Become Your Own SLEEPexpert: a Behavioral Treatment Program for Insomnia in Patients With Psychiatric Disorders
Phase: NA
Conditions: Insomnia Disorder
Sponsor: University of Bern

 
SleepExpert: a behavioral treatment program for insomnia in 
patients with psychiatric disorders 
 
 
 
Ethic Commission of the Canton of Bern Number: 
2020-01897 
 
 
 
 
Document Date: 26.05.2021 
 
 
 
 
 

Clinical Study Protocol 
SleepExpert: a behavioral treatment program for insomnia in 
patients with psychiatric disorders 
Study Type: 
Study Categorisation: 
Study Registration: 
Study Identifier: 
Sponsor-Investigator: 
lnvestigational Product: 
Protocol Version and Date: 
Clinical trial with Medical Device 
Risk category A according to HRA 
Intended Registry: Swiss National Clinical Trial Portal and 
clinicaltrials.gov 
SleepExpert Pilot 
Prof. Dr. Christoph Nissen 
UPO Bern 
Chefarzt, Stv. Ärztlicher Direktor 
Bolligenstrasse 111 
CH-3000 Bern 
christoph.nissen@upd.ch 
Internet-based 
self-help 
program 
("SleepExpert" 
Web 
Application), European CE marking for medical devices: 
approved (released on 01.10.2018) and valid for five years 
Version 4 - 26.05.2021 
CONFIDENTIALITY ST ATEM ENT 
The information contained in this document is confidential and the property of the sponsor-investigator. 
The information may not - in full or in part - be transmitted, reproduced, published, or disclosed to others 
than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) without prior written 
authorisation from the sponsor except to the extent necessary to obtain informed consent from those 
who will participate in the study. 

PROTOCOL SIGNATURE FORM 
Study number 
Study Title 
SleepExpert Pilot 
SleepExpert: a behavioural treatment program for insomnia in 
patients with psychiatric disorders 
The Sponsor-Investigator has approved the protocol version 4 dated 26.05.2021, and confirms hereby 
to conduct the study according to the protocol, current version of the World Medical Association 
Declaration of Helsinki, ISO 14155 norm and the local legally applicable requirements. 
Sponsor-Investigator: 
Name: Prof. Dr. Christoph Nissen 
Bern, 09.06.2021 
Place/Date 
S/eepExperl Pilot, SleepExpert Version 4, 26/05/2021 
Page 2 of 41 

Table of Contents 
STUDY SYNOPSIS 
7 
ABBREVIATIONS 
10 
1. 
STUDY ADMINISTRATIVE STRUCTURE 
11 
1.1 
Study Plan 
11 
1.2 
Sponsor, Sponsor-Investigator 
12 
1.3 
Principal Investigator 
12 
1.4 
Statistician ("Biostatistician") 
12 
1.5 
Laboratory 
12 
1.6 
Monitoring institution 
12 
1.7 
Data Safety Monitoring Committee 
12 
1.8 
Any other relevant Committee, Person, Organisation, Institution 
12 
2. 
ETHICAL AND REGULATORY ASPECTS 
13 
2.1 
Study registration 
13 
2.2 
Categorisation of study 
13 
2.3 
Competent Ethics Committee (CEC) 
13 
2.4 
Competent Authorities (CA) 
13 
2.5 
Ethical Conduct of the Study 
13 
2.6 
Declaration of interest. 
13 
2.7 
Patient Information and Informed Consent. 
14 
2.8 
Participant privacy and confidentiality 
14 
2.9 
Early termination of the study 
14 
2.10 Protocol amendments 
14 
3. 
BACKGROUND AND RATIONALE 
16 
3.1 
Background and Rationale 
16 
3.2 
lnvestigational Product (treatment, device) and Indication 
17 
3.3 
Preclinical Evidence 
17 
3.4 
Clinical Evidence to Date 
17 
3.5 
Dose Rationale / Medical Device: Rationale for the intended purpose in study (pre-market 
MD) 17 
3.6 
Explanation for choice of comparator ( or placebo) 
17 
3.7 
Risks/ Benefits 
18 
3.8 
Justification of choice of study population 
18 
4. 
STUDY OBJECTIVES 
19 
4.1 
Overall Objective 
19 
4.2 
Primary Objective 
19 
4.3 
Secondary Objectives 
19 
4.4 
Exploratory objectives 
19 
4.5 
Safety Objectives 
19 
5. STUDY OUTCOMES 
20 
5.1 
Primary Outcome 
20 
5.2 
Secondary Outcomes 
20 
5.3 
Exploratory Outcomes 
20 
5.4 
Safety Outcomes 
20 
6. STUDY DESIGN 
20 
6.1 
General study design and justification of design 
20 
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Local Principal Investigator at study site*: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ISO 14155 norm 
and the local legally applicable requirements. 
Site 
Principal investigator 
Universitäre Psychiatrische Dienste Bern, UPO 
Prof. Dr. Christoph Nissen 
Bern, 09.06.2021 
Place/Date 
Signature 
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6.2 
Methods of minimising bias 
21 
6.2.1 Randomisation 
21 
6.2.2 Blinding procedures 
21 
6.2.3 Other methods of minimising bias 
21 
6.3 
Unblinding Procedures (Code break) 
21 
7. 
STUDY POPULATION 
22 
7 .1 
Eligibility criteria 
22 
7.2 
Recruitment and screening 
22 
7.3 
Assignment to study groups 
22 
7.4 
Criteria for withdrawal/ discontinuation of participants 
23 
8. 
STUDY INTERVENTION 
24 
8.1 
Identity of lnvestigational Products (treatment/ medical device) 
24 
8.1.1 Experimental Intervention (treatment/ medical device) 
24 
8.1.2 Control Intervention (standard/routine/comparator treatment I medical device) 
25 
8.1.3 Packaging, Labelling and Supply (re-supply) 
25 
8.1.4 Storage Conditions 
25 
8.2 
Administration of experimental and control interventions 
25 
8.2.1 
Experimental Intervention and Control Intervention 
25 
8.2.2 Control Intervention 
25 
8.3 
Dose I Device modifications 
25 
8.4 
Compliance with study intervention 
25 
8.5 
Data Collection and Follow-up for withdrawn participants 
25 
8.6 
Trial specific preventive measures 
25 
8.7 
Concomitant Interventions (treatments) 
26 
8.8 
Medical Device Accountability 
26 
8.9 
Return or Destruction of Medical Device 
26 
9. 
STUDY ASSESSMENTS 
27 
9.1 
Study flow chart(s) I table of study procedures and assessments 
27 
9.2 
Assessments of outcomes 
27 
9.2.1 Assessment of primary outcome 
27 
9.2.2 Assessment of secondary outcomes 
27 
9.2.3 Assessment of exploratory outcomes 
27 
9.2.4 Assessment of safety outcomes 
27 
9.2.5 Assessments in participants who prematurely stop the study 
28 
9.3 
Procedures at each visit 
28 
9.3.1 Screening 
28 
9.3.2 Timepoints TO to T4 
28 
10. SAFETY 
30 
10.1 Drug studies 
30 
10.2 Medical Device Category C studies 
30 
10.3 Medical Device Category A studies 
30 
10.3.1 Foreseeable adverse events and anticipated adverse device effects 
30 
10.3.2 Definition and Assessment of safety related events 
30 
10.3.3 Reporting of Safety related events 
31 
10.4 Assessment, notification and reporting on the use of radiation sources 
31 
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11. STATISTICAL METHODS 
32 
11.1 Hypothesis 
32 
11.2 Determination of Sample Size 
32 
11.3 Statistical criteria of termination of trial 
32 
11.4 Planned Analyses 
32 
11.4.1 Datasets to be analysed, analysis populations 
32 
11.4.2 Primary Analysis 
32 
11.4.3 Secondary Analyses 
33 
11.4.4 Interim analyses 
33 
11.4.5 Safety analysis 
33 
11.4.6 Deviation(s) from the original statistical plan 
33 
11.5 Handling of missing data and drop-outs 
33 
12. QUALITY ASSURANCE AND CONTROL 
34 
12.1 Data handling and record keeping/ archiving 
34 
12.1.1 Case Report Forms 
34 
12.1.2 Specification of source documents 
34 
12.1.3 Record keeping /archiving 
34 
12.2 Data management 
34 
12. 3 Data Management System 
34 
12.4 Data security, access and back-up 
35 
12.4.1 Analysis and archiving 
35 
12.4.2 Electronic and central data validation 
35 
12.5 Monitoring 
35 
12.6 Audits and Inspections 
35 
12.7 Confidentiality, Data Protection 
36 
12.8 Storage of biological material and related health data 
36 
13. PUBLICATION AND DISSEMINATION POLICY 
37 
14. FUNDING AND SUPPORT 
38 
14.1 Funding 
38 
14.2 Other Support 
38 
15. INSURANCE 
38 
16. REFERENCES 
39 
17. APPENDICES 
41 
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Page 6 of 41 

STUDY SYNOPSIS 
Sponsor- 
Prof. Dr. Christoph Nissen 
Investigator: 
Study Títle: 
SleepExpert: a behavioural treatment program for insomnia in patients 
with psychiatric disorders 
Short Title/ Study ID: 
SleepExpert Pilot 
Protocol Version and 
Date: 
Version 4 - 
26/05/2021 
Trial registration: 
intended: clinicaltrials.gov & Swiss National Clinical Trial Portal 
Study category and 
Risk category A according to HRA. The Medical Device has a CE 
Rationale: 
mark.(see below for further explanations) 
Clinical Phase: 
Medical Device Study Risk category A, Phase of development I 
Background and 
Mental disorders are highly prevalent, undertreated, and associated with 
Rationale: 
substantial disability and reduced quality of life (Demyttenaere et al., 
2004). One third of patients with mental disorders comorbidly suffer from 
insomnia disorder according to the Diagnostic and Statistical Manual of 
Mental Disorders (American Psychiatric Association, 2013, S. 5). 
Following current European and American practice guidelines for adult 
patients, cognitive behavioral therapy for insomnia (CBT-1) is the first line 
treatment (Qaseem et al., 2016; Riemann et al., 2017). Various 
adaptations of CBT-1 for different target groups and settings have been 
developed. One of them is Brief Behavioral Treatment for Insomnia (BBT- 
I}, consisting of four sessions centering of bedtime restriction (Troxel et 
al., 2012). This demonstrates that brief versions of CBT-1 can be similarly 
effective as the complete program. The intervention "SleepExpert" is 
based on BBT-1 as a brief version of CBT-1, the first-line treatment for 
insomnia according to current guidelines. There has been a feasibility 
study, however this study was uncontrolled. ln the proposed project, we 
aim to compare treatment as usual (TAU) plus SleepExpert to TAU plus 
sleep monitoring in a pilot randomized controlled trial. The objective is to 
target sleep to improve mental health and to investigate the efficacy of 
SleepExpert for the improvement of sleep and mental health. 
Objective(s ): 
The primary objective is to assess whether there is a significantly greater 
reduction in self-assessed insomnia severity (as measured by the 
Insomnia Severity Index, ISi) across six months (interaction effect Group 
and Timepoint) in patients in the Tau plus SleepExpert group, compared 
to patients in the TAU plus sleep monitoring group. 
The secondary objective is to assess whether there is a significantly 
greater improvement in general mental health (Brief Symptom Inventory) 
across six months (interaction effect Group and Timepoint) in patients in 
the TAU plus SleepExpert group, compared to patients in the TAU plus 
sleep monitoring group. 
Outcome(s): 
The primary outcome will be insomnia severity measured with the 
Insomnia Severity Index (ISi) (Bastien et al., 2001 ). The ISi will be 
administered before the intervention (TO) and one, two, 12, and 26 weeks 
after the start of the intervention 
Study design: 
This project is a prospective randomized controlled clinical pilot trial with 
a cluster-crossover design involving two groups: An interventional group 
(TAU, plus SleepExpert) and a control croup (TAU plus sleep rnonitorinc). 
SleepExpert Pilot, SleepExpert Version 4, 26/05/2021 
Page 7 of 41 

Inclusion / Exclusion 
criteria: 
Inclusion criteria: 
- 
Age 18 years or older 
- 
Documented diagnosis of acute insomnia, i.e. insomnia criteria 
according to ICD-10 for at least 2 weeks (Ellis, Gehrman, Espie, 
Riemann, & Perlis, 2012) 
- 
Insomnia Severity Index (ISi) total score > 7, equivalent to relevant 
insomnia (Gagnon, Bélanger, Ivers, & Morin, 2013) 
- 
Inpatient in one of the two participating psychiatric wards in the UPO 
Bern 
Ability to understand the aims and procedures of the study 
Willingness to participate and ability to provide written informed 
consent 
Exclusion criteria: 
lncabability of judgement 
Inability to participate in a low-threshold behavioral treatment 
program, e.g. due to severe cognitive impairment or high symptom 
severity precluding participation (e.g., severe catatonic symptoms, 
massive hallucinations, acute endangerment to self or others, 
involuntary commitment). Note that the named symptoms will lead to 
exclusion only if they lead to inability to give informed consent or an 
inability to participate in the program. Excluded patients will be re- 
assessed regularly and included if symptoms improve and 
participation is possible at a later point in time. 
Measurements and 
procedures: 
Patients will first be screened and assessed for eligibility. Eligible patients 
who signed the informed consent form will undergo a first assessment (TO) 
and then participate in the intervention. Additional assessments will be 
made one, two, 12, and 26 weeks after the start of the intervention. 
Study Product/ 
Intervention: 
TAU plus "SleepExpert" behavioral treatment program for insomnia (face- 
to-face combined with a web application) 
Control Intervention 
(if applicable): 
Treatment as Usual (TAU) plus sleep monitoring 
Number of 
Participants with 
Rationale: 
Assuming an alpha error level of 0.05 (two-sided) and a power of 0.8, a 
total sample size of n=60 will be sufficient to detect a medium effect 
(Cohen's d=0.65).This is a pilot trial with the primary aim of collecting 
qualitative experience and preliminary efficacy data. 
Study Duration: 
Two years 
Study Schedule: 
Month Year of First-Participant-ln (planned): August 2021 
Month Year of Last-Participant-Out (planned}: January 2024 
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Page 8 of 41 

lnvestigator(s): 
Prof. Dr. Christoph Nissen (Sponsor-lnvestogator) 
Institution: UPO Bern 
Position: 
Chefarzt, Stv. Ärztlicher Direktor 
Address: 
Bolligenstrasse 111, 3000 Bern 
Mail: 
christoph.nissen@upd.ch 
Dr. phil. Elisabeth Hertenstein (Sub-Investigator) 
Institution: UPO Bern 
Position: 
Psychologist 
Address: 
Bolligenstrasse 111, 3000 Bern 
Mail: 
elisabeth.hertenstein@upd.ch 
Study Centre(s): 
Single-centre 
Universitäre Psychiatrische Dienste Bern 
Statistical 
Our primary analysis will be a linear mixed model with the following co- 
Considerations: 
variables: fixed intervention effect (TAU plus Sleep Expert versus TAU plus 
sleep monitoring), fixed baseline ISi score effect, random patient effect 
(multiple ISi scores during follow-up}, random cluster effect. Depending on 
model fit, we may need to simplify the model. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ISO EN 14155 norm as well as 
all national legal and regulatory requirements. 
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Page 9 of41 

ABBREVIATIONS 
AE 
ASR 
BASEC 
CA 
CEC 
CRF 
ClinO 
eCRF 
CTCAE 
DSUR 
GCP 
18 
Ho 
H1 
HRA 
IMP 
IIT 
ICH 
ISO 
ITT 
MD 
MedDO 
Pl 
SAE 
SDV 
SOP 
SPC 
SUSAR 
TMF 
Adverse Event 
Annual Safety Report 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
Competent Authority (e.g. Swissmedic) 
Competent Ethics Committee 
Case Report Form 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OC/in, in Italian: OSRUm) 
Electronic Case Report Form 
Common terminology criteria for adverse events 
Development safety update report 
Good Clinical Practice 
Investigator's Brochure 
Null hypothesis 
Alternative hypothesis 
Federal Act on Research involving Human Beings (in German: HFG, in French: 
LRH, in Italian: LRUm) 
lnvestigational Medicinal Product 
Investigator-initiated Trial 
International 
Council 
for Harmonisation of Technical 
Requirements for 
Pharmaceuticals for Human use 
International Organisation for Standardisation 
Intention to treat 
Medical Device 
Medical Device Ordinance (in German: Mep V, in French: ODim) 
Principal Investigator 
Serious Adverse Event 
Source Data Verification 
Standard Operating Procedure 
Summary of product characteristics 
Suspected Unexpected Serious Adverse Reaction 
Trial Master File 
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1. STUDY ADMINISTRATIVE STRUCTURE 
1.1 
Study Plan 
Table 1. Patient schedule 
screening 
TO Tl 
T2 
T3 
T4 
debriefing*** 
(weekl) (week2) 
(week12) (week 26) 
Time point 
at 
or 
after o 
7±2 
14±2 
84±7 
182±7 
(days) 
admission 
to 
ward until TO 
Eligibility 
X 
screen 
Informed 
x (signature 24 
consent 
hours or more 
after first 
information) 
Medical 
X 
History 
Insomnia 
X 
X 
X 
X 
X 
X 
Severity Index 
Brief Symptom 
X 
X 
X 
Inventory 
Beck 
X 
X 
X 
Depression 
Inventory 
Visual 
X 
X 
X 
X 
X 
analogue 
scales* 
Daily sleep 
X 
X 
X 
X 
Diary** 
Medication 
X 
X 
X 
X 
X 
X 
status 
TAU plus 
SleepExpert 
TAU plus sleep 
monitoring*** 
Adverse 
X 
X 
X 
X 
X 
Events 
* self-constructed visual analogue scales will be used to measure subjective sleep quality, mood, 
concentration, and tiredness 
** the sleep diary will be used continuously throughout the study period (baseline until T4) 
*** debriefing: All patients, i.e. the TAU plus sleep monitoring and TAU plus SleepExpert group will have an 
individual appointment with a sleep expert (physician or psychologist) after completion of the study, i.e. 
after 6 months, in which the gathered information (sleep diaries and actigraphy data) will be discussed and 
individualized further diagnostics and treatments, if needed, will be initiated. 
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1.2 
Sponsor, Sponsor-Investigator 
Name: 
Institution: 
Position: 
Address: 
Mail: 
Prof. Dr. Christoph Nissen 
UPO Bern 
Chefarzt, Stv. Ärztlicher Direktor 
Bolligenstrasse 111, 3000 Bern 
christoph.nissen@upd.ch 
1.3 
Principal Investigator 
Name: 
Prof. Dr. Christoph Nissen 
Institution: 
Position: 
Address: 
Mail: 
UPO Bern 
Chefarzt, Stv. Ärztlicher Direktor 
Bolligenstrasse 111, 3000 Bern 
christoph.nissen@upd.ch 
1.4 
Statistician ("Biostatistician") 
Mattia Branca, PhD 
CTU Bern 
Mittelstrasse 43 
3012 Bern 
mattia.branca@ctu.unibe.ch 
+41316315529 
1.5 
Laboratory 
Not applicable 
1.6 
Monitoring institution 
Clinical Trial Unit- 
CTU, Mittelstrasse 43 I CH-3012 Bern 
1.7 
Data Safety Monitoring Committee 
A DSMC is not needed because the study doesn't come along with great risks. 
1.8 
Any other relevant Committee, Person, Organisation, Institution 
Not applicable. 
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2. 
ETHICAL AND REGULATORY ASPECTS 
The decision of the CEC concerning the conduct of the study will be made in writing to the Sponsor- 
Investigator before commencement of this study. The clinical study can only begin once approval from 
all required authorities has been received. Any additional requirements imposed by the authorities shall 
be implemented. 
2.1 
Study registration 
Intended registry: clinicaltrials.gov & Swiss National Clinical Trial Portal 
2.2 
Categorisation of study 
The psychotherapeutic protocol used in this study (Cognitive Behavioral Therapy for Insomnia) is non- 
invasive. Comparable therapeutic protocols have been thoroughly investigated in patients with insomnia 
without adverse events. Sleep restriction as used in this therapy may be associated with temporary 
daytime sleepiness. No long-lasting or serious adverse effects of these psychotherapies are known. ln 
addition, multiple previous studies have shown that Cognitive Behavioral Therapy for insomnia is also 
feasible as an online application. The new aspect of this study is a change of the target group: instead 
of patients with insomnia only, the intervention will be applied in patients with insomnia and mental 
disorders (both disorder groups are category Fin the ICD-10). We have no reason to assume that the 
psychotherapeutic protocol is associated with unexpected risks in this target group. The internet-based 
self-help program platform developed by Prof. Thomas Berger, University of Bern, that will be used in 
this study has received a CE mark in 2018 that is valid for 5 years. All examinations and interventions 
in this study are in accordance with current safety standards and the risk associated with a participation 
in this study is regarded as minimal. Thus, this study belongs to category A. 
2.3 
Competent Ethics Committee (CEC) 
The Sponsor-Investigator ensures that approval from an appropriately constituted Competent Ethics 
Committee (CEC; Kantonale Ethikkommission (KEK) Bern) is sought for the clinical study. 
The Sponsor-Investigator further ensures that no changes will be made to the protocol or in research 
activities without his prior approval and, in case of significant changes according to ClinO Art.29, CEC 
approval. Exempt from this requirement are measures, which have to be taken immediately in order to 
protect the study participants. Any safety or protective measures that have to be taken during the 
conduct of the clinical trial due to unanticipated risks to humans will be reported to the CEC within 7 
days. Amendments will be reported according to section 2.1 O and intermediary reports (annual safety 
reports) will be forwarded to the CECs yearly. 
Premature study end or interruption of the study will be reported within 15 days. The regular end of the 
study will be reported to the CECs within 90 days and the final study report shall be submitted within 
one year after study end. 
2.4 
Competent Authorities (CA) 
Approval from Swissmedics is not necessary because this is a category A study. 
2.5 
Ethical Conduct of the Study 
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the European Regulation on medical devices 2017/745 and the 
ISO Norm 14155 and ISO 14971, the Swiss Law and Swiss regulatory authority's requirements. The 
CEC and regulatory authorities will receive annual safety and interim reports and be informed about 
study stop/end in agreement with local requirements. 
2.6 
Declaration of interest 
The investigators of this study have no intellectual, financial, proprietary or other conflict of interest 
related to the proposed study. 
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Page 13 of 41 

2.7 
Patient Information and Informed Consent 
The investigators will explain the following to each potential participant: 
• The nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits and any discomfort it may entail 
• That participation in the study is voluntary and that he/she may withdraw from the study at any 
time 
• That withdrawal of consent only will terminate study related treatment and investigations, but 
not affect subsequent medical assistance and treatment 
• That the participant's medical records may be examined by authorised individuals other than 
their treating physician 
During the informed consent procedure, the candidate will have the opportunity to ask questions 
concerning the study and he or she will receive a patient information sheet and a consent form 
describing the study. The patient information sheet will provide all the information necessary for the 
candidate to make an informed decision about study participation. 
The candidate should read and consider the patient information and be given at least 24 hours to 
consider study participation. 
When willing to take part in the study, the candidate will sign and date the informed consent form. The 
investigator having discussed the study with the participant must also sign and date the form. The signed 
form will be retained as part of the study records, and a copy will be given to the participant. 
The formal consent of a participant, using the approved consent form, will be obtained before the 
participant is submitted to any study specific procedure. 
Asymmetric information of patients on wards randomized to the control- vs. intervention-arm will be 
performed because patients in the control-arm have no opportunity to receive the treatment and thus 
information about SleepExpert may be demotivating. All patients, including those in the control arm, will 
receive treatment as usual, i.e. psychiatric treatment following the current standard clinical practice 
according to clinical guidelines. Whether or not SleepExpert has an additional benefit is the research 
question of the proposed trial, but is not yet clear. Thus, it is ethical to not give SleepExpert to the 
patients in the control arm and to not inform them about the intervention. 
2.8 Participant privacy and confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured using unique 
subject identification code numbers to correspond to treatment data in any computer files. 
The investigators affirm and uphold the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals. 
For study related monitoring, audits, EC review and CA inspections, the investigator will provide direct 
access to source data and source documents including parts of patients' medical record relevant to the 
study (e.g. medical history) to authorised representatives of the Sponsor-Investigator, the CA, or a CEG. 
2.9 
Early termination of the study 
Based on general expertise regarding the significance of the accumulating data, or other important 
reasons such as accumulating external evidence, quality concerns etc. the Sponsor-Investigator may 
terminate the study at any time. Termination will be in accordance with relevant regulatory, scientific, 
and ethical principles. 
Premature study end or interruption of the study will be reported to the CEG to chapter 2.3. 
2.10 Protocol amendments 
Substantial amendments are only implemented after approval of the CEC. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety, and well- 
being of human subjects may proceed without prior approval of the sponsor and the CEG. Such 
deviations shall be documented and reported to the Sponsor-Investigator and the CEG as soon as 
possible. 
All non-substantial amendments are communicated to the CEG within the Annual Safety Report (ASR). 
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3. 
BACKGROUND AND RATIONALE 
3.1 
Background and Rationale 
Mental disorders are highly prevalent, undertreated, and associated with substantial disability and 
reduced quality of life (Demyttenaere et al., 2004). The 12 months prevalence of any mental disorder is 
12% in Europe, whereby anxiety disorders and mood disorders are the most prevalent (Demyttenaere 
et al., 2004). One third of patients with mental disorders comorbidly suffer from insomnia disorder 
according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria (American 
Psychiatric Association, 2013, S. 5), i.e. persistent sleep disturbances and associated daytime 
impairments for at least three months (Seow et al., 2018). The prevalence of acute insomnia symptoms 
(< 3 months) is up to 68% in patients with mental disorders (Seow et al., 2018). Having comorbid acute 
or chronic insomnia is associated with significantly higher impairment compared to having a mental 
disorder without insomnia (Seow et al., 2018). As opposed to early lines of research aiming at the 
identification of disorder-specific patterns of sleep disturbance (e.g., early morning awakening as a 
marker of depression), recent work demonstrates that disruptions of sleep continuity (insomnia) 
represent a highly prevalent and trans-diagnostic problem in a wide range of mental disorders including 
anxiety disorders, affective disorders, schizophrenia, substance use disorders, eating disorders, 
borderline personality disorder and autism spectrum disorders (Baglioni et al., 2016). 
Following current European and American practice guidelines for adult patients, cognitive behavioral 
therapy for insomnia (CBT-I) is the first line treatment (Qaseem et al., 2016; Riemann et al., 2017). 
CBT-I is a treatment package including psychoeducation, restriction of time in bed, relaxation, and 
cognitive restructuring. Implementation of bedtime restriction is the best predictor for therapeutic 
success of CBT-I (Harvey, Inglis, & Espie, 2002), and bedtime restriction is also efficacious as a stand- 
alone treatment for insomnia (Miller et al., 2014). The major mechanism of action of bedtime restriction 
is an increase of homeostatic sleep pressure, thereby shortening sleep-onset latency and increasing 
sleep depth. 
Various adaptations of CBT-I for different target groups and settings have been developed. One of them 
is Brief Behavioral Treatment for Insomnia (BBT-I), consisting of four sessions centering of bedtime 
restriction (Troxel, Germain, & Buysse, 2012). This demonstrates that brief versions of CBT-I can be 
similarly effective as the complete program. 
ln addition to shortening the program as in BBT-I, another promising approach for improving the 
implementation and dissemination of CBT-I is internet-assisted treatment using online programs or apps. 
This approach seems well feasible and effective in patients with insomnia without comorbidity (Seyffert 
et al., 2016). CBT-I and BBT-I have primarily been conceptualized and thoroughly evaluated for patients 
with primary insomnia, somatic comorbidity or minor psychiatric comorbidity (Trauer, Qian, Doyle, 
Rajaratnam, & Cunnington, 2015). A large number of trials has shown that in these patient groups, CBT- 
I and BBT-I improve insomnia with large effect sizes and can also improve comorbid mental symptoms 
such as mild depression with small to medium effect sizes (Ballesio et al., 2018). Both CBT-I and BBT- 
I, however, are insufficiently researched in patients with severe psychiatric disorders and symptoms 
including psychosis, severe addiction, borderline personality disorder and suicidality. These patients are 
rarely included because most trials are conducted in outpatient settings. Only a minority of studies have 
been conducted in psychiatric wards (Sheaves et al., 2016), and insomnia in this patient group is still 
frequently treated pharmacologically. According to current guidelines, however, CBT-I is also the first- 
line treatment for patients with insomnia and comorbid severe mental disorders (Riemann et al., 2017). 
Pharmacological treatment should only be considered if CBT-I is not available or not effective (Qaseem 
et al., 2016; Riemann et al., 2017). The reason is that the most thoroughly evaluated medication for 
insomnia, benzodiazepines and benzodiazepine receptor agonists, are not suitable for long-term 
treatment due to tolerance, dependency, and adverse effects such as cognitive impairment (Wilt et al., 
2016). Together, the evidence for efficacy as a prerequisite for dissemination and implementation of 
CBT-I in patients with severe mental disorders, including those in an acute crisis, is insufficient. 
The overarching objective of the proposed project is to target sleep to improve mental health. The 
specific aim is to investigate the efficacy of SleepExpert, a pragmatic behavioral treatment program for 
insomnia, in patients with severe mental disorders on psychiatric wards. 
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3.2 
lnvestigational Product (treatment, device) and Indication 
SleepExpert 1.0 is the first version of an online Program to treat Insomnia. The internet-based self-help 
platform used for the implementation of CBT-I in this study has been developed by the University of 
Bern (Prof. Dr. Thomas Berger), has been used successfully in previous trials (Krieger et al., 2019) and 
has received a CE mark in 2018. 
The device is intended for patients with mental disorders and insomnia who are treated for mental 
disorders in a hospital or an outpatient unit. 
A CE Declaration of Conformity will be submitted with this ethics application. 
No parts of the device are in contact with body tissues or fluids, it is an online application. No specific 
training is needed to operate the application. 
3.3 
Preclinical Evidence 
Not applicable, device does not need Swissmedic notification. 
3.4 
Clinical Evidence to Date 
There is no available clinical research data to date on exactly this product (SleepExpert). However, the 
therapeutic content that is used in this study is based on Cognitive Behavioral Therapy for insomnia 
(CBT-I). This intervention has been found to be highly effective and without lasting adverse effects in 
many studies and is recommended for the treatment of insomnia in current clinical guidelines (Qaseem 
et al., 2016; Riemann et al., 2017). A meta-analysis of randomized controlled trials has shown that CBT- 
I is also effective and without adverse effects when delivered online (Seyffert et al., 2016). 
3.5 
Dose Rationale / Medical Device: Rationale for the intended purpose in study (pre- 
market MD) 
ln this study, SleepExpert will be applied in three steps, namely i) a face-to-face group session held by 
a psychologist or physician, ii) self-management with coaching by nurses, and iii) self-management 
without systematic support. This form of administration has been developed to adapt CBT-I, the gold 
standard treatment for insomnia, to the needs of patients with severe mental disorders and insomnia. 
Patients with severe mental disorders, especially those hospitalized on psychiatric wards in an acute 
crisis, often suffer from cognitive impairments and motivational problems that make it impossible to 
implement CBT-1 as usual. The gradual adaptation of support from face-to-face therapy to self- 
management is supposed to make CBT-I accessible for this specific patient group. 
3.6 
Explanation for choice of comparator (or placebo) 
SleepExpert, an app-assissted treatment program with a face-to-face component, will be embedded into 
routine clinical care (treatment-as-usual, TAU). The comparison group in this trial will receive inpatient 
psychiatric treatment-as-usual (TAU) plus sleep monitoring. TAU comprises standard clinical care, 
including intensive daily contacts with health care providers on the wards, medical treatment, 
pharmacotherapy, psychotherapy in individual and group setting, nurse support, additional therapies 
such as music or ergotherapy and social support, informed by current guidelines for the respective 
disorder and adapted to individual needs. Of note, no change to any aspects of TAU will be made. Sleep 
monitoring will consist of daily sleep diary entries with the help of a smartphone app. ln contrast to the 
Sleep Expert version, the sleep monitoring version will not give any feedback or advice concerning sleep 
behavior. Patients in the control group will receive TAU plus sleep monitoring, whereas patients in the 
experimental group will receive TAU plus Sleep Expert. We chose TAU, and not an active placebo control, 
as a comparator for the following reasons: Placebo control groups are mostly used to control for 
unspecific effects of attention by health professionals or contact with other patients. ln our trial, patients 
in the TAU group will also get an extensive level of daily attention by health professionals and will also 
have the possibility to get to know other patients with similar problems. SleepExpert will be associated 
with a minimal amount of added therapist attention and contact time. Thus, an active control group is 
not necessary to control for these context aspects. Moreover, participants in an active control group 
would likely notice that they receive a "dummy treatment" that is unlikely to improve their sleep. This 
would reduce motivation to participate, may increase the dropout rate and reduce vaildity. Due to the 
inpatient and selected setting, TAU, in this study, can be well controlled and described and will be 
comparable across groups. 
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3.7 
Risks/ Benefits 
The study will potentially be associated with direct advantages for the participating patients and indirect 
/ potential advantages for the treatment of sleep disorders in patients with mental disorders in the case 
of positive results. No health related or other ethical problems are expected for the participants. Thus, 
the benefits of the study are supposed to outweigh the risks. 
3.8 
Justification of choice of study population 
Patients with mental disorders and insomnia have been chosen because insomnia is highly prevalent in 
patients with mental disorders and the goal of this study is to improve treatment options for insomnia in 
this group. No vulnerable participants will be included into the study. Minors and patients incapable of 
judgement or under tutelage for health issues will be excluded from participation in the study. During 
the screening procedures, it will be made sure that patients understand the purpose and content of the 
study, potential risks and benefits, and that patients are able to comply with the study procedures 
(participation in group session, handling of web application). Patients who do not fulfil these criteria will 
be excluded from participation. 
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4. STUDY OBJECTIVES 
4.1 
Overall Objective 
The main hypothesis is to investigate whether SleepExpert improves insomnia and general mental 
health in patients with severe mental disorders. 
4.2 
Primary Objective 
The primary objective is to assess whether there is a significantly greater reduction in self-assessed 
insomnia severity (as measured by the Insomnia Severity Index, ISi) across six months (interaction 
effect Group and Timepoint) in patients in the Tau plus SleepExpert group, compared to patients in the 
TAU plus sleep monitoring group. 
4.3 
Secondary Objectives 
The secondary objective is to assess whether there is a significantly greater improvement in general 
mental health (Brief Symptom Inventory) across six months (interaction effect Group and Timepoint) in 
patients in the TAU plus SleepExpert group, compared to patients in the TAU plus sleep monitoring 
group. 
4.4 
Exploratory objectives 
Exploratory objectives include the effect of TAU plus SleepExpert versus TAU plus SleepMonitoring on 
the following parameters: 
• Severity of depressive symptoms (Beck Depression Inventory, BDI) 
• mood, tiredness, concentration, and subjective sleep quality (self-construced visual analogue 
scales) 
• 
Daytime sleepiness (Epworth Sleepiness Scale) 
• Medication 
• 
Hospitalization 
4.5 
Safety Objectives 
The study aims to assess short- and long-term safety of SleepExpert and its tolerability in terms of 
incidence of sleep- and mental-health related side effects and use of sleep medication. 
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5. STUDY OUTCOMES 
5.1 
Primary Outcome 
The primary outcome will be insomnia severity measured with the Insomnia Severity Index (ISi) (Bastien 
et al., 2001). The ISi will be administered before the intervention (TO) and one, two, 12, and 26 weeks 
after the start of the intervention. 
5.2 
Secondary Outcomes 
The secondary outcome will be general mental health measured with the Brief Symptom Inventory (BSI) 
(Derogatis and Melisaratos, 1983). The BSI will be administered before the intervention (TO) and one, 
two, 12, and 26 weeks after the start of the intervention. 
5.3 
Exploratory Outcomes 
Exploratory outcomes will be the severity of depressive symptoms (Beck Depression Inventory, BOI) 
(Beck et al., 1988), self-constructed visual analogue scales measuring mood, tiredness, concentration 
and subjective sleep quality, daytime sleepiness (Lapin et al., 2018), medication (self-reported) and 
hospitalization (self-reported number of inpatient stays within the follow-up period). Timepoints when 
the different exploratory outcomes will be administered can be found in table 1 (section 9.1 ). 
5.4 
Safety Outcomes 
At TO, T1, T2, T3, and T4, participants will be asked about significant negative life events in order to 
assess possible adverse effects of the treatment. AEs will be categorized concerning the type of the 
reaction, severity, relatedness to the intervention, action taken and outcome (Raisch, Troutman, Sather, 
& Fudala, 2001 ). 
6. STUDY DESIGN 
6.1 
General study design and justification of design 
This project is a prospective randomized controlled clinical pilot trial with a cluster-crossover design 
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involving two groups: An interventional group (TAU, plus SleepExpert) and a control group (TAU plus 
sleep monitoring). 
Two different wards in the trial site (UPO Bern) will constitute the clusters. The study is conceptualized 
with a crossover, i.e. clusters (wards) will first be randomized to one of the groups for a duration of 4 
months. After a washout-phase of two months, they will then be allocated to the other group for another 
4 months. The order (TAU plus SleepExpert first vs. TAU plus sleep monitoring first) will be randomly 
allocated in a 1 :1 fashion. 
A total of 60 patients will be included. Patients will be assessed before the intervention (TO) and at the 
following time-points after the start of the intervention: 1 week (T1), 2 weeks (T2), 12 weeks (T3) and 
26 weeks (T4). 
6.2 
Methods of minimising bias 
6.2.1 
Randomization 
Wards will be randomly assigned to one of the two treatment conditions (cluster-randomization). A 
random list will be generated via the website random.erg. 
Randomization, data acquisition, data entry, and data analysis will be performed by staff members that 
are blinded regarding the treatment condition. 
6.2.2 
Blinding procedures 
Study participants and care providers cannot be blinded because they will notice whether they receive 
/ deliver an actual treatment or a monitoring control. Due to the crossover cluster design (randomization 
of wards to either TAU plus sleep monitoring or TAU plus SleepExpert), patients who are on the same 
ward at the same time will not get in contact with patients who are in the other arm. Thus, contamination 
due to exchange between patients will be reduced as far as possible. There will be two different 
participant information sheets, one for patients in the SleepExpert group and one for patients in the 
control group. Patients in the control group will not be informed about the SleepExpert treatment 
program - they will only be informed about the sleep monitoring they will receive. 
Outcome assessors (interviewers) and data analysts will be blinded. ln the respective documents and 
database entries, patients will be identified with a code. The key for assigning the codes to patients will 
not be known to the interviewers and data analysts. 
6.2.3 
Other methods of minimising bias 
The primary applicant is a staff member at the sleep clinic of the University Psychiatric Services 
Bern. The resources at this established, specialized sleep clinic will ensure that included patients 
are carefully diagnosed, i.e. that only patients fulfilling the defined eligibility criteria will be included. 
This ensures generalizability of the results to the intended population. 
Study attrition and reasons for dropout will be carefully documented throughout the study period. 
An intention to treat analysis will be provided since a per-protocol analysis may result in biased 
effects if many patients drop out due to (perceived) inefficacy. 
The outcome measures are widely used, valid, and reliable measures that have been recommended 
by experts for the research assessment of insomnia (Buysse, Ancoli-lsrael, Edinger, Lichstein, & 
Morin, 2006). 
Therapists will be experienced, well-trained, and supervised. 
The trial will be registered in a publicly accessible database before recruitment of the first subject. 
Hypotheses and the analysis plan will be made publicly available. This precludes that the analysis 
plan is changed after inspection of the data ("fishing for significances"). 
6.3 
Unblinding Procedures (Code break) 
The code will only be broken if it is necessary in order to avert an immediate risk to the health of the 
person concerned or to guarantee the rights of the person or a legal basis exists for breaking the code. 
ln this study, blinding of care providers and patients is not possible and will not be performed. Care 
providers on the wards will always be aware whether or not their patients received SleepExpert and 
data regarding the participation in the study intervention will be documented according to Good Clinical 
Practice. Thus, it is unlikely that circumstances under which the code has to be broken will occur. 
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7. STUDY POPULATION 
7.1 
Eligibility criteria 
Minimal exclusion criteria will be defined with the aim of improving care for a broad population of patients 
with severe mental disorders and with the aim of maximizing generalizability and external validity. 
Inclusion criteria: 
Age 18 years or older 
Documented diagnosis of acute insomnia, i.e. insomnia criteria according to ICD-10 for at least 2 
weeks (Ellis et al., 2012) 
Insomnia Severity Index (ISi) total score> 7, equivalent to relevant insomnia (Gagnon et al., 2013) 
Inpatient in one of the two participating psychiatric wards in the UPO Bern 
Ability to understand the aims and procedures of the study 
Willingness to participate and ability to provide written informed consent 
Exclusion criteria: 
lncabability of judgement 
Inability to participate in a low-threshold behavioral treatment program, e.g. due to severe cognitive 
impairment or high symptom severity precluding participation (e.g., severe catatonic symptoms, 
massive hallucinations, acute endangerment to self or others, involuntary commitment). Note that 
the named symptoms will lead to exclusion only if they lead to inability to give informed consent or 
an inability to participate in the program. Excluded patients will be re-assessed regularly and 
included if symptoms improve and participation is possible at a later point in time. 
7.2 
Recruitment and screening 
During the enrolment phase, all patients admitted to the participating wards of the UPO Bern will be 
screened in person. The screening will consist of a few questions regarding sleep, implemented into the 
routine clinical interview at enrolment, and filling in the insomnia severity index (Gagnon et al., 2013). 
The clinical interview as well as the questionnaire (insomnia severity index) are part of the clinical routine 
in our hospital and not specific for this study. Eligible patients will be contacted by study staff, informed 
about the study, and invited to participate. For further information about the study a flyer containing the 
most important details will be given to the participants. The screening and enrolment process will be 
standardized across the wards to minimize the risk of selection bias. 
Each patient in the clinic fills in a general consent form at admission, stating whether or not they agree 
to be approached for information about ongoing studies. Only patients who gave their written general 
consent will be contacted. There will be two different study information documents with attached consent 
forms, one for the active study phase where TAU plus SleepExpert is running, and one for the control 
phase where TAU plus sleep monitoring is running. Since patients are not randomized on an individual 
basis, but clusters (wards) are randomized, patients who are screened for the project in a phase where 
TAU plus sleep monitoring is running on their ward cannot be randomized to TAU plus SleepExpert. ln 
these phases, it may be demotivating for patients to be informed about the SleepExpert treatment, 
because it is not available for them. Thus, we decided to give them extensive relevant information about 
the project they can participate in (sleep monitoring) and only basic information about the use of their 
data within a clinical trial. 
7.3 
Assignment to study groups 
The two clusters (UPO wards) will be assigned to one of the following two study sequences - while one 
cluster will follow the first sequence, the other one will follow the second sequence. Which ward will 
follow which study sequence will be randomly assigned. 
TAU plus SleepExpert first for 4 months; fade-out for one month; wash-out for one month; TAU plus 
sleep monitoring for 4 months 
TAU plus sleep monitoring for 4 months; fade-out for one month, wash-out for one month; TAU plus 
SleepExpert for 4 months 
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During the TAU plus Sleep Expert and TAU plus sleep monitoring phases, patients will be actively 
recruited. During the fade-our phases, no active recruitment will take place, but already recruited 
patients will be able to complete their treatment. During the wash-out phase, no recruitment and no 
study-related treatment will take place. 
Depending at which stage of the study the ward stands at the time point when a subject is admitted to 
the ward, her or she will either receive TAU plus SleepExpert or TAU plus sleep monitoring, or, if 
admitted during the wash-out phase, the subject will not be able to participate in the trial. 
7 .4 
Criteria for withdrawal/ discontinuation of participants 
Participants will be withdrawn from the study immediately if there are any concerns about the 
participants' safety. Participants can also choose to withdraw from the study at any time, and are not 
required to provide their reason for withdrawing from the study. Coded data acquired before withdrawal 
will be analyzed. 
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8. STUDY INTERVENTION 
8.1 
Identity of lnvestigational Products (treatment/ medical device) 
8.1.1 
Experimental Intervention (treatment I medical device) 
General information 
Both groups will receive psychiatric inpatient treatment-as-usual (TAU). TAU will be provided according 
to current treatment guidelines for the respective mental disorders. Within the trial period, TAU will be 
delivered as usual in the respective hospitals. No restrictions with regard to pharmacotherapy, 
psychotherapy, or any other inpatient therapy or subsequent outpatient care will result from participation 
in the SleepExpert trial. 
TAU will consist of the following interventions: daily visit by a physician or psychologist, if necessary 
individualized pharmacological treatment according to current guidelines, individualized disorder- 
specific psychotherapy according to current guidelines, daily contact with a psychiatric nurse, ergo 
therapy, and other group therapies according to a personalized schedule (e.g. music therapy, art 
therapy, relaxation therapy, etc.). The duration of the inpatient stay will be adapted to the progress of 
the individual patient and will vary from participant to participant. The duration of the stay is typically 
between one to eight weeks, exceptions are possible. 
The TAU plus SleepExpert group will receive a specific treatment for insomnia. This treatment will 
consist of the following three phases: 
1) a face-to-face treatment initiation guided by a medical doctor/ psychologist in a group format (1 
hour), 
2) self-managed implementation of behavioral changes assisted by an online application 
("Become your own SleepExpert") and coached by nurses (two individual contacts per week of 
about 5 min duration), and 
3) self-management by the patients assisted by the same online application after discharge from 
the hospital. 
The treatment initiation will be a psycho-educative group session held by a physician or psychologist. 
During this group session, basic information about sleep regulation will be provided, including the two 
components i) homeostatic build-up of sleep pressure as a function of prior wake time, and ii) relevance 
of individual circadian sleep-wake preferences. At the end of the group session, an individual sleep 
window (duration of bed time and timing) will be worked out with every patient. ln most patients, the time 
in bed is shortened and 'lights-off' is delayed compared to the previous behavior with the aim of 
increasing sleep pressure and moving sleep time into a physiological time frame. The background is 
that patients with insomnia often increase their time in bed in order to catch more sleep -which, however, 
is actually detrimental for sleep quality. The online application will be introduced in this group therapy 
session. ln the second phase of the treatment program, nurses will regularly meet with the patients to 
discuss their sleep behavior. Patients will be assisted in keeping or, if necessary, adapting their 
prescribed sleep window, and will receive advice, motivation and assistance in using the application. 
Patients will learn how to use the application in order to document and adjust their sleep behavior. ln 
the third phase (defined as starting from discharge from the psychiatric ward), patients will use the online 
application in self-management to keep optimizing their sleep behavior. All patients, i.e. the TAU plus 
sleep monitoring and TAU plus SleepExpert group will have an individual appointment with a sleep 
expert (physician or psychologist) after completion of the study, i.e. after 6 months, in which the gathered 
information (sleep diaries) will be discussed and individualized further diagnostics and treatments, if 
needed, will be initiated. 
Online application 
The online application 'Become your own SleepExpert' is currently developed in cooperation with Prof. 
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Thomas Berger, University of Bern. Prof. Berger has a longstanding experience in the field of internet- 
and app-based prevention and treatments of mental problems and disorders. His publication record 
includes a multitude of studies investigating the efficacy of online treatments for different mental health 
problems and disorders, including anxiety, depression, insomnia, adjustment problems and self-criticism 
(e.g., Krieger et al., 2019; Moser et al., 2019; Schuster et al., 2019; Weisel et al., 2019). 
8.1.2 
Control Intervention (standard/routine/comparator treatment I medical device) 
Patients in the control group will receive the same TAU as the experimental group (see 8.1.1 ). 
ln addition, patients in the control group (TAU plus sleep monitoring) receive a smartphone app (sleep 
monitoring). No further interventions will be provided through this app. 
8.1.3 
Packaging, Labelling and Supply (re-supply) 
Not applicable. 
8.1.4 
Storage Conditions 
Not applicable. 
8.2 
Administration of experimental and control interventions 
8.2.1 
Experimental Intervention and Control Intervention 
This chapter can also be merged with chapter 8.1.1. 
8.2.2 
Control Intervention 
This chapter can also be merged with chapter 8.1.2. 
8.3 
Dose / Device modifications 
Not applicable. 
8.4 
Compliance with study intervention 
Adherence will be monitored using subjective patient data from the SleepExpert application. ln the 
application, patients will log their bed times and rise times as well as subjective sleep times. 
Treatment contamination (i.e., patients in the TAU plus sleep monitoring group learning about details of 
the SleepExpert intervention) will be prevented by cluster randomization of wards. One entire ward will 
be randomized to one of the conditions. The other ward will receive the remaining condition (preventing 
that both wards get the same condition). Patients in the control group will not get in close contact with 
patients in the intervention group. Additional measures to increase adherence include a start of the 
intervention in the inpatient setting along with individual coaching by nurses and a helpdesk that can be 
called in case of problems with the program. Please note that no further extensive contacts are planned 
to increase generalizability of the program after completion of the study. 
8.5 
Data Collection and Follow-up for withdrawn participants 
If a patient withdraws consent for further study participation, the data collected up to the time point of 
withdrawal will be included in the study and no further data will be collected. The data of withdrawn 
participants will not be anonymized but will remain coded after analysis of the data set. 
For participants who discontinue the study intervention but do not withdraw from participation in the 
study, study visits and data collection will continue in the same way as for non-withdrawn participants. 
8.6 
Trial specific preventive measures 
No specific preventive measures will be taken in this trial. There will be no restrictions to treatment or 
daily life related to this trial. 
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8.7 
Concomitant Interventions (treatments) 
All concomitant treatments I interventions are permitted and will be recorded in the CRF. The aim of this 
trial is to implement SleepExpert into the clinical routine care for patients with severe mental disorders, 
thus no artificial / trial-specific restrictions will be applied. Careful documentation of concomitant 
treatment will prevent biasing of the results. 
8.8 
Medical Device Accountability 
Not applicable, patients will use the trial-specific web applications from their own devices. 
8.9 
Return or Destruction of Medical Device 
Not applicable. 
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9. 
STUDY ASSESSMENTS 
9.1 
Study flow chart(s) / table of study procedures and assessments 
The overall planned study duration is 2.5 years. Patients will first be screened and assessed for 
eligibility. Eligible patients who signed the informed consent form will undergo a first assessment (TO) 
and then participate in the intervention. Additional assessments will be made one, two, 12, and 26 weeks 
after the start of the intervention. A plan of each patients' schedule within the study is outlined in table 1 
which is illustrated in chapter 1.1. 
9.2 
Assessments of outcomes 
9.2.1 
Assessment of primary outcome 
The ISi is a valid, reliable and change-sensitive self-rating questionnaire that is widely used as an 
outcome measure in clinical trials in insomnia research (Buysse et al., 2006). lt ranges from O to 28 with 
higher values indicating more severe problems. A self-rating questionnaire in contrast to objective sleep 
measures such as polysomnography or actigraphy is reasonable and widely accepted for measuring 
insomnia severity because insomnia is defined on the basis of subjective sleep dissatisfaction (American 
Psychiatric Association, 2013; Medicine, 2014; Organization, 2004) and objective measures often 
deviate from this perception (Harvey and Tang, 2012). An advantage of the ISi, compared to a sleep 
diary, is that it combines different aspects of insomnia such as sleep onset difficulties, sleep 
maintenance difficulties, and daytime impairment in one summary score. For more information, see 
chapter 5.1. 
9.2.2 
Assessment of secondary outcomes 
The BSI is a brief version of the Symptom Checklist 90 (SCL-90) (Derogatis et al., 1976). lt shows high 
correlation with the long version and has a good test-retest reliability (Derogatis and Melisaratos, 1983). 
We chose the BSI because it is an efficient measure of general mental health. ln our sample, patients 
will suffer from different mental disorders including but not limited to depression, psychosis, anxiety and 
substance abuse. ln addition, we expect that many patients suffer from more than one mental disorder 
(comorbidity). A general measure, beyond the severity of specific disorders, is thus needed to picture 
changes in general mental health. For more information, see chapter 5.2 
9.2.3 
Assessment of exploratory outcomes 
Exploratory outcomes will be the severity of depressive symptoms (Beck Depression Inventory, BOI) 
(Beck et al., 1988), self-constructed visual analogue scales measuring mood, tiredness, concentration 
and subjective sleep quality, daytime sleepiness (Lapin et al., 2018), medication (self-reported) and 
hospitalization (self-reported number of inpatient stays within the follow-up period). 
For all mentioned questionnaires, the primary metric will be the total score of the respective 
questionnaire. We will also perform additional analyses to compare the number of patients with 
response and remission between the two trial groups. Following Morin et al., response is defined as an 
improvement of> 7 points on the ISi (Morin et al., 2011 ). Remission is defined as an ISi score of< 8. 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events 
At TO, T1, T2, T3, and T 4, participants will be asked about significant negative life events in order to 
assess possible adverse effects of the treatment. AEs will be categorized concerning the type of the 
reaction, severity, relatedness to the intervention, action taken, and outcome (Raisch et al., 2001). 
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9.2.4.2 Laboratory parameters 
Not applicable. No laboratory parameters will be assessed in this study. 
9.2.4.3 Vital signs 
Not applicable. No vital signs will be assessed in this study. 
9.2.5 
Assessments in participants who prematurely stop the study 
For participants who discontinue the study intervention but do not withdraw from participation in the 
study, study visits and data collection will continue in the same way as for non-withdrawn participants. 
Dropouts before start of treatment (i.e. non-starters) will be replaced by recruitment of new participants. 
Patients who started the intervention but who were prematurely withdrawn from the study will not be 
replaced by newly enrolled patients. 
9.3 
Procedures at each visit 
The following visits will be conducted: screening, TO, T1, T2, T3 and T4. 
9.3.1 
Screening 
The screening will be performed on the day patients are admitted to the participating wards. All patients 
admitted to these respective wards will be screened. The screening will consist in a brief clinical 
interview and filling in the Insomnia Severity Index. ln the clinical interview, patients will briefly be asked 
about their sleep problems and their medical history by a trained physician. The aim is to determine 
whether the diagnostic criteria for acute insomnia are fulfilled and whether any exclusion criteria are 
fulfilled. Patients need a total score > 7 on the Insomnia Severity Index to be included. For details 
regarding this questionnaire, please see chapter 5. 
9.3.2 
Timepoints TO to T4 
Time point TO (day O): 
• 
Insomnia Severity Index 
• Brief Symptom Inventory 
• Beck Depression Inventory 
• Visual analogue scales (subjective sleep quality, mood, concentration, and tiredness) 
• 
Sleep diary will be handed out 
• 
medication status 
• 
adverse events 
Time point T1 (day 7±2): 
• 
Insomnia Severity Index 
• Visual analogue scales (subjective sleep quality, mood, concentration, and tiredness) 
• sleep diary will be checked 
• medication status 
• adverse events 
Time point T2 (day 14±2): 
• 
Insomnia Severity Index 
• 
Brief Symptom Inventory 
• 
Beck Depression Inventory 
• Visual analogue scales (subjective sleep quality, mood, concentration, and tiredness) 
• 
sleep diary will be checked 
• 
medication status 
• 
adverse events 
Time point T3 (day 84±7): 
• 
Insomnia Severity Index 
• Visual analogue scales (subjective sleep quality, mood, concentration, and tiredness) 
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• 
sleep diary will be checked 
• 
medication status 
• 
adverse events 
Time point T4 (day 182±7): 
• 
Insomnia Severity Index, 
• 
Brief Symptom Inventory 
• 
Beck Depression Inventory 
• 
Visual analogue scales (subjective sleep quality, mood, concentration, and tiredness) 
• 
sleep diary will be checked 
• 
medication status 
• 
adverse events 
For details regarding the mentioned questionnaires, please see chapter 5. 
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10. SAFETY 
10.1 Drug studies 
Not applicable 
10.2 Medical Device Category C studies 
Not applicable 
10.3 Medical Device Category A studies 
Device deficiencies and all adverse events (AE) including all serious adverse events (SAE) are 
collected, fully investigated, and documented in the source document and appropriate case report form 
(CRF) during the entire study period, i.e. from patient's informed consent until the last protocol-specific 
procedure. Documentation includes dates of event, treatment, resolution, assessment of seriousness, 
and causal relationship to device and/or study procedure [ISO 14155, 6.4.1.]. 
10.3.1 
Foreseeable adverse events and anticipated adverse device effects 
Potential adverse events are transitional worsening of the sleep disorder and / or the mental disorder, 
daytime tiredness and daytime sleepiness. No SAE that could be related to the investigational device 
or study procedures are expected during this clinical trial. 
10.3.2 
Definition and Assessment of safety related events 
Adverse Event (AE): 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including 
an abnormal laboratory finding) in participants, users or other persons whether or not related to the 
investigational medical device [ISO 14155: 3.2]. 
This includes events related to the investigational device or the comparator and to the procedures 
involved. For users or other persons this is restricted to events related to the investigational medical 
device. 
Adverse Device Effect (ADE): 
Adverse event related to the use of an investigational medical device [ISO 14155: 3.1]. 
This includes any adverse event resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, operation, or any malfunction of the investigational medical 
device. This includes any event that is a result of a use error or intentional misuse. 
Serious Adverse Event (SAE) [European regulation on medical devices 2017/7 45, art. 58]: 
Any adverse event that led to any of the following: 
(a) death, 
(b) serious deterioration in the health of the subject that resulted in any of the following: 
(i) life-threatening illness or injury, 
(ii) permanent impairment of a body structure or a body function, 
(iii) hospitalisation or prolongation of patient hospitalisation, 
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
(v) chronic disease, 
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect. 
These are submitted to the EC via BASEC within 7 days (see below chapter 10.2.3). A planned 
hospitalisation for pre-existing condition, or a procedure required by the protocol, without a serious 
deterioration in health, is not considered to be a serious adverse event. 
Device deficiency: 
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance, 
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such as malfunction, misuse or use error and inadequate labelling [ISO 14155: 3.15]. 
Device deficiency with SAE potential: 
Device deficiencies that might have led to a serious adverse event if a) suitable action had not been 
taken orb) intervention had not been made or c) if circumstances had been less fortunate. 
Health hazards that require measures: 
Findings in the trial that may affect the safety of study participants and, which require preventive or 
corrective measures intended to protect the health and safety of study participants SAE [ClinO Art. 37). 
Causal Relationship of SAE [MEDDEV 2.7/3 revision 3, May 2015]: 
A causal relationship towards the medical device or study procedure should be rated as follows: 
• Not related: The relationship to the device or procedures can be excluded. 
• 
Unlikely: The relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
• 
Possible: The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible. 
• 
Probable: The relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably be explained by another cause. 
• 
Causal relationship: The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt. 
Device deficiencies that might have led to an SAE are always related to the medical device. 
10.3.3 
Reporting of Safety related events 
Reporting to Sponsor-Investigator: 
All SAEs, device deficiencies and health hazards that require measures are reported to the Sponsor- 
Investigator within 24 hours upon becoming aware of the event. Device deficiencies are assessed 
regarding their potential to lead to an SAE. 
Pregnancies 
Reporting of pregnancy is not necessary in this study. 
Reporting to Authorities: 
The sponsor-investigator will apply to the notification requirements specified in Art. 15 of the MedDO of 
17October2011 (SR812.213). 
The sponsor investigator will report to the Ethics Committee via BAS EC device deficiencies that could 
have led to serious adverse events if suitable action had not been taken, intervention had not been 
made, or circumstances had been less fortunate within 7 days [ClinO Art. 42]. 
Health hazards that require measures are reported to the Ethics Committee via BASEC within 2 days 
[ClinO Art. 37]. 
Periodic safety reporting: 
A yearly safety update-report is submitted by the Investigator to the Ethics Committee via BASEC. 
A report is submitted to Swissmedic by the Sponsor-Investigator, as defined in Art. 15a,b of the MedDO 
of17October2011 (SR812.213). 
10.4 Assessment, notification and reporting on the use of radiation sources 
Not applicable. 
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11. STATISTICAL METHODS 
11.1 Hypothesis 
Hypothesis: SleepExpert improves insomnia and general mental health in patients with severe mental 
disorders. 
Primary objective: To assess whether there is a significantly greater reduction in self-assessed insomnia 
severity (as measured by the Insomnia Severity Index, ISi) across six months (interaction Group x Time) 
in patients in the Tau plus SleepExpert group, compared to patients in the TAU plus sleep monitoring 
group. 
Secondary objective: To assess whether there is a significantly greater improvement in general mental 
health (Brief Symptom Inventory) across six months (interaction Group x Time) in patients in the TAU 
plus SleepExpert group, compared to patients in the TAU plus sleep monitoring group. 
Exploratory objectives: Additional objectives include the effect of TAU plus SleepExpert versus TAU 
plus SleepMonitoring on the following parameters: 
• 
severity of depressive symptoms (Beck Depression Inventory, BOI) 
• 
mood, tiredness, concentration, and subjective sleep quality (self-construced visual analogue 
scales) 
• daytime sleepiness (Epworth Sleepiness Scale) 
• 
medication 
• hospitalization 
11.2 Determination of Sample Size 
A power analysis was conducted with G-Power (Faul, Erdfelder, Lang, & Buchner, 2007). Assuming an 
alpha error level of 0.05 (two-sided) and a power of 0.8, a total sample size of n=60 will be sufficient to 
detect a medium effect (Cohen's d=0.65). This is a pilot trial with the primary aim of collecting qualitative 
experience and preliminary efficacy data. A large confirmatory trial will be conducted if the results of this 
pilot trial are encouraging. 
11.3 Statistical criteria of termination of trial 
no statistical criteria for termination of trial have been formulated. 
11.4 Planned Analyses 
At the start of recruitment, a statistical analysis plan (SAP) will be written. The plan determines all 
necessary data preparation steps (e.g. additional validations, generation of new variables), definitions 
(e.g. analysis sets), and statistical analyses (e.g. models, outputs such as tables and graphs). 
11.4.1 
Datasets to be analysed, analysis populations 
All analyses will be done on the as-treated analysis considering the cross-over design. 
11.4.2 
Primary Analysis 
The primary outcome, i.e. the four overall scores of the ISi of all follow-up time-points will be analyzed 
with a mixed effects linear model. The model will take into account the hierarchical structure of the data: 
multiple ISi scores per patient and clusters (cross-over). Because of the complexity of the data and the 
small number of clusters we assume that we will not be able to introduce random effects for patients 
and clusters. However, our first approach will still be a linear mixed model with the following co-variables: 
fixed intervention effect (TAU plus SleepExpert versus TAU plus sleep monitoring), fixed baseline ISi 
score effect, random patient effect (multiple ISi scores during follow-up), random cluster effect. 
Depending on model fit, we may need to simplify the model and modify the random effects. This model 
is pre-specified and the rationale for switching will be made explicit. The analysis will be made after all 
data has been collected by one of the principal investigators. 
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11.4.3 
Secondary Analyses 
Continuous outcomes (Brief Symptom Inventory, Beck Depression Inventory) will also be analyzed by 
a mixed effects linear model using the same procedure used to estimate the primary outcome. Binary 
outcome data will be analysed using mixed effect logistic regression with odds-ratio as the effect 
measure. The number of hospitalizations will be also analyzed by a mixed effects model. Interim 
analyses 
No planned interim analysis 
11.4.4 
Safety analysis 
The frequency of occurrence of adverse events of different categories will be analysed using descriptive 
statistics and compared between the two groups using Chi square tests. 
11.4.5 
Deviation(s) from the original statistical plan 
The SAP is a version-controlled document which allows to track all changes to the statistical analysis. 
Any post-hoc changes will be transparently reported in all publications. 
11.5 Handling of missing data and drop-outs 
Dropouts before start of treatment (i.e. non-starters) will be replaced by recruitment of new participants. 
Multiple imputation will be used in case data are not available for more than 5-10% of the sample. 
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12. QUALITY ASSURANCE AND CONTROL 
12.1 Data handling and record keeping / archiving 
The investigator will maintain appropriate medical and research records for this trial. The records will be 
kept in compliance with IS014155 and meeting regulatory and institutional requirements for 
confidentiality. The principal investigator, sub-investigators, and clinical research nurses or coordinators 
will have access to the records. The principal investigator will permit authorized representatives of the 
Sponsor and the CEG to examine clinical records for the purposes of inspections, quality control, quality 
assurance, and evaluation of study safety and progress. 
12.1.1 
Case Report Forms 
Data is recorded in paper CRFs as source documents. ECRFs will be given as an option for direct 
anonymized data entry from participants for follow-up time points when they are not patients on the 
wards anymore. The eCRFs will be created and stored on the database RedCap which is a database 
recommended from the Clinical Trial Unit Bern. Data entry from the source paper CRFs to eCRFs should 
only be performed by authorised personnel and data should be consistent with the available source 
documents. When this is not the case, a detailed explanation of the discrepancies should be provided. 
The principal investigator should ensure the accuracy, completeness, and timeliness of the data 
reported and sign off the completed eCRFs. ln order to reflect the current patient status throughout the 
study, eCRFs will be kept up to date. This means that eCRFs should be completed no later than two 
weeks after a participant's visit and that data entry not should be delayed unnecessarily. 
12.1.2 
Specification of source documents 
Source documents for each study participant, including original study related documents, treatment and 
medical history, must be available at the sites. 
When hospital medical records are electronic, key-data should be printed and filed as certified copies in 
the patient binders of the investigator site file. A certified copy is a copy of the original record that has 
been verified, i.e. by a dated signature, to have the same information, including data that describe the 
context, content, and structure, as the original. 
Any change or correction to a source document should be dated, signed (by identifiable initials), and if 
necessary explained. The change should under no circumstances obscure the original entry. 
All data captured in the eCRF should be itemised on a source data location list, which will be stored in 
the investigator site file at each study site. This list should reflect the work flow at the study site, clearly 
indicating the source data location corresponding to each eCRF entry. If several sources are possible 
for one eCRF entry, the priority order of these must be specified in the list. 
12.1.3 
Record keeping/ archiving 
All study data (written and electronic) and in particular the investigator site file (ISF), must be retained 
for a period of at least 1 O years from the completion or premature termination of the trial. The Investigator 
should take measures to prevent accidental or premature destruction of these documents. 
12.2 Data management 
Data of all subjects will be coded and data analysis will be performed using these codes only. Unblinding 
of subject-specific data is possible after consent has been given by the subjects and the project leader. 
The code will only be broken if it is necessary in order to avert an immediate risk to the health of the 
person concerned or to guarantee the rights of the person (e.g. in revoking the consent) or a legal basis 
exists for breaking the code. Range checks for data values will be performed to exclude data entry 
errors. 
Project data will be handled with uttermost discretion and only be accessible to authorized personnel 
who will have access to data for study purposes (e.g. data analysis) for the whole study duration. Only 
the investigators and Ethics Commission are allowed to have inspections on the original data, and will 
be allowed direct access to source documents will be permitted for purposes of monitoring, audits or 
inspections. 
12.3 Data Management System 
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Our technical implementation for data management uses the database RedCap which is recommended 
from the Clinical Trial Unit Bern. he sponsor-investigator is responsible and will ensure correct and 
conscientious use of the data management system, and will monitor the data management. The system 
is tested before the start of data collection in consultation with the institution's IT experts. 
12.4 Data security, access and back-up 
Access to parts of the data will be granted only to individuals that require it to conduct the research. For 
instance, only individuals that need to contact or communicate with participants have access to the 
participant's identity and contact details. Researchers that do statistical analysis of the study cohort get 
only access to pseudonyms. Access is granted through personal accounts, usually the CampuslD by 
the University of Bern. Exchange of data is strictly channeled through a system that tracks all changes 
and prevents permanent deletion of files by researches. The system provides a full audit trail and 
centralized access control. Data processing is done on personal computers/laptops and institutional 
servers. The personal devices are protected against theft/loss by a full system encryption (Bitlocker). 
12.4.1 
Analysis and archiving 
Before final analysis, data files will be extracted from the database into statistical packages to be 
analyzed. The status of the database at this time is recorded in archive tables. 
The study database with all archive tables will be securely stored by UPO Bern. The Sponsor also 
archives the Trial Master File and the final report for at least 1 O years. 
ln accordance to Data Protection Directive of the UPD Bern and the SAMW-guidelines for creating 
biological databases, all study data will be archived for a minimum of 1 O years after study termination 
or premature study termination. ln case of paper form, data will be archived in lockable drawers at the 
research facility (Research Dept. of the Translational Research Center, University Hospital of Psychiatry, 
Bolligenstr. 111, CH-3000 Bern 60.). ln case of digital data, the raw data, derived data, code, meta-data, 
and all history will be exported from the version control system and archived for 10 years at the 
University of Bern on an archival system that stores two copies of the data in two geographically distinct 
locations. At the end of the project, researchers are asked to remove study data from their devices and 
local servers. Raw data, code, and all intermediate data can be restored and/or transferred in its entirety 
or partially. 
12.4.2 
Electronic and central data validation 
Data edit checks will be implemented into the EDC system, limiting entries to appropriate, realistic values 
(e.g. not allowing future dates, missing values etc.). Furthermore, selected data points are cross- 
checked for plausibility with previously entered data for each individual participant. 
Before database lock each Pl will validate the collected data from his site with his signature. 
12.5 Monitoring 
On-site will be part of the quality control activities implemented for this study. Monitoring will be 
performed according to a separate monitoring plan. 
For the purposes of monitoring, the Pl at the site will provide the monitor with access to study 
documentation, patient records, facilities and any other resources necessary. During on-site monitoring 
visits, the Pl or his designee will support the monitor in his/her activities and answer questions arising. 
Questions and queries arising during central data monitoring will be handled in a timely manner. 
All involved parties will keep participant data strictly confidential. 
12.6 Audits and Inspections 
No site audits by the sponsor are planned for this study, but the sponsor reserves the right to perform 
such an audit should it be considered necessary. 
ln case of an audit or an inspection, the auditors/ the inspectors will get access to study documentation, 
patient records, facilities and any other resource deemed related to the study by the authority. Before, 
during and after the audit or inspection, the investigator will support the auditors/inspectors in their 
activities and answer any questions arising. 
All involved parties will keep participant data strictly confidential. 
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12.7 Confidentiality, Data Protection 
The principal investigator safeguards the confidentiality of participating patients' data, ensuring that no 
patient information containing identifying data will leave the study site. 
Direct access to source documents and other study related records at the participating study sites will 
be permitted for purposes of monitoring, audits and inspections. The monitoring institution (i.e. CTU 
Bern) and the CEC will have access to all information necessary to accomplish their tasks. 
12.8 Storage of biological material and related health data 
Not applicable. 
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13. PUBLICATION AND DISSEMINATION POLICY 
Trial results will be published in a peer-reviewed journal and presented at national and international 
conferences. The principal investigator has all rights for publication and will have ultimate authority over 
all publication activities. 
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14. FUNDING AND SUPPORT 
14.1 Funding 
The project is financed with intramural money of the UPO Bern. External funding by the Velux 
Foundation has been applied for. 
14.2 Other Support 
Not applicable. 
15. INSURANCE 
Not applicable (study category A). 
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16. REFERENCES 
American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM- 
5®) American Psychiatric Pub. 
Baglioni, C., Nanovska, S., Regen, W., Spiegelhalder, K., Feige, B., Nissen, C., ... Riemann, D. (2016). 
Sleep and mental disorders: A meta-analysis of polysomnographic research. Psychological Bulletin, 142, 
969-990. 
Ballesio, A, Aquino, M. R. J. V., Feige, B., Johann, A F., Kyle, S. D., Spiegelhalder, K., ... Baglioni, C. 
(2018). The effectiveness of behavioural and cognitive behavioural therapies for insomnia on depressive 
and fatigue symptoms: A systematic review and network meta-analysis. Sleep Medicine Reviews, 37, 
114-129. 
Buysse, D. J., Ancoli-lsrael, S., Edinger, J. D., Lichstein, K. L., & Morin, C. M. (2006). Recommendations 
for a standard research assessment of insomnia. Sleep: Journal of Sleep and Sleep Disorders Research, 
29, 1155-1173. 
Demyttenaere, K., Bruffaerts, R., Posada-Villa, J., Gasquet, l., Kovess, V., Lepine, J. P., ... WHO World 
Mental Health Survey Consortium. (2004). Prevalence, severity, and unmet need for treatment of mental 
disorders in the World Health Organization World Mental Health Surveys. JAMA, 291, 2581-2590. 
Ellis, J. G., Gehrman, P., Espíe, C. A, Riemann, D., & Perlis, M. L. (2012). Acute insomnia: Current 
conceptualizations and future directions. Sleep Medicine Reviews, 16, 5-14. 
Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A (2007). G*Power 3: A flexible statistical power analysis 
program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175-191. 
Gagnon, C., Bélanger, L., Ivers, H., & Morin, C. M. (2013). Validation of the Insomnia Severity Index in 
primary care. Journal of the American Board of Family Medicine: JABFM, 26, 701-71 O. 
Harvey, L., Inglis, S. J., & Espie, C. A (2002). Insomniacs' reported use of CBT components and 
relationship to long-term clinical outcome. Behaviour Research and Therapy, 40, 75-83. 
Kahawage, P., Jumabhoy, R., Hamill, K., de Zambotti, M., & Drummond, S. P. A (2019). Validity, 
potential clinical utility, and comparison of consumer and research-grade activity trackers in Insomnia 
Disorder I: ln-lab validation against polysomnography. Journal of Sleep Research, e12931. 
Krieger, T., Urech, A, Duss, S. B., Blättler, L., Schmitt, W., Gast, H., ... Berger, T. (2019). A randomized 
controlled trial comparing guided internet-based multi-component treatment and internet-based guided 
sleep restriction treatment to care as usual in insomnia. Sleep Medicine, 62, 43-52. 
Miller, C. B., Espie, C. A., Epstein, D. R., Friedman, L., Morin, C. M., Pigeon, W. R., ... Kyle, S. D. (2014). 
The evidence base of sleep restriction therapy for treating insomnia disorder. Sleep Medicine Reviews, 
18, 415-424. 
Qaseem, A, Kansagara, D., Forciea, M. A, Cooke, M., Denberg, T. D., & Clinical Guidelines Committee 
of the American College of Physicians. (2016). Management of Chronic Insomnia Disorder in Adults: A 
Clinical Practice Guideline From the American College of Physicians. Annals of Internal Medicine, 165, 
125-133. 
Raisch, D. W., Troutman, W. G., Sather, M. R., & Fudala, P. J. (2001 ). Variability in the assessment of 
adverse events in a multicenter clinical trial. Clinical Therapeutics: The International Peer-Reviewed 
Journal of Drug Therapy, 23, 2011-2020. 
Riemann, D., Baglioni, C., Bassetti, C., Bjorvatn, B., Dolenc Groselj, L., Ellis, J. G., ... Spiegelhalder, K. 
(2017). European guideline for the diagnosis and treatment of insomnia. Journal of Sleep Research, 26, 
675-700. 
Seow, L. S. E., Verma, S. K., Mok, Y. M., Kumar, S., Chang, S., Satghare, P., ... Subramaniam, M. 
(2018). Evaluating DSM-5 Insomnia Disorder and the Treatment of Sleep Problems in a Psychiatric 
Population. Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of 
Sleep Medicine, 14, 237-244. 
Seyffert, M., Lagisetty, P., Landgraf, J., Chopra, V., Pfeiffer, P. N., Conte, M. L., & Rogers, M. A M. 
(2016). Internet-Delivered Cognitive Behavioral Therapy to Treat Insomnia: A Systematic Review and 
Meta-Analysis. P/oS One, 11, e0149139. 
Sheaves, B., Bebbington, P. E., Goodwin, G. M., Harrison, P. J., Espie, C. A, Foster, R. G., & Freeman, 
D. (2016). Insomnia and hallucinations in the general population: Findings from the 2000 and 2007 
British Psychiatric Morbidity Surveys. Psychiatry Research, 241, 141-146. 
Trauer, J. M., Qian, M. Y., Doyle, J. S , Rajaratnam, S. M. W., & Cunnington, D. (2015). Cognitive 
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Behavioral Therapy for Chronic Insomnia: A Systematic Review and Meta-analysis. Annals of Internal 
Medicine, 163, 191-204. 
Troxel, W. M., Germain, A, & Buysse, D. J. (2012). Clinical management of insomnia with brief 
behavioral treatment (BBTI). Behavioral Sleep Medicine, 10, 266-279. 
Wilt, T. J., MacDonald, R., Brasure, M., Olson, C. M., Carlyle, M., Fuchs, E., ... Kane, R. L. (2016). 
Pharmacologie Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline 
by the American College of Physicians. Annals of Internal Medicine, 165, 103-112. 
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17. APPENDICES 
ICH: (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant 
information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.) 
Please consider well with adding documents here that are very frequently changing, they may be 
mentioned as separately provided documents and listed here. 
Except for medical devices, the section headings can be renamed accordingly. 
1. 
IMP: IB or SPC 
2. 
Medical Devices: 1B (according to ISO 14155) 
3. 
Medical Devices: Assurance of producer 
4. 
Medical Devices: List of norms (vollständig eingehaltene, teilweise eingehaltene) 
5. 
Radiolabelled products: Strahlenschutzverordnung 
6. e.g. List of study sites/ Pis 
List of countries or centres where data will be collected or reference to where list of study sites can be 
obtained 
7. 
Other 
e.g. Specific protocols (e.g. MRI) 
e.g. Case Report Form (e.g. CRF) 
e.g. Patient Information and informed consent 
Model of consent form and other related documentation given to participants and authorised surrogates 
and additional consent provisions for collection and use of participant data and biological specimens in 
ancillary studies, if applicable 
e.g. Other material to patients 
Model of consent form and other related documentation given to participants and authorised surrogates 
and additional consent provisions for collection and use of participant data and biological specimens in 
ancillary studies, if applicable 
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