known as to whether timely intervention of sleep disturbance could 
potentially serve as a preventive measure to alter the trajectory of youth depression. 
Nevertheless, previous studies showed that improving sleep via e-CBT-I in college 

Protocol version 5. 08/12/2022. NCT04069247 
 
4
students leaded to a reduction in psychotic symptoms such as hallucinations and 
paranoia,53 and e-CBT-I could also alleviate anxiety severity in college students with 
insomnia.54 Therefore, further research is warranted to evaluate the effects of e-CBT-I on 
reducing depressive symptoms in youth. Another issue is that it is still unclear by which 
mechanisms e-CBT-I might affect mental health. The improvement of mental health 
achieved with e-CBT-I might simply attribute to the reduction of insomnia symptoms as 
indicated in previous study,52 or it might due to reverse the effects of poor sleep hygiene, 
sleep-related unhelpful thoughts and maladaptive behaviors, circadian rhythm disruption 
and chronic sleep deprivation.54 Additionally, previous studies mainly focused on 
evaluating the changes of psychological outcomes, and only one study showed that e-
CBT-I could lower the risk of depression. In this study, depression was assessed by self-
report scale instead of clinical assessment. Thus, the findings should be replicated and 
assessments that are more reliable should be adopted in other independent studies. 
 
To address the limitations in the existing literature, we propose to conduct a RCT of 
targeted prevention intervention to validate the treatment effect of e-CBT-I on insomnia 
disorder and examine whether digitally delivered insomnia treatment can reduce the risk 
of depression in a high-risk group of youth population. To further explore the 
mechanisms underlying the association between insomnia treatment and depression, we 
will evaluate whether changes in candidate factors including insomnia symptoms, mood 
symptoms, sleep-related unhelpful thoughts and maladaptive behaviours, and circadian 
rhythm disruption will mediate the changes in depressive symptoms. On a conceptual 
level, the proposed interventional study will also allow us to further test the causal 
pathway between sleep disturbance and major depression, by intervening and treating 
insomnia as a preventive measure of depression. On a pragmatic level, digital approach to 
insomnia intervention for prevention of youth depression, if effective, may have 
important public health implications given its high accessibility to the young populations. 
 
Methodology 
Study Design 
A randomized, assessor-blind, parallel group-controlled trial will be conducted in youth 
with insomnia and subclinical depression. All qualified participants will be randomly 
assigned via online system to receive e-CBT-I or health education (HE). Randomization 
will be stratified by sex and the severity of insomnia. Assessments will be carried out at 
baseline, post-treatment, 6-month follow-up and 12-month follow-up. Additional 
assessments will be given upon the completion of sessions 2 (post-session 2) and 4 (post-
session 4) to evaluate sleep symptoms, mood symptoms, circadian rhythms and sleep 
parameters of participants. Saliva collection kit will be mailed to participants at baseline 
to collect their salivary cortisol and DNA, and at 12-month follow-up to collect their 
salivary DNA. Semi-structural individual interviews about user experience and 
satisfaction towards e-CBT-I intervention via phone calls will be given to part of the 
participants in e-CBT-I group after intervention. 
 
Main hypothesis in the present study include: 
1. Youth receiving e-CBT-I will have fewer onsets of depressive disorder and higher rates 
of remission in insomnia disorder at post-intervention, 6-month and 12-month compared 

Protocol version 5. 08/12/2022. NCT04069247 
 
5
to those in control group. 
2. Youth in e-CBT-I group will have fewer insomnia symptoms, depressive symptoms, 
suicidal ideation, plans and attempts than those in control group at each timepoint.  
3. Changes in candidate factors including insomnia symptoms, mood symptoms, 
circadian rhythms and sleep parameters will mediate the outcomes. 
 
Recruitment and Screening 
Potential participants will be recruited from colleges and senior secondary school in 
Hong Kong and mainland China and will be identified from various sources. These will 
include the local partner schools in Hong Kong established from our previous research 
projects. Partner schools in mainland China will be recruited by our collaborators with 
the school links in mainland China. Through our partner schools, students will be 
introduced to this study, and they will be asked to return the signed informed consents 
and leave their contact (e.g., email) in the reply slip to the research team if they are 
interested in taking part in the study. Furthermore, potential participants will be recruited 
through community referrals and advertising via social media and emails in Hong Kong 
and mainland China. Interested participants will be asked to complete the screening 
assessments, including Patient Health Questionnaire-9 (PHQ-9) 55 and Insomnia Severity 
Index (ISI) 56 via an online portal (Qualtrics). Participants who have an ISI score of no 
less than 15 and a PHQ-9 score between 4 and 20 will be further invited for diagnostic 
interview through telephone to screen for insomnia (International Statistical 
Classification of Diseases and Related Health Problems10th Revision Classification of 
Mental and Behavioral Disorders, ICD-10 Classification of Mental and Behavioral 
Disorders 57), MDD and suicidality including ideation, plans and attempts (Mini 
International Neuropsychiatric Interview, MINI 58). A potential participant who meets the 
inclusion criteria (see below) will be eligible to take part in the study. 
 
Participants 
Inclusion criteria and exclusion criteria for participants are as follows:  
Inclusion criteria 
1. Native Han youth in Hong Kong and mainland China, aged between15-25 
2. A diagnosis of insomnia disorder measured by ICD-10 Classification of Mental and 
Behavioral Disorders 
3. The presence of moderate or severe insomnia measured by a score of 15 or above on 
ISI  
4. The presence of subclinical depression assessed by a score of more than 4 but less 
than 20 on PHQ-9  
5. Access to smartphones   
6. Ability to read and understand research protocol 
 
Exclusion criteria 
1. Shift workers 
2. The presence of prominent suicidality (suicide plans and suicide attempts) measured 
by MINI via telephone interview 
3. A clinical diagnosis of psychosis, schizophrenia, bipolar disorder, or 
neurodevelopmental disorders 

Protocol version 5. 08/12/2022. NCT04069247 
 
6
4. Current medical conditions that could cause poor sleep quality and sleep continuity 
disruption, such as eczema  
5. The presence of current MDD or a prior episode of MDD within past two months 
measured by MINI via telephone interview  
6. Women during pregnancy or lactation 
7. Currently receiving psychological treatment for insomnia provided by a psychologist 
and/or pharmacological treatment for depression 
 
Intervention 
The e-CBT-I will be delivered by a mobile application (eSleep) which contains a digital, 
self-paced, and highly interactive programme. The Chinese version (simplified 
Chinese/Mandarin) of the application has been designed to adapt for the language 
background of the participants in China. The program is developed as based on well-
established CBT-I treatment protocol and consists of six 20-30 minutes sequential 
modules unlocked weekly with animated elements, including an overview of sleep, sleep 
restriction, stimulus control, cognitive therapy, structured worry time and relapse 
prevention. During sleep restriction module (session 2), participants will obtain a “sleep 
prescription” from the application, specifying their sleep window (from initial bedtime to 
final arising time) for the next seven days. The setting of the sleep window is based on 
individual’s average total sleep time from the previous week, while adhering to the 5-
hour minimum rule. The sleep prescription is adjusted weekly based on the following 
criteria: 1) if sleep efficiency > 85%, increase sleep window by 15-20 min; 2) if sleep 
efficiency < 80%, decrease sleep window by 15-20 min; and 3) if sleep efficiency is 
between 80%-85%, keep sleep window the same. The application control management 
system provides online analytics, which allows the researchers to monitor individual’s 
participation during the intervention by assessing how many sessions were completed and 
the number of weeks to complete the course. Participants will have access to the e-CBT-I 
treatment for 12 weeks, allowing them additional time to complete the intervention in 
case they were unable to completed it within the initial 6-week period. Individualized text 
messages will be sent to the participants regularly, asking them to complete the treatment 
sessions and sleep diaries on time. The participants will also be contacted weekly to 
prevent possible dropout from occurring during the intervention. The PI and collaborators 
have had the research and clinical experiences in delivering CBT-I, and the e-CBT-I 
treatment protocol has been tested and modified from our previous studies [Trial 
registration: clinicaltrials.gov Identifier: NCT03438331; funded by Early Career Scheme, 
Ref. 27613017] 59. 
 
The HE, a psychoeducation/information-approach, delivered in control group has been 
adopted in the previous study 50. It also consists of six consecutive sessions which 
contains information about general sleep knowledge, functions of human organs, 
nutrition, environmental health, brain health, identification and treatments of common 
diseases, but the contents are not related to any active therapeutic components of CBT-I. 
Each module was unlocked weekly, and participants will have access to the intervention 
for 12 weeks. The general sleep knowledge session was purposively added in this sleep 
related RCT to meet the expectation of the participants. Individualized text messages will 
be sent to the participants regularly to remind them of completing the sessions and sleep 

Protocol version 5. 08/12/2022. NCT04069247 
 
7
diaries on time. The participants will also be contacted weekly to prevent possible 
dropout from occurring during the intervention. 
 
Assessments 
Assessments will be delivered at baseline, post-treatment, 6-month follow-up and 12-
month follow-up. At baseline, all participants will be interviewed for their basic 
demographic and clinical characteristics (age, sex, education, height, weight, current 
medications etc). Self-administered questionnaires will be completed online to assess 
depressive symptoms and severity (PHQ-9), anxiety (Generalised Anxiety Disorder 7-
item, GAD-7 60), suicidal ideation (Beck Scale for Suicide Ideation, BSSI 61), sleep 
symptoms (ISI, 7-Day Daily Sleep Diary), daytime symptoms (Multidimensional Fatigue 
Inventory, MFI 62), chronotype (reduced Morningness-Eveningness Questionnaire, rMEQ 
63), sleep-related thoughts and behaviors (brief version of dysfunctional beliefs and 
attitudes about sleep, DBAS-16 64), circadian rhythms and sleep parameters (7-Day Daily 
Sleep Diary). During the intervention, participants will additionally complete ongoing 
assessments to evaluate their sleep symptoms, mood symptoms and sleep parameters 
(ISI, PHQ-9, GAD-7, 7-Day Daily Sleep Diary) at post-session 2 and post-session 4. 
Saliva collection kit will be mailed to participants at baseline to collect their salivary 
cortisol and DNA, and at 12-month follow-up to collect their salivary DNA. After 
finishing the intervention, each participant will be paid CNY100 (or HKD equivalent) for 
his or her participation. Part of the participants in e-CBT-I group will be invited to 
receive semi-structural individual interviews about user experience and satisfaction 
towards e-CBT-I intervention via phone after intervention, and will be additionally paid 
CNY100 (or HKD equivalent) for his or her participation. 
 
At post-treatment, 6-month follow-up and 12-month follow-up, participants will receive 
phone calls from the independent researcher blinded to the randomization status for 
diagnostic interviews to examine whether they have current insomnia measured by ICD-
10 Classification of Mental and Behavioral Disorders, MDD or suicidality measured by 
MINI. Part of the diagnostic interviews will be audiotaped and second-rated by an 
independent rater to assess interrater reliability after obtaining participants’ consents. In 
addition, participants will complete online questionnaires similar to those at baseline. 
After finishing the 12-month follow-up, each participant will be paid CNY50 (or HKD 
equivalent) for his or her participation. 
 
Outcomes 
The primary outcomes include remission rate of insomnia disorder conformed by ICD-10 
Classification of Mental and Behavioral Disorders, change of insomnia symptoms 
measured by ISI, occurrence of MDD conformed by MINI and change of depressive 
symptoms measured by PHQ-9. Secondary outcomes include incidence of suicidality 
which includes plans and attempts as measured by MINI and change of anxiety 
symptoms measured by GAD-7. Other pre-specified outcome include incidence of 
suicidal ideation measured by BSSI, change of daytime symptoms measured by MFI, 
change of sleep-related thoughts and behaviors measured by DBAS-16, change of 
circadian rhythms measured by 7-Day Daily Sleep Diary and MEQ, and change of sleep 
parameters including time in bed (TIB), total sleep time (TST), sleep onset latency 

Protocol version 5. 08/12/2022. NCT04069247 
 
8
(SOL), wake after sleep onset (WASO), sleep efficiency (SE) measured by 7-Day Daily 
Sleep Diary. 
 
Sample Size Estimation 
The sample size calculation was based on the occurrence of diagnosed depressive 
disorder because the primary aim of the current study was to prevent clinical depression. 
According to the previous meta-analysis, the incidence rate of depression is 
approximately 11% in the individuals with insomnia 15. As the study sample included a 
mixture of individuals without prior depression and those with a history of MDD, an 
expected 50% increase in the cumulative one-year occurrence of diagnosed depressive 
disorder is anticipated (16.5%). Based on the previous research on CBT-I and our trial 
data on sleep-focused treatment for depression, a 50% reduction of occurrence rate is 
expected for the intervention group. Power analysis using Stata suggested that a total of 
282 participants per condition would be required to achieve a power of 0.80 whilst 
allowing a type I error of 0.05 detect a hazard ratio of 0.5 under 1:1 randomization. In 
view of the attrition rate from previous study (40%), a total of 940 participants would be 
required (470 participants in each group x 2 groups). A protocol amendment was 
submitted to reduce the sample size to 708 (354 per group) based on an estimated 
attrition rate of approximately 20%, as it was determined that the attrition rate was lower 
than initially expected. 
 
Data Analysis 
All main analyses will be based on the intent-to-treat (ITT) approach. We aim to obtain 
full follow-up data on every participant, but missing data may be inevitably expected due 
to withdrawal, loss-to-follow-up, or non-response questionnaire items. Baseline 
characteristics will be presented as percentage for categorical variables and as  
means (standard deviations) for continuous variables. The primary and secondary 
outcomes with continuous variables will be examined by using linear mixed-effects 
model (LMM) analysis. The changes of efficacy indicators (e.g., PHQ-9) from baseline to 
each follow-up time points and intervention differences were tested by the MIXED 
module of Stata, with major measures at each time point nested within each participant. 
Interaction effects of group by time will be examined to compare the effects of treatment 
on the major outcomes. Between-group difference in the estimated mean change from 
baseline to each time points from mixed models and Cohen’s d will be used to calculate 
effect sizes. Current MDD will be analyzed by the survival analysis and the Mentel-Cog 
log rank test. An observation will be right censored to the day after the last point of 
interview when a participant is no longer eligible to experience a depressive episode, e.g., 
lost to follow-up or completed the trial without experiencing a depressive episode (12-
month follow-up after intervention). The effect of the intervention on insomnia remission 
will be analyzed using generalized estimating equations (GEE). The GEE analysis will be 
conducted by using the XTGEE module of Stata. Mediation analysis using maximum 
likelihood estimation within a structural equation modeling framework will be used to 
determine which outcomes are mediated by changes in candidate factors including sleep 
symptoms, mood symptoms, sleep-related unhelpful thoughts and maladaptive behaviors, 
circadian rhythm disruption and sleep parameters at follow-up. Sensitivity analyses will 
be conducted using imputation methods to examine the robustness of the results based on 

Protocol version 5. 08/12/2022. NCT04069247 
 
9
different assumptions about the missing data. Strata variables (sex and insomnia severity) 
at baseline will be included as covariates in all analyses. Variables with a p value ≤ 0.05 
will be considered statistically significant.  
 
Ethics & Other Considerations 
All participants will provide their online informed consent before participation. Potential 
adverse effects will be evaluated by self-reporting of existing adverse effects for 
frequency and severity 65. Participants will be excluded from the study and provided with 
information for further treatment if they are diagnosed with MDD or show a suicidal risk 
upon assessments. The proposed study will be conducted in compliance with the 
protocol, the ICH-CGP Guideline, and all other applicable regulatory requirements. The 
ICH shall include the elements required by the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) Guideline and local regulation 
requirements, and will adhere to the ethical principles based on the Declaration of 
Helsinki. 
 
 

Protocol version 5. 08/12/2022. NCT04069247 
 
10
References: 
1. 
Mokdad AH, Forouzanfar MH, Daoud F, Mokdad AA, El Bcheraoui C, Moradi-
Lakeh M, et al. Global burden of diseases, injuries, and risk factors for young people's 
health during 1990-2013: a systematic analysis for the Global Burden of Disease Study 
2013. Lancet. 2016;387(10036):2383-401. 
2. 
Eisenberg D, Gollust SE, Golberstein E, Hefner JL. Prevalence and correlates of 
depression, anxiety, and suicidality among university students. The American journal of 
orthopsychiatry. 2007;77(4):534-42. 
3. 
Rotenstein LS, Ramos MA, Torre M, Segal JB, Peluso MJ, Guille C, et al. 
Prevalence of Depression, Depressive Symptoms, and Suicidal Ideation Among Medical 
Students: A Systematic Review and Meta-Analysis. Jama. 2016;316(21):2214-36. 
4. 
Steptoe A, Tsuda A, Tanaka Y, Wardle J. Depressive symptoms, socio-economic 
background, sense of control, and cultural factors in university students from 23 countries. 
International journal of behavioral medicine. 2007;14(2):97-107. 
5. 
Fergusson DM, Woodward LJ. Mental health, educational, and social role outcomes 
of adolescents with depression. Arch Gen Psychiatry. 2002;59(3):225-31. 
6. 
Gould MS, King R, Greenwald S, Fisher P, Schwab-Stone M, Kramer R, et al. 
Psychopathology associated with suicidal ideation and attempts among children and 
adolescents. J Am Acad Child Adolesc Psychiatry. 1998;37(9):915-23. 
7. 
Fergusson DM, Boden JM, Horwood LJ. Recurrence of major depression in 
adolescence and early adulthood, and later mental health, educational and economic 
outcomes. Br J Psychiatry. 2007;191:335-42. 
8. 
Lewinsohn PM, Rohde P, Klein DN, Seeley JR. Natural course of adolescent major 
depressive disorder: I. Continuity into young adulthood. J Am Acad Child Adolesc 
Psychiatry. 1999;38(1):56-63. 
9. 
Curry J, Silva S, Rohde P, Ginsburg G, Kratochvil C, Simons A, et al. Recovery 
and recurrence following treatment for adolescent major depression. Arch Gen Psychiatry. 
2011;68(3):263-9. 
10. 
Gulliver A, Griffiths KM, Christensen H. Perceived barriers and facilitators to 
mental health help-seeking in young people: a systematic review. BMC Psychiatry. 
2010;10:113. 
11. 
American College Health Association-National College Health Assessment Spring 
2008 Reference Group Data Report (abridged): the American College Health Association. 
Journal of American college health : J of ACH. 2009;57(5):477-88. 
12. 
Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for 
subsequent depression and therapeutic implications. Dialogues in clinical neuroscience. 
2008;10(4):473-81. 
13. 
Fernandez-Mendoza J, Vgontzas AN. Insomnia and its impact on physical and 
mental health. Current psychiatry reports. 2013;15(12):418. 
14. 
Luo C, Zhang J, Pan J. One-year course and effects of insomnia in rural Chinese 
adolescents. Sleep. 2013;36(3):377-84. 
15. 
Baglioni C, Battagliese G, Feige B, Spiegelhalder K, Nissen C, Voderholzer U, et 
al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal 
epidemiological studies. J Affect Disord. 2011;135(1-3):10-9. 
16. 
Manglick M, Rajaratnam SM, Taffe J, Tonge B, Melvin G. Persistent sleep 
disturbance is associated with treatment response in adolescents with depression. The 

Protocol version 5. 08/12/2022. NCT04069247 
 
11
Australian and New Zealand journal of psychiatry. 2013;47(6):556-63. 
17. 
Li S, Chan J, Lam J, Yu M, Wing Y. Can nocturnal sleep disturbances predict non-
remission and relapse in patients with major depressive disorder? VA 5-year naturalistic 
longitudinal study. Sleep medicine. 2013;14:e48. 
18. 
Li SX, Lam SP, Chan JW, Yu MW, Wing YK. Residual sleep disturbances in 
patients remitted from major depressive disorder: a 4-year naturalistic follow-up study. 
Sleep. 2012;35(8):1153-61. 
19. 
Li SX, Lam SP, Yu MW, Zhang J, Wing YK. Nocturnal sleep disturbances as a 
predictor of suicide attempts among psychiatric outpatients: a clinical, epidemiologic, 
prospective study. J Clin Psychiatry. 2010;71(11):1440-6. 
20. 
Pigeon WR, Pinquart M, Conner K. Meta-analysis of sleep disturbance and suicidal 
thoughts and behaviors. The Journal of clinical psychiatry. 2012;73(9):e1160-7. 
21. 
Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science. Sleep Med 
Rev. 2010;14(1):9-15. 
22. 
Riemann D, Spiegelhalder K, Feige B, Voderholzer U, Berger M, Perlis M, et al. 
The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med 
Rev. 2010;14(1):19-31. 
23. 
Rodenbeck A, Huether G, Ruther E, Hajak G. Interactions between evening and 
nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary 
insomnia. Neuroscience letters. 2002;324(2):159-63. 
24. 
Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, et al. 
Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-
pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab. 2001;86(8):3787-94. 
25. 
Young E, Korszun A. Sex, trauma, stress hormones and depression. Molecular 
psychiatry. 2010;15(1):23-8. 
26. 
Staner L. Comorbidity of insomnia and depression. Sleep medicine reviews. 
2010;14(1):35-46. 
27. 
Staner L, Duval F, Haba J, Mokrani MC, Macher JP. Disturbances in hypothalamo 
pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed 
patients. Journal of psychiatric research. 2003;37(1):1-8. 
28. 
Vgontzas AN, Tsigos C, Bixler EO, Stratakis CA, Zachman K, Kales A, et al. 
Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res. 
1998;45(1):21-31. 
29. 
Blake MJ, Trinder JA, Allen NB. Mechanisms underlying the association between 
insomnia, anxiety, and depression in adolescence: Implications for behavioral sleep 
interventions. Clin Psychol Rev. 2018;63:25-40. 
30. 
Buysse DJ, Angst J, Gamma A, Ajdacic V, Eich D, Rossler W. Prevalence, course, 
and comorbidity of insomnia and depression in young adults. Sleep. 2008;31(4):473-80. 
31. 
Johnson EO, Roth T, Breslau N. The association of insomnia with anxiety disorders 
and depression: exploration of the direction of risk. J Psychiatr Res. 2006;40(8):700-8. 
32. 
Roane BM, Taylor DJ. Adolescent insomnia as a risk factor for early adult 
depression and substance abuse. Sleep. 2008;31(10):1351-6. 
33. 
Roberts RE, Shema SJ, Kaplan GA, Strawbridge WJ. Sleep complaints and 
depression in an aging cohort: A prospective perspective. The American journal of 
psychiatry. 2000;157(1):81-8. 
34. 
Morin CM, Bootzin RR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. 

Protocol version 5. 08/12/2022. NCT04069247 
 
12
Psychological and behavioral treatment of insomnia:update of the recent evidence (1998-
2004). Sleep. 2006;29(11):1398-414. 
35. 
Wu JQ, Appleman ER, Salazar RD, Ong JC. Cognitive Behavioral Therapy for 
Insomnia Comorbid With Psychiatric and Medical Conditions: A Meta-analysis. JAMA 
internal medicine. 2015;175(9):1461-72. 
36. 
Smith MT, Perlis ML, Park A, Smith MS, Pennington J, Giles DE, et al. 
Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent 
insomnia. American Journal of Psychiatry. 2002;159(1):5-11. 
37. 
Riemann D, Nissen C, Palagini L, Otte A, Perlis ML, Spiegelhalder K. The 
neurobiology, investigation, and treatment of chronic insomnia. The Lancet Neurology. 
2015;14(5):547-58. 
38. 
Friedrich A, Schlarb AA. Let's talk about sleep: a systematic review of 
psychological interventions to improve sleep in college students. Journal of sleep research. 
2018;27(1):4-22. 
39. 
Yi MJ, Kim TW, Jeong JH, Joo SH, Hong SC, Suh SY. Case Studies of Chronic 
Insomnia Patients Participating in Group Cognitive Behavioral Therapy for Insomnia. 
Sleep Medicine Research (SMR). 2012;3(2):45-9. 
40. 
Everitt H, McDermott L, Leydon G, Yules H, Baldwin D, Little P. GPs' 
management strategies for patients with insomnia: a survey and qualitative interview study. 
The British journal of general practice : the journal of the Royal College of General 
Practitioners. 2014;64(619):e112-9. 
41. 
van der Zweerde T, Lancee J, Slottje P, Bosmans J, Van Someren E, Reynolds C, 
3rd, et al. Cost-effectiveness of i-Sleep, a guided online CBT intervention, for patients with 
insomnia in general practice: protocol of a pragmatic randomized controlled trial. BMC 
psychiatry. 2016;16:85. 
42. 
Zachariae R, Lyby MS, Ritterband LM, O'Toole MS. Efficacy of internet-delivered 
cognitive-behavioral therapy for insomnia - A systematic review and meta-analysis of 
randomized controlled trials. Sleep medicine reviews. 2016;30:1-10. 
43. 
Koffel EA, Koffel JB, Gehrman PR. A meta-analysis of group cognitive behavioral 
therapy for insomnia. Sleep medicine reviews. 2015;19:6-16. 
44. 
de Bruin EJ, Bögels SM, Oort FJ, Meijer AM. Efficacy of Cognitive Behavioral 
Therapy for Insomnia in Adolescents: A Randomized Controlled Trial with Internet 
Therapy, Group Therapy and A Waiting List Condition. Sleep. 2015;38(12):1913-26. 
45. 
de Bruin EJ, Oort FJ, Bogels SM, Meijer AM. Efficacy of internet and group-
administered cognitive behavioral therapy for insomnia in adolescents: a pilot study. 
Behavioral sleep medicine. 2014;12(3):235-54. 
46. 
De Bruin EJ, van Steensel FJ, Meijer AM. Cost-Effectiveness of Group and Internet 
Cognitive Behavioral Therapy for Insomnia in Adolescents: Results from a Randomized 
Controlled Trial. Sleep. 2016;39(8):1571-81. 
47. 
Richardson T, Stallard P, Velleman S. Computerised cognitive behavioral therapy 
for the prevention and treatment of depression and anxiety in children and adolescents: a 
systematic review. Clin Child Fam Psychol Rev. 2010;13(3):275-90. 
48. 
King R, Bambling M, Lloyd C, Gomurra R, Smith S, Reid W, et al. Online 
counselling: The motives and experiences of young people who choose the Internet instead 
of face to face or telephone counselling. Counselling and Psychotherapy Research. 
2006;6(3):169-74. 

Protocol version 5. 08/12/2022. NCT04069247 
 
13
49. 
Burns JM, Davenport TA, Durkin LA, Luscombe GM, Hickie IB. The internet as a 
setting for mental health service utilisation by young people. The Medical journal of 
Australia. 2010;192(11 Suppl):S22-6. 
50. 
Christensen H, Batterham PJ, Gosling JA, Ritterband LM, Griffiths KM, Thorndike 
FP, et al. Effectiveness of an online insomnia program (SHUTi) for prevention of 
depressive episodes (the GoodNight Study): a randomised controlled trial. Lancet 
Psychiatry. 2016;3(4):333-41. 
51. 
Cheng P, Kalmbach DA, Tallent G, Joseph CL, Espie CA, Drake CL. Depression 
prevention via digital cognitive behavioral therapy for insomnia: a randomized controlled 
trial. Sleep. 2019;42(10). 
52. 
Espie CA, Emsley R, Kyle SD, Gordon C, Drake CL, Siriwardena AN, et al. Effect 
of Digital Cognitive Behavioral Therapy for Insomnia on Health, Psychological Well-being, 
and Sleep-Related Quality of Life: A Randomized Clinical Trial. JAMA psychiatry. 2018. 
53. 
Freeman D, Sheaves B, Goodwin GM, Yu LM, Nickless A, Harrison PJ, et al. The 
effects of improving sleep on mental health (OASIS): a randomised controlled trial with 
mediation analysis. Lancet Psychiatry. 2017;4(10):749-58. 
54. 
Morris J, Firkins A, Millings A, Mohr C, Redford P, Rowe A. Internet-delivered 
cognitive behavior therapy for anxiety and insomnia in a higher education context. Anxiety 
Stress Coping. 2016;29(4):415-31. 
55. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression 
severity measure. J Gen Intern Med. 2001;16(9):606-13. 
56. 
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as 
an outcome measure for insomnia research. Sleep Med. 2001;2(4):297-307. 
57. 
Organization WH. The ICD-10 classification of mental and behavioral disorders: 
clinical descriptions and diagnostic guidelines: Geneva: World Health Organization; 1992. 
58. 
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The 
Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation 
of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 
1998;59 Suppl 20:22-33;quiz 4-57. 
59. 
Wing YK, Li AM, Lam JS, Li SX, Kwok AP. Brief integrated sleep-focused 
treatment for persistent sleep disturbance in residual depression: an assessor-blind, parallel 
group, randomised controlled study. Hong Kong Med J. 2018;24 Suppl 2(1):8-11. 
60. 
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing 
generalized 
anxiety 
disorder: 
the 
GAD-7. 
Archives 
of 
internal 
medicine. 
2006;166(10):1092-7. 
61. 
Beck AT, Steer RA, Ranieri WF. Scale for Suicide Ideation: psychometric 
properties of a self-report version. J Clin Psychol. 1988;44(4):499-505. 
62. 
Smets E, Garssen B, Bonke Bd, De Haes J. The Multidimensional Fatigue 
Inventory (MFI) psychometric qualities of an instrument to assess fatigue. Journal of 
psychosomatic research. 1995;39(3):315-25. 
63. 
Adan A, Almirall H. Horne & Östberg morningness-eveningness questionnaire: A 
reduced scale. Personality and Individual Differences. 1991;12(3):241-53. 
64. 
Morin CM, Vallières A, Ivers H. Dysfunctional beliefs and attitudes about sleep 
(DBAS): validation of a brief version (DBAS-16). Sleep. 2007;30(11):1547-54. 
65. 
Kyle SD, Morgan K, Spiegelhalder K, Espie CA. No pain, no gain: an exploratory 
within-subjects mixed-methods evaluation of the patient experience of sleep restriction 

Protocol version 5. 08/12/2022. NCT04069247 
 
14
therapy (SRT) for insomnia. Sleep Med. 2011;12(8):735-47. 
 
 
 

Protocol version 5. 08/12/2022. NCT04069247 
 
15
Appendix: Amendment history 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Details of Changes made 
1 
 
2.0 
 
24/10/2019 Broadened the age range of participants from 18-25 years to 15-
25 years to examine the effectiveness of e-CBT-I in a wider 
population. Wording clarification of the study population being 
youth population instead of college students. 
Wording clarification of the assessments time points. 
Addition of saliva collection, which had to be discontinued later 
due to COVID-19 pandemic. 
Addition to inclusion and exclusion criteria for clarification 
Wording clarification of diagnostic criteria of insomnia disorder 
and outcome measures. 
Addition of a description of the application control management 
system for e-CBT-I. 
Correction of typographic errors. 
2 
3.0 
28/08/2020 Addition of recruitment methods to identify potential 
participants. 
3 
4.0 
07/01/2022 Adding a focus group to investigate the user experience and 
satisfaction towards e-CBT-I intervention. 
Reduced the total sample size from 940 to 708 for a lower attrition 
rate than expected. 
4 
 
5.0 
 
08/12/2022 Addition to assess interrater reliability. 
Correction of typographic errors. 
 
All amendments to the original protocol were approved by the Joint Chinese University of 
Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC Ref. 
No.: 2019.044).