ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000543886

Ethics application status

Approved

Date submitted

10/03/2021

Date registered

10/05/2021

Date last updated

9/08/2024

Date data sharing statement initially provided

10/05/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Investigating the effect of melatonin on myocardial tissue when administered before cardiac surgery in adults.

Scientific title

A randomized controlled trial investigating the effect of pre-operative melatonin on the extend of ischemic-reperfusion injury in adult patients undergoing coronary artery bypass grafting (CABG) surgery.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1265-9842

Trial acronym

METEOR

Linked study record

Health condition

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

myocardial reperfusion injury

oxidative damage

inflammation

Condition category

Condition code

Cardiovascular

Coronary heart disease

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This study will consist of three groups, the group a participant is allocated to will dictate whether he/she receives placebo, higher or low dose melatonin. Low dose of melatonin being 10mg, higher dose of melatonin being 30mg and placebo will be a tablet with no active ingredients. The study medications will be visually identical and placed in identical envelopes labelled either A, B or C. All participants will receive a once-off sublingual tablet, taken orally 20minutes before surgery. The relevant tablet will be administered to the participant under direct supervision of one of the investigators, and individual pre-operative, intra-operative and post-operative plasma melatonin levels monitored.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Prevention

Comparator / control treatment

The placebo (control treatment) will look similar than the melatonin tablet but will not contain any active ingredients, it will consist of microcystelline cellulose.

Control group

Placebo

Outcomes

Primary outcome [1]

Assessment of high-sensitivity troponin (hsTnT) levels by serum assay analysis.

It is designed to have 80% power to detect a small effect size (25% decrease in TnT levels from the control group).

Timepoint [1]

This will be tested pre-operatively (to determine a baseline value) and at 6h, 12h and 24 hours following surgery.

Secondary outcome [1]

Assessment of plasma melatonin levels, following two different preoperative melatonin dosages, by mass spectrometry.

Timepoint [1]

Pre-operative (baseline), intra-operative and 6 hours post-operative levels.

Secondary outcome [2]

Inflammatory markers as reflected by CRP. The CRP will be measured from a blood sample.

Timepoint [2]

Pre-operative (baseline), intra-operative and 6, 12 and 24 hours post-operative levels.

Eligibility

Key inclusion criteria

1. Aged between 18 and 90 years.
2. Undergoing elective cardiac surgery, requiring cardiopulmonary bypass (coronary artery bypass grafting (CABG)) at Sir Charles Gairdner Hospital and Saint John of God Subiaco.
3. Being willing and able to provide informed consent.

Minimum age

18 Years

Maximum age

90 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Patients will be ineligible for study entry if they have concomitant hepatic failure, an autoimmune disease or the inability to give informed consent. Patients on immunosuppressive drugs, oral contraceptives, fluvoxamine, and those consuming melatonin within two weeks before the operation, will also be excluded.
The exclusion criteria further includes patients who are pregnant, breastfeeding, and those requiring urgent or emergency surgery (resulting in insufficient time to take melatonin).

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Study medications will be visually identical and placed in identical envelopes labelled either A, B or C. The allocation will indicate whether the participant receives placebo, high or low dose melatonin.

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

Participants will be randomised according to a list of computer-generated random numbers in blocks of 9, with a 1:1:1 allocation to placebo, low or high dose melatonin. The list will be generated and maintained by an independent biostatistician and unblinding will only occur after completion of the study, or if it is required due to a serious adverse event.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data

Intervention assignment

Parallel

Other design features

N/A

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

The sample size has been calculated making use of the available troponin data for the patient population that will be used in the study. According to this a sample of n=114 (n=38 per group) has 80% power to detect a small effect size f=0.23 (based on standardised mean difference 1500, SD=3200 (25% decrease in TnT levels from the control group)) in a repeated measures between groups ANOVA with 3 groups over 4 time points (alpha=0.05, G*Power 3.1.92).

Statistical advice for the data analysis will be provided by Angela Jacques, Statistician, SCGH/Notre Dame University. Generalised linear mixed models incorporating random subject effects will be used to examine changes in primary outcome TnT between 3 randomised groups over 4 timepoints. Results will be summarised using predicted marginal means and corresponding 95% confidence intervals. Stata v16.0 (StataCorp LLC, College Station, Texas) will be used for data analysis. Secondary endpoints of a binary nature will be evaluated with a Chi-squared test.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/05/2024

Actual

5/07/2024

Date of last participant enrolment

Anticipated

1/12/2025

Actual

Date of last data collection

Anticipated

30/12/2025

Actual

Sample size

Target

114

Accrual to date

Final

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 - Nedlands

Recruitment postcode(s) [2]

6008 - Subiaco

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra
ACT
2601

Country [1]

Australia

Primary sponsor type

Hospital

Name

Sir Charles Gairdner Hospital

Address

Hospital Ave
Nedlands
Western Australia
6009

Country

Australia

Secondary sponsor category [1]

University

Name [1]

University of West Australia

Address [1]

35 Stirling Hey
Crawley
Western Australia
6009

Country [1]

Australia

Other collaborator category [1]

University

Name [1]

Metabolomics Australia (UWA), Centre for microscopy, characterisation and analysis (CMCA).

Address [1]

Metabolomics Australia (UWA), Centre for microscopy, characterisation and analysis (CMCA)
6 Verdun Street
Nedlands
WA
6009

Country [1]

Australia

Other collaborator category [2]

University

Name [2]

University of Notre Dame

Address [2]

University of Notre Dame Australia, Institute for Health research
32 Mouat St,
Fremantle
Perth
Western Australia
6009

Country [2]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee

Ethics committee address [1]

Sir Charles Gairdner Hospital
2nd Floor A Block
Hospital Avenue
NEDLANDS Western Australia 6009

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

11/01/2021

Approval date [1]

19/02/2021

Ethics approval number [1]

RGS0000004476

Summary

Brief summary

Heart disease is the leading cause of death worldwide. The only way to lessen the detrimental effects on the heart during oxygen poor circumstances is to re-introduce oxygen to the cells of the heart (by getting rid of the obstruction responsible for the problem). Re-introduction of blood flow and oxygen to cells that was oxygen poor however also results in damage to the cells. This is known as “reperfusion injury”, the medical world still doesn’t have a treatment option to eliminate reperfusion injury.
The aim of this study is to investigate a new treatment option (melatonin) to lessen or eliminate the damage to the heart following reperfusion injury. Although we know that this treatment option is extremely effective in animals (it halved the size of heart attacks in rats), we still don’t have a clear answer to its role in humans. More research is required to determine how melatonin can benefit patients undergoing heart surgery. We thus hypothesize that preoperative, sublingual melatonin will have cardio-protective properties during reperfusion injury, and that the cardio-protection will be as a result of the anti-oxidant and anti-inflammatory effects associated with melatonin supplementation. The degree of cardio-protection, anti-inflammatory and anti-oxidative properties will be assessed by biomarkers (CRP and hsTnT levels found in blood samples).
This study will be performed at two centres (Sir Charles Gairdner Hospital and Saint John of God, Subiaco) and is a prospective, randomized, double-blind, placebo-controlled, phase 2 study investigating the oral, preoperative administration of melatonin. Double-blind means that neither you nor your study doctor will know which treatment you are receiving. This research project has specifically been designed this way to make sure the researchers interpret the results in a fair and appropriate way and avoids study doctors or participants jumping to conclusions. However, in the event it is medically necessary your study doctor can find out which treatment you are receiving.
The participants will be allocated into three study groups: The control group (receiving placebo with no active ingredients), the low dose melatonin group and the higher dose melatonin group.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Marli Smit

Address

Department of Anaesthesia
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Western Australia
6004

Country

Australia

Phone

+61 8 6457 3011

Fax

+61 8 6457 4375

smitmarli@yahoo.com

Contact person for public queries

Name

Marli Smit

Address

Department of Anaesthesia
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Western Australia
6004

Country

Australia

Phone

+61 8 6457 3011

Fax

+61 8 6457 4375

smitmarli@yahoo.com

Contact person for scientific queries

Name

Marli Smit

Address

Department of Anaesthesia
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
Western Australia
6004

Country

Australia

Phone

+61 8 6457 3011

Fax

+61 8 6457 4375

smitmarli@yahoo.com

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
10949	Informed consent form					381578-(Uploaded-12-04-2021-11-57-51)-Study-related document.doc

Results publications and other study-related documents

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No additional documents have been identified.

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