Personalised Electronic Record Supported Two-Stage Observational Study of Sleep in Patients With Breast Cancer
Conditions: Insomnia, Breast Cancer
Sponsor: Closed Loop Medicine

 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
 
 
 
    
PERSONAL-SLEEP IN BREAST CANCER  
Protocol 28Sept2021 V1.0 
Clinical Study Protocol 
 
 
 
 
 
Personalised Electronic Record Supported Two-Stage Observational 
Study of Sleep in Patients with Breast Cancer 
 
 
 
 
 
 
 
 
 
Short title:  
PERSONAL-SLEEP IN BREAST CANCER 
 
 
 
Principal Investigator:  
Dr Anne Armstrong 
PhD, MRCP (UK), MBChB. BSc (Hons) 
 
 
 
 
Protocol Version and date: 
Protocol 28Sept2021 Version 1.0 
 
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 2 of 45 
28 Sept 2021 
 
RESEARCH REFERENCE NUMBERS: 
 
 
 
 
 
 
 
Trial Registry Number and date: 
(EudraCT/Clinicaltrials.gov) 
NCT05093426 
IRAS Number: 
302786 
 
REC Number: 
21/SW/0156 
Sponsor Number: 
CLM-INS-004 
Funder Number: 
Closed Loop Medicine 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 3 of 45 
28 Sept 2021 
 
SIGNATURE PAGE: 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Principal Investigator agrees to conduct the study in compliance with the approved protocol and will 
adhere to the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other 
regulatory requirements. 
 
I agree to ensure that the confidential information contained in this document will not be used for 
any other purpose other than the evaluation or conduct of the investigation without the prior written 
consent of the Sponsor. 
 
I also confirm that I will make the findings of the study publicly available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
For and on behalf of the Study Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): Dr Leanne Gardner 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Principal Investigator: 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): Dr Anne Armstrong 
...................................................................................................... 
 
 
 
 
Statistician: 
 
 
 
Signature:  
 
...................................................................................................... 
 
Date: 
....../....../...... 
 
Name: (please print): Sarah Lockwood 
...................................................................................................... 
 
 
 
 
 
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
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28 Sept 2021 
 
KEY TRIAL CONTACTS: 
Principal Investigator 
Name: Dr Anne Armstrong 
Breast Research Team   
Christie Hospital, Wilmslow Rd,  
Manchester, M20 4BX,  
United Kingdom 
Email: anne.armstrong3@nhs.net 
Phone: 
Sponsor/Funder 
Name: Dr Leanne Gardner 
Closed Loop Medicine Ltd. 
Babraham Research Campus, 
Babraham,  
Cambridge, CB22 3AT, 
United Kingdom 
Phone: 07500557515 
Email: leanne.gardner@closedloopmedicine.com 
Statistician 
Name: Sarah Lockwood 
Phone: 07739224476 
Email: sarah.lockwood@pivotalstatistics.com 
Sponsor’s CMO and Medical 
Monitor 
 
Name: Dr Paul Goldsmith 
Email: paul.goldsmith@closedloopmedicine.com 
 
 
 
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
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I. 
TABLE of CONTENTS 
 
RESEARCH REFERENCE NUMBERS: ........................................................................................................................... 2 
SIGNATURE PAGE: .................................................................................................................................................. 3 
KEY TRIAL CONTACTS: ............................................................................................................................................. 4 
I. 
TABLE OF CONTENTS ...................................................................................................................................... 5 
II. 
LIST OF ABBREVIATIONS ................................................................................................................................. 7 
III. 
STUDY SUMMARY .......................................................................................................................................... 8 
IV. 
FUNDING AND SUPPORT IN KIND ................................................................................................................. 10 
V. 
ROLE OF TRIAL SPONSOR AND FUNDER ........................................................................................................ 10 
VI. 
ROLES AND RESPONSIBILITIES OF TRIAL MANGEMENT GROUPS AND INDIVIDUALS ........................................ 10 
VII. 
KEYWORDS ............................................................................................................................................. 10 
VIII. 
STUDY FLOW CHART ................................................................................................................................ 11 
1 
INTRODUCTION AND BACKGROUND ............................................................................................................. 12 
2 
RATIONALE .................................................................................................................................................. 13 
2.1 
ASSESSMENT AND MANAGEMENT OF RISK ................................................................................................................... 13 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .................................................................................... 13 
3.1 
PRIMARY OBJECTIVE ................................................................................................................................................ 13 
3.2 
SECONDARY OBJECTIVES .......................................................................................................................................... 13 
3.3 
PRIMARY ENDPOINT/OUTCOME ................................................................................................................................ 14 
3.4 
SECONDARY ENDPOINTS/OUTCOMES ......................................................................................................................... 14 
3.5  
TABLE OF ENDPOINTS/OUTCOMES ............................................................................................................................. 16 
4 
TRIAL DESIGN .............................................................................................................................................. 17 
5 
TRIAL SETTING ............................................................................................................................................. 17 
6 
PARTICIPANT ELIGIBILITY CRITERIA ............................................................................................................... 17 
6.1 
INCLUSION CRITERIA ................................................................................................................................................ 17 
6.2 
EXCLUSION CRITERIA ............................................................................................................................................... 17 
6.3 
CONCOMITANT MEDICATION ................................................................................................................................... 18 
7 
TRIAL PROCEDURES ..................................................................................................................................... 18 
7.1 
RECRUITMENT ....................................................................................................................................................... 19 
7.2 
PARTICIPANT IDENTIFICATION ................................................................................................................................... 19 
7.3  
STAGE 1 ............................................................................................................................................................... 19 
7.3.1  
STAGE 1 ELECTRONIC CONSENT (ECONSENT) .............................................................................................................. 19 
7.3.2 
PARTICIPANT REGISTRATION ..................................................................................................................................... 20 
7.3.3  
QUESTIONNAIRE COMPLETION.................................................................................................................................. 21 
7.4 
STAGE 2 ............................................................................................................................................................... 21 
7.4.1  
STAGE 2 ELIGIBILITY ASSESSMENT ............................................................................................................................. 22 
7.4.2  
STAGE 2 ECONSENT ................................................................................................................................................ 22 
7.4.3  
DIGITAL SLEEP DIARY .............................................................................................................................................. 22 
7.4.4  
CLINICAL DATA CAPTURE ......................................................................................................................................... 23 
7.4.5  
END OF STUDY PROCEDURES .................................................................................................................................... 23 
7.5 
WITHDRAWAL CRITERIA ........................................................................................................................................... 24 
7.6 
STORAGE AND ANALYSIS OF CLINICAL SAMPLES............................................................................................................ 24 
7.7 
END OF STUDY DEFINITION ...................................................................................................................................... 24 
8 
DIGITAL SLEEP DIARY ................................................................................................................................... 24 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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8.1 
DESCRIPTION OF DIGITAL SLEEP DIARY ........................................................................................................................ 24 
8.2 
REGULATORY STATUS OF THE DIGITAL SLEEP DIARY ........................................................................................................ 24 
8.3 
CONCOMITANT MEDICATION .................................................................................................................................... 25 
8.4 
TRIAL RESTRICTIONS ................................................................................................................................................ 25 
8.5 
ADHERENCE TO THE DIGITAL SLEEP DIARY AND STUDY QUESTIONNAIRES ............................................................................ 25 
9 
SAFTEY REPORTING...................................................................................................................................... 25 
9.1 
DEFINITIONS.......................................................................................................................................................... 25 
9.2 
OPERATIONAL DEFINITIONS FOR (S)AES ..................................................................................................................... 26 
9.3 
RECORDING AND REPORTING OF SAES ....................................................................................................................... 26 
9.4 
SITE INVESTIGATOR ASSESSMENT .............................................................................................................................. 26 
9.5 
SPONSOR MEDICAL ASSESSMENT .............................................................................................................................. 26 
9.6 
NOTIFICATION OF DEATHS ........................................................................................................................................ 27 
9.7 
PREGNANCY REPORTING .......................................................................................................................................... 27 
10 
STATISTICS AND DATA ANALYSIS .................................................................................................................. 27 
10.1 
SAMPLE SIZE CALCULATION....................................................................................................................................... 27 
10.2 
PLANNED RECRUITMENT RATE................................................................................................................................... 27 
10.3 
STATISTICAL ANALYSIS PLAN ...................................................................................................................................... 27 
10.3.1 
SUMMARY OF BASELINE DATA .............................................................................................................................. 27 
10.3.2 
PRIMARY OUTCOME ANALYSIS .............................................................................................................................. 27 
10.3.3 
SECONDARY OUTCOME ANALYSIS .......................................................................................................................... 28 
10.4 
PROCEDURE(S) TO ACCOUNT FOR MISSING OR SPURIOUS DATA ....................................................................................... 28 
10.5 
OTHER STATISTICAL CONSIDERATIONS ........................................................................................................................ 29 
10.6 
ECONOMIC EVALUATION ......................................................................................................................................... 29 
11 
DATA MANAGEMENT ................................................................................................................................... 29 
11.1 
DATA COLLECTION TOOLS ......................................................................................................................................... 29 
11.2 
DATA ENTRY ......................................................................................................................................................... 29 
11.3 
SECURITY FOR EDC ................................................................................................................................................. 30 
11.4 
DATA QUALITY PROCESSES....................................................................................................................................... 30 
11.5 
DATABASE LOCK..................................................................................................................................................... 30 
11.6 
DIRECT ACCESS TO DATA, SOURCE DATA AND DOCUMENTS ........................................................................................... 30 
11.7 
ARCHIVING ........................................................................................................................................................... 31 
12 
MONITORING, AUDIT & INSPECTION ............................................................................................................ 31 
13 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................................. 31 
13.1  
RESEARCH ETHICS COMMITTEE (REC) REVIEW, AMENDMENTS & REPORTS ....................................................................... 31 
13.2 
PUBLIC AND PATIENT INVOLVEMENT .......................................................................................................................... 31 
13.3 
PROTOCOL COMPLIANCE .......................................................................................................................................... 31 
13.4  
NOTIFICATION OF SERIOUS BREACHES TO GCP AND/OR THE PROTOCOL ........................................................................... 31 
13.5  
DATA PROTECTION AND PATIENT CONFIDENTIALITY ....................................................................................................... 32 
13.6  
INDEMNITY ........................................................................................................................................................... 32 
13.7 
ACCESS TO THE FINAL STUDY DATASET ........................................................................................................................ 32 
14 
DISSEMINIATION POLICY .............................................................................................................................. 32 
15 
REFERENCES ................................................................................................................................................ 33 
16.    APPENDICIES ................................................................................................................................................ 36 
APPENDIX 16.1 – INSOMNIA SEVERITY INDEX ............................................................................................................................ 36 
APPENDIX 16.2 – QUALITY OF LIFE QUESTIONNAIRE (EQ-5D-5L) ................................................................................................ 37 
APPENDIX 16.3 – BREAST CANCER-SPECIFIC QUALITY OF LIFE QUESTIONNAIRE (FACT-ES) ............................................................... 39 
APPENDIX 16.4 – USER EXPERIENCE QUESTIONNAIRE ................................................................................................................. 42 
APPENDIX 16.4 – AMENDMENT HISTORY ................................................................................................................................. 45 
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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II. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BDZ 
Benzodiazepine 
DCR 
Data Clarification Requests 
CMO 
Chief Medical Officer 
eConsent 
Electronic Consent 
ePRO  
Electronic Patient Reported Outcomes  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ER 
Oestrogen Receptors 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HER2 
Human Epidermal Growth Factor Receptor 2 
HRA 
Health Research Authority 
ICF 
Informed Consent Form 
ISF 
Investigator Site File 
ISI 
Insomnia Severity Index 
ISMS 
Information Security Management System  
ISRCTN 
International Standard Randomised Controlled Trials 
 
Number 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
PI 
Principal Investigator 
PIN 
Participant Identification Number 
PIS 
Participant Information Sheet 
PR 
Progesterone Receptors 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation  
SDV 
Source Data Verification 
TMF 
Trial Master File 
UEQ 
User Experience Questionnaire 
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
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III. 
STUDY SUMMARY 
 
Study Title 
Personalised Electronic Record Supported Two-Stage Observational Study of 
Sleep in Patients with Breast Cancer 
Short Title 
PERSONAL - SLEEP IN BREAST CANCER 
Primary registry and trial 
identifying number 
 
Secondary identifying 
numbers 
REC: 
IRAS: 302786 
Sponsor Number: CLM-INS-004 
Sponsor/Funder 
Closed Loop Medicine  
Sponsor Contact 
Leanne Gardner 
Co-ordinating Principal 
Investigator (PI) 
Anne Armstrong 
Countries of recruitment  
United Kingdom 
Conditions or focus of study 
Sleep and insomnia in breast cancer 
Interventions 
N/A 
Eligibility criteria 
Stage 1: 
Inclusion criteria: 
To be eligible to participate in Stage 1, the following criteria must be met: 
1) Age > 18 years. 
2) Informed consent to Stage 1 of the study 
3) Diagnosis of Stage I, II or III breast cancer within the previous 12 
months 
Exclusion criteria: 
Participants are not permitted to enrol in the study if one or more of the following 
criteria are met: 
1. Participants who have limited or no understanding of spoken and/or 
written English. 
2. Other diagnosis of cancer, not including basal cell carcinoma of the skin 
or cervical carcinoma in situ, within the previous 5 years. 
Stage 2: 
Inclusion criteria:  
To be eligible for the second stage of the study, the following criteria must be 
met: 
1) Informed consent to Stage 2 of the study 
2) Current Sleep Disturbance; a score of 8 or more on the Insomnia 
Severity Index.                                                                                            
3) History of sleep disturbance prior to the screening/baseline 
consultation; with beginning or worsening of sleep disturbance since 
breast cancer diagnosis e.g. sleep problems began or get worse with the 
diagnosis of breast cancer or with chemotherapy. 
4) Possession of a suitable smartphone that participant can use 
independently.  
Exclusion criteria: 
Participants are not permitted to take part in Stage 2 if one or more of the 
following criteria are met: 
1. Co-morbidities incompatible with study participation e.g. that result in 
a participant being unable to complete daily entries satisfactorily via 
his/her smartphone.  

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 9 of 45 
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2. Known and/or treated sleep apnoea 
3. Regular shift work or night work (defined as >1 overnight shift per 
month) 
4. Breast feeding 
Clinical Phase  
N/A 
Study Design 
Two-Stage Observational Study 
Study Participants 
Tertiary-care-based breast cancer cohort in the UK 
Planned Sample Size 
Plan to enrol a minimum of 285 breast cancer patients into Stage 1, with 125 
of the participants expected to be eligible for Stage 2 of the study.   
Observational duration 
3 weeks 
Study duration 
<8 weeks 
Planned Trial Period 
5 months 
Primary Objective 
To assess the prevalence of insomnia in a cohort of breast cancer patients. 
Secondary Objectives 
 
1. 
In patients with breast cancer experiencing insomnia (defined as score 
of 8 or more on the Insomnia Severity Index; ISI scale), to assess the 
following parameters over a three-week period 
i) 
Insomnia Severity 
ii) 
Sleep efficiency 
iii) 
Quality of Life 
2. 
To assess, at the end of the three-week assessment period, 
i)         Compliance of data entry into the digital sleep diary 
ii)         Feasibility and experience of patients with breast 
cancer to input data relating to their sleep into a 
mobile phone application daily 
iii)        Safety related to using the digital sleep diary 
3. 
To determine associations between insomnia prevalence and 
severity and quality of life with clinical or treatment characteristics 
of breast cancer patients. 
Primary Outcome Measures 
Prevalence of insomnia defined as the proportion of screened patients 
determined as having insomnia defined as a score of 8 or more on the ISI. 
 
Prevalence of insomnia will be determined by administration of the Insomnia 
Severity Index questionnaire to participants in Stage 1 of the study. 
Participants scoring 8 or above will be categorised as having insomnia.   
Secondary Outcome Measures 
1. 
In patients with breast cancer experiencing insomnia (defined as score 
of 8 or more on the Insomnia Severity Index; ISI scale), to assess the 
following parameters over a three-week period 
i) 
Proportion of patients in each Insomnia Severity category 
measured using the ISI  
ii) 
Sleep efficiency calculated from sleep diary entries 
iii) 
Quality of Life index values obtained from EQ-5D-5L and 
Functional Assessment of Cancer Therapy - Endocrine 
Symptoms (FACT-ES). 
iv) 
Compliance of data entry into the digital sleep diary 
v) 
User experience and feasibility of the digital sleep diary 
assessed using the User Experience Questionnaire (UEQ) 
vi) 
Safety assessed by Adverse events (AEs), particularly AEs 
considered associated with the digital sleep diary. 
2. 
Insomnia prevalence and severity and quality of life assessed by 
clinical or treatment characteristics of breast cancer patients. 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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Protocol 28Sept2021 V1.0   
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IV. 
FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL organizations providing funding and/or support in kind for this 
trial) 
Closed Loop Medicine Ltd.  
Babraham Research Campus  
Babraham 
Cambridge  
CB22 3AT 
Email: leanne.gardner@closedloopmedicine.com  
 
 
V. 
ROLE OF TRIAL SPONSOR AND FUNDER  
Closed Loop Medicine will be the Sponsor and funder of this study, and is responsible, in 
conjunction with the PI, for the design, writing the protocol, data analysis and interpretation of 
results. 
 
VI. 
ROLES AND RESPONSIBILITIES OF TRIAL MANGEMENT GROUPS AND 
INDIVIDUALS 
Trial oversight group members will be confirmed prior to commencement of the study. Roles and 
responsibilities of the trial oversight group include co-ordination of the study, maintaining data 
quality and managing the budget. This group will meet regularly throughout the study period. The 
group will act where needed to ensure successful recruitment and follow up of study participants.   
 
VII. 
KEYWORDS 
 
Sleep, insomnia, breast cancer, sleep diary, prevalence. 
 
 
 
 
 
 
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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Protocol 28Sept2021 V1.0   
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VIII. 
STUDY FLOW CHART   
 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
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1 
INTRODUCTION AND BACKGROUND 
 
Sleep is vital for human functioning, immunity, and well-being 1, 2. Sleep disturbance and insomnia 
cause significant health problems and impact on the quality of life in a substantial proportion of the 
general population1. Insomnia, defined as difficulty initiating or maintaining sleep, is highly prevalent 
in primary care, more commonly affecting women, older adults, and individuals suffering from co-
existing medical and psychiatric disorders 1. Studies show incidence of insomnia to be 
disproportionately high in cancer patients; up to three times higher than the general population 3. Breast 
cancer patients experience the highest rates, with prevalence ranging from 19% to 69% 4-10. Further to 
this, up to 60% breast cancer survivors continue to suffer from sleep difficulties and associated health 
problems including cognitive impairment 11.  
 
Within the UK, more than 55,000 women are diagnosed with breast cancer each year. Insomnia is one 
of the most commonly reported health complaints in the general population in the UK, with cancer 
patients being disproportionately affected by the condition12. The impact of insomnia on cancer 
patients’ lives can be pronounced and is associated with many adverse psychological and physical side 
effects, being closely linked with depression, cancer-related fatigue, increased pain, reduced quality 
of life, decreased immunity, disease progression, and survival 2, 13-15. Moreover, insomnia can 
dysregulate circadian rhythm, a 24-h system in part responsible for regulation of the sleep-wake cycle. 
Disruption in circadian rhythm is linked to worse overall health outcomes including shorter survival 
in cancer 16. The treatment options for insomnia range from nonpharmacological including sleep 
hygiene, and cognitive behavioural interventions to pharmacological interventions such as the 
benzodiazepine (BDZ) group of drugs, BDZ-like drugs such as zolpidem. These drugs are associated 
with unwanted side effects; and there remains an unmet medical need 17, 18. 
 
Early diagnosis and more effective breast cancer treatments have led to improved survival rates 5. 
Thus, more individuals are now living with and surviving breast cancer. As the prevalence of sleeping 
difficulties and insomnia are significant within this population, improved insomnia treatments and 
increased access to these treatments is required to better the quality of the life for these individuals. 
However, prior to this, a better characterisation of sleeping difficulties and insomnia in patients with 
breast cancer is required. To date, studies in breast cancer cohorts show large variation in reported 
insomnia prevalence rates, as mentioned, and the type and severity of sleep complaints in these patients 
have been difficult to assess. This is due in part to differences in sleep disturbance definitions, types 
of assessment used, and length of and variation in sample characteristics. Thus, there is a need to 
investigate these issues further using standardised and validated measures. 
 
The Insomnia Severity Index (ISI) is a validated self-report instrument for detection of insomnia 19. 
The ISI comprises seven items which assess perceived severity of difficulties initiating sleep, staying 
asleep, early morning waking, satisfaction of sleep pattern, interference with daily functioning, any 
impairments attributable to the sleep problem, and the degree of personal distress or concern about the 
sleep problem 19. The seven items are allocated a score between 1-4 and are added to give a total score. 
Total scores are categorised as: 0–7 no significant insomnia; 8-14 subthreshold insomnia; 15-21 
clinical insomnia (moderate severity); and 22-28 clinical insomnia (severe). With relevance to this 
current study, the ISI has been validated for detection of insomnia in breast cancer patients and a 
clinical cut-off score of 8 is associated with optimal sensitivity and specificity for the detection of sleep 
difficulties in this population 20.  Further to this, ISI is also sensitive to therapeutic changes and as such 
will be invaluable for evaluating the effect of future treatments in clinical trials for insomnia in breast 
cancer 20. 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
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Using validated measures, this two-stage observation study is designed to generate valuable data 
regarding insomnia in a tertiary-care-based breast cancer cohort in the UK. Specifically, we will assess: 
• Insomnia prevalence, severity, and concurrent self-reported quality of life (Stage 1) 
• Daily sleep diary including sleep efficiency and sleep quality in an eligible group of patients 
with insomnia (Stage 2) 
• Feasibility and acceptability of self-inputting by patients of data relating to their sleep into a 
mobile phone application (Stage 2). 
 
The first stage of the study will involve the assessment of insomnia prevalence in the breast cancer 
cohort. Eligible participants will be asked to consent to the study and complete an ISI and two Quality 
of Life Questionnaires (EQ-5D-5L and FACT-ES). Eligible participants experiencing insomnia will 
be asked to consent to the second stage of the study. In this stage, participants will be asked to keep a 
sleep diary and to input their sleep timings into a digital sleep diary provided as a mobile phone 
application (app) over a three-week period. This will replace the paper sleep diaries participants are 
usually asked to keep as part of a sleep study. At the end of the three-week observation period, 
participants will be asked to complete a User Experience Questionnaire (UEQ) to report feasibility and 
acceptability of the mobile phone application, repeat the ISI, EQ-5D-5L and Functional Assessment 
of Cancer Therapy - Endocrine Symptoms (FACT-ES), and report any adverse events (AE) 
experienced.  
  
2 
RATIONALE  
This two-stage observational study will generate results that provide a better understanding and 
characterisation of the insomnia disease burden in patients with breast cancer in the UK. It will inform 
future target clinical trial population definition (eligibility criteria) and inform selection of a future 
panel of clinical trial assessments. This study will also establish a well-defined cohort of breast cancer 
patients with insomnia in readiness for potential recruitment into a subsequent interventional trial.  
 
In the long-term (outside the scope of the present study), there is interest in whether modifying 
melatonin could be used therapeutically to improve sleep in breast cancer patients.  To date, exogenous 
melatonin has been reported to positively influence sleep quality in cancer patients 21. Further to this, 
completion of a questionnaire to evaluate user experience of participants at conclusion of this study, 
will provide invaluable information regarding the ability of breast cancer patients to self-input data 
relating to sleep into a mobile phone application in the community setting. Using the data generated it 
should be possible to refine the application and optimize user acceptability and experience. 
 
2.1 
Assessment and management of risk 
There are no perceived risks in for participants in this study. There are no direct benefits for patients 
taking part however this study is designed to generate valuable data regarding insomnia in a tertiary-
care-based breast cancer cohort. Results will be used to design future clinical trials aimed at testing 
the efficacy of treatments for insomnia. 
 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
3.1 
Primary objective 
To assess the prevalence of insomnia in a cohort of breast cancer patients. 
 
3.2 
Secondary objectives 
1. In patients with breast cancer experiencing insomnia (defined as score of 8 or more ISI scale), 
to assess the following parameters over a three-week period: 
a. Insomnia Severity (ISI scale; Appendix 16.1)  

Study Number: CLM-INS-004 
 
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b. Sleep efficiency (sleep diary) 
c. Quality of Life (EQ-5D-5L and FACT-ES; Appendix 16.2 and 16.3)  
2. To assess, at the end of the three-week assessment period, the feasibility and experience of 
patients with breast cancer to input data relating to their sleep into a mobile phone application 
daily (UEQ; Appendix 16.3). 
3. To determine associations between severity of insomnia and clinical or treatment 
characteristics of breast cancer patients. 
4. To assess safety of participants using the digital sleep diary. 
 
3.3 
Primary endpoint/outcome 
Primary evaluation criteria: 
i. 
Prevalence of insomnia in the screened cohort of patients with breast cancer; 
including subsidiary breakdown by breast cancer stage and type of breast cancer 
treatment. Prevalence of insomnia will be assessed as the proportion of screened 
patients determined as having insomnia according to the ISI total score (where a score 
of 8 or more indicates insomnia). 
 
3.4 
Secondary endpoints/outcomes 
Secondary evaluation criteria: 
i. 
Insomnia Severity (ISI): Severity of insomnia will be determined at screening/baseline (all 
screened patients in Stage 1 of the study) and following the 3-week observational period 
(all patients enrolled in Stage 2 of the study), based on the total ISI score obtained by 
summing the seven items to provide a score from 0-28 categorised as follows:  
• 0–7 = No clinically significant insomnia 
• 8–14 = Subthreshold insomnia 
• 15–21 = Clinical insomnia (moderate severity) 
• 22–28 = Clinical insomnia (severe) 
ii. 
Sleep efficiency (Sleep diary): Participants’ responses collected from the sleep diary will 
be used to calculate sleep efficiency during the observational period: Sleep efficiency 
=Total sleep time/Total time in bed. 
iii. 
Quality of Life (EQ-5D-5L): Data from the EQ-5D-5L self-classifier, which includes five 
dimensions (mobility, self-care, daily activities, pain/discomfort, and anxiety/depression) 
will be used to calculate an index value as a measure of the participant’s health, both at 
screening/baseline (all screened patients) and following the observational period (all 
enrolled patients). 
iv. 
Quality of Life (FACT-ES): Data from the FACT-ES, which includes five subscale 
domains (physical well-being, social/family well-being, emotional well-being, functional 
well-being and endocrine symptom subscale), will be used to calculate an index value as a 
measure of the participant’s health, both at screening/baseline (all screened patients) and 
following the observational period (all enrolled patients). 
v. 
Compliance of data entry into the digital sleep diary: Compliance will be assessed as the 
proportion of participants completing the digital sleep diary on at least 17 out of 21 days. 
vi. 
User Experience Questionnaire (UEQ): Patient experience, feedback, and satisfaction 
rating from use of digital diary. This will be assessed once (at the end of study), using the 
UEQ designed to evaluate the participant’s experience of the digital sleep diary. 
Participants who withdraw from the study will be offered the questionnaire.  
vii. 
Adverse events: The numbers of AEs and serious adverse events (SAEs) will be 
determined. Participants enrolled in Stage 2 will report AEs at the conclusion of the three-

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week observational period in a telephone consultation with the clinical study team. Any 
relationship with the AE/SAE to the usage of the digital sleep diary will be recorded.  
viii. 
Assessment of any associations between prevalence and severity of insomnia and quality 
of life with clinical or treatment characteristics of breast cancer patients. In addition to the 
full analysis set (all enrolled patients), analyses will be conducted on subgroups for the 
primary and secondary evaluation criteria i)-iii) including assessment according to breast 
cancer stage, treatment regime and baseline insomnia severity (ISI). 
 

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3.5  
Table of endpoints/outcomes 
Objectives 
Outcome Measures  
Timepoint(s) of evaluation of this 
outcome measure (if applicable) 
Primary Objective: 
 
 
Prevalence of insomnia in a 
cohort of breast cancer patients. 
Proportion of screened patients with 
insomnia defined as a total ISI score of 8 
or more. 
 
Stage 1 assessment of insomnia 
severity performed at baseline via 
administration of the ISI.  
Secondary Objectives: 
 
 
To assess insomnia severity in 
breast 
cancer 
patients 
experiencing insomnia (ISI≥8) 
Proportion of participants in each ISI 
category of insomnia severity based on the 
ISI total score.  
Assessment of insomnia severity 
will 
be 
performed 
at 
baseline/screening and day 21 via 
administration of the ISI. 
To assess sleep efficiency in 
breast 
cancer 
patients 
experiencing insomnia (ISI≥8) 
Sleep efficiency defined as total sleep time 
relative to total time in bed. 
Sleep efficiency will be assessed via 
the digital sleep diary completed 
daily over the 3-week observation 
period for patients enrolled in Stage 
2. 
To assess quality of life in breast 
cancer 
patients 
experiencing 
insomnia (ISI≥8).  
Data from the EQ-5D-5L questionnaire 
which includes five dimensions (mobility, 
self-care, daily activities, pain/discomfort, 
and anxiety/depression), will be used to 
calculate an index value as a measure of 
the participant’s health.   
Quality of life will be evaluated at 
baseline on all eligible participants 
in Stage 1 and at Day 21 on all 
participants enrolled in Stage 2. 
To assess quality of life in breast 
cancer 
patients 
experiencing 
insomnia (ISI≥8). 
Data from the FACT-ES questionnaire 
which includes five subscale domains 
(physical well-being, social/family well-
being, emotional well-being, functional 
well-being, 
and 
endocrine 
symptom 
subscale), will be used to calculate an 
index value as a measure of the 
participant’s health. 
Quality of life will be evaluated at 
baseline on all eligible participants 
in Stage 1 and at Day 21 on all 
participants enrolled in Stage 2. 
To assess compliance of data 
entry into the digital sleep diary. 
Compliance will be assessed as the 
proportion of participants completing the 
digital sleep diary on at least 17 out of 21 
days. 
Compliance will be calculated for 
each participant completing the 
three-week observational period in 
Stage 2. 
To assess the feasibility and 
experience of patients with breast 
cancer to input data relating to 
their sleep into a mobile phone 
application daily. 
Feasibility and experience of patients 
using the digital sleep diary will be 
assessed using the UEQ. 
Performed at Day 21 on all 
participants enrolled in Stage 2. 
Participants who withdrew from the 
study 
will 
be 
offered 
the 
questionnaire.  
To assess safety of patients using 
the digital sleep diary. 
Numbers of AEs and SAEs. 
Participants will be asked to report 
any AEs experienced during the 
three-week observational period at 
Day 21 in a telephone consultation 
with the study team. 
To 
determine 
associations 
between severity of insomnia and 
clinical 
or 
treatment 
characteristics of breast cancer 
patients. 
Assessment 
of 
insomnia 
prevalence, 
severity, and quality of life in subgroups 
based on clinical/treatment characteristics 
including breast cancer stage, treatment 
regime and baseline insomnia severity. 
Performed on data collected at Stage 
1 and across Stage 2.  
 
 
 

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4 
TRIAL DESIGN 
This is a two-stage prospective observational study of insomnia in patients with breast cancer. This is 
designed as a remote observational study to be conducted in the community with no participant visits 
required to investigational site. However, there will be the option to recruit participants in-person, if 
required. 
 
In the first stage of the study, eligible breast cancer patients consenting to participate will complete the 
ISI scale to determine prevalence of insomnia. Additional data will be collected from participants and 
is described in the Assessment Schedule (Table 1). Participants scoring 8 on the ISI, will then be 
assessed for eligibility to Stage 2.  
 
Following stage 1, eligible participants will be invited to consent to taking part in Stage 2 of the study. 
Those consenting will be asked to download and complete a daily digital sleep diary on their 
smartphone over a three-week observation period. At the end of the three-week observation period, 
participants will be asked to complete a series of questionnaires and additional procedures as outlined 
in the Assessment Schedule (Table 1).  
 
5 
TRIAL SETTING 
This is a single centre study to be carried out at the Christie NHS Foundation Trust. Breast cancer 
patients at the hospital will be screened for eligibility to the study.  
 
6 
PARTICIPANT ELIGIBILITY CRITERIA 
6.1 Inclusion criteria 
To be eligible to participate in Stage 1, the following criteria must be met: 
1. Age > 18 years. 
2. Informed consent to Stage 1 of the study.  
3. Diagnosis of Stage I, II or III Breast Cancer within the previous 12 months. 
 
To be eligible for Stage 2 of the study, the following criteria must be met: 
1. Informed consent to Stage 2 of the study. 
2. Current Sleep Disturbance; a score of 8 or more on the Insomnia Severity Index.                                        
• Total ISI score categories:  
0–7 = No clinically significant insomnia 
8–14 = Subthreshold insomnia 
15–21 = Clinical insomnia (moderate severity) 
22–28 = Clinical insomnia (severe) 
3. History of sleep disturbance prior to the screening/baseline consultation; with beginning or 
worsening of sleep disturbance since breast cancer diagnosis e.g. sleep problems began or get 
worse with the diagnosis of breast cancer or with chemotherapy. 
4. Possession of a suitable smartphone that participant can use independently.  
 
6.2 
Exclusion criteria 
Participants are not permitted to enrol in the study if one or more of the following criteria are met: 
1. Participants who have limited or no understanding of spoken and/or written English. 
2. Other diagnosis of cancer, not including basal cell carcinoma of the skin or cervical 
carcinoma in situ, within the previous 5 years. 
 
Participants are not permitted to take part in Stage 2 if one or more of the following criteria are met: 
1. Co-morbidities incompatible with study participation e.g. that result in a participant being 
unable to complete daily entries satisfactorily via his/her smartphone.  

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2. Known and/or treated Sleep apnoea. 
3. Regular shift work or night work (defined as >1 overnight shift per month) 
4. Breast feeding. 
 
6.3 
Concomitant Medication 
Concomitant Sleep Medication: 
Participants are permitted to continue taking existing sleep medication (usage to be documented). 
Introduction of new sleep medication during the three-week study period is not permitted. 
 
7 TRIAL PROCEDURES  
Table 1. Assessment Schedule 
 
Stage 1 
Stage 2 
Assessment/ 
Procedure 
Screening 
(-14 
days) 
Day 
0 
Screening 
(-28 
days)5 
Day 
0 
Days 
1-21 
Day 
21 
(+8 
days) 
Stage 1: 
 
 
 
 
 
 
Informed Consent1 for Stage 1 & Registration 
x 
 
 
 
 
 
ISI2 
 
x 
 
 
 
 
EQ-5D-5L2 
 
x 
 
 
 
 
FACT-ES2 
 
x 
 
 
 
 
Demographics2 
 
x 
 
 
 
 
Sleep History2 
 
x 
 
 
 
 
Stage 2: 
 
 
 
 
 
 
Informed Consent for Stage 21 
 
 
x 
 
 
 
Review Eligibility Criteria 
 
 
x 
 
 
 
Cancer Medical History 
 
 
 
x 
 
 
Current Cancer Treatment 
 
 
 
x 
 
 
Current Co-Morbidities 
 
 
 
x 
 
 
Digital Diary Download3 
 
 
 
x 
 
 
Daily Sleep Diary Entry3 
 
 
 
 
x 
 
ISI2 
 
 
 
 
 
x 
EQ-5D-5L2 
 
 
 
 
 
x 
FACT-ES2 
 
 
 
 
 
x 
UEQ2 
 
 
 
 
 
x 
Adverse Events4 
 
 
 
 
 
x 
1 Where possible will be online remote eConsent but can be completed in clinic (online/paper). 
2 Participant completes online questionnaire (paper questionnaires will be available for clinic use). 
3 Participants completes on their own smartphone. 
4 AEs will be collected at follow-up telephone consultation at Day 21 (+8 days). 
5 Stage 2 Consent should occur no later than 28 days post Stage 1 Consent, however ideally this 
would occur as soon as possible after consent for Stage 1 has been provided.   
 

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7.1 
Recruitment  
Recruitment will take place at the Christie NHS Foundation Trust over a four-month period and is 
planned to end (last participant enrolled) by January 2022.  
 
7.2 
Participant identification 
Stage 1 of the study will involve members of the clinical team identifying potential participants from 
the breast cancer clinic database at the Christie Hospital. Patient records will be used to assess inclusion 
and exclusion criteria to identify participants who are potentially eligible for the first stage of the study. 
These potentially eligible breast cancer participants will be invited to take part in the study. 
Recruitment will be complete when we reach the target sample size of 285 participants.   
 
7.3  
Stage 1 
Participants will be recruited to Stage 1 of the study remotely and if required, in-person through 
attendance at the breast cancer clinic at the Christie NHS Foundation Trust.  
 
7.3.1  Stage 1 Electronic Consent (eConsent)  
Participants will be contacted by the clinical study team by text message. This text message will give 
some brief information about the study and an internet link to the study information including the 
Patient Information Sheet (PIS) and Informed Consent Form (ICF). If required, initial contact can also 
occur by email, telephone and/or online video conferencing. In these instances, the potentially eligible 
participant will be provided with the same internet link as above. Moreover, the initial contact can also 
be face to face in the clinic. The PIS and ICF to be used in the study will be approved by the Research 
Ethics Committee (REC) and follow GCP guidelines. These documents have been designed to be 
viewed and completed by patients on their smartphone. If required, these documents can also be 
accessed by a computer or tablet. Patients will be given time to consider taking part in the study and 
provided with contact details of the clinical study team to discuss any questions they may have 
regarding the study. If willing to participate, they will be asked to complete the ICF. At this stage the 
participant will be asked to provide their email address and mobile phone number for the purposes of 
sending study questionnaires and further study information. If no response has been received from 
potential participants within 3 days of the receiving the first text message, the initial text message will 
be sent again. 
 
A proportionate approach to eConsent in guidance with the MHRA/HRA Joint Statement regarding 
seeking consent using electronic methods will be taken22. The HRA indicate that it is not necessary to 
include a PIS or ICF for online questionnaire-based research23. However, we have taken the decision 
to provide patients with these documents to ensure they have sufficient information to enable them to 
reach an informed decision to take part.  As the study is observational and low risk, participants will 
confirm participation in the trial by simple e-signature on the ICF. Within the ICF, participants will be 
asked to consent to the use of their personal data for the purposes of sending online questionnaires and 
for the Sponsor to have access to this data for monitoring purposes. Participants will also be asked to 
consent to being contacted to take part in Stage 2 of the study. See Figure 1 for an outline of the 
eConsent process. 
 

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Figure 1. Outline of eConsent process using QualtricsXM platform. 
 
QualtricsXM will be used as the online platform for providing patients with the study information, PIS 
and ICF, remotely. This platform is General Data Protection Regulation (GDPR) compliant and is ISO 
27001 certified ensuring QualtricsXM meets the international standard defining requirements for 
Information Security Management System (ISMS). The clinical study team will be provided with a 
secure Clinical Study Team QualtricsXM User Account. This user account will be given a username 
and password for access only by authorised individuals in the clinical study team.  
 
Once a participant completes and submits their online ICF, the information is saved within the Clinical 
Study Team QualtricsXM User Account. The QualtricsXM platform will be directed to send a copy of 
the PIS and completed ICF to the participant via email. A copy of the ICF will also be forwarded via 
email to the study team for downloading and storage in the Investigator Site File (ISF) and patient 
medical record. 
 
As mentioned, the eConsent process can be performed face-to-face in clinic. Participants can complete 
the consent process directly online on their smartphone. If this is unavailable, a tablet can be provided, 
or paper documentation can be supplied. If completed on paper, clinic study staff will need to enter 
relevant data into QualtricsXM platform to activate downstream processes for Stage 2 of the study.  
 
7.3.2 Participant Registration 
The clinical study team will be notified of consenting participants through the delivery of completed 
ICFs via email from the QualtricsXM platform. Upon receiving an ICF, they will review ICF to ensure 
completeness and register the patient into the eCRF. This will include entering the patient’s mobile 
number and email address into the eCRF for remote questionnaire delivery. An anonymous participant 
identification number (PIN) will be assigned to the patient by the Electronic Data Capture (EDC) 
system. This PIN will also be used as a unique identifier within the QualtricsXM platform. See Figure 
2 for an outline of Stage 1 study procedures. 
 

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Figure 2. Outline of Stage 1 study procedures including informed consent.  
 
Upon submission of a completed ICF, the QualtricsXM platform will store the participant’s contact 
details within the QualtricsXM Directory which is securely located within the Clinical Study Team 
QualtricsXM User Account. These contact details will be used for sending Stage 2 specific-study 
information to participants who are eligible for the second stage of the study. 
 
7.3.3  Questionnaire Completion  
Following completion of patient registration into the eCRF, the electronic Patient Reported Outcomes 
(ePRO) module of the eCRF will be activated to send a text message (or email, if required) containing 
a link to the baseline questionnaire set to consenting participants. This questionnaire set consists of 
five short questionnaires including: 
• Insomnia Severity Index: ISI 
• Quality of life: EQ-5D-5L and FACT-ES 
• Demographics and sleep history: age, gender, weight, height, ethnicity, marital status, 
educational level, current occupation, pregnancy, breastfeeding, menopausal status, shift-
work/night-work and smartphone access. Sleep-related questions to determine if the patient 
has experienced sleep disturbance prior to the screening/baseline consultation with beginning 
or worsening of sleep disturbance since breast cancer diagnosis and if patient has suffered or 
currently suffering from sleep apnoea. 
 
The participant can complete the questionnaires on their smartphone. It is estimated the participant 
will take 20-25 minutes to complete these questionnaires. If the participant does not complete the 
baseline questionnaire within 3 days, the eCRF will send a questionnaire reminder text message (or 
email, if required). This will be repeated on two subsequent occasions if the questionnaire remains 
uncompleted for the three preceding days. The eCRF can be configured to notify the clinical study 
team by email when a participant completes the questionnaire set. Questionnaires can also be 
completed on computer or tablet however smartphone completion is preferred.  
 
The baseline questionnaire set can be completed on paper if the clinic, however clinic study staff will 
be required to subsequently enter the data recorded by the participant directly into eCRF. 
 
7.4 
Stage 2  
Briefly, Stage 2 will run separately from Stage 1 to aid the timely recruitment and flow of participants 
through the study. Participants will be asked to consent to taking part in Stage 2, separately from the 
consent to take part in Stage 1. As participants in Stage 1 will have consented to the use of their contact 
details for the purposes of being invited to take part in Stage 2, all recruitment and procedures in Stage 
2 will be carried out remotely. Figure 3 describes Stage 2 procedures. 

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Figure 3. Outline of Stage 2 study procedures.  
 
7.4.1  Stage 2 Eligibility Assessment  
All questionnaire-derived eligibility-related data for each participant will be present within the eCRF. 
This will enable the clinical study team to populate the eligibility eCRF including ISI scores and data 
related to self-reported sleep history, sleep apnoea, shift-work or night-work, possession of smartphone 
and breast feeding.  The EDC will be configured to automatically calculate the total ISI score required 
for assessment of eligibility to Stage 2. The clinical research team will be required to confirm from 
patient medical records the stage of breast cancer, any other diagnosis of cancer, not including basal 
cell carcinoma of the skin or cervical carcinoma in situ, within the previous 5 years, and any co-
morbidities incompatible with study participation. 
 
7.4.2  Stage 2 eConsent  
Within 28 days of consenting to Stage 1 of the study and following confirmation of a participants’ 
eligibility to Stage 2, a clinical study team member will activate the QualtricsXM platform to send a 
Stage 2-specific PIS and ICF to the eligible participant via text message (or email, if required). Again, 
the patient will be given time to consider taking part in the study and provided with contact details of 
the clinical study team to discuss any questions they may have regarding the study. Once a participant 
completes and submits their online Stage 2-specific ICF, the QualtricsXM platform will send a copy of 
the Stage 2 PIS and completed ICF to the participant via email and a copy of the ICF to the study team. 
If no response has been received from potential participants within 3 days of the receiving the Stage 2 
invite text message, this text message will be sent again. This will be repeated once more, 3 days later 
if no response has been received.  
 
7.4.3  Digital Sleep Diary  
Upon receiving and reviewing completed Stage 2-specific ICF, the study team will assign a 
participant-specific digital sleep diary code to the participant provided by Closed Loop Medicine and 
enter this code into the eCRF. Within the eCRF the study team will confirm consent for Stage 2 has 
been obtained and then instruct the ePRO module of the eCRF to send the participant via text message 
(or email if required) instructions for downloading, enrolling, and using the digital sleep diary app on 
their smartphone. The participant will also be asked to complete a short questionnaire to confirm they 
have downloaded and enrolled into the app. This is required for the automation of delivery of End of 
Study Questionnaire Set by the eCRF at day 21. If the short questionnaire is not completed by the 
participant within 3 days, the eCRF will send a questionnaire reminder email or text message. This 
will be repeated again 3 days later if the if the download and enrolment procedure is not confirmed. If 
after 9 days the questionnaire still remains unanswered, a member of the research team will call the 
participant to determine if they are experiencing any issues with downloading the digital sleep diary 
app and provide assistance.  

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The participant will then complete the digital sleep diary each day for three weeks. Participants will 
be provided with contact information if they require assistance with downloading or using the app 
during the study period. This will be a study-specific email address to be received by members of the 
clinical study team. Participants requiring assistance will be contacted by a clinical study team member 
either by email or telephone. Where required, the clinical study team will access technical support 
directly from Closed Loop Medicine. 
 
7.4.4  Clinical Data Capture  
Upon receiving and reviewing completed Stage 2-specific ICF, the study team will review patient 
medical records and capture required data for the following eCRFs: 
 
Cancer Medical History: capturing data regarding, time since cancer diagnosis, cancer stage, primary 
or secondary cancer, surgery type, neoadjuvant or adjuvant treatment, and positivity for oestrogen 
receptors (ER), progesterone receptors (PR) or human epidermal growth factor receptor 2 (HER2).  
 
Cancer Treatment: current breast cancer treatment broken down by chemotherapy, radiotherapy, and 
hormonal therapy and information regarding current medication cycle. 
 
Current Co-morbidities: current co-morbidities and whether each co-morbidity is being treated with 
medication. 
 
7.4.5  End of Study Procedures  
At day 21 of follow up, the ePRO module of the eCRF will automatically send by text message (or 
email, if required) each participant in Stage 2 of the study the End of Study Questionnaire set 
consisting of: 
• ISI 
• EQ-5D-5L 
• FACT-ES 
• User experience questionnaire (UEQ)  
 
The participant can complete the questionnaires on their smartphone. It is estimated the participant 
will take 20-25 minutes to complete these questionnaires. If the questionnaire set is not completed by 
the participant within 3 days, the eCRF will send a questionnaire reminder email or text message. This 
will be repeated on two subsequent occasions if the questionnaire remains uncompleted within the 
three preceding days. Questionnaires can also be completed on computer or tablet however smartphone 
completion is preferred. 
 
On day 21 (+8 days), a member of the clinical study team will phone each participant and record any 
AEs and SAEs that the participants have experienced in the previous 3 weeks. AE’s and SAEs will be 
entered into the eCRF and patient health records. Prior to the phone call, the eCRF will be checked to 
determine if the participant has completed the End of Study Questionnaire set. If this has not been 
completed, the staff member will remind the participant to complete these questionnaires. The clinical 
study team will attempt to telephone the participants on three occasions. If unsuccessful, this will be 
recorded as a missed visit in the site protocol deviation log.  
 

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7.5 
Withdrawal criteria  
Participants have the right to withdraw from the study at any time for any reason.  The investigator 
also has the right to withdraw patients from the study for any reason.  An excessive rate of withdrawals 
can render the study uninterpretable; therefore, unnecessary withdrawal of patients should be avoided.   
 
Efforts will be made to continue to obtain 3-week follow-up data, even if the participant did not 
complete their sleep diary and with the permission of the patient. Participants who withdraw from the 
study will be offered the User Experience Questionnaire. 
 
Should a patient decide to withdraw from follow up data collection, all efforts will be made to report 
the reason for withdrawal as thoroughly as possible. Participants who discontinue from the study will 
not be replaced. Clinical study team will complete the withdrawal form in the eCRF when participants 
chose to discontinue. Data already collected from a participant prior to withdrawal will be retained and 
used in the study.  
 
7.6 
Storage and Analysis of Clinical Samples  
No biological samples will be collected in this study.  
 
7.7 
End of Study Definition  
End of study will be defined as the last participant to complete their end of study visit (remote). 
 
8 
DIGITAL SLEEP DIARY 
 
8.1 
Description of digital sleep diary 
The digital sleep diary has been designed by Closed Loop Medicine Ltd. This diary will be hosted, 
monitored, and managed by the digital sleep diary designers at Closed Loop Medicine. The digital 
sleep diary comes in the form of a patient-facing mobile phone application intended to be installed on 
the participant’s smartphone. The application will be available in both iOS and Android, and we will 
establish a list of supported operating systems. A risk-based approach will be taken for supporting 
updates to these versions over the course of the study. All sleep data will be collected in the app. The 
sleep diary question set is consistent with previously published sleep diaries24-28 and will collect the 
following data daily from each participant: 
• what time the patient got into bed last night 
• what time did the patient try to go to sleep last night 
• how long it took the patient to fall asleep 
• how many times the patient woke up last night 
• in total, how long the patient was awake during the night 
• what was the patient’s final wake-up time that morning 
• how long the patient stayed in bed after waking up 
• how did the patient rate their quality of sleep last night 
• did something in particular affect the patient’s sleep 
No recommendations regarding diagnosis, intervention, treatment, or care planning will be made by 
the app. 
 
8.2 
Regulatory status of the digital sleep diary  
The digital sleep diary used in this study is not a medical device. 
 

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8.3 
Concomitant medication 
Participants are permitted to continue taking existing concomitant medication, including sleep 
medication. During the three-week study period introduction of new sleep medication is not permitted. 
 
8.4 
Trial restrictions  
There are no study restrictions. 
 
8.5 
Adherence to the digital sleep diary and study questionnaires 
As compliance of data entry into the digital sleep diary is a secondary outcome, adherence to the digital 
sleep diary will not be monitored during the three-week study period. Adherence to the enrolment 
procedure required for downloading and setting up the digital sleep dairy on participants smartphones 
will be assessed remotely by Closed Loop Medicine. If digital sleep diary has not been downloaded 
within three days of the participant receiving instructions to do so, the eCRF will send a reminder by 
email or text. If after another three days, the digital sleep diary has not been downloaded the clinical 
study team will attempt to call the participant to remind participant to download the app and determine 
if they require any assistance doing so. Compliance of data entry into the digital sleep diary during 
three-week study period will be assessed at the end of the three-week study period by Closed Loop 
Medicine. 
 
Questionnaire adherence will be monitored by the clinical study team throughout the study period. 
Questionnaire reminders, at baseline and end of study, will be sent by email or text message to 
participants by the QualtricsXM platform. Reminder email or text messages will be sent up to three 
times, three days apart. If the end of study questionnaire set remains uncompleted, the clinical research 
team will remind the participant to complete the questionnaire during remote telephone consultation 
at day 21. 
 
Non-compliance to the protocol study procedures will be documented by the investigator in the 
participant study files and site deviation log. 
 
 
9 
SAFTEY REPORTING 
9.1 
Definitions 
Term 
Definition 
Adverse Event 
Any untoward medical occurrence in a study participant which does 
not necessarily have a causal relationship with the procedure involved.  
Serious Adverse Event  A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 

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9.2 
Operational definitions for (S)AEs  
The risks to participants enrolled in this observational study are considered very low.  
 
All AEs and SAEs experienced during the three-week study period by participants enrolled in Stage 2 
will be recorded in the eCRF and in the patients’ medical records. AEs and SAEs can either be 
volunteered by the participant or detected by the clinical research team through physical examination 
or in the patients’ medical notes. 
 
Only SAEs that the Principal Investigator (PI) considers to be directly related to the digital sleep diary 
will be reported to the Sponsor via the EDC system. 
 
9.3     Recording and reporting of SAEs  
For each AE, the investigator must pursue and collect information to adequately determine the 
outcome of the AE and to assess whether it meets the classification criteria of an SAE. All SAEs 
considered to be directly related to the digital sleep diary, occurring from the time of participant 
consent to Stage 2 of the study to the conclusion of the 3-week observation period, must be reported 
to the Sponsor within 24 hours of awareness of the event by the PI. In the rare situation that the PI 
does not become immediately aware of the occurrence of a safety event, the PI must report the event 
within 24 hours of learning about it and record the time of awareness of the event.  
 
For each SAE, the following information will be collected: full details in medical terms and case 
description, event duration (start and end dates, if applicable), action taken, outcome, seriousness 
criteria, and causality (i.e. relatedness to the digital sleep diary), in the opinion of the PI. Any change 
of condition or other follow-up information should be updated in the EDC system. The Sponsor should 
be notified as soon as it is available or at least within 24 hours of the information becoming available. 
Events will be followed up until the event has resolved or a final outcome has been reached. 
 
9.4 
Site Investigator Assessment 
The PI is responsible for the care of the participant, or in his/ her absence an authorised clinician within 
the research team is responsible for assessment of any event for: 
• Seriousness: assessing whether the event is serious according to above definitions (Section 9.1). 
• Causality: assessing the causality of all serious adverse events/reactions in relation to use of the 
digital sleep diary according to the definition given.  
• Severity: assessing the severity of the event according to the following terms and assessments. The 
intensity of an event should not be confused with the term “serious” which is a regulatory definition 
based on patient/event outcome criteria. 
o Mild: Some discomfort noted but without disruption of daily life 
o Moderate: Discomfort enough to affect/reduce normal activity 
o Severe: Complete inability to perform daily activities and lead a normal life. 
 
The PI will ensure all SAEs are recorded and reported to the Sponsor within 24 hours of becoming 
aware of the event and provide further follow-up information as soon as available.  
 
9.5 
Sponsor Medical Assessment 
The Sponsor’s Chief Medical Officer (CMO) will oversee medical assessment of all reported SAEs. 
The CMO review all SAEs within 24 hours of receipt. This review will encompass seriousness and 
relatedness and be in accordance with the trial risk assessment and protocol as detailed in the Safety 
Monitoring Plan. As this observational study was deemed not to require Data Monitoring Committee 

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and / or Trial Steering Committee, the CMO is not required to report safety information to the 
independent oversight committees. 
 
9.6 
Notification of deaths  
Only deaths that are assessed to be caused by use of the digital sleep diary app will be reported to the 
Sponsor. This report will be immediate from the point the assessment is made. 
  
9.7 
Pregnancy reporting  
Pregnancy is not considered an AE unless a negative or consequential outcome is recorded for the 
mother or child/foetus. If the outcome meets the serious criteria, this would be considered an SAE. 
 
10 STATISTICS AND DATA ANALYSIS 
10.1 
Sample size calculation 
The sample size required for Stage 1 is based on an assumed prevalence of insomnia of 44% in breast 
cancer patients (midway point of insomnia prevalence range found in breast cancer patients 19-69%)4-
10. A sample size of 267 participants is required for estimating the expected prevalence rate with 5% 
absolute precision and 90% confidence or 6% absolute precision and 95% confidence29.   
 
The target for Stage 2 is for approximately 100 participants to complete the study, to provide sufficient 
data to assess the secondary objectives. With an assumed prevalence of 44% and a 20% drop out rate, 
then 285 participants in Stage 1 would give an expected 125 eligible participants for Stage 2 with 100 
participants assumed to complete the 3-week observation period.  
   
Therefore, the study will aim to recruit a minimum of 285 patients into Stage 1 to cover the sample 
size requirements for Stage 1 and Stage 2. 
 
10.2 
Planned recruitment rate 
Recruitment will take place over a four-month period and is planned to end (last participant enrolled) 
by January 2022. Expected recruitment rate for Stage 1 is aimed at 15 participants per week with 
approximately half of these (7-8 participants per week) being eligible for Stage 2 of the study.  
 
10.3 
Statistical analysis plan 
The analyses will be carried out according to the statistical analysis plan (SAP) which will be prepared 
prior to database lock. The SAP will describe the statistical methods to be used in the analysis and 
reporting of study data.  
 
10.3.1 Summary of baseline data 
Baseline demographic data will be summarised for all participants enrolled in Stage 1, and separately 
for those in Stage 2. In general, continuous variables will be summarised using the following standard 
descriptive summary statistics: number of observations, mean, standard deviation (SD), median, 
minimum, and maximum. Categorical data will be summarised as the number and percentage of 
participants in each category.  
 
10.3.2 Primary outcome analysis 
The prevalence estimates for insomnia in the breast cancer cohort studied will be reported as the 
number and percentage of screened patients in Stage 1 determined as having insomnia by the ISI (total 
score of 8 or more) and accompanied with exact 95% confidence intervals. Prevalence rates and 95% 
confidence intervals will also be reported by breast cancer stage (Stages I, II and III) and type of breast 
cancer treatment.  
 

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10.3.3 Secondary outcome analysis 
Insomnia severity will be assessed by calculating proportions (number and percentage) of participants 
within each of the ISI categories:   
• no clinically significant insomnia (ISI score 0-7) 
• subthreshold insomnia, (ISI score 8-14) 
• clinical insomnia of moderate severity (ISI score 15-21)  
• severe clinical insomnia (ISI score 22-28).  
 
Percentage of participants in each severity category at baseline/screening will be derived and 
summarised based on all screened patients from data obtained during stage 1 (baseline/screening 
assessment). In addition, percentage of patient in each severity category will also be assessed only in 
those patients determined to have insomnia (i.e. enrolled patient in Stage 2) at both screening/baseline 
and day 21. 
 
To determine sleep efficiency, the % of time a participant is asleep whilst in bed will be derived based 
on total time asleep relative to total time in bed. Sleep efficiency will be derived and assessed over the 
last 2 weeks of the 3-week observation period to correspond with the insomnia severity assessment 
which is also based on the last 2 weeks. Other timepoints may also be assessed (e.g. weekly). 
 
Quality of Life Data from the EQ-5D-5L self-classifier, which includes five dimensions (mobility, 
self-care, daily activities, pain/discomfort, and anxiety/depression), will be used to calculate an index 
value as a measure of the participant’s health, both at screening/baseline (all screened patients; Stage 
1) and following the observational period (all enrolled patients; Stage 2). Data will be summarised 
descriptively.  
 
Quality of Life Data from the FACT-ES self-report measure, which includes five subscale domains 
(physical well-being, social/family well-being, emotional well-being, functional well-being, and 
endocrine symptom subscale), will be used to calculate an index value as a measure of the participant’s 
health, both at screening/baseline (all screened patients; Stage 1) and following the observational 
period (all enrolled patients; Stage 2). Data will be summarised descriptively.  
 
Compliance of entry into the digital sleep diary will be assessed as the proportion of participants 
completing the digital sleep diary on at least 17 out of 21 days and summarised descriptively.  
 
Reporting of user experience data collected from the UEQ at Day 21 will be descriptive. 
 
All Reported AEs and SAEs will be coded according to the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA) and presented by SOC and PT. In addition, any AEs/SAE 
considered related to the usage of the sleep diary will be summarised separately (or listed if numbers 
are low). 
 
To assess any association with treatment/clinical characteristics and insomnia prevalence, insomnia 
severity, sleep efficiency and Quality of Life, data will be reported and summarised by breast cancer 
stage, treatment regimen and baseline insomnia severity. Other clinical or treatment groups may also 
be explored. Full details of the characteristics to be assessed will be provided in the SAP. 
 
10.4 
Procedure(s) to account for missing or spurious data  
The amount and type of missing data will be reviewed and if necessary, imputation methods for 
missing data may be implemented. 

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10.5 
Other Statistical Considerations  
Any changes made to the original analysis plan will be recorded in the Statistical Analysis Plan 
along with dates, updated SAP version number and description and reason for the changes. If a 
participant withdraws from the study, they will not be replaced. 
 
10.6 
Economic Evaluation 
Not applicable. 
 
11 DATA MANAGEMENT  
 
11.1 
Data collection tools  
There are two datasets in the study: the SMART-Trial EDC system dataset and the Closed Loop 
Medicine digital sleep diary dataset. The Sponsor will act as custodian for the study data. SMART-
TRIAL will be used as the primary Electronic Data Capture tool in this study. SMART-TRIAL is 
designed and developed in compliance with the PIC/S Guidance, PI-011-3 Good Practices for 
Computerised Systems in Regulated “GxP” Environments, with software validation based on IEC 
62304. SMART-TRIAL is designed to enable its users to comply with Good Clinical Practice (such 
as the ISO 14155:2020 standard), ICH GCP, and other industry requirements, such as FDA 21 CFR 
Part 11, HIPAA and the EU GDPR. All data in SMART-TRIAL is collected, transferred, and stored 
encrypted in databases, which are hosted on ISO certified servers that are managed by SMART-TRIAL 
within the European Union (Ireland and the Netherlands).  
 
11.2 
Data Entry  
Authorised staff at the clinical site will transcribe baseline and follow up data directly from electronic 
patient records into the eCRF in the EDC system. This will be performed by going to https://app.smart-
trial.co/#/authentication/login and entering username and password to access the study database. A full 
audit trail of data entry and any subsequent changes to entered data will be automatically date and time 
stamped, alongside information about the user making the entry/changes within the system. Authorised 
users delegated by the PI at the investigational site will have access to the eCRF and each user will be 
assigned specific user roles and rights. This will be reflected on the delegation log.  
 
Patient-reported data will be entered into the eCRF by participants submitting completed 
questionnaires as described in throughout Section 7. Four validated questionnaires will be used for 
self-reported data collection and include: 
• ISI: a validated self-report instrument for detection of insomnia19. 
• EQ-5D-5L: a validated self-report instrument for health-related quality of life data30. 
• FACT-ES: a validated self-report measure for health-related quality of life data in breast 
cancer patients31. 
• UEQ: a validated self-report instrument for measurement of usability aspects (efficiency 
and dependability) and user experience aspects (originality and stimulation)32. 
 
Closed Loop Medicine will be responsible for creating the digital sleep diary database and preparing 
and an enrolment code list. Closed Loop Medicine will provide a unique enrolment code for the digital 
sleep diary for each participant and monitor the use of these codes. Following the downloading and 
enrolment into the digital sleep diary, each participant will enter their sleep data into the diary every 
day for three weeks. Data collected in the digital sleep diary will be hosted, monitored, and managed 
by the digital designers at Closed Loop Medicine. This data will be linked to each participant by a 
unique identifier code. No patient identifiable data will be collected in this dataset. Closed Loop 

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Medicine designers of the digital sleep diary will only have read-only access to the database to ensure 
accurate data transfer and can request downloads intermittently, when required. Closed Loop Medicine 
designers will also be responsible for withdrawing participants, where necessary, from the digital sleep 
diary during the study and preventing access at the completion of the three-week observational period. 
 
11.3 
Security for EDC 
Clinical site staff will request usernames and passwords for the EDC from the Sponsor. Systems access 
will be strictly restricted through user-specific passwords to the authorised research team members. It 
is a legal requirement that passwords are not shared, and that only those authorised to access the system 
are allowed to do so. If new staff members join the study, a user-specific username and password must 
be requested and a request for access to be revoked must be requested when staff members leave the 
project.  
 
Participant initials and date of birth will be entered into the study database. Participant mobile phone 
number and email address will also be entered into the study database for the purpose of remote 
questionnaire delivery. All other patient identifiable information such as hospital number, names and 
addresses, and full postcodes will not be entered. The study site will maintain a master patient log 
linking full participant identifiers to study numbers. No data will be entered into the eCRF unless a 
participant has signed a consent form to participate in the trial.  
 
11.4 
Data Quality Processes 
At the database design stage, validations will be programmed into the systems to minimise data entry 
errors by querying the data entered in real time with sites. The Sponsor will undertake appropriate 
reviews of the entered data, where appropriate for the purpose of data cleaning and will request 
amendments to the EDC system data as required. No data will be amended independently of the study 
site responsible for entering the data. 
 
The Sponsor will prepare a Data Management Plan for EDC system once the system is made live. This 
plan will be filed in the Trial Master File (TMF). Using this Data Management Plan a Sponsor-delegate 
will raise Data Clarification Requests (DCRs) with the site in the eCRF. The study site will periodically 
review raised DCR’s and respond to the queries raised. During site monitoring visits, monitor will 
raise any queries with sites via the Source Data Verification (SDV) function.  
 
11.5 
Database Lock 
The site PI’s will review participant data held in EDC system and provide sign-off to verify that all 
the data are complete and correct at the end of the study. The Sponsor will confirm all data checks are 
complete and all monitors queries have been resolved prior to database lock. At this point, with the 
agreement of the statistician, data will be formally locked for analysis. The Sponsor will remove all 
data entry user access whilst retaining only ‘monitor’ access for the investigational site PI. The dataset 
will be exported, the site will receive a copy of their site-specific dataset and confirm receipt.  
 
The dataset from the EDC system will be reconciled with the Closed Loop Medicine digital sleep diary 
dataset prior to analysis. Closed Loop Medicine will be responsible for the final data export from the 
digital sleep diary database. A copy of the complete dataset will be stored in the TMF. 
 
11.6 
Direct access to Data, Source Data and Documents 
Direct access will be granted to authorised representatives from the Sponsor, host institution and 
regulatory authorities to permit study-related monitoring, audits and inspections.  
 

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11.7 
Archiving 
Archiving will be authorised by the Sponsor following submission of the end of trial report. The PI 
will be responsible for archiving the ISF at site. The Sponsor will be responsible for archiving the 
TMF, associated documents and the trial dataset. All essential documents will be archived for 25 years 
after completion of trial. Destruction of essential documents will require authorisation from the 
Sponsor. 
 
12 
MONITORING, AUDIT & INSPECTION 
Monitoring of this study to ensure compliance with applicable provisions of GCP will be managed by 
Closed Loop Medicine. The PI will permit trial-related monitoring, audits, REC review, and 
inspections by providing the Sponsor(s) and REC with direct access to source data and other 
documents (e.g. patients’ case sheets, blood results, imaging reports, study protocol, statistical code, 
and etc).  
 
Closed Loop Medicine will prepare a monitoring plan. The recruiting study site will have a Site 
Initiation Visit prior to recruitment of the first participant and regular site visits thereafter to verify the 
data. These visits may be performed remotely, if required. 
 
13 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1  Research Ethics Committee (REC) review, amendments & reports 
Before the start of the study, approval will be sought from a REC for the study protocol, ICFs, PISs 
and other relevant documents. Amendments to the protocol that require Health Research Authority 
(HRA) and REC review will not be implemented until the REC grants a favourable opinion for the 
trial. Closed Loop Medicine will be responsible for preparing and submitting protocol amendments to 
the HRA and REC and circulating updated document versions to the study site. Where required, site 
PI will be responsible for communicating relevant information to study participants. 
 
All correspondence with the HRA and REC will be retained in the TMF/ISF. An Annual Progress 
Report will be submitted to the REC within 30 days of the anniversary date on which the favourable 
opinion was given, and annually until the trial is declared ended. 
 
13.2 
Public and Patient Involvement 
Patients and public will be involved in reviewing the study design, protocol, and patient-facing 
documentation. They will also have a role in the dissemination of findings of the study.  
 
13.3 
Protocol compliance  
Protocol non-compliances are departures from the approved protocol. Accidental protocol deviations 
can happen at any time. They must be adequately documented in the site deviation log and reported to 
the Sponsor, on a regular basis.  Deviations from the protocol which are found to frequently recur are 
not acceptable, will require immediate action and could potentially be classified as a serious breach. 
 
13.4  Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to effect to a significant degree the safety or physical or 
mental integrity of the participants of the study, or the scientific value of the study. As this is an 
observational study, we believe the risk of a serious breach to be very minimal. However, the Sponsor 
will be notified immediately of any case where the above definition applies during the study conduct 
phase. The Sponsor will notify the REC were required of any serious breach of the conditions and 
principles of GCP in connection with the study or the study protocol relating within 7 days of becoming 
aware of the breach. 
 

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13.5  Data protection and patient confidentiality  
All study data will be stored in line with GCP, UK GDPR and UK Data Protection Act 2018. All 
participant data will be pseudo-anonymised. 
 
When consent forms are signed, a copy will be provided to the patient, a copy will be filed in the 
medical records and the original will be retained in the ISF. This ISF will be maintained by the site PI. 
No data will be entered into the EDC system or QualtricsXM database unless a participant has signed a 
consent form to participate in the trial. Participants will be asked to consent to the use of their contact 
details including name, email address and mobile phone number in the QualtricsXM platform and eCRF 
for the purpose of remote consent and subsequent questionnaire delivery. The eCRF and QualtricsXM 
Directory will be accessed only by authorised clinical study team members. Participants will also be 
asked to consent to the Sponsor representative having access to these platforms for monitoring and 
audit purposes.  
 
When the study is complete, a data sharing dataset will be created from the raw data by the study 
analyst, which will not include patient initials, date of birth or any other identifiable data and study ID 
will be altered so that individuals are not recognisable from the dataset.   
 
13.6  Indemnity 
Closed Loop Medicine provides no fault liability insurance in the event of harm arising from the study 
design. UK NHS recruiting sites provide indemnity in the event of clinical negligence.  
 
13.7 
Access to the final study dataset 
Data will be available for sharing upon request for future research, subject to approval by the Sponsor. 
 
14 
DISSEMINIATION POLICY 
The outcomes form the study will be published in a peer reviewed open-source medical journal as early 
as possible. The study site will be informed of the results and will be asked to disseminate the findings 
to participants. Patient groups will be informed of the results for dissemination among their members.  

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15 
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32.    Laugwitz B, Held T and Schrepp M. Construction and Evaluation of a User Experience Questionnaire. 
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16.    APPENDICIES 
 
Appendix 16.1 – Insomnia Severity Index 
 
 

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Appendix 16.2 – Quality of Life Questionnaire (EQ-5D-5L) 
 
 
 

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Appendix 16.3 – Breast Cancer-Specific Quality of Life Questionnaire (FACT-ES) 
 
 
 
FACT-ES (Version 4) 
English (Universal) 
 
30 November 2015 
Copyright  1987, 1997 
 
Page 1 of 3 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy ................................ ........................
0 
1 
2 
3 
4 
GP2 
I have nausea ................................ ................................ .......
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ................................ ..........
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ................................ ................................ ...........
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ..........................
0 
1 
2 
3 
4 
GP6 
I feel ill ................................ ................................ ................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ................................ .........
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends ................................ .....................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family .............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends ................................ ..............
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ................................ .....
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ................................ ................................ ...................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ................................ ................................ ...............
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ................................ ............
0 
1 
2 
3 
4 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 40 of 45 
28 Sept 2021 
 
 
FACT-ES (Version 4) 
English (Universal) 
 
30 November 2015 
Copyright  1987, 1997 
 
Page 2 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad ................................ ................................ ..............
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous ................................ ................................ .......
0 
1 
2 
3 
4 
GE5 
I worry about dying ................................ ..............................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse .............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ...........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ................................ ...........................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ................................ ...................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................ ................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..............
0 
1 
2 
3 
4 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 41 of 45 
28 Sept 2021 
 
 
FACT-ES (Version 4) 
English (Universal) 
 
30 November 2015 
Copyright  1987, 1997 
 
Page 2 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad ................................ ................................ ..............
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous ................................ ................................ .......
0 
1 
2 
3 
4 
GE5 
I worry about dying ................................ ..............................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse .............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ...........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ................................ ...........................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ................................ ...................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................ ................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ..............
0 
1 
2 
3 
4 
 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 42 of 45 
28 Sept 2021 
 
 
Appendix 16.4 – User Experience Questionnaire 
 
 
 
 
CLINICAL TRIAL USABILITY QUESTIONNAIRE 
Please make your evaluation now. 
 
For the assessment of the product, please fill out the following questionnaire. 
The questionnaire consists of pairs of contrasting attributes that may apply to 
the product. The circles between the attributes represent gradations between 
the opposites. You can express your agreement with the attributes by ticking 
the circle that most closely reflects your impression. 
 
 
Example: 
 
attractive 0 ® 0 0 0 0 0 unattractive 
This response would mean that you rate the application as more attractive than 
unattractive. 
 
 
Please decide spontaneously. Don’t think too long about your decision to make 
sure that you convey your original impression. 
 
Sometimes you may not be completely sure about your agreement with a 
particular attribute or you may find that the attribute does not apply completely 
to the particular product. Nevertheless, please tick a circle in every line. 
 
It is your personal opinion that counts. Please remember: there is no wrong or 
right answer! 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 43 of 45 
28 Sept 2021 
 
 
 
 
Please assess the product now by ticking one circle per line. 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
annoying 0 0 0 0 0 0 0 enjoyable 
not understandable 0 0 0 0 0 0 0 understandable 
creative 0 0 0 0 0 0 0 dull 
easy to learn 0 0 0 0 0 0 0 difficult to learn 
valuable 0 0 0 0 0 0 0 inferior 
boring 0 0 0 0 0 0 0 exciting 
not interesting 0 0 0 0 0 0 0 interesting 
unpredictable 0 0 0 0 0 0 0 predictable 
fast 0 0 0 0 0 0 0 slow 
inventive 0 0 0 0 0 0 0 conventional 
obstructive 0 0 0 0 0 0 0 supportive 
good 0 0 0 0 0 0 0 bad 
complicated 0 0 0 0 0 0 0 easy 
unlikable 0 0 0 0 0 0 0 pleasing 
usual 0 0 0 0 0 0 0 leading edge 
unpleasant 0 0 0 0 0 0 0 pleasant 
secure 0 0 0 0 0 0 0 not secure 
motivating 0 0 0 0 0 0 0 demotivating 
meets expectations 0 0 0 0 0 0 0 does not meet expectations 
inefficient 0 0 0 0 0 0 0 efficient 
clear 0 0 0 0 0 0 0 confusing 
impractical 0 0 0 0 0 0 0 practical 
organized 0 0 0 0 0 0 0 cluttered 
attractive 0 0 0 0 0 0 0 unattractive 
friendly 0 0 0 0 0 0 0 unfriendly 
conservative 0 0 0 0 0 0 0 innovative 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 44 of 45 
28 Sept 2021 
 
 
Please tell us about your experience using the product. 
 
 
 
 
 
 
What is the one thing you liked most about the application? 
What is the one thing you liked least about the application? 
 
Is there something else that comes to mind regarding the application you would like to 
share? 

Study Number: CLM-INS-004 
 
Clinical Study Protocol 
CONFIDENTIAL 
 
PERSONAL-SLEEP IN BREAST CANCER 
Protocol 28Sept2021 V1.0   
Page 45 of 45 
28 Sept 2021 
 
 
Appendix 16.4 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
 
 
 
 
 
 
List details of all protocol amendments here whenever a new version of the protocol is produced. 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee.