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Trial registered on ANZCTR

Registration number

ACTRN12615000819527

Ethics application status

Approved

Date submitted

21/07/2015

Date registered

10/08/2015

Date last updated

20/01/2020

Date data sharing statement initially provided

20/01/2020

Date results provided

20/01/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

The Healthy Heart-Mind Trial: Efficacy of melatonin for decreasing the incidence and severity of delirium following cardiac surgery

Scientific title

The Healthy Heart-Mind Trial: Efficacy of melatonin versus placebo for decreasing the incidence and severity of delirium following cardiac surgery in adults

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1172-4046

Trial acronym

Nil

Linked study record

Health condition

Health condition(s) or problem(s) studied:

delirium

cardiac surgery

Condition category

Condition code

Mental Health

Other mental health disorders

Surgery

Other surgery

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

melatonin 3mg oral capsules once daily for 7 days (2 days prior and 5 days after surgery). Medication adherence monitored through pill count and review of medication charts

Intervention code [1]

Prevention

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

microcrystalline cellulose placebo capsules

Control group

Placebo

Outcomes

Primary outcome [1]

The primary outcome of interest for this trial is the difference in the incidence of delirium (as determined by the Confusion Assessment Method and DSM-5 criteria) between the groups after cardiac surgery.

Timepoint [1]

7 days

Secondary outcome [1]

Severity of delirium as assessed with the Memorial Delirium Assessment Scale

Timepoint [1]

Assessed daily for 7 days or until discharge

Secondary outcome [2]

Duration of delirium

Timepoint [2]

Assessed daily with Confusion Assessment Method and DSM 5 criteria from day 1 post surgery until discharge

Secondary outcome [3]

Use of psychiatric medications during admission - assessed by review of medication charts

Timepoint [3]

From admission to hospital discharge

Secondary outcome [4]

Change in cognitive performance at discharge and 3 months as measured by Telephone Interview for Cognitive Status

Timepoint [4]

Cognition assessed at baseline (enrollment), day 7 post surgery or day of discharge and at 3 months post surgery

Secondary outcome [5]

Mood and anxiety symptoms as rated by Hospital Anxiety and Depression Scale

Timepoint [5]

Assessed at baseline, day7/hospital discharge and 3 months after surgery

Secondary outcome [6]

Hospital length of stay

Timepoint [6]

Assessed at time of discharge

Eligibility

Key inclusion criteria

1. Aged 50 years and older
2. Undergoing elective or semi-elective cardiac surgery (on or off cardiopulmonary bypass) for coronary artery bypass grafting (CABG) and/or valvular surgery

Minimum age

50 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Decline or are unable to give informed consent
2. Are undergoing emergency surgery
3. Are not fluent in written or spoken English (for the purposes of being able to complete the study assessments and questionnaires)
4. Have a contraindication to taking melatonin, such as a prior allergic reaction
5. Are currently using melatonin
6. Have a diagnosis of dementia or score 19 or less on the Telephone Interview for Cognitive Status
7. Score 15 or greater on the alcohol use disorders identification test (AUDIT)

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)

We will recruit 210 participants undergoing elective/semi-elective cardiac surgery in Perth, Western Australia. Participants will be randomly allocated to melatonin 3mg or matching placebo. The randomisation list will be generated and maintained by the hospital pharmacy and not accessible to the investigators.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomised to treatment with melatonin or matching placebo on a ratio of 1:1 according to a list of computer-generated random numbers.

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

Intervention assignment

Parallel

Other design features

Phase

Phase 2 / Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

Baseline data will be compared using descriptive statistics, Student t tests for normally distributed continuous variables, Mann-Whitney test for skewed variables and Pearson’s chi-square statistic for categorical variables. Analyses will be based on completers and intention-to-treat. The primary hypothesis (difference in the proportion of participants who develop delirium) will be tested using intention-to-treat analysis of panel data (xtlogit). This approach to the analysis of the data allows for the inclusion of all available information and for the investigation of interactions between terms (such as intervention and time). A similar approach will be used to analyse other binary outcomes (e.g., use of psychotropic medication). We will use multilevel mixed models to investigate changes in scores of the MDAS and TICS (continuous variables). All probability tests will be two-tailed and will be declared as significant when p<0.05.

We based our sample size on a previous trial (Al-Aama et al. 2011) that reported a 15.6% absolute reduction (19.2% versus 3.6%, p<0.02) in the incidence of delirium in their sample. Assuming a 15.6% absolute risk reduction in our patients with a conservative 25% incidence of delirium in the control group and an incidence of 9.4% in the intervention group, we will require 91 participants per group (182 participants in total) to detect a difference of this magnitude with a power of 80% and a two-sided alpha of 0.05. Allowing for a drop out rate of around 15%, we plan to recruit 210 participants.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/10/2015

Actual

2/02/2016

Date of last participant enrolment

Anticipated

31/05/2018

Actual

10/07/2018

Date of last data collection

Anticipated

Actual

2/10/2018

Sample size

Target

210

Accrual to date

Final

210

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [2]

St John of God Hospital, Subiaco - Subiaco

Recruitment postcode(s) [1]

6009 - Broadway Nedlands

Recruitment postcode(s) [2]

6008 - Subiaco

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

WA Department of Health

Address [1]

PO Box 8172
Perth Business Centre
Perth
WA 6849

Country [1]

Australia

Primary sponsor type

University

Name

University of Western Australia

Address

35 Stirling Highway
Crawley
WA
6009

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sir Charles Gairdner Hospital

Ethics committee address [1]

Hospital Avenue
Nedlands
Perth 
WA 6009

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

22/07/2015

Approval date [1]

17/09/2015

Ethics approval number [1]

2015-118

Summary

Brief summary

Delirium is common in patients recovering from surgical procedures, particularly those involving major cardiac surgery. It is associated with numerous adverse consequences, including increased patient suffering, longer hospital stays, increased postoperative complications, increased mortality and poorer cognitive outcomes. Current strategies are only modestly effective in treating delirium and the cornerstone of management is prevention, however even best practice multifactorial interventions only result in a modest reduction in delirium incidence. Melatonin is a naturally occurring compound that is important in the regulation of sleep. Melatonin metabolism dysregulation has been implicated in the development of delirium, although only sparse evidence about its possible role in delirium prevention exists. 

The main aim of this randomised, placebo-controlled, double blind clinical trial is to determine if 3mg melatonin can reduce the incidence, severity and complications of delirium following cardiac surgery.  

We plan to enrol 210 participants due to undergo elective cardiac surgery. Participants will be randomly allocated to melatonin 3mg or matching placebo for 7 days beginning two nights prior to the scheduled surgery. We are primarily interested in whether those given melatonin have a lower rate of new-onset delirium but will also be interested to see if they experience less delirious symptoms, less depression and anxiety, less cognitive impairment, require less medications during their admission (especially sedative medications) and have shorter stays in hospital and ICU. 

Melatonin is safe, inexpensive and readily available and thus offers a potentially simple, cost effective intervention suitable for use in routine clinical practice.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Andrew Ford

Address

University of Western Australia (M573)
35 Stirling Highway
Crawley
Western Australia
6009

Country

Australia

Phone

+61892242855

Fax

[email protected]

Contact person for public queries

Name

Andrew Ford

Address

University of Western Australia (M573)
35 Stirling Highway
Crawley
Western Australia
6009

Country

Australia

Phone

+61892242855

Fax

[email protected]

Contact person for scientific queries

Name

Andrew Ford

Address

University of Western Australia (M573)
35 Stirling Highway
Crawley
Western Australia
6009

Country

Australia

Phone

+61892242855

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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

Source	Title	Year of Publication	DOI
Embase	The Healthy Heart-Mind trial: Melatonin for prevention of delirium following cardiac surgery: Study protocol for a randomized controlled trial.	2016	https://dx.doi.org/10.1186/s13063-016-1163-1
Embase	The Healthy Heart-Mind Trial: Randomized Controlled Trial of Melatonin for Prevention of Delirium.	2020	https://dx.doi.org/10.1111/jgs.16162

N.B. These documents automatically identified may not have been verified by the study sponsor.

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