Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001694101
Ethics application status
Approved
Date submitted
12/11/2019
Date registered
2/12/2019
Date last updated
25/04/2024
Date data sharing statement initially provided
2/12/2019
Date results information initially provided
25/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Can the double orexin receptor antagonist suvorexant increase rapid eye movement (REM) sleep and improve sleep-dependent processing of emotional memories in healthy adults?
Scientific title
A randomized placebo controlled trial to investigate the effect of suvorexant on REM sleep and fear extinction recall in healthy volunteers.
Secondary ID [1] 299778 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
PTSD 315145 0
Condition category
Condition code
Mental Health 313461 313461 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This Randomized Controlled Trial (RCT) investigates whether the double orexin receptor antagonist suvorexant increases rapid eye movement (REM) sleep and improves fear extinction recall compared to an active control condition (temazepam) and placebo control.

Participant will be recruited and randomly assigned to the double-blinded drug condition. The intervention group receives one dose of 20mg suvorexant orally about 30 minutes before bedtime.
On the test day, participants will complete a standardized and well-validated fear conditioning and extinction task which examines their capacity to acquire conditioned fear (via recording skin conductance response [SCR] reflecting physiological arousal to stimuli paired with a mild electric shock) and extinguishing fear. For the fear acquisition phase, they will look at visual images of a scene containing a desktop lamp which lights up with a color. One color will be associated with a mild electrical shock (the CS+), the other colored circle is never associated with shock (the CS-). This will be followed immediately by the fear extinction phase in which they will look at both colored lights which will never be followed by shock. This paradigm is adapted from Milad, Orr, Pitman, & Rauch (2005). SCR will be recorded to reflect sympathetic arousal. SCR amplitude typically increases to the CS+ compared to the CS- in the acquisition phase, and then gradually reduces over the extinction phase. The slope of decline of SCR over the fear extinction phase reflects how well an individual can inhibit/regulate their fear and reflects their capacity for fear extinction learning. Next, participants view emotive and neutral images selected from the International Affective Picture System (IAPS). Then, participants will take the drug and sleep at the lab while polysomnography (PSG) records sleep including REM sleep during the test night. This is followed by a recovery night at home to allow full drug washout (an ambulatory PSG records REM sleep during the recovery night). The participants return to the lab the next morning for the follow up. First they are asked to remember, recognized and rate the IAPS images they have seen two days before. Then, they complete the extinction phase again while SCR is recorded to measure recall of fear extinction. The extent that their fear returns reflects how well they remember the fear extinction from the first test day. The following week, participants record any intrusive memories that they have of the IAPS images.
Intervention code [1] 316032 0
Treatment: Drugs
Comparator / control treatment
The participants in the placebo control group will receive the tablet in the form of a capsule (ingredient: hypromellose) filled with sugar 30 minutes before bedtime.
The second, active control group will receive 20mg temazepam in form of a tablet, which will also be administered 30 minutes before bedtime.
Control group
Placebo

Outcomes
Primary outcome [1] 321930 0
Amount of REM sleep visually scored from the PSG output.
Timepoint [1] 321930 0
1. Test night (night after drug intake)
2. Home sleep recording (2nd night after drug intake)
Primary outcome [2] 321931 0
Fear extinction recall measured via SCR
Timepoint [2] 321931 0
Follow up (about 48h after drug intake).
Secondary outcome [1] 376726 0
Group differences on fear conditioning measured via SCR.
Timepoint [1] 376726 0
Test day
Secondary outcome [2] 376727 0
Number and description of intrusive memories (assessed from the open-ended question of the intrusive memory diary).
Timepoint [2] 376727 0
Every day during the week after the follow up.
Secondary outcome [3] 377164 0
Group differences on fear extinction learning measured via SCR.
Timepoint [3] 377164 0
Test day
Secondary outcome [4] 377494 0
Rating of vividness of intrusive memories (0=not at all, 10=extremely).
Timepoint [4] 377494 0
Every day during the week after the follow up
Secondary outcome [5] 377495 0
Rating of distress of intrusive memories (0=not at all, 10=extremely).
Timepoint [5] 377495 0
Every day during the week after the follow up.

Eligibility
Key inclusion criteria
1. Aged between 18 – 50 years’ old
2. Physically and mentally healthy
3. Proficient in English
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Diagnosis of psychiatric disorder including personality disorder and bipolar disorder and/or total score on PTSD Checklist-5 greater or equal to 30 (Weathers et al., 2013), subscores on Depression, Anxiety Stress Scale 21 greater or equal to 7 (Depression), greater or equal to 6 (Anxiety) and/or greater or equal to 10 (Stress; Henry & Crawford, 2005)
2. Physical disorders including severe hepatic or renal impairments, neurological disorders including narcolepsy, epilepsy or seizures and/ or cardiac disorders, including hypotension or hypertension (blood pressure outside 90/60mmHg - 140/90mmHg)
3. Sleep disorders and/or sleep disturbances including jetlag or shift work.
4. Currently taking any medication that interacts with the study drugs or the central nervous system (e.g. sedatives). Contraceptive pills are ok.
5. Regular smokers (social smokers are ok)
6. BMI (body mass index) outside of 18.5 – 30kg m2
7. Women only: pregnant, breastfeeding and/or trying to get pregnant

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The drug will be administered in a white, opaque, numbered plastic bottle.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation will be done by a non-involved third party that has no contact with participants and will prepare the drug and the randomisation list for the researcher.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analysis of variance (ANOVA) with fixed effects, omnibus, (one-way at a 5% level of significance) and effect size analyses will test difference in REM sleep and fear extinction amongst drug conditions. To assess group differences on fear conditioning and extinction learning, 3 (Drug Condition: Suvorexant, Temazepam, Placebo) x 2 (Condition: CS+/CS-) x 5 (trial) mixed model ANOVAs will be conducted.
To assess for fear extinction recall, we will conduct a 3 (Drug condition) x 2 (Stimulus) x 2 (trial [last trial late extinction/ last trial extinction recall]) repeated measure ANOVA.
To assess differences in fear conditioning and fear extinction, we will conduct a 3 (Drug) x 2 (Stimulus) x 4 (conditioning trials) or 5 (extinction trials) repeated measure ANOVA on SCR amp data of the conditioning or extinction phase.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Other reasons/comments
Other reasons
COVID-19 related delays.
Date of first participant enrolment
Anticipated
13/01/2020
Actual
21/01/2020
Date of last participant enrolment
Anticipated
31/12/2023
Actual
26/03/2024
Date of last data collection
Anticipated
1/01/2024
Actual
9/04/2024
Sample size
Target
60
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 304242 0
University
Name [1] 304242 0
The University of Melbourne
Country [1] 304242 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Parkville VIC 3010
Country
Australia
Secondary sponsor category [1] 304481 0
None
Name [1] 304481 0
Address [1] 304481 0
Country [1] 304481 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304701 0
The University of Melbourne, Psychology, Health and Applied Sciences Human Ethics Sub-Committee (HESC)
Ethics committee address [1] 304701 0
Psychology, Health and Applied Sciences Human Ethics Sub-Committee (HESC):
Office of Research Ethics & Integrity
Level 4, 161 Barry Street
The University of Melbourne
Parkville, VIC 3010
Ethics committee country [1] 304701 0
Australia
Date submitted for ethics approval [1] 304701 0
06/06/2019
Approval date [1] 304701 0
06/09/2019
Ethics approval number [1] 304701 0
1954820.2

Summary
Brief summary
Dysregulated fear memory processing as well as disrupted sleep (particularly rapid eye movement sleep) are important factors in the development of posttraumatic stress disorder. Sleep is one of the few modifiable variables in the aftermath of a traumatic event, which might be utilized to prevent PTSD onset. Therefore, the aim of this project is to examine the effect of two insomnia drugs that alter REM sleep (suvorexant and temazepam) on processing of fear extinction learning and emotional memory consolidation compared to placebo in healthy individuals. Impairments in fear conditioning and extinction is the prevailing model of mechanisms involved in the development of PTSD. We hypothesize that suvorexant increases REM sleep and adaptive emotional memory processing compared to temazepam and placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97922 0
Prof Amy Jordan
Address 97922 0
Level 9, Redmond Barry Building, Tin Alley
The University of Melbourne
Parkville, VIC, 3010
Country 97922 0
Australia
Phone 97922 0
+61 38344 6357
Fax 97922 0
Email 97922 0
[email protected]
Contact person for public queries
Name 97923 0
Miss Maya Schenker
Address 97923 0
Level 9, Redmond Barry Building, Tin Alley
The University of Melbourne
Parkville, VIC, 3010
Country 97923 0
Australia
Phone 97923 0
+61 383444911
Fax 97923 0
Email 97923 0
[email protected]
Contact person for scientific queries
Name 97924 0
Prof Kim Felmingham
Address 97924 0
Level 12, Redmond Barry Building, Tin Alley
The University of Melbourne
Parkville, VIC, 3010
Country 97924 0
Australia
Phone 97924 0
+61 383443935
Fax 97924 0
Email 97924 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.