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Trial registered on ANZCTR


Registration number
ACTRN12615000751572
Ethics application status
Approved
Date submitted
10/06/2015
Date registered
21/07/2015
Date last updated
11/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Can enhanced insomnia phenotyping aid prediction of treatment response?
Scientific title
Can objective measures of phenotypes of Insomnia Disorder built on either polysomnographic sleep or dim light melatonin onset predict treatment response (insomnia severity index scores, sleep onset latency & wake-time after sleep onset) to cognitive behavioural therapy compared to classic insomnia clinical phenotypes?
Secondary ID [1] 286007 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Insomnia Disorder 293969 0
Mental Health 293970 0
Condition category
Condition code
Mental Health 294272 294272 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients with insomnia will be recruited to undergo three phenotyping assessments (A, B & C) followed by treatment for insomnia disorder: standardised online cognitive behavioral therapy.

(A) The first phenotyping assessment will take place at the initial clinic screening and consent visit for classic subjective insomnia phenotype, diagnosed by a Sleep Physician / Sleep Psychologist interview (based on DSM-V criteria) will be used to identify four insomnia phenotypes characterised by a main complaint of either: (i) difficulty with sleep onset, (ii) difficulty with sleep maintenance, (iii) early morning awakenings, or (iv) mixed insomnia (a combination of at least two previously mentioned main sleep impairments).

We do not have a directional hypothesis for this method as we do not know which phenotypes will respond.

(B) Two-weeks after (A), patients will visit the sleep-laboratory and undergo one overnight polysomnographic assessment of sleep which will be used to quantify insomnia patients with either (i) short objective sleep with both sleep onset and maintenance impairments, (ii) short objective sleep with primarily sleep maintenance impairments, or (iii) long objective sleep. Participants will be assigned to either group (i, ii or iii) through a pre-specified algorithm developed from previous insomnia clustering data (Miller et al., in preparation).

We hypothesise that those with long objective sleep (iii) will improve significantly better on post-treatment insomnia severity index change scores than those with short objective sleep (i & ii). Furthermore, those in
the short objective sleep group with both sleep onset and sleep maintenance impairments (i) will not improve as much those with short objective sleep with primarily sleep maintenance impairments (ii). (i.e. iii > ii >i)

(C) On the subsequent evening, patients will return to the laboratory to complete an in-laboratory dim light melatonin onset assessment (saliva) to quantify insomnia patients with (i) late phase angle: the most severe 30% of the study sample with the greatest evening phase angle (i.e. melatonin rise after bedtime resulting in a mostly positive phase angle) and a melatonin rise time after 22:00 compared to (ii) normal phase angle: the remaining 70% of the sample. Phase angle onset is defined as the difference between 14 days (minimum of 5 days) of average actigraphy time for bed and the in-laboratory dim light melatonin onset rise time.

We hypothesise that those without a melatonin defined circadian delay will improve significantly better on post-treatment insomnia severity index change scores than those with a circadian delay.

On the next day, all patients will be asked to begin the online standardised version of cognitive behavioural therapy for insomnia (CBT-I). Internet based CBT-I consists of six online sessions to address worries and anxieties about sleeping, relaxation techniques, sleep hygiene procedures, and sleep scheduling involving stimulus control and sleep restriction therapy. Each session will take approximately an hour to complete over six weeks (maximum allowed time to complete the course is 16 weeks). The website is completely interactive and moderated by a team of Psychologists.
Intervention code [1] 290989 0
Behaviour
Intervention code [2] 291960 0
Diagnosis / Prognosis
Comparator / control treatment
This is an open label study as all patients will receive the same treatment (online standardised cognitive behavioural therapy for insomnia). There is no control condition, the primary comparison will be made between different phenotyping methods of insomnia disorder in response to treatment.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294068 0
Insomnia Severity Index
Timepoint [1] 294068 0
At Week 17 compared to Week 0.
Primary outcome [2] 295200 0
Sleep Diary Defined Sleep Onset Latency
Timepoint [2] 295200 0
Average of Weeks 17 & 18 compared to Average of Weeks -2 & -1.
Primary outcome [3] 295201 0
Sleep Diary Defined Wake-time After Sleep Onset
Timepoint [3] 295201 0
Average of Weeks 17 & 18 compared to Average of Weeks -2 & -1.
Secondary outcome [1] 312456 0
At home twice-daily (morning and evening) online computer based measures of neurocognitive performance including processing speed, attention, visual learning and memory through the Cogstate Brief Battery.
Timepoint [1] 312456 0
At Week 17 compared to Week -1.
Secondary outcome [2] 315038 0
Daily measures of mood (between 4-7pm for 1-week) measured through the daytime insomnia symptom scale.
Timepoint [2] 315038 0
Average of daily measures of mood during week 17 compared to week -1.
Secondary outcome [3] 315039 0
Actigraphic assessments of sleep
Timepoint [3] 315039 0
Average of daily measures of sleep during weeks 17 & 18 compared to weeks -2 & -1
Secondary outcome [4] 315040 0
In laboratory simulated driving performance
Timepoint [4] 315040 0
This will be assessed prior to the delivery of cognitive behavioural therapy for insomnia as part of the phenotyping assessment at the following two time points: (i) During the in-laboratory visit at 6pm and at (ii) one hour after habitual bedtime (from sleep diaries) for between insomnia phenotype differences.
Secondary outcome [5] 315042 0
In laboratory computer based neurocognitive performance measures of processing speed, attention, visual learning and memory through the Cogstate Battery and the Psychomotor Vigilance Task.
Timepoint [5] 315042 0
This will be assessed prior to the delivery of cognitive behavioural therapy for insomnia as part of the phenotyping assessment at the following four time points: (i) During the morning of the first overnight sleep assessment after a full sleep opportunity with a patient preferred wake-time compared to (ii) the second morning (same wake-time as the first morning) after a reduced sleep opportunity (by going to bed two hours later than average sleep-diary defined habitual bedtime) for between insomnia phenotype differences. (iii) During the second in-laboratory visit from 6pm and at (iv) sleep-diary defined habitual bedtime for between insomnia phenotype differences.
Secondary outcome [6] 315188 0
Sleep Diary Defined Sleep Efficiency
Timepoint [6] 315188 0
Average of Weeks 17 & 18 compared to Average of Weeks -2 & -1.
Secondary outcome [7] 315248 0
Sleep Diary Defined Total Sleep Time
Timepoint [7] 315248 0
Average of weeks 17 & 18 compared to Average of Weeks -2 & -1.

Eligibility
Key inclusion criteria
1. Symptoms of Insomnia Disorder as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for insomnia disorder (APA, 2013) specifically: Difficulty initiating or maintaining sleep or waking up too early for at least 3 nights per week, for at least 3 months, with adequate opportunity and circumstances for sleep and at least one daytime impairment related to the sleep difficulty.
2. Insomnia Severity Index score more than or equal to 10
3. Fluent speaker of English
4. Aged >18 years
5. Stable sleep/wake schedule (habitual bedtime 22:00-00:00 +/- 2 hours)
6. Able to give informed, written consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy or lactation
2. Active illicit substance use or alcohol/caffeine dependence
3. Medications that interfere with sleep (within 1 month of assessment)
4. Psychiatric disorders, other than mild to moderate depression (on the
Depression Anxiety Stress Scales)
5. Another sleep disorder evaluated by a Sleep Physician / Sleep Psychologist that better explains the complaint of sleep loss.
6. Severe cognitive impairment that does not allow patients to consent or follow study instructions
7. Overnight shift workers and recent time-zone travel (within last 2 months)
8. Actively treated sleep disorder (e.g. CPAP/CBT-I)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All participants will receive 16 weeks access to online cognitive behavioural therapy for insomnia immediately on completion of the in-laboratory phenotyping assessment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?

The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Single group
Other design features
All patients will receive the same open label treatment (online computer based cognitive behavioral therapy for insomnia). Therefore, treatment will be delivered blinded by automated computer program.

The primary outcome (insomnia severity index scores at post treatment) will be collected by computer or by a researcher blinded to the participant group allocation.

Those people grouping insomnia participants will not be involved in the primary outcome collection (Sleep Physician / Psychologist for subjective insomnia grouping, laboratory staff for melatonin results and staff running the automated algorithm for objective sleep grouping).
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Methods/Analysis - The aim of this project is to evaluate differences between phenotypes of insomnia disorder for treatment response to online cognitive behavioural therapy at 17 weeks after phenotyping compared to before.

For primary outcome variables, we aim to evaluate differences pre-to-post treatment for insomnia phenotypes for the following outcomes:

(i) Insomnia severity (insomnia severity index scores: ISI) at 17 weeks after baseline phenotyping compared to before between groups of patients with insomnia using 3 linear mixed effects models. Overall we will compare the 3 phenotyping methods for explanatory power using the -2 likelihood from each of the 3 mixed models. We will also confirm any patterns with visual data plots and with a comparative analysis of patients correctly classified as responders (a reduction of 6 or more points on the ISI: Yang et al., 2009) and remitters (a post treatment ISI score of less than 8: Morin et al., 2009).

(ii) Sleep-diary defined average sleep onset latency for weeks 17 & 18 compared to weeks -2 & -1 using linear mixed effects models.

(iii) Sleep-diary defined average wake-time after sleep onset for weeks 17 & 18 compared to weeks -2 & -1 using linear mixed effects models.

For secondary outcome variables, we aim to evaluate differences pre-to-post treatment for insomnia phenotypes for the following outcome:

(i) Average home-based neurocognitive performance measures of memory, attention and executive functioning during week 17 compared to week -1 using linear mixed effects models.

(ii) Daily measures of mood (6pm for 1-week) measured through the daytime insomnia symptom scale during week 17 compared to week -1 using repeated measures using linear mixed effects models.

(iii) Average actigraphic assessments of sleep measured during weeks 17 & 18 compared to weeks -2 & -1 using linear mixed effects models.

We also aim to evaluate differences between insomnia phenotypes for secondary outcome variables during the in-laboratory assessment for the following outcomes:

(iv) Sixty minute simulated driving performance during the laboratory testing at 6pm and at one hour after sleep-diary defined habitual bedtime between phenotype groups using linear mixed effects models.

(v) Neurocognitive performance measures of memory, attention and executive functioning during the laboratory testing from 6pm and at sleep-diary defined habitual bedtime between phenotype groups using linear mixed effects models.

(vi) Neurocognitive performance measures of memory, attention and executive functioning during the laboratory first morning (after a full sleep opportunity with a patient preferred wake-time) and the laboratory second morning (same wake-time as the first morning) after a reduced sleep opportunity (by going to bed two hours later than average sleep-diary defined habitual bedtime) between phenotype groups using linear mixed effects models.

(vii) Sleep-diary defined average sleep efficiency for weeks 17 & 18 compared to weeks -2 & -1 using linear mixed effects models.

(viii) Sleep-diary defined average total sleep time for weeks 17 & 18 compared to weeks -2 & -1 using linear mixed effects models.

We are not sure however of exact group numbers for assessments of (A), (B) or (C) as such detailed insomnia phenotyping in large numbers of participants has not been attempted previously. Therefore more groups or different spreads of patients may become apparent with testing. There is no formal power analysis, our target sample size however of 325 was acquired based on predicted phenotype grouping for potentially three groups with approximately 80 in each and allowing for 85 dropouts.

Linear mixed effects models will be used to investigate outcomes as these contain both fixed (time) and random effects (participants & site) and are used in settings where repeated measures are made on groups of participants. They are deemed more robust over traditional repeated measures ANOVA's as they can deal more effectively with intra-patient correlations and missing data by avoiding imputation of missing data.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 3831 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 3832 0
Repatriation Hospital - Daw Park
Recruitment postcode(s) [1] 9723 0
2050 - Camperdown
Recruitment postcode(s) [2] 9724 0
5041 - Daw Park

Funding & Sponsors
Funding source category [1] 290600 0
Other
Name [1] 290600 0
Cooperative Research Centre for Alertness, Safety and Productivity
Address [1] 290600 0
Cooperative Research Centre for Alertness, Safety and Productivity
270 Ferntree Gully Road
Notting Hill, Victoria, 3168
Country [1] 290600 0
Australia
Primary sponsor type
Other
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Road
Glebe
NSW
2037
Country
Australia
Secondary sponsor category [1] 289288 0
None
Name [1] 289288 0
Address [1] 289288 0
Country [1] 289288 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292235 0
Sydney Local Health District (SLHD)
Ethics committee address [1] 292235 0
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 292235 0
Australia
Date submitted for ethics approval [1] 292235 0
27/01/2015
Approval date [1] 292235 0
02/04/2015
Ethics approval number [1] 292235 0
HREC/14/RPAH/517

Summary
Brief summary
Insomnia is a highly prevalent, complex and heterogeneous disorder. Diagnostically, insomnia is problematic due to a lack of objective markers and with the diagnosis based primarily on patient self-report. Patients with insomnia also have high rates of absenteeism, increased health risks and health-care utilisation, a higher risk of depression and neurocognitive impairments than good sleepers.

The main nonpharmacological treatment for insomnia is Cognitive behavioral therapy for insomnia (CBT-I), which is an evidence-based psychological intervention, usually delivered by a psychologist individually, in small groups, or through automated web-based programs. CBT-I seeks to manage insomnia by targeting maladaptive thoughts, behaviors, and beliefs about sleep. CBT-I is a multicomponent approach and in the context of clinical trials improves sleep in 70% of insomnia patients and is considered the first-line treatment for insomnia by the American Academy of Sleep Medicine, National Institutes of Health, and British Association of Psychopharmacology.

CBT-I is effective but it does not work for all patients with insomnia. As insomnia is a highly heterogeneous disorder it may be that certain phenotypes of insomnia respond differently to certain components of CBT-I. To date, insomnia phenotyping has focused on subjective clinical impressions by Sleep Physicians or Psychologists to label patients with a chief complaint of either: difficulty initiating sleep, difficulty maintaining sleep, early morning awakenings or mixed insomnia (a combination of at least two of the previously mentioned factors). Currently, there is a lack of objectivity in classifying insomnia phenotypes and evaluating phenotype treatment response to CBT-I.

Our aim is to develop phenotyping toolkits to produce an objective diagnostic assessment of insomnia that will assist clinicians to determine the likelihood of an insomnia phenotype responding to treatment (CBT-I). We aim to phenotype all patients for the following three methods including:

(A) Classic subjective insomnia phenotyping, diagnosed by a Sleep Physician / Sleep Psychologist interview (based on DSM-V criteria) will be used to identify four insomnia phenotypes characterised by a main complaint of either: (i) difficulty with sleep onset, (ii) difficulty with sleep maintenance, (iii) early morning awakenings, or (iv) mixed insomnia (a combination of at least two previously mentioned main sleep impairments).

(B) One in-laboratory overnight polysomnographic assessment of sleep will also be used to quantify insomnia patients with either (i) short objective sleep with both sleep onset and maintenance impairments, (ii) short objective sleep with primarily sleep maintenance impairments, or (iii) long objective sleep. Based on previous results, participants will be assigned to either groups i, ii or iii through a pre-specified algorithm developed from insomnia clustering data (Miller et al., in preparation).

(C) One in-laboratory dim light melatonin onset assessment (saliva) will be used to quantify insomnia patients with (i) late phase angle: the most severe 30% of the study sample with the greatest evening phase angle (i.e. melatonin rise after bedtime resulting in a mostly positive phase angle) and a melatonin rise time after 22:00 compared to (ii) normal phase angle: the remaining 70% of the sample. Phase angle onset is defined as the difference between 14 days (minimum of 5 days) of average actigraphy time for bed and the in-laboratory dim light melatonin onset rise time.

We primarily aim to evaluate treatment response for these phenotypes of insomnia to standardised online CBT-I for measures of insomnia severity, sleep diary defined sleep onset latency and wake-time after sleep onset.

Secondly, we aim to evaluate changes in neurocognition, mood, and actigraphy pre-to-post therapy for insomnia phenotypes.

Third, we will compare phenotypes for differences in simulated driving (at 6pm and at one hour after habitual bedtime) and neurocognitive performance (at i. 6pm, ii. habitual bedtime, iii. in the morning after a full sleep opportunity with a patient preferred wake-time and iv. after a reduced sleep opportunity, by going to bed two hours later than average sleep-diary defined habitual bedtime).

This study aims to provide evidence of tools to objectively phenotype insomnia by differentiating patients who may or may not respond well to CBT-I prior to the delivery of treatment. In turn, this will facilitate better treatment plans and lead to enhanced sleep, health and daytime performance.
Trial website
www.sleepresearch.com.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54234 0
Prof Ron Grunstein
Address 54234 0
Woolcock Institute of Medical Research
PO Box M77
Missenden Road, Camperdown
NSW 2050
Country 54234 0
Australia
Phone 54234 0
+61291140000
Fax 54234 0
Email 54234 0
ron.grunstein@sydney.edu.au
Contact person for public queries
Name 54235 0
Dr Christopher Gordon
Address 54235 0
Woolcock Institute of Medical Research
PO Box M77
Missenden Road, Camperdown
NSW 2050
Country 54235 0
Australia
Phone 54235 0
+61291140000
Fax 54235 0
Email 54235 0
christopher.gordon@sydney.edu.au
Contact person for scientific queries
Name 54236 0
Dr Christopher Gordon
Address 54236 0
Woolcock Institute of Medical Research
PO Box M77
Missenden Road, Camperdown
NSW 2050
Country 54236 0
Australia
Phone 54236 0
+61291140000
Fax 54236 0
Email 54236 0
christopher.gordon@sydney.edu.au

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Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary