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Trial registered on ANZCTR


Registration number
ACTRN12619001456145
Ethics application status
Approved
Date submitted
23/09/2019
Date registered
22/10/2019
Date last updated
21/06/2024
Date data sharing statement initially provided
22/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Does supplemental brexpiprazole affect sleep-wake and circadian parameters in youth with depressive syndromes?
Scientific title
Effects of adjunctive brexpiprazole on sleep-wake and circadian parameters in youth with depressive syndromes – an open-label, mechanistic study
Secondary ID [1] 299155 0
None
Universal Trial Number (UTN)
U1111-1239-6629
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
circadian parameters 314224 0
depression 314225 0
Condition category
Condition code
Mental Health 312587 312587 0 0
Other mental health disorders
Mental Health 312588 312588 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is designed as a 16-week (8 weeks active treatment, 8 weeks follow-up), open-label, phase IV clinical trial. It comprises only one treatment arm, with all participants receiving 8 weeks of adjunctive pharmacotherapy with brexpiprazole.

Experimental Study Arm:
Brexpiprazole for 8 weeks (1mg once daily in week 1, titrated to 2mg once daily in weeks 2 to 8)
Intervention: Drug: Brexpiprazole

Intervention in detail:
After baseline clinical, self-report, sleep-wake, and circadian assessments (including blood tests, clinical ratings, self-report questionnaires, ambulatory sleep-wake monitoring, and in lab-circadian circadian assessments) all participants will attend a 1-hour psychoeducational session (baseline visit). Subsequently, participants will receive 8 weeks of open-label treatment with brexpiprazole as adjunctive treatment to TAU*. Patients will receive 2mg/day, once daily as tablets, for oral use. The brexpiprazole dosage will be steadily increased from 1mg/day during week 1, to 2mg/day during weeks 2-8 (up-titration). Participants will be contacted by telephone on a weekly basis to monitor side-effects and adherence. After 4 weeks, clinical ratings and self-report questionnaires will be done to assess changes in clinical and functional measures. Ambulatory sleep-wake monitoring will be conducted continuously for the duration of treatment. After 8 weeks of treatment, blood tests, circadian assessments, clinical ratings and self-report questionnaires will be repeated. Follow-up visits will be conducted 4 weeks and 8 weeks after trial completion (including sleep-wake, clinical, and self-report assessments)
*TAU (Treatment As Usual) is a current antidepressant treatment with either SSRI or SNRI.
Intervention code [1] 315439 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321242 0
The primary outcome will be depressive symptoms assessed by QIDS-CR total score (minus sleep items)
Timepoint [1] 321242 0
Week 8 from Baseline assessment
Primary outcome [2] 321243 0
Primary circadian variable of interest is an actigraphy parameters of Sleep onset time measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [2] 321243 0
2-week period prior to baseline and prior to week 8
Primary outcome [3] 321244 0
In-lab circadian measure:
- Dim Light Melatonin Onset (DLMO) timing, assessed by taking a saliva sample every hour as per the study in-lab circadian assessment protocol.

Timepoint [3] 321244 0
Saliva samples will be collected every hour over an 8-hour period (i.e. until 2-hours after habitual sleep onset) during the in-lab circadian assessments at Baseline and Week 8 timepoints.
Secondary outcome [1] 374443 0
The secondary outcome of interest is the level of functioning assessed by the SOFAS rating,
Timepoint [1] 374443 0
Week 8 after Baseline assessment
Secondary outcome [2] 375823 0
Please note that this is another primary outcome -
Actigraphy parameters of Sleep offset (wake) time measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [2] 375823 0
2-week period prior to baseline and prior to week 8
Secondary outcome [3] 375825 0
Please note that this is another primary outcome -
Depressive symptoms assessed by QIDS-SR total score (minus sleep items)
Timepoint [3] 375825 0
Week 8 from Baseline assessment
Secondary outcome [4] 375826 0
Please note that this is another primary outcome -
Depressive symptoms assessed by MADRS total score (minus sleep items)
Timepoint [4] 375826 0
Week 8 from the Baseline assessment
Secondary outcome [5] 375827 0
Please note that this is another primary outcome -
Actigraphy parameters of Total sleep time (duration) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [5] 375827 0
2-week period prior to baseline and prior to week 8
Secondary outcome [6] 375828 0
Please note that this is another primary outcome -
Actigraphy parameters of Wake after sleep onset (estimation of number of minutes awake during the sleep period) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [6] 375828 0
2-week period prior to baseline and prior to week 8
Secondary outcome [7] 375829 0
Please note that this is another primary outcome -
Actigraphy parameters of Sleep efficiency (% of sleep period estimated as sleep) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [7] 375829 0
2-week period prior to baseline and prior to week 8
Secondary outcome [8] 375830 0
Please note that this is another primary outcome -
Actigraphy parameters of Inter-daily stability measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [8] 375830 0
2-week period prior to baseline and prior to week 8
Secondary outcome [9] 375831 0
Please note that this is another primary outcome -
Actigraphy parameters of Intra-daily variability measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [9] 375831 0
2-week period prior to baseline and prior to week 8
Secondary outcome [10] 375832 0
Please note that this is another primary outcome -
Phase angle (time lapse) between DLMO and habitual sleep (assessed by saliva samples collected every hour over an 8-hour period (i.e. until 2-hours after habitual sleep onset) during the in-lab circadian assessments
Timepoint [10] 375832 0
Baseline and Week 8 timepoints
Secondary outcome [11] 375833 0
Please note that this is another primary outcome -
Core body temperature nadir (assessed by the ingestible temperature sensor during the in-lab circadian assessment)
Timepoint [11] 375833 0
Baseline and Week 8 timepoints
Secondary outcome [12] 375834 0
Please note that this is another primary outcome –
Self-report measure of Non-restorative sleep score (assessed by a 4-point Likert scale).
Timepoint [12] 375834 0
Baseline and Week 8
Secondary outcome [13] 375835 0
Please note that this is another primary outcome –
Self-report measure of Pittsburgh Sleep Quality Inventory (PSQI) total score
Timepoint [13] 375835 0
Baseline and Week 8
Secondary outcome [14] 375836 0
Please note that this is another primary outcome –
Self-report measure of Epsworth Sleepiness Scale (ESS) total score
Timepoint [14] 375836 0
Baseline and Week 8
Secondary outcome [15] 375837 0
Please note that this is another primary outcome –
Self-report measure of Insomnia Severity Index (ISI) total score
Timepoint [15] 375837 0
Baseline and Week 8
Secondary outcome [16] 375838 0
Please note that this is another primary outcome –
Self-report measure of Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) total score
Timepoint [16] 375838 0
Baseline assessment (baseline scores will be used rather than change scores as these are trait measures)
Secondary outcome [17] 375839 0
Please note that this is another primary outcome –
Self-report measure of Seasonal Patterns Assessment Questionnaire (SPAQ) total score
Timepoint [17] 375839 0
Baseline assessment (baseline scores will be used rather than change scores as these are trait measures)

Eligibility
Key inclusion criteria
- Aged 18-30
- Major Depressive Disorder diagnosis according to DSM-5 criteria using the Structured Clinical Interview for DSM-5 (SCID)
- Current Major Depressive Episode of moderate severity as indexed by QIDS-CR score greater than or equal to 11 at two assessments 2 weeks apart
- Failure to respond to at least one adequate trial (i.e., at least 4 weeks) of a pharmacological therapy for the current episode
- Current antidepressant treatment must include an SSRI or SNRI (citalopram, fluoxetine, paroxetine, sertraline, escitalopram, venlafaxine, desvenlafaxine, duloxetine) for at least 6 weeks, at a stable dose for 2 weeks prior to study initiation.
- Perturbed 24-hour sleep-wake cycle as evidenced by: delayed sleep onset; delayed sleep offset; disrupted sleep; high day-to-day variability of sleep-wake; non-restorative sleep; or daytime fatigue.
Minimum age
18 Years
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Receipt of other adjunctive antipsychotic medication for the current episode
- Use of medications that affect sleep, melatonin, circadian rhythms or alertness
- Evidence of other sleep, respiratory (e.g., sleep apnoea), neurological or primary medical conditions that could contribute to sleep-wake dysfunction
- A primary psychotic diagnosis (e.g. schizophrenia)
- Acute suicidal behaviour (score of 6 on Comprehensive Assessment of At-Risk Mental States (CAARMS) item 7.3)
- Significant alcohol or other substance misuse or substance dependence
- Regular shift-work within 60-days prior to entry into the study.
- Recent transmeridian travel (participants will be required to wait three days for each jet lag hour before entering the study)
- A history of previous hypersensitivity to brexpiprazole or any of the excipients.
- Taking moderate to strong CYP2D6 or CYP3A4 inhibitors (e.g., quinidine, ketoconazole) or strong CYP3A4 inducers (e.g., rifampicin)
- Pregnancy or lactation

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size Calculation:
In our previous study of circadian changes in response to Agomelatine (*see full reference below) we found a correlation coefficient of .54 for the key outcome of interest, namely correlation between change in Dim Light Melatonin Onset (DLMO) and change in depressive symptoms. We conservatively estimate that the correlation coefficient for Brexpiprazole would be smaller- around .35 (i.e. a medium effect size), as the effects on the circadian system may be less direct. Assuming an alpha of .05 and 80% power for a one tailed correlation analysis, a sample size of 49 would be required to detect this effect (power analyses completed in G*Power 3.1.9.4)

Analysis Plan:
Correlations will be performed between change scores for sleep and circadian measures and change scores for depressive symptoms. Intention to treat will be used for missing data. Pearson’s or Spearman’s correlations will be selected based on normative or non-normative data distribution. A significance level will be set at a=.05. Correlations will be performed between other change scores to assess secondary and tertiary endpoints using the same methodology.

*Ref: Robillard, Rebecca et al. “Parallel Changes in Mood and Melatonin Rhythm Following an Adjunctive Multimodal Chronobiological Intervention With Agomelatine in People With Depression: A Proof of Concept Open Label Study.” Frontiers in psychiatry vol. 9 624. 11 Dec. 2018, doi:10.3389/fpsyt.2018.00624

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
3/04/2023
Actual
30/11/2023
Date of last participant enrolment
Anticipated
3/04/2024
Actual
30/11/2023
Date of last data collection
Anticipated
2/09/2024
Actual
9/05/2024
Sample size
Target
50
Accrual to date
Final
1
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 14682 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 27714 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 303698 0
Commercial sector/Industry
Name [1] 303698 0
Lundbeck Australia Pty Ltd
Country [1] 303698 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 303803 0
None
Name [1] 303803 0
Address [1] 303803 0
Country [1] 303803 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304221 0
SLHD RPAH Zone HREC
Ethics committee address [1] 304221 0
Ethics committee country [1] 304221 0
Australia
Date submitted for ethics approval [1] 304221 0
30/10/2019
Approval date [1] 304221 0
11/12/2019
Ethics approval number [1] 304221 0
X19-0417 and 2019/ETH12986

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96186 0
Prof Ian B. Hickie
Address 96186 0
Brain and Mind Centre
Level 4, 94 Mallett Street
Camperdown NSW 2050
Mallett Street Campus (M02F)
Country 96186 0
Australia
Phone 96186 0
+612 9351 0810
Fax 96186 0
Email 96186 0
[email protected]
Contact person for public queries
Name 96187 0
Ian B. Hickie
Address 96187 0
Brain and Mind Centre
Level 4, 94 Mallett Street
Camperdown NSW 2050
Mallett Street Campus (M02F)
Country 96187 0
Australia
Phone 96187 0
+612 9351 0810
Fax 96187 0
Email 96187 0
[email protected]
Contact person for scientific queries
Name 96188 0
Ian B. Hickie
Address 96188 0
Brain and Mind Centre
Level 4, 94 Mallett Street
Camperdown NSW 2050
Mallett Street Campus (M02F)
Country 96188 0
Australia
Phone 96188 0
+612 9351 0810
Fax 96188 0
Email 96188 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
We are not planning to deposit the data with an archive or repository or publish them on the web. For the purposes of the study very specific research question, the sharing of individual participant information is not going to be meaningful. However, the aggregate de-identified participant data will be used for publications in high quality, peer-reviewed scientific journals and/or scientific conferences.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
5025Ethical approval    The letter of ethical approval will be attached wh... [More Details]



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