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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
12/04/2024
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] 303646 0
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 321036 0
oxidative damage 321037 0
inflammation 321038 0
Condition category
Condition code
Cardiovascular 318836 318836 0 0
Coronary heart disease
Cardiovascular 318837 318837 0 0
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] 319939 0
Treatment: Drugs
Intervention code [2] 319940 0
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] 326787 0
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] 326787 0
This will be tested pre-operatively (to determine a baseline value) and at 6h, 12h and 24 hours following surgery.
Secondary outcome [1] 392680 0
Assessment of plasma melatonin levels, following two different preoperative melatonin dosages, by mass spectrometry.
Timepoint [1] 392680 0
Pre-operative (baseline), intra-operative and 6 hours post-operative levels.
Secondary outcome [2] 392681 0
Inflammatory markers as reflected by CRP. The CRP will be measured from a blood sample.
Timepoint [2] 392681 0
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?
No
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
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2024
Actual
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)
WA
Recruitment hospital [1] 18881 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 33386 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 308068 0
Government body
Name [1] 308068 0
National Health and Medical Research Council
Country [1] 308068 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Hospital Ave
Nedlands
Western Australia
6009
Country
Australia
Secondary sponsor category [1] 308802 0
University
Name [1] 308802 0
University of West Australia
Address [1] 308802 0
35 Stirling Hey
Crawley
Western Australia
6009
Country [1] 308802 0
Australia
Other collaborator category [1] 281683 0
University
Name [1] 281683 0
Metabolomics Australia (UWA), Centre for microscopy, characterisation and analysis (CMCA).
Address [1] 281683 0
Metabolomics Australia (UWA), Centre for microscopy, characterisation and analysis (CMCA)
6 Verdun Street
Nedlands
WA
6009
Country [1] 281683 0
Australia
Other collaborator category [2] 281684 0
University
Name [2] 281684 0
University of Notre Dame
Address [2] 281684 0
University of Notre Dame Australia, Institute for Health research
32 Mouat St,
Fremantle
Perth
Western Australia
6009
Country [2] 281684 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308057 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 308057 0
Sir Charles Gairdner Hospital
2nd Floor A Block
Hospital Avenue
NEDLANDS Western Australia 6009
Ethics committee country [1] 308057 0
Australia
Date submitted for ethics approval [1] 308057 0
11/01/2021
Approval date [1] 308057 0
19/02/2021
Ethics approval number [1] 308057 0
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 109370 0
Dr Marli Smit
Address 109370 0
Department of Anaesthesia
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Western Australia
6004
Country 109370 0
Australia
Phone 109370 0
+61 8 6457 3011
Fax 109370 0
+61 8 6457 4375
Email 109370 0
smitmarli@yahoo.com
Contact person for public queries
Name 109371 0
Dr Marli Smit
Address 109371 0
Department of Anaesthesia
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Western Australia
6004
Country 109371 0
Australia
Phone 109371 0
+61 8 6457 3011
Fax 109371 0
+61 8 6457 4375
Email 109371 0
smitmarli@yahoo.com
Contact person for scientific queries
Name 109372 0
Dr Marli Smit
Address 109372 0
Department of Anaesthesia
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
Western Australia
6004
Country 109372 0
Australia
Phone 109372 0
+61 8 6457 3011
Fax 109372 0
+61 8 6457 4375
Email 109372 0
smitmarli@yahoo.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
10949Informed 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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