Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000876190
Ethics application status
Approved
Date submitted
6/05/2019
Date registered
19/06/2019
Date last updated
22/11/2022
Date data sharing statement initially provided
19/06/2019
Date results information initially provided
22/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Melatonin Supplementation in Mild Cognitive Impairment.
Scientific title
The effect of 3 months Melatonin supplementation on brain oxidative stress and sleep in mild cognitive impairment - A Randomised Placebo Controlled Pilot Study
Secondary ID [1] 295835 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mild Cognitive Impairment 309281 0
Condition category
Condition code
Neurological 308154 308154 0 0
Dementias
Neurological 311251 311251 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A three-month randomised controlled, double-blind, parallel group trial in participants with mild cognitive impairment. Participants will be randomly allocated to Melatonin (25mg) or placebo capsules nightly for 3 months. Participants will fill out a compliance sheet where they are required to tick a box every day to show they remembered to take the medication. Further, the amount of capsules returned will be counted.
Intervention code [1] 312170 0
Prevention
Comparator / control treatment
Matching placebo capsules for the 3 month study period. They will be composed of a microcrystalline cellulose filler.
Control group
Placebo

Outcomes
Primary outcome [1] 307787 0
Percent of people who meet inclusion and exclusion criteria and could potentially joint the study,
Timepoint [1] 307787 0
After all participants have been recruited.
Primary outcome [2] 319685 0
The amount of people who agree to be randomised (and take part in the trial).
Timepoint [2] 319685 0
After all participants have been recruited.
Primary outcome [3] 319686 0
The amount of people who correctly adhere to the study medication as instructed using both patient medication diary and capsule counts.
Timepoint [3] 319686 0
After all participants have concluded the study.
Secondary outcome [1] 352878 0
Brain oxidative stress as assessed by Glutathione concentration in the anterior and posterior cingulate from Magnetic Resonance Spectroscopy.
Timepoint [1] 352878 0
Baseline, 3 months after commencement of treatment.
Secondary outcome [2] 369153 0
Blood pressure, assessed using an automatic blood pressure monitor using standard procedures.
Timepoint [2] 369153 0
3 months after commencement of treatment.
Secondary outcome [3] 369154 0
Morning pulse wave velocity assessed by the procedure Pulse Wave Velocity using the ATCor Medical SphygmoCor system.
Timepoint [3] 369154 0
3 months after commencement of treatment.
Secondary outcome [4] 369156 0
Sleep using the self administered Pittsburgh Sleep Quality Index questionnaire.
Timepoint [4] 369156 0
6 weeks after commencement of treatment and 3 months after commencement of treatment.
Secondary outcome [5] 369157 0
Sleep parameters, measured by total sleep time, using actigraphy.
Timepoint [5] 369157 0
3 months after commencement of treatment.
Secondary outcome [6] 369159 0
Depressive symptoms assessed via the self administered Geriatric Depression Scale questionnaire
Timepoint [6] 369159 0
6 weeks after commencement of treatment and 3 months after commencement of treatment.
Secondary outcome [7] 369162 0
Chronotype as assessed by the self administered Horne & Ostberg Morningness-Eveningness Composite Questionnaire.
Timepoint [7] 369162 0
6 weeks after commencement of treatment and 3 months after commencement of treatment.
Secondary outcome [8] 369164 0
Encoding, recall and recognition in a single modality as assessed by the assessor administered California verbal learning test.
Timepoint [8] 369164 0
3 months after commencement of treatment.
Secondary outcome [9] 369165 0
Visual search, scanning, speed of processing, mental flexibility assessed via the assessor administered Trail Making Test.
Timepoint [9] 369165 0
3 months after commencement of treatment.
Secondary outcome [10] 369167 0
Memory, processing speed and executive functioning via the computerised Cambridge Neuropsychological Test Automated Battery.
Timepoint [10] 369167 0
3 months after commencement of treatment.
Secondary outcome [11] 369168 0
Sustained attention via the computerised Psychomotor Vigilance Test.
Timepoint [11] 369168 0
3 months after commencement of treatment.
Secondary outcome [12] 370155 0
24 hour central aortic pressure and arterial stiffness (assessed by 24 hour ambulatory pulse wave velocity using a standard ambulatory blood pressure monitor).
Timepoint [12] 370155 0
3 months after commencement of treatment.
Secondary outcome [13] 370156 0
Circadian rhythmicity, using sleep midpoint, using wrist actigraphy.
Timepoint [13] 370156 0
3 months after commencement of treatment.
Secondary outcome [14] 370208 0
Anxiety symptoms assessed using the self assessed Geriatric Anxiety Scale questionnaire.
Timepoint [14] 370208 0
6 weeks after commencement of treatment and 3 months after commencement of treatment
Secondary outcome [15] 370209 0
Morning central aortic pressure assessed by Pulse Wave Analysis procedure using the ATCor Medical SphygomoCor System
Timepoint [15] 370209 0
3 months after commencement of treatment.
Secondary outcome [16] 370211 0
Glucose control as assessed by Glycated Haemoglobin (Hba 1C) in blood samples.
Timepoint [16] 370211 0
3 months after commencement of treatment.
Secondary outcome [17] 370212 0
Oxidative stress as assessed by Glutothione in blood samples
Timepoint [17] 370212 0
3 months after commencement of treatment.
Secondary outcome [18] 370213 0
Biomarkers of neurodegeneration from blood samples
Timepoint [18] 370213 0
3 months after commencement of treatment.
Secondary outcome [19] 370214 0
Makers of the glymphatic system as assessed by blood samples.
Timepoint [19] 370214 0
6 weeks after commencement of treatment and 3 months after commencement of treatment
Secondary outcome [20] 370218 0
Melatonin levels as assessed by blood samples
Timepoint [20] 370218 0
3 months after commencement of treatment.
Secondary outcome [21] 371577 0
Sleep using the self-administered Insomnia Severity Index questionnaire.
Timepoint [21] 371577 0
3 months after commencement of treatment.
Secondary outcome [22] 371578 0
Sleep parameters, measured by sleep onset latency using actigraphy.
Timepoint [22] 371578 0
3 months after commencement of treatment.
Secondary outcome [23] 371579 0
Sleep parameters, measured by wake after sleep onset using actigraphy.
Timepoint [23] 371579 0
3 months after commencement of treatment.
Secondary outcome [24] 371580 0
Sleep parameters, measured by sleep efficiency using actigraphy.
Timepoint [24] 371580 0
3 months after commencement of treatment.
Secondary outcome [25] 371581 0
Circadian rhythmicity, measured by sleep offset, using actigraphy
Timepoint [25] 371581 0
3 months after commencement of treatment.
Secondary outcome [26] 371582 0
Circadian rhythmicity, measured by cosinar variables, using actigraphy
Timepoint [26] 371582 0
3 months after commencement of treatment.

Eligibility
Key inclusion criteria
1. Between 60-80 years of age.
2. Diagnosis of multi-domain MCI
3.Stability of at least four weeks on permitted medications.
4. Fluent in English
Minimum age
60 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suspected dementia seen by less than or equal to 18 on MoCA Blind
2. History of cerebrovascular events (e.g. stroke, TIA) associated with persisting cognitive changes
3. Shift-work or trans meridian travel within 14 days of assessment
4. Neurological disorders (e.g. Parkinson’s Disease, Epilepsy, Multiple Sclerosis)
5. Head trauma with associated loss of consciousness > 30 mins
6. Current psychiatric disorder including; Bipolar Disorder (I and II) and schizophrenia.
7. Currently regularly taking benzodiazepines, sedatives and hypnotics
8. Current substance abuse or dependence (alcohol and/or other illicit substances)
9. Any significant systematic illness or medical condition that may hinder compliance with protocol
10. Contraindication to MRI scanning such as pace devices, coronary or peripheral artery stents, cochlear implants and renal insufficiency
11. Current major depressive episode (not excluded if receiving treatment using anti-depressants for maintenance of depression or subthreshold depression unless a medication listed in 12.)
12. Currently taking medications such as beta blockers, MAO inhibitors, macrolides, and melatonergics.

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)
Central randomisation:
Randomisation will occur after baseline assessment and will be on a 1:1 basis. Secure randomisation will be achieved through the electronic data capture system that will be used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A unique participant randomisation number will be assigned sequentially, in ascending order and will comprise a 2-digit number prefixed by “R” (e.g. R01, R02 etc.). This randomisation number will be used to internally identify the treatment group the participant is assigned. The randomisation list will be computer generated by an individual not involved in the conduct of the study.
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 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
20 participants in each group (40 total) will be required for this pilot trial. The sample size calculation of N = 40, allows for 10% attrition, and assumes a medium effect size of melatonin. Between group differences will be determined using linear mixed models. Analysis will be conducted as per intention to treat principles.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2019
Actual
23/10/2019
Date of last participant enrolment
Anticipated
15/03/2021
Actual
29/11/2021
Date of last data collection
Anticipated
15/06/2021
Actual
14/04/2022
Sample size
Target
40
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 12774 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 24348 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 300430 0
Government body
Name [1] 300430 0
National Health Medical and Research Council
Country [1] 300430 0
Australia
Primary sponsor type
Other
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Road
Glebe NSW 2037 Sydney, Australia
Country
Australia
Secondary sponsor category [1] 302619 0
None
Name [1] 302619 0
None
Address [1] 302619 0
None
Country [1] 302619 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301234 0
Sydney Local Health District (RPAH zone) - Research Ethics and Governance Office
Ethics committee address [1] 301234 0
REGO
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Ethics committee country [1] 301234 0
Australia
Date submitted for ethics approval [1] 301234 0
20/03/2018
Approval date [1] 301234 0
21/06/2018
Ethics approval number [1] 301234 0
X18-0077 & HREC/18/RPAH/114

Summary
Brief summary
Melatonin has multiple therapeutic benefits. It has anti-oxidant and anti-hypertensive properties, it synchronises the circadian system and also promotes sleep. These are all pathways that could be targeted to slow cognitive decline. Previous randomised controlled studies have all targeted patients with developed dementia/AD in whom the cognitive decline may be too far advanced to modify clinical trajectory. We therefore propose using Melatonin in participants with Mild Cognitive Impairment (the prodromal phase of dementia) who report reduced sleep quality to target modifiable risk factors in this population at risk of for future cognitive decline. The study participants will be 40 older adults (aged 60-80 years) with multi-domain Mild Cognitive Impairment (non-amnestic or amnestic) with subjective sleep disturbance. Participants will be randomised to either daily melatonin or placebo, but both the participants and the experimenters will be blind to which treatment they are on. Primary outcomes include feasibility, acceptability and adherence. Secondary outcomes include the effect of melatonin on brain oxidative stress and sleep disturbance while neurocognition, memory, glucose, mood, blood pressure and other inflammatory biomarkers will also be measured.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86322 0
Dr Camilla Hoyos
Address 86322 0
88 Mallett Street, Brain and Mind Centre, University of Sydney, Campderdown NSW 2050
Country 86322 0
Australia
Phone 86322 0
+61 2 9114 0409
Fax 86322 0
Email 86322 0
[email protected]
Contact person for public queries
Name 86323 0
Miss Zoe Menczel Schrire
Address 86323 0
88 Mallett Street, Brain and Mind Centre, University of Sydney, Campderdown NSW 2050
Country 86323 0
Australia
Phone 86323 0
+61 2 9114 0409
Fax 86323 0
Email 86323 0
[email protected]
Contact person for scientific queries
Name 86324 0
Dr Camilla Hoyos
Address 86324 0
88 Mallett Street, Brain and Mind Centre, University of Sydney, Campderdown NSW 2050
Country 86324 0
Australia
Phone 86324 0
+61 2 9114 0409
Fax 86324 0
Email 86324 0
[email protected]

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 data 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
SourceTitleYear of PublicationDOI
EmbaseFeasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study.2021https://dx.doi.org/10.1136/bmjopen-2020-041500
N.B. These documents automatically identified may not have been verified by the study sponsor.