Sleep, Wake and Light Therapy for Depression
Phase: NA
Conditions: Depression, Depressive Disorder, Major, Depression, Unipolar, Depression Moderate
Sponsor: King's College London

King’s Clinical Trials Unit 
 
Confidential 
Confidentiality and Copyright: This document is confidential and property of King’s Clinical Trials Unit. This document may not be 
copied, disclosed, distributed used or destroyed in whole or in part without the prior written consent of King’s Clinical Trials Unit 
The electronic version of this document is the latest version. It is responsibility of the individual to ensure that any paper material is the 
current version. Printed material is uncontrolled documentation. 
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Sleep, Wake and Light therapy for depression 
Informed Consent Form 
 
1st July 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL IDENTIFICATION NUMBER 1st July 2017 version 1 
 
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1. 
PROTOCOL FULL TITLE 
Triple Chronotherapy compared to treatment as usual for the rapid treatment of depression: a 
feasibility study for a randomised controlled trial 
Protocol Short Title 
Sleep, Wake and Light therapy for depression 
 
Trial Identifiers  
ISRCTN: 
Not yet registered 
REC Number: 
Application not yet made  
UKCRN Number: 
Application not yet made  
Protocol Version 
Number: 
1.0 
Date: 
1st July 2017 
 
(Co) Sponsor(s) 
This is usually the substantive employer of the CI. If this is KCL then co-sponsorship with the 
participating NHS Trust may be required.  
Name: 
South London and Maudsley NHS Foundation Trust 
Address: 
c/o Jennifer Liebscher, The Institute of Psychiatry, Psychology and 
Neurosciences, London SE5 8Af 
Telephone: 
020 7848 0251 
Email: 
Jennifer.liebscher@kcl.ac.uk 
 
Chief Investigator  
Name: 
Professor David Veale 
Address: 
CADAT, The Maudsley Hospital, 99 Denmark Hill, London SE5 8AZ  
Telephone: 
020 3228 2101 
Email: 
 David.Veale@kcl.ac.uk 
 
Name and address of Co-Investigator(s), Statistician, Therapy Service, Laboratories etc 
Name: 
Professor Allan Young 
Position/ Role: 
Co-investigator, Professor in Psychiatry  
Address: 
Institute of Psychiatry, Psychology and Neuroscience, King’s College 
London 

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Telephone: 
020 7848 0002 x0088 
Email: 
allan.young@kcl.ac.uk 
 
Name: 
Dr Marc Serfaty 
Position/ Role: 
Co-investigator, Reader in Psychiatry  
Address: 
University College London  
Telephone: 
020 7679 9712 
Email: 
m.serfaty@ucl.ac.uk 
 
Name: 
Dr Sarah Markham 
Position/ Role: 
Co-investigator, Visiting researcher & user perspective 
Address: 
Department of Biostatistics, King’s College London 
Telephone: 
020 7848 0002 
Email: 
sarah.markham@kcl.ac.uk 
 
2. 
Study Synopsis 
3. 
Revision History 
Document ID - (Document 
Title) revision X.Y 
Description of changes from previous revision 
Effective Date 
 
 
 
 
 
 
 
4. Protocol Contents 
 
1. 
PROTOCOL FULL TITLE ...........................................................................................................................1 
2. 
STUDY SYNOPSIS .....................................................................................................................................3 
3. 
REVISION HISTORY ..................................................................................................................................3 
4. 
PROTOCOL CONTENTS ...........................................................................................................................3 
5. 
BACKGROUND & RATIONALE ................................................................................................................5 
6. 
TRIAL OBJECTIVES AND DESIGN ..........................................................................................................6 
6.1 
TRIAL OBJECTIVES .............................................................................. ERROR! BOOKMARK NOT DEFINED. 
6.1.1 
Primary endpoints .........................................................................................................................7 

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6.1.2 
Secondary endpoints ....................................................................................................................7 
6.2 
TRIAL DESIGN ........................................................................................................................................7 
6.3 
TRIAL FLOWCHART .................................................................................................................................8 
8. 
TRIAL INTERVENTION ..............................................................................................................................9 
8.1 
THERAPY/INTERVENTION DETAILS ...........................................................................................................9 
8.2 
FREQUENCY AND DURATION OF INTERVENTION ...................................................................................... 10 
8.3 
INTERVENTION RECORDS ..................................................................................................................... 10 
8.4 
SUBJECT COMPLIANCE. ....................................................................................................................... 10 
8.5 
5.5 CONCOMITANT MEDICATION ........................................................................................................... 11 
9. 
RESEARCH ENVIRONMENT .................................................................................................................. 11 
10. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................................................ 11 
10.1 
INCLUSION CRITERIA ........................................................................................................................ 11 
10.2 
EXCLUSION CRITERIA ....................................................................................................................... 11 
10.3 
SELECTION OF PARTICIPANTS ........................................................................................................... 12 
10.4 
RANDOMISATION PROCEDURE / CODE BREAK ................................................................................... 13 
10.5 
WITHDRAWAL OF SUBJECTS ............................................................................................................. 13 
10.6 
EXPECTED DURATION OF TRIAL. ....................................................................................................... 13 
11. 
TRIAL PROCEDURES ......................................................................................................................... 13 
11.1 
BY VISIT .......................................................................................................................................... 13 
11.2 
LABORATORY TESTS ........................................................................................................................ 13 
12. 
ASSESSMENT OF EFFICACY ............................................................................................................ 13 
12.1 
PRIMARY EFFICACY PARAMETERS .................................................... ERROR! BOOKMARK NOT DEFINED. 
12.2 
SECONDARY EFFICACY PARAMETERS ............................................... ERROR! BOOKMARK NOT DEFINED. 
12.3 
PROCEDURES FOR ASSESSING EFFICACY PARAMETERS .................................................................... 15 
13. 
ASSESSMENT OF SAFETY ................................................................................................................ 15 
13.1 
SPECIFICATION, TIMING AND RECORDING OF SAFETY PARAMETERS. .................................................. 15 
13.2 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS .................................................. 15 
13.2.1 
Adverse events that do not require reporting ............................................................................. 16 
13.3 
STOPPING RULES ............................................................................................................................ 16 
14. 
STATISTICS ......................................................................................................................................... 16 
14.1 
SAMPLE SIZE ................................................................................................................................... 16 
14.2 
RANDOMISATION .............................................................................................................................. 16 
14.3 
ANALYSIS ........................................................................................................................................ 17 
15. 
TRIAL STEERING COMMITTEE ......................................................................................................... 17 
16. 
DATA MONITORING COMMITTEE ..................................................................................................... 17 
17. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS .............................................................. 17 
18. 
ETHICS & REGULATORY APPROVALS ........................................................................................... 17 
19. 
QUALITY ASSURANCE ...................................................................................................................... 17 
20. 
DATA HANDLING ................................................................................................................................ 17 
21. 
DATA MANAGEMENT ......................................................................................................................... 18 
22. 
PUBLICATION POLICY ....................................................................................................................... 18 
23. 
INSURANCE / INDEMNITY .................................................................................................................. 18 
24. 
FINANCIAL ASPECTS ........................................................................................................................ 18 
25. 
SIGNATURES ...................................................................................................................................... 18 

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26. 
REFERENCES ..................................................................................................................................... 19 
27. 
APPENDIXES ....................................................................................................................................... 21 
 
5. Background & Rationale 
Depressive disorders are common mental conditions with a prevalence of about 17% in urban UK 
(Ayuso-Mateos, 2001). The impact of depression on social, occupational and physical health and 
mortality is substantial. Depression causes a greater impairment in health state than the major 
chronic physical illnesses such as angina, arthritis, asthma, and diabetes. Although evidence 
based treatments for depression exist in the form of anti-depressant medication and cognitive 
behaviour therapy (CBT), there is much room for improvement. Remission rates are 43% for 
antidepressants and 29% for placebo (Gibbons et al, 2012). Even fewer patients will sustain 
response in the long–term. Response rates using CBT are generally equivalent to antidepressant 
medication (Amick et al, 2015). Efficacy of CBT in a meta-analysis was a modest d=0.42 after the 
effect of publication bias was removed (Cuijpers, 2010). There is little enthusiasm amongst 
pharmaceutical companies to develop new anti-depressant medications that would then compete 
with cheaper generic drugs. Psychological therapies have reached a plateau and newer 
developments focus on more efficient ways of delivering therapy (e.g. computerised CBT). A 
significant additional problem is that the response for any established treatment of depression may 
not occur for 6 weeks or more. There is some research in evaluating newer compounds such as 
intravenous ketamine. However, this requires a hospital setting, may have significant adverse 
effects and would be unacceptable to many patients.   
One of the most rapid anti-depressants known is a night of total sleep deprivation (or “wake 
therapy”) (Beneditti & Colombo, 2011); up to 60% of patients respond by the next day with a 50% 
reduction on the Hamilton Rating Scale for depression and a final score of <9 (Gillin et al 2001). 
However, there is a very high rate of relapse amongst responders. Several combination strategies 
have been used in pilot studies to augment and maintain the rapid response after wake therapy. 
These have included adding daily bright “light therapy” in the morning and advancing the sleep 
phase for 3 days after sleep deprivation (“wake therapy”) (the combination is called “triple 
chronotherapy”) which has resulted in long-term maintenance of response in 3 RCTs. For example, 
Wu et al (2009) randomly assigned 49 bipolar inpatients with depression to triple chronotherapy, as 
an adjunct to medication, or to a medication-only group. Significant decreases in depression were 
found on day 2 in the triple chronotherapy group compared to treatment as usual.  This was 
maintained over 7 weeks. Martiny et al (2012, 2013, 2015) randomly allocated 75 inpatients with 
non-seasonal unipolar depression on an anti-depressant (duloxetine) to either triple chronotherapy 
or to daily exercise for 5 days. (Sleep deprivation in this study consisted of a variation of three 
alternate nights of being awake). The triple chronotherapy was superior to exercise at Day 2-7 with 
a large effect size of 1.45. This is a larger effect size than medication or CBT and acted within 5 

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days. It was maintained at 6 month follow up, when the remission rate was 61.9% in the triple 
chronotherapy group compared to 37.9% in the exercise group. Lastly, Neumeister et al (1995) 
recruited 20 non-seasonal depressed in-patients on medication. They all received Partial Sleep 
Deprivation (sleep from 9:30 to 1am) and were then randomly allocated to either Bright Light or 
Dim Light. Patients receiving Bright Light did significantly better than those on Dim Light from Day 
2 to 7. All three RCTs have small numbers and therefore the effect size may be exaggerated. 
There are also several open label case series of triple chronotherapy in both unipolar depression 
(for example Sahlem, 2014; Moscovici & Kotler, 2009) and bipolar disorder (Bendetti et al, 2005). 
Triple chronotherapy has so far been conducted in in-patients although one group has 
demonstrated the feasibility in a case series of 27 non-medicated out-patients with major 
depression in the Netherlands (Dallaspezia, 2016). These patients were supported during the night 
to stay awake. The Beck Depression Inventory score reduced from a mean of 25.8 (SD 
7.7)(moderate range) to 13.7 (SD 7.7) (mild range) at one week and to 11.8 (SD 10.2) (mild range) 
at 3 months.  
In the UK, the large majority of patients with depression in the NHS are treated in the community 
and are only admitted to hospital if there is a severe risk of suicide or self-neglect that cannot be 
managed in the community. Psychological treatment as usual usually consist of behavioural 
activation delivered by Psychological Well-Being Practitioners (PWPs) in the Improving Access to 
Psychological Therapies service and/or anti-depressant medication. Thus, one of the major 
objectives of the study one is to determine if triple chronotherapy is a practical treatment in the 
community. We will also focus on patients with unipolar depression, as this is far more common 
than bipolar.  Our study will therefore be a randomised controlled trial that is designed as a 
feasibility study to answer the question whether Triple Chronotherapy enhances standard 
treatment of care for depression after 1 week and whether this is maintained at follow up.    
Rationale: There are no major breakthroughs on the horizon in the field of pharmacotherapy 
or psychotherapy for the rapid treatment of depression (within one week) without any 
significant side effects, so this is a novel approach. Triple chronotherapy is a term used to 
describe a combination of total sleep deprivation, followed by advance of sleep cycle and 
bright light therapy. Three small RCTs suggest that this is a promising treatment for the rapid 
treatment of depression. In addition, depression is a heterogeneous condition and this study 
has the potential in a larger trial to be part of a paradigm shift to determine subtypes of 
depression that may determine the type of treatment offered.  
 
Trial Objectives and Design  
Our objective is to determine the feasibility of conducting a larger randomized controlled trial (RCT) 
of triple chronotherapy in a community sample of patients with depression, and enable us to 
determine   

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1) agreement to be randomised.  
2) whether clinicians can recruit participants. 
3) estimates of participant flow.  
4) the feasibility of delivering the intervention in the community. 
5) adherence to the protocol. 
 
Aims: To conduct a double blind RCT comparing adding triple chronotherapy to standard 
treatment of care. Both groups will receive standard treatment as usual (TAU).  
We hypothesise that:  
1) 
Triple chronotherapy (Total Sleep Deprivation, Phase Advance and Bright Light Therapy) 
with standard care will be more effective than the control treatment with standard care on the 
Hamilton Depression Rating Scale (6 item) at 1 week. 
2) 
The superiority of Triple Chronotherapy over the control treatment will be maintained at 
follow up at 2, 4, 8 weeks and at 6 months.  
3.1.1 
Primary endpoints 
Our outcome measures are    
1) agreement to be randomised.  
2) whether clinicians can recruit participants. 
3) estimates of participant flow.  
4) the feasibility of delivering the intervention in the community. 
5) adherence to the protocol. 
3.1.2 
Secondary endpoints 
We will explore the means and SDs of the 6 item Hamilton Depression Rating Scale (Bech, 1981; 
O’Sullivan, 1997) outcomes to help inform the power analysis for a larger RCT. 
 
Trial Design  
This is a randomised parallel group single blind design. We will evaluate adding either Triple 
Chronotherapy or a control treatment to standard care. This design aims to show that we are able 
to recruit participants and that participants are able to adhere to the interventions.  We will explore 
whether Triple Chronotherapy plus treatment as usual is more effective than treatment as usual on 
the HDRS (6 item). 
 
 
 
 

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Trial Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed for eligibility  
Excluded   
   Not meeting inclusion criteria  
   Declined to participate 
   Other reasons 
Analysed 
 Excluded from analysis 
Lost to follow-up 
Discontinued intervention 
Allocated to Triple Chronotherapy  
 Received allocated intervention 
 Did not receive allocated intervention 
Lost to follow-up (give reasons) 
Discontinued intervention (give reasons) 
Allocated to Control 
 Received allocated intervention 
 Did not receive allocated intervention (with 
reasons) 
Analysed 
 Excluded from analysis 
 
Allocation 
Analysis 
Follow-Up 1 week,  
2 weeks, 4 weeks,  
8 weeks, 6 months  
Randomized  
Enrollment 

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Screen 
Visit 
Visit 2  
re-baseline 
before 
intervention  
Visit 3 
(1 week 
follow 
up)  
Visit 4 
(2 
weeks 
follow 
up) 
Visit 5 
(4 
weeks 
follow 
up) 
Visit 6 
(8 
weeks 
follow 
up) 
Visit 7 
(6 
month 
follow 
up) 
Patient 
information and 
informed consent 
X 
 
 
 
 
 
 
Intervention 
 
X  
 
 
 
 
 
Outcome 
measures 
(observer rated 
rating scale)  
X  
X  
X 
X 
X 
X 
X 
Self-report 
outcome 
measures   
X 
X 
X 
X 
X 
X 
X 
Actigraphy and 
sleep diary  
X 
 
X 
 
 
 
 
 
 
4. 
Trial Intervention 
Intervention Details 
All participants who provide informed consent to participate will t be randomised to receive either 
Triple Chronotherapy or a Control Treatment. Both groups will receive treatment as usual.   
1) Triple Chronotherapy  
This consists of (a) Total Sleep Deprivation with group support on days one and two; (b) Phase 
Advance of Sleep over 5 days and daily Light Therapy. On Day 1 (e.g. Monday), patients are 
supported in a group to stay up all night. We will arrange various activities to help patients stay 
awake accompanied by a Health Care Assistant (HCA) at the Hospital (e.g. watch a film; 
exercise; receive information on sleep hygiene; listen to music; short walk) and have access to 
coffee/ tea and snacks.  
The next step is to advance the phase of sleep. Patients are helped to stay awake on Day 2 
(Tuesday) at the hospital. They will either be collected by a relative or sent home by a taxi to go 
to bed at about 5pm. They should not drive or operate machinery. They wake by about 1am 
and will be invited to come to the hospital with support by a HCA in a group to stay awake. 
They will leave to go home by about 8am. They will then go to bed on Day 3 (Wednesday) at 
about 7.30pm. They will be asked to sleep until 3am. No further support is provided by the 
Hospital to stay awake at night. They then go to bed on Day 4 (Thursday) from 9.30pm to 5am 
and on Day 5 (Friday) at 11pm to resume a normal sleep routine waking by 6.30 to 7am. They 
will be given an information leaflet on sleep hygiene and given the opportunity to ask questions. 

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(c) Bright Light Therapy is given on Day 2 onwards daily. This is provided by a Carex Day 
Classic Light. The time of the therapy is optimised in the morning according to the patient’s 
pattern of sleep. A patient sits about one foot away from a bright light box, that emits 10,000 
Lux. It is positioned slightly above the head and pointing downwards at 45 degrees. Patients 
are free to have breakfast, read or use a computer while facing towards the light. Treatment 
normally last 30 minutes or more and will continue for 6 months. Possible side effects in the 
triple chronotherapy group include tiredness after sleep deprivation. A few people may 
experience nausea or headache after beginning light therapy. (In healthy individuals bright light 
therapy was not associated with any significant difference in side effects compared to dim light 
therapy (Botanov, 2013). However, patients with any significant side effects may be asked to 
reduce the exposure time by 10 minutes. Active treatment may theoretically trigger a manic 
episode, but patients with bipolar disorder are excluded and so this should be rare. We will 
however warn the patient and carer of this rare possibility. Patients may also receive standard 
care. 
2) Control treatment  
Participants will be given information on sleep hygiene and getting a good night’s sleep in a 
written leaflet and given the opportunity to ask questions. They are then given SomniLight  
Amber Light daily for 1 week. Like the Bright Light Therapy, the timing is optimised in the 
morning according to the patient’s pattern of sleep. A patient sits about one foot away from a 
light box, which is positioned slightly at 45 degrees above the head and pointing downwards. 
Patients are free to have breakfast, read or use a computer while facing towards the light. 
Treatment normally last 30 minutes. 
The frequency of any side effect from either group will be monitored and clinicians would continue 
with treatment as usual. Participants with any significant side effects will be withdrawn, but 
included in the analysis. 
Frequency and duration of intervention 
The duration of the intervention is 1 week. 
 
Intervention records 
Therapy sessions (e.g wake therapy or sleep hygiene information) will be recorded in ePJS hospital 
records.  
Subject Compliance. 
Compliance to the intervention will be monitored and documented by the Health Care Assistant.  
 
Study adherence 
Participants will be encouraged to stay up during sleep deprivation as described above.   

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5.5 Concomitant Medication 
A patient may be taking anti-depressant medication so long as the dose has been stable for 6 weeks 
and there are no plans to increase the dose or to alter the medication.  
A wash out time for a patient deciding to stop anti-depressant medication and recruitment is 6 weeks.  
Surgery/radiotherapy is allowed after the first week of the intervention.  
5. 
Research environment 
This is a single centre trial at the South London and Maudsley NHS Foundation Trust. There are no 
specific site requirements. Recruitment will be from local GPs on the Clinical Research Network; 
Improving Access to Psychological Therapies (IAPT); clinicians on the Home Treatment Teams 
(secondary care) in Southwark, Lewisham, Lambeth and Croydon; through Consent for Contact on 
CRIS and on a dedicated website. For all settings, the intervention will be conducted at a hospital 
where support will be provided by a health care assistant for two nights and for one day to help patients 
stay awake (e.g. watch a film; exercise; short walk) and have access to coffee/ tea and snacks.  
6. 
Selection and Withdrawal of Subjects  
Inclusion Criteria  
1) Diagnosis of Depressive Episode (ICD10 F32) or Recurrent Depressive Disorder 
(F33).  
2) Minimum score of 8 or more on the Hamilton Depression Rating Scale (6 item) 
(Range 0-22) (Bech,1981). This represents at least moderate depression. 
3) Age 18-65 
4) Able to give informed consent  
5) Women of child bearing age may be included and no methods of contraception is 
required to enable inclusion into the trial.   
Exclusion Criteria  
1) Current diagnosis of Seasonal Affective Disorder  
2) Current diagnosis of anorexia nervosa or bulimia. 
3) Current diagnosis of an obsessive compulsive or related disorder  
4) Current diagnosis of post-traumatic stress disorder 
5) History of schizophrenia, schizoaffective disorder or bipolar disorder 
6) Severe cognitive impairment, dementia, intellectual disability or organic brain disorder.  
7) History of stimulant or hallucinogenic misuse, alcohol or substance misuse or 
dependence in past 3 months.  
8) Borderline Personality Disorder or other personality disorder considered to be the 
main problem.  
9) Duration of depression more than 2 years.  
10) Significant risk of suicide that requires hospitalisation.   

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11) Severe eye disease or cataracts or traumatic injury or visual impairment affecting both 
eyes. 
12) History of epilepsy, uncontrolled severe headaches, or stroke as this may lower 
seizure threshold through sleep deprivation. 
13) Unstable medical condition that would make wake therapy intolerable 
14) Untreated sleep disorder such as obstructive sleep apnoea or narcolepsy  
15) Use of photo-sensitizing drugs. 
16) Current night-shift work. 
17) Non-English speaker. 
If a patient meets the inclusion criteria but has withdrawal symptoms from alcohol or other 
substances, the patient will be re-assessed for eligibility when the patient has been abstinent for 3 
months.  
A patient may be taking anti-depressant medication so long as the dose has been stable for 6 
weeks and there are no plans to increase the dose or to alter the medication. 
 
Selection of Participants  
Anonymised information on participants who are not randomised will be reported on according to 
CONSORT guidelines and will include age, gender, ethnicity, whether the patient is recruited or not 
recruited, the reason not eligible for trial participation, or if they are eligible but declined. 
Participant identification 
Participants will be identified by  
a) A member of the patient’s existing clinical care team will be asked to review the 
identifiable personal information of patients and check whether they meet the inclusion 
criteria or make the initial approach to patients. This may occur at the point of their initial 
assessment in Improving Access to Psychological Therapies (IAPT) or on Home 
Treatment Teams (secondary care) in Southwark, Lewisham, Croydon and Lambeth. 
Within IAPT settings, this is likely to be following their initial telephone screening (if 
appropriate), or at their high intensity assessment appointment, where depression is 
indicated as the client’s primary problem. GPs will be encouraged to refer direct to the 
study. 
b) Participants may be contacted directly under the Consent for Contact (C4C). This the 
Trust’s patient research participation register. Patients are routinely asked for consent for 
contact and participation in research. This creates a registry for patients who are willing 
for researchers to contact them about research conducted in the Trust. Consent is 
recorded on the electronic notes. Researchers using C4C are required to notify the 

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patient’s care team prior to contacting a patient, so the responsible clinician is aware their 
patient is being invited to take part in a research study. Researchers are also required to 
document any contact made with patients on the notes under ‘Approaches and 
participation’ on the consent form.  
c) Participants may also refer themselves (for example on the registry of Clinical trials or by 
an advertisement on the web).  
 
Randomisation Procedure / Code Break 
The method of randomisation will consist of simple randomisation based constant allocation ratio 
of 1:1. It will be stratified according to the season.  The King’s Clinical Trials Unit will provide a 
secure web-based randomisation service. The unit is fully registered by the UKCRC and receives 
support funding from NIHR. A new patient alert will be sent by email (a) to the CI (b) to a research 
worker (non-blinded), who will inform the patient registration by telephone and arrange the 
intervention.  
Withdrawal of Subjects 
A patient would be withdrawn from the intervention if they were to become acutely manic, 
psychotic or suicidal or no longer wishes to continue. The reasons for withdrawal would be 
recorded. 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 drug in the event of inter-current 
illness, AEs, SAE’s, SUSAR’s, protocol violations, cure, administrative reasons or other reasons.  It 
is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided.  Should a patient 
decide to withdraw from the study, all efforts will be made to report the reason for withdrawal as 
thoroughly as possible.  Should a patient withdraw from the intervention efforts will be made to 
continue to obtain all follow-up data as per protocol, with the permission of the patient. 
Expected Duration of Trial. 
The trial will last 6 months from randomisation to last follow up.  
7. 
 Trial Procedures  
 By Visit 
Describe the sequence of procedures to be performed at each visit as detailed in the time/event flowchart in section.2.3.  
 
Laboratory Tests 
None required 
8. 
Assessment of Efficacy  
 

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Parameter 
Outcome Measures  
Timepoint(s) of evaluation of 
this outcome measure (if 
applicable) 
Primary Efficacy  
Parameter  
To compare the rate of recruitment 
and adherence to the treatments in 
both groups  
Number of participants recruited per 
month  
 
Adherence to the protocol 
This includes the number of length 
of naps in the active intervention.  
 
At Week 1 
 
 
At Week 1  
 
Secondary Efficacy Parameter  
To compare the effects of the 
following measures in both groups  
1) Hamilton Depression Rating 
Scale  
 
2) Clinical Global Impression 
and Improvement Scale 
(Guy, 1976)  
 
3) Quick Inventory of 
Depressive Symptomatology 
– SR version (Triveni et al, 
2004).  
 
4) Brief Ruminative Response 
Scale (Topper et al, 2014).  
 
5) Pittsburgh Sleep Index 
(Bysse et al, 1999)  
6) Euroquol 5D (EQ5-D) 
(1990).  
 
7) Wrist actigraph from 
GeneActiv daily for 3 days 
pre-randomisation and 7 
days post-randomisation.  
8) Sleep diary daily for 3 days 
pre-randomisation and 7 
days post-randomisation.  
9) The credibility of the 
intervention and expectation 
of whether their mood will 
improve rapidly (Devilly, 
2000).  
10) Amount of anti-depressant 
drugs (in mg of anti-
depressant equivalents) 
(Hayasaka et al, 2015) or 
 
 
 
An observer rated measure of 
depression 
 
An observer rated measure of 
global severity  
 
 
 
A subjective measure of 
depression  
 
 
A measure of ruminative style  
 
 
A measure of sleep disturbance  
 
A measure of quality of life  
 
A measure of the sleep/wake 
activity, which correlates with the 
gold standard of sleep 
physiology (polysomnography).  
A subjective measure of total 
sleep time 
 
A measure of the credibility of 
the intervention  
 
 
 
Any additional treatment 
received 
 
 
 
 
 
Baseline, rebaseline and at 1, 
2, 4, 8 weeks and 6-month 
post-randomisation. 
Baseline, rebaseline and at 1, 
2, 4, 8 weeks and 6-month 
post-randomisation. 
 
 
Baseline, rebaseline and at 1, 
2, 4, 8 weeks and 6-month 
post-randomisation. 
 
Baseline, and at 1, 2, 4, 8 
weeks and 6-month post-
randomisation. 
Baseline, and at 1, 2, 4, 8 
weeks and 6-month post-
randomisation. 
Baseline, and at 1, 2, 4, 8 
weeks and 6-month post-
randomisation. 
Baseline, and at 1 week post-
randomisation. 
Baseline, and at 1 week post-
randomisation 
 
 
Baseline  
 
 
 
Baseline, and at 1, 2, 4, 8 
weeks and 6-month post-
randomisation 
 
 

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benzodiazepine drugs (in 
mg of diazepam equivalents 
11) The amount of Cognitive 
Behaviour Therapy or any 
other counselling or 
psychotherapy (number of 
hours)  
12) Reported side effects at 1 
week.   
 
 
 
 
Any additional treatment 
received 
 
 
 
Any reported side effects  
 
Baseline, and at 1, 2, 4, 8 
weeks and 6-month post-
randomisation 
 
 
At 1, 2, 4, 8 weeks and 6-
month post  
 
 
Procedures for Assessing Efficacy Parameters 
The procedures are questionnaire based apart from the Actigraphy. This consist of a band worn 
around the wrist.   
9. 
Assessment of Safety  
 
Specification, Timing and Recording of Safety Parameters.  
Sleep Deprivation has no reported side effects apart from tiredness. For light therapy, a few people 
may experience nausea or headache after beginning treatment. (In healthy individuals bright light 
therapy was not associated with any significant difference in side effects compared to dim light 
therapy (Botanov, 2013). However, patients with any significant side effects may be asked to 
reduce the exposure time by 10 minutes. Triple Chronotherapy may theoretically trigger a manic 
episode, but patients with bipolar disorder are excluded and so this should be rare. We will 
however warn the patient and carer of this rare possibility.  
Procedures for Recording and Reporting Adverse Events 
Adverse Event (AE): Any untoward medical occurrence in a subject to whom a therapy has 
been administered including occurrences which are not necessarily caused by or related to that 
therapy. 
Adverse Reaction (AR): Any untoward and unintended response in a subject to a therapy 
which is related to any duration of therapy administered to that subject. 
Unexpected Adverse Reaction (UAR): An adverse reaction the nature and severity of which is 
not consistent with the information known about the therapy in question in the view of the 
investigator 

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Serious adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected Serious 
Adverse Reaction (USAR): Any adverse event, adverse reaction or unexpected adverse 
reaction, respectively, that 
• 
Results in death; 
• 
Is life-threatening; 
• 
Required hospitalisation or prolongation of  existing hospitalisation; 
• 
Results in persistent or significant disability or incapacity; 
• 
Consists of a congenital anomaly or birth defect. 
Reporting Responsibilities 
All SARs and SUSARs (excepting those specified in this protocol as not requiring reporting) will 
be reported immediately by the Chief Investigator to the REC and Sponsor.  
 
9.1.1 
Adverse events that do not require reporting 
Symptoms such as tiredness, nausea, headache as described above do not require reporting. An 
episode of mania may be regarded as Adverse Reaction.   
 
Stopping Rules 
The trial may be prematurely discontinued by the Sponsor or Chief Investigator on the basis of 
new safety information or for other reasons given by the regulatory authority or ethics committee 
concerned. 
The trial may also be prematurely discontinued due to lack of recruitment.  If the study is 
prematurely discontinued, active participants will be informed and no further participant data will 
be collected. 
10. 
Statistics 
Sample Size 
N=30 equally randomized to each group is usually adequate for a feasibility study exploring the 
rates of recruitment and attrition (Browne,1995). We will explore the data for an estimate of effect 
size to determine consistency with previous studies.  
Randomisation 
The method of randomisation will consist of simple randomisation based on a  constant allocation 
ratio of 1:1. It will be stratified according to the season.  

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Analysis 
We will explore the means and SDs of outcomes to help inform the power analysis for a larger 
RCT of clinical and cost effectiveness of adding triple chronotherapy in depression. Follow-up will 
be maximised to prevent missing data by reminding participants at each visit of the importance of 
collecting data. Participants will be telephoned when they do not provide follow up data. The 
reasons for missing data will be recorded. Missing data for the primary outcome will be handled by 
multiple imputation to estimate missing outcome data. The self-report depressive symptom 
measures will be used in the imputation process.  
11. 
Trial Steering Committee  
There is no trial Steering Committee as this is a feasibility study with no significant risks.  
12. 
Data Monitoring Committee  
There is no Data Monitoring Committee as this is a feasibility study with no significant risks.  
13. 
Direct Access to Source Data and Documents 
The Investigator(s) will permit trial-related monitoring, audits and REC review by providing the 
Sponsor(s), and REC direct access to source data and other documents (eg patients’ case 
sheets, blood test reports, X-ray reports, histology reports etc). 
14. 
Ethics & Regulatory Approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the 
principles of GCP and in accordance with all applicable regulatory requirements including but not limited to 
the Research Governance Framework. 
This protocol and related documents will be submitted for review to XXXXXX Research Ethics Committee 
(REC) 
The Chief Investigator will submit a final report at conclusion of the trial to the funder, the REC and the 
Sponsor  
15. 
Quality Assurance 
Monitoring of this trial will be to ensure compliance with Good Clinical Practice and scientific integrity will 
be managed by the study team. Reports will be made on progress of the trial and any violations by the 
research worker to the Chief Investigator and Trial Management Committee.   
16. 
Data Handling  
The Chief Investigator will act as custodian for the trial data. The following guidelines will be strictly 
adhered to: 

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Patient data will be anonymised. 
• 
All anonymised data will be stored on a password protected computer. 
• 
All trial data will be stored in line with the Data Protection Act. 
• 
and archived in line with Sponsor requirements 
17. 
Data Management 
An anonymised paper and electronic CRF will be used, which will be based on the outcome measures and 
demographic data. Participants are asked to consent to their data being shared anonymously with other 
researchers. They are also asked to consent to their General Practitioner being informed of participation in 
the study including any necessary exchange of information between their GP and the research team. 
18. 
Publication Policy  
It is intended that the results of the study will be reported and disseminated at international 
conferences and in peer-reviewed scientific journals. 
 
19. 
Insurance / Indemnity  
Insurance an indemnity is arranged by the South London and Maudsley NHS Foundation Trust  
 
20. 
Financial Aspects  
Funding to conduct the trial is provided by King’s Health Partners.  
 
 
 
21. 
Signatures 
 
 
 
______________________________________ 
 
Chief Investigator 
1/7/2017  
David Veale 
 
N/A  
______________________________________ 
_________________________ 
Statistician (if applicable) 
Date 
Print name 

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22. 
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23. 
Appendixes 
This section should contain all pertinent documents associated with the management of the study.  The 
following lists a few examples of potential attachments: 
• 
Patient Information Sheet 
• 
Consent Form