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Trial registered on ANZCTR


Trial ID
ACTRN12614001293651
Ethics application status
Approved
Date submitted
7/11/2014
Date registered
11/12/2014
Date last updated
10/10/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Sleep Restriction Therapy + Armodafinil for Insomnia Disorder
Scientific title
Armodafinil to reduce the sleepiness related side-effects of Sleep Restriction Therapy being used to treat Insomnia Disorder: An open label pilot study compared to historical matched controls.
Secondary ID [1] 285278 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Insomnia Disorder 292940 0
Condition category
Condition code
Mental Health 293237 293237 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
30 patients with insomnia will be asked to undergo sleep restriction therapy with armodafinil. This is an open label pilot study to determine if armodafinil is acceptable, tolerated, and ameliorates the side effects of sleep restriction therapy.

As part of sleep restriction therapy, participants will be asked to ‘restrict’ their sleep-wake schedules (the minimum time in bed for all participants will be at least five hours). This causes excessive sleepiness, fatigue, & irritability during the initial stages. It is hypothesised that the use of armodafinil will prevent these transient effects of sleep loss.

As part of one hour long intervention, participants are instructed to keep a stable bedtime and wake-up time for the length of the treatment (4 weeks). The therapist will devise a "sleep window" that is approved by the participant. The sleep window will be evaluated every week for four weeks via telephone (10 minutes). Time in bed may be modified at weekly intervals by the achievement of 90% sleep efficiency (SE) = Total sleep time / Time in bed * 100) from a one week sleep diary (10 minute session per week via telephone). If 90% SE is achieved on average for any week of the therapy then time in bed is expanded by 15 minutes (either at bedtime or in the morning, depending on the participant). If <85% SE is achieved time in bed is reduced by 15 minutes (but not if it is at the minimum of five hours). If SE = 85-90% Time in bed is held constant. For patients who deem the sleep window too difficult, restrictive, or impossible compromise will be established between the therapist and the patient.

Armodafinil (initially 50mg, rising in 50mg amounts to a maximum of 150mg oral dose) once daily (to be taken before 09:00 am) for four weeks during SRT for Insomnia Disorder only. Up titration of armodafinil will take place based on the discretion of the assigned medical practitioner in consultation with the patient. Participants will be prescribed armodafinil by their assigned medical practitioner as part of the first visit to receive sleep restriction therapy. The weekly telephone calls to monitor the effects of sleep restriction therapy will also be used as a method to raise any concerns regarding the use and dose of armodafinil. The assigned medical practitioner will be informed of this and will decide if any action is required.

The intervention will end after four weeks of treatment.

Adherence to armodafinil will be established with drug tablet return. Adherence to sleep restriction therapy will be evaluated by sleep-wake dairies, actigraphy and a specific weekly sleep restriction therapy adherence scale.
Intervention code [1] 290165 0
Treatment: Drugs
Intervention code [2] 290168 0
Behaviour
Comparator / control treatment
30 Historical controls from studies that have undergone the exact same sleep restriction therapy intervention previously without armodafinil will act as controls for this study (from the UK: n=16: Kyle et al., 2014, SLEEP, Vol 37; n=6, unpublished, and Australia: n=8: ACTRN# 12612000057886). These data were collected between November 2011 - November 2013).
Control group
Historical

Outcomes
Primary outcome [1] 293086 0
Insomnia severity measured self-report capture of the Insomnia Severity Index at 12 weeks from the start of sleep restriction therapy, by either online or paper version.
Timepoint [1] 293086 0
We are measuring this at screening (baseline), weeks 1, 2, 3, 4, 6 & 12 from treatment start. For the statistical model we are using all data. Week 12 of treatment is the primary endpoint.
Secondary outcome [1] 310309 0
Daytime sleepiness before and during sleep restriction therapy for Insomnia Disorder measured by a weekly version of the Epworth Sleepiness Scale (Kyle et al., 2014, SLEEP, Vol 37).
Timepoint [1] 310309 0
We are measuring this at baseline and screening (baseline), weeks 1, 2, 3, 4, 6 & 12 from treatment start. For the statistical model we are using all data. Weeks 1, 2, 3 & 4 from treatment start are combined secondary endpoints.
Secondary outcome [2] 310464 0
Active Safety Mood Screening before and during sleep restriction therapy for Insomnia Disorder measured through the Depression Anxiety Stress Scales (DASS-21).
Timepoint [2] 310464 0
We are measuring this at baseline and screening (baseline), weeks 1, 2, 3, 4, 6 & 12 from treatment start. For the statistical model we are using all data.
Secondary outcome [3] 323124 0
Adherence to the sleep restriction therapy intervention measured through the sleep restriction therapy adherence scale
Timepoint [3] 323124 0
We are measuring this at weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [4] 323125 0
Health-related quality of life measured through the Short-form 12-question health survey.
Timepoint [4] 323125 0
We are measuring this at screening (baseline) and at the follow-up 12-weeks from treatment start. For the statistical model we are using all data.
Secondary outcome [5] 323126 0
Self-efficacy measured through the Self-efficacy questionnaire.
Timepoint [5] 323126 0
We are measuring this at screening (baseline) and at the follow-up 12-weeks from treatment start. For the statistical model we are using all data.
Secondary outcome [6] 323127 0
Treatment related side effects measured through the Side Effects Inventory.
Timepoint [6] 323127 0
We are measuring this at the follow-up timepoint only, 12-weeks from treatment start.
Secondary outcome [7] 323128 0
Genetic testing (blood) for COMT (Val158Met) polymorphism type.
Timepoint [7] 323128 0
We are measuring this once after the face-to-face consent into the trial visit before treatment start.
Secondary outcome [8] 323129 0
Genetic testing (blood) for PER3 polymorphism type
Timepoint [8] 323129 0
We are measuring this once after the face-to-face consent into the trial visit before treatment start.
Secondary outcome [9] 323130 0
Sleep Diary Defined Sleep Onset Latency
Timepoint [9] 323130 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [10] 323131 0
Sleep Diary Defined Total Sleep Time
Timepoint [10] 323131 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [11] 323132 0
Sleep Diary Defined Wake-time After Sleep Onset
Timepoint [11] 323132 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [12] 323133 0
Sleep Diary Defined Total Time in Bed
Timepoint [12] 323133 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [13] 323134 0
Actigraphy Defined Sleep Onset Latency
Timepoint [13] 323134 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [14] 323135 0
Actigraphy Defined Total Sleep Time
Timepoint [14] 323135 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [15] 323136 0
Actigraphy Defined Wake-time After Sleep Onset
Timepoint [15] 323136 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.
Secondary outcome [16] 323137 0
Actigraphy Defined Total Time in Bed
Timepoint [16] 323137 0
We are measuring this at screening (baseline) for two weeks (weeks -2-0 from treatment start) and weeks 0-1, 1-2, 2-3, and 3-4, from treatment start. For the statistical model we are using all data.

Eligibility
Key inclusion criteria
1. Males & Females aged 18-70 years.
2. Able to give informed written consent.
3. Literacy in English.
4. Symptoms of Insomnia Disorder as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for Insomnia Disorder 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. Assessed by telephone screening interview.
5. Insomnia Severity Index scale scores of 15 or more.
6. Never previously treated with CBT-I or armodafinil.
7. At least one month hypnotic free and willing to not take hypnotics for the duration of the trial.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy or lactation.
2. Patients with moderate-severe skin allergies and/or eczema.
3. Shift workers who rotate to night shift.
4. Drug addiction or alcoholism.
5. Severe unstable Psychiatric disorders.
6. Sleep disorders (other than untreated insomnia) and an apnea-hypopnea index >15 if suspected for sleep apnea.
7. Severe cognitive impairment that does not allow patients to consent or follow treatment instructions.
8. Recent time-zone travel (within last 1 month).
9. Conditions that contraindicate armodafinil or sleep restriction therapy in the opinion of the Principal Investigator (Medical Practitioner).
9. (a) Liver function tests exceeding the 95% confidence limits of normal which in the opinion of the medical PI contraindicate armodafinil.

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)
This trial is an open-label with no attempt at masking.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
As an open label trial there will be no randomisation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Type of endpoint(s)
Safety
Statistical methods / analysis
Those recruited in the armodafinil + sleep restriction therapy arm will be compared against previous historical controls who have underwent the exact same sleep restriction therapy intervention but with no drug for all primary and secondary analyses. For continuous repeated measures data, we will employ linear mixed effects models on all of the data collected at all time-points but with specific hypotheses testing at the pre-determined time-points depending on the outcome being tested using least square means differences. We will examine the residuals to assess model assumptions and goodness-of-fit. Change scores of continuous data collected at baseline and posttreatment only will be examined between groups by T-test. P-values will be reported to four decimal places with p-values less than 0.001 reported as p <0.001. Up-to-date versions of SAS (Cary, NC) and SPSS (Chicago, IL) will be used to conduct analyses. For all tests, we will use 2-sided p-values with alpha = <0.05 level of significance.

Recruitment
Recruitment status
Recruiting
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
Recruitment hospital [1] 2974 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 8685 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 289899 0
Government body
Name [1] 289899 0
NeuroSleep, a NHMRC Center of Research Excellence (CRE)
Address [1] 289899 0
Woolcock Institute of Medical Research
PO BOX M77, Missenden Rd
Sydney University
2050
NSW
Country [1] 289899 0
Australia
Funding source category [2] 293435 0
University
Name [2] 293435 0
University of Sydney Medical School Kickstart Grant (with financial support provided through the Balnaves Foundation)
Address [2] 293435 0
Sydney Medical School
University of Sydney
Camperdown NSW 2006
Country [2] 293435 0
Australia
Primary sponsor type
University
Name
Woolcock Institute of Medical Research, Sydney University
Address
PO BOX M77, Missenden Rd
Sydney University
2050
NSW
Country
Australia
Secondary sponsor category [1] 288586 0
Hospital
Name [1] 288586 0
Royal Prince Alfred Hospital
Address [1] 288586 0
Missenden Rd, Camperdown NSW 2050
Country [1] 288586 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291621 0
Bellberry Limited
Ethics committee address [1] 291621 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 291621 0
Australia
Date submitted for ethics approval [1] 291621 0
24/03/2016
Approval date [1] 291621 0
07/06/2016
Ethics approval number [1] 291621 0
2016-02-104

Summary
Brief summary
The aim of this study is to use a morning dose of armodafinil (50mg) as a short-term aid (4-weeks) to protect against daytime impairments in those with Insomnia Disorder who are undergoing effective sleep restriction therapy.

We hypothesise that overall insomnia severity measured through self-report of the Insomnia Severity Index (Primary Outcome) at 12 weeks (14 weeks into study protocol) from the start of treatment will reduce significantly more in patients receiving adjunctive armodafinil and sleep restriction therapy compared to those receiving sleep restriction therapy only (non-drug historical controls).

This may then increase adherence by augmenting wakefulness and in turn promote sleep in those with Insomnia Disorder. This is in line with a previous finding involving modafinli and overall CBT-I for insomnia (Perlis et al., 2004, SLEEP, Vol 27). This will be the first study to fully profile the acute effects of sleep restriction therapy + armodafinil for the treatment of insomnia. This study is a pilot study to determine acceptability, safety, efficacy and tolerability of armodafinil specifically in the context of sleep restriction therapy alone for Insomnia Disorder.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 51182 0
A/Prof Brendon Yee
Address 51182 0
Woolcock Institute of Medical Research
PO BOX M77, Missenden Rd
Sydney University
2050
NSW
Country 51182 0
Australia
Phone 51182 0
+61291140445
Fax 51182 0
Email 51182 0
Brendon.Yee@sswahs.nsw.gov.au
Contact person for public queries
Name 51183 0
Dr Christopher Miller
Address 51183 0
Woolcock Institute of Medical Research
PO BOX M77, Missenden Rd
Sydney University
2050
NSW
Country 51183 0
Australia
Phone 51183 0
+61291140411
Fax 51183 0
Email 51183 0
chris.miller@sydney.edu.au
Contact person for scientific queries
Name 51184 0
Dr Nathaniel Marshall
Address 51184 0
Sydney Nursing School
Sydney University
2006
NSW
Country 51184 0
Australia
Phone 51184 0
+61293510829
Fax 51184 0
Email 51184 0
nathaniel.marshall@sydney.edu.au