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Trial registered on ANZCTR


Registration number
ACTRN12619001728123
Ethics application status
Approved
Date submitted
27/11/2019
Date registered
9/12/2019
Date last updated
28/10/2024
Date data sharing statement initially provided
9/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Pharmacologically Targeting Sleep Spindles to Improve Cognition in Ageing
Scientific title
Pharmacologically Targeting Sleep Spindles to Improve Cognition in Ageing
Secondary ID [1] 295339 0
Nil
Universal Trial Number (UTN)
U1111-1216-3513
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitively-intact ageing cohort which includes adults with and without subjective memory complaints 308545 0
Condition category
Condition code
Neurological 307512 307512 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This proof of concept study will test a drug intervention to boost sleep spindle brain activity during non-REM sleep and to improve memory consolidation in cognitively-intact older adults.

Zolpidem (5mg) a short-acting, non-benzodiazepine, will be administered orally. Zolpidem is a widely prescribed hypnotic, has a low risk of dependence, fewer side effects than benzodiazepines and is safe for long-term use.

Zolpidem and placebo will be administered orally in the evening prior to the 8-hour sleep opportunity on two nights in a randomised order with a 5-10 day washout between administration.

Participants’ sleep will be monitored in an overnight study in the laboratory
using high-density electroencephalography (EEG).
Intervention code [1] 301663 0
Treatment: Drugs
Comparator / control treatment
A matched placebo compounded from mircocrystalline cellulose will be administered in a randomised order with a 5-10 day washout between administration.
Control group
Placebo

Outcomes
Primary outcome [1] 307828 0
Change in overnight memory consolidation scores (declarative and procedural) as assessed by word-pair association declarative task and finger tapping task.
Timepoint [1] 307828 0
At Visit 1 and Visit 2
Secondary outcome [1] 348658 0
Change in sleep spindle density per minute of NREM (defined as N2 and N3) as assessed by high-density electroencephalography.
Timepoint [1] 348658 0
At Visit 1 and Visit 2
Secondary outcome [2] 441073 0
Tertiary outcome: Declarative memory (evening and morning recall total) pre and post sleep scores measured word-pair association declarative task
Timepoint [2] 441073 0
Secondary outcome [3] 441074 0
Tertiary outcome: Declarative memory (evening and morning recall total) pre and post sleep scores measured word-pair association declarative task
Timepoint [3] 441074 0
visit 1 and 2
Secondary outcome [4] 441075 0
Tertiary outcome: Sleep macroarchitecture metrics measured by EEG: Amount and percentage of sleep stages 1-3, NREM sleep, REM sleep, arousal index (total, REM and NREM)
Timepoint [4] 441075 0
visit 1 and 2
Secondary outcome [5] 441076 0
Tertiary outcome: Sleep macroarchitecture metrics measured by EEG: Amount and percentage of sleep stages 1-3, NREM sleep, REM sleep, arousal index (total, REM and NREM)
Timepoint [5] 441076 0
visit 1 and visit 2
Secondary outcome [6] 441077 0
Tertiary outcome: Sleep spindle event metrics in NREM (N2 and N3) sleep derived from sleep EEG (mean sleep spindle duration (s) and mean peak-to-peak amplitude (µV)).
Timepoint [6] 441077 0
visit 1 and visit 2
Secondary outcome [7] 441078 0
Tertiary outcome: Sleep spindle event metrics in NREM (N2 and N3) sleep derived from sleep EEG (mean sleep spindle duration (s) and mean peak-to-peak amplitude (µV)).
Timepoint [7] 441078 0
visit 1 and visit 2
Secondary outcome [8] 441079 0
Tertiary outcome: Slow oscillation events in NREM sleep derived from sleep EEG (event markers are slow oscillation count per minute (n/min), mean slow oscillation duration (s) and mean peak-to-peak amplitude (µV))
Timepoint [8] 441079 0
visit 1 and visit 2
Secondary outcome [9] 441080 0
Tertiary outcome: Slow oscillation events in NREM sleep derived from sleep EEG (event markers are slow oscillation count per minute (n/min), mean slow oscillation duration (s) and mean peak-to-peak amplitude (µV))
Timepoint [9] 441080 0
visit 1 and visit 2
Secondary outcome [10] 441081 0
Tertiary outcome: Sleep spindle and slow oscillation coupling events measured by EEG (metrics of interest are: (i) coupled spindle density (calculated as the count of spindles that are coupled to a slow oscillation per minute; n/min); (ii) ratio of coupled spindles to total slow oscillations; and (iii) ratio of coupled spindles to total spindles (%))
Timepoint [10] 441081 0
visit 1 and visit 2
Secondary outcome [11] 441082 0
Tertiary outcome: Sleep spindle and slow oscillation coupling events measured by EEG (metrics of interest are: (i) coupled spindle density (calculated as the count of spindles that are coupled to a slow oscillation per minute; n/min); (ii) ratio of coupled spindles to total slow oscillations; and (iii) ratio of coupled spindles to total spindles (%))
Timepoint [11] 441082 0
visit 1 and visit 2
Secondary outcome [12] 441083 0
Tertiary outcome: Global and regional EEG power during NREM and REM sleep (high-density EEG, spectral power for frequency ranges delta:1-4.5Hz; theta: 4.5-8Hz; alpha: 8-12Hz; sigma: 12-15 Hz; beta: 15-25 Hz; gamma: 25-40Hz). Measured by EEG. Calculated by fast-fourier transform.
Timepoint [12] 441083 0
visit 1 and visit 2
Secondary outcome [13] 441084 0
Tertiary outcome: Global and regional EEG power during NREM and REM sleep (high-density EEG, spectral power for frequency ranges delta:1-4.5Hz; theta: 4.5-8Hz; alpha: 8-12Hz; sigma: 12-15 Hz; beta: 15-25 Hz; gamma: 25-40Hz). Measured by EEG. Calculated by fast-fourier transform.
Timepoint [13] 441084 0
visit 1 and 2
Secondary outcome [14] 441085 0
Tertiary outcome: Actigraphy activity and rest metrics measured by a wrist worn actigraphy device
Timepoint [14] 441085 0
visit 1 and 2
Secondary outcome [15] 441086 0
Tertiary outcome: Actigraphy activity and rest metrics measured by a wrist worn actigraphy device
Timepoint [15] 441086 0
1 week prior to visit 1 and visit 2
Secondary outcome [16] 441087 0
Tertiary outcome: Epworth Sleepiness Scale score
Timepoint [16] 441087 0
1 week prior to visit 1 and visit 2
Secondary outcome [17] 441088 0
Tertiary outcome: Epworth Sleepiness Scale score
Timepoint [17] 441088 0
visit 1
Secondary outcome [18] 441089 0
Tertiary outcomes: Karolinska Sleepiness Scale before and after sleep
Timepoint [18] 441089 0
visit 1
Secondary outcome [19] 441090 0
Tertiary outcomes: Karolinska Sleepiness Scale before and after sleep
Timepoint [19] 441090 0
visit 1 and visit 2
Secondary outcome [20] 441091 0
Tertiary outcome: Procedural memory (pre and post-training learning score) pre and post sleep scores measured by the finger tapping task.
Timepoint [20] 441091 0
visit 1 and visit 2
Secondary outcome [21] 441092 0
Tertiary outcome: Procedural memory (pre and post-training learning score) pre and post sleep scores measured by the finger tapping task.
Timepoint [21] 441092 0
visit 1 and 2
Secondary outcome [22] 441093 0
Tertiary outcome: Respiratory metrics measured by respiratory flow and oximetry: AHI, ODI
Timepoint [22] 441093 0
visit 1 and 2
Secondary outcome [23] 441094 0
Tertiary outcome: Respiratory metrics measured by respiratory flow and oximetry: AHI, ODI
Timepoint [23] 441094 0
visit 1 and 2
Secondary outcome [24] 441095 0
Tertiary outcome: Karolinska sleep diary activity and rest metrics
Timepoint [24] 441095 0
visit 1 and 2
Secondary outcome [25] 441096 0
Tertiary outcome: Karolinska sleep diary activity and rest metrics
Timepoint [25] 441096 0
1 week prior to visit 1 and visit 2
Secondary outcome [26] 441097 0
Tertiary outcome: Pittsburgh Sleep Quality Index
Timepoint [26] 441097 0
1 week prior to visit 1 and visit 2
Secondary outcome [27] 441098 0
Tertiary outcome: Pittsburgh Sleep Quality Index
Timepoint [27] 441098 0
visit 1
Secondary outcome [28] 441099 0
Tertiary outcome: Depression Anxiety Stress Scale-21 item
Timepoint [28] 441099 0
visit 1
Secondary outcome [29] 441100 0
Tertiary outcome: Depression Anxiety Stress Scale-21 item
Timepoint [29] 441100 0
visit 1
Secondary outcome [30] 441101 0
Tertiary outcomes: Resting wake EEG power (high-density EEG recordings - Karolinska Drowsiness Test) (high-density EEG, spectral power for frequency ranges delta:1-4.5Hz; theta: 4.5-8Hz; alpha: 8-12Hz; sigma: 12-15 Hz; beta: 15-25 Hz; gamma: 25-40Hz).
Timepoint [30] 441101 0
visit 1
Secondary outcome [31] 441102 0
Tertiary outcomes: Resting wake EEG power (high-density EEG recordings - Karolinska Drowsiness Test) (high-density EEG, spectral power for frequency ranges delta:1-4.5Hz; theta: 4.5-8Hz; alpha: 8-12Hz; sigma: 12-15 Hz; beta: 15-25 Hz; gamma: 25-40Hz).
Timepoint [31] 441102 0
visit 1 and 2

Eligibility
Key inclusion criteria
1. Males and Females;
2. Age 50-75;
3. Ability to perform neurobehavioural tests;
4. Able to give informed consent;
5. Fluent in English;
6. Cognitively intact (may have subjective memory complaint)
Minimum age
50 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Mild cognitive impairment, suspected or confirmed dementia or Mini Mental State Examination <24 ;
2. History of cerebrovascular events (e.g. stroke, TIA) associated with persisting cognitive changes
3. Neurological disorders (e.g. Parkinson’s Disease, Epilepsy, Multiple Sclerosis)
4. Myasthenia Gravis
5. Severe hepatic impairment
6. Acute ± severe pulmonary insufficiency
7. Head trauma with associated loss of consciousness > 30 mins
8. Psychiatric disorder including; Bipolar Disorder (I and II) and schizophrenia
9. Current major depressive episode
10. Currently regularly taking regular benzodiazepines, sedatives and hypnotics, and other sleep-affecting medications or any centrally active medications including anti-depressants /polypharmacy.
11. Current substance abuse or dependence (alcohol and/or other illicit substances)
12. Shift-work or trans-meridian travel within 14 days of assessment
13. Obstructive Sleep Apnoea and other sleep disorders;
14. Severe insomnia (insomnia severity index score of 22 or more)
15. Contraindication to MRI scanning.
16. Clinically significant medical condition that may hinder compliance with protocol as determined by the study physician.
17. Pregnancy

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)
Randomisation log.
Numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software.

Secure randomization will be achieved through Research Tools. Participants will be enrolled sequentially according to a computer-generated randomization list using a random block size (2, 4 or 6) that is not available to staff who enroll participants. A unique participant randomization number will be assigned sequentially, in ascending order and will comprise a three-digit number prefixed by "r" (e.g. R001, R002 etc.). This randomization number will be used to internally identify the treatment group the participant is assigned to.
At randomization, the randomization module in Research Tools system requires that the trial coordinator enter a screening number and then confirm that the displayed participant name and DOB match the participant they intend to randomize. All previously entered eligibility data are then automatically assessed. If the participant meets all inclusion and none of the exclusion criteria, then the trial unblinded researcher is able to commit online to automatically randomizing the participant. Once this occurs, the participant is irrevocably allocated the next available randomization number and previously concealed treatment assignment. Both the randomization number and allocated treatment are then displayed and permanently recorded against that participant's online record.
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
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Efficacy
Statistical methods / analysis
24 participants completing a crossover study (aim to recruit 26 to allow for withdrawals and missing data) will provide sufficient power to detect a moderate effect size of 0.6 standard deviations with 80% power and an adjusted two-tailed significance level to 0.05 for two primary outcomes. This sample of 24 patients is powered to show moderately strong correlations (Pearson’s r of 0.52 and above).

The primary outcome will be compared between treatment and placebo conditions by paired t-test.

To study if spindle density influences individual variability in subjective memory impairment we will use bivariate correlations to relate Zolpidem minus placebo differences in spindles to Zolpidem minus placebo differences in performance on the Word Pairs task and the Finger Tapping Task.

Variables will be transformed as necessary to satisfy assumptions of the analyses used.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/11/2021
Actual
22/03/2022
Date of last participant enrolment
Anticipated
12/06/2023
Actual
12/12/2023
Date of last data collection
Anticipated
30/06/2023
Actual
30/01/2024
Sample size
Target
24
Accrual to date
Final
23
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11254 0
Woolcock Institute of Medical Research - Glebe
Recruitment postcode(s) [1] 23131 0
2037 - Glebe

Funding & Sponsors
Funding source category [1] 299932 0
Government body
Name [1] 299932 0
NHMRC
Country [1] 299932 0
Australia
Funding source category [2] 299933 0
Other Collaborative groups
Name [2] 299933 0
Neurosleep NHMRC Centre for Research Excellence
Country [2] 299933 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] 304655 0
None
Name [1] 304655 0
None
Address [1] 304655 0
None
Country [1] 304655 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300799 0
SLHD RPA - Research Ethics and Governance Office
Ethics committee address [1] 300799 0
Ethics committee country [1] 300799 0
Australia
Date submitted for ethics approval [1] 300799 0
08/05/2019
Approval date [1] 300799 0
29/07/2019
Ethics approval number [1] 300799 0
X19-0138 & 2019/ETH00569

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

Contacts
Principal investigator
Name 84850 0
Prof Ronald Grunstein
Address 84850 0
Woolcock Institute of Medical Research.
431 Glebe Point Rd
Glebe. NSW. 2037
Country 84850 0
Australia
Phone 84850 0
+61291140438
Fax 84850 0
Email 84850 0
ron.grunstein@sydney.edu.au
Contact person for public queries
Name 84851 0
Angela D'Rozario
Address 84851 0
Woolcock Institute of Medical Research.
431 Glebe Point Rd
Glebe. NSW. 2037
Country 84851 0
Australia
Phone 84851 0
+61291140435
Fax 84851 0
Email 84851 0
angela.drozario@sydney.edu.au
Contact person for scientific queries
Name 84852 0
Angela D'Rozario
Address 84852 0
Woolcock Institute of Medical Research.
431 Glebe Point Rd
Glebe. NSW. 2037
Country 84852 0
Australia
Phone 84852 0
+61291140435
Fax 84852 0
Email 84852 0
angela.drozario@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant underlying published results only.
When will data be available (start and end dates)?
Data will be made available upon request, after publication, with no end date determined.
Available to whom?
Data will be made available upon request, after publication and will be determined upon negotiation with researchers who provided a methodologically sound proposal.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Secure data transfer and signed data access agreement.


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.