Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000502639
Ethics application status
Approved
Date submitted
4/04/2023
Date registered
17/05/2023
Date last updated
7/03/2024
Date data sharing statement initially provided
17/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Melatonin supplementation effect on the Induction of labour rates in first-time MothErs:
The MyTIME Trial
Scientific title
A double-blind, randomised, placebo-controlled trial to evaluate the effect of oral Melatonin administered to nulliparous women at 39 weeks' gestation, on the rate of induction of labour.
Secondary ID [1] 308934 0
None
Universal Trial Number (UTN)
Trial acronym
MyTIME
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Induction of labour 328940 0
Condition category
Condition code
Reproductive Health and Childbirth 325928 325928 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention for this trial is 3mg oral melatonin encapsulated tablet.
Study participants will be dispensed the trial intervention (3mg oral melatonin encapsulated tablet) tablet.

On the first evening of gestation week 39, women will take their first tablet. Participants will be advised to take the trial medication at 2000hrs each evening as this is a time of onset of (relative) darkness coincidental to the natural rise in circulating melatonin levels.

Night-time administration will continue each night until labour spontaneously commences or until an alternative intervention for birth is implemented. Administration will occur for a maximum of 3 weeks, if spontaneous labour does not occur within this time women will have an alternative plan for birth implemented. A text message will be sent each evening with a link to record the time of administration, which will build a medication diary database to determine adherence and facilitate analysis of primary and secondary outcomes.

A small group of women (n=30) will be asked to participate in a sub-study aimed at measuring and confirming peak melatonin levels after oral dosing. Women will be recruited to the sub-study and consented to provide a blood sample taken approximately 1 hour after dosing (n=15 from each of the placebo and melatonin groups). Blood will be collected by a phlebotomist in the participants’ homes and transported to the laboratory for processing and storage at -80oC. Plasma melatonin concentrations will be determined by liquid chromatography/mass spectrometry according to the method of Wang et al38. The limit of quantitation is 1 pg/ml. Plasma samples will be analysed in a single batch to minimise inter-assay variability.

Routine antenatal and intrapartum care will continue; no changes to usual care will be required as a result of participation in this trial.
Intervention code [1] 325379 0
Treatment: Drugs
Comparator / control treatment
The control for this trial is oral placebo tablet (microcellulose capsule) identical in appearance to the intervention.
Study participants will be dispensed the trial placebo tablets.

On the first evening of gestation week 39, women will take their first tablet. Participants will be advised to take the trial medication at 2000hrs each evening as this is a time of onset of (relative) darkness coincidental to the natural rise in circulating melatonin levels.

Night-time administration of placebo will continue each night until labour spontaneously commences or until an alternative intervention for birth is implemented.

Routine antenatal and intrapartum care will continue; no changes to usual care will be required as a result of participation in this trial.
Control group
Placebo

Outcomes
Primary outcome [1] 333775 0
Induction of labour extracted from mandatory notification system/ perinatal database.
Timepoint [1] 333775 0
At any time post-enrolment
Secondary outcome [1] 418250 0
Length of trial medication administration to: commencement of spontaneous labour extracted from mandatory notification system/ perinatal database.
Timepoint [1] 418250 0
At time of established labour
Secondary outcome [2] 418251 0
Gestation weeks and days at birth extracted from mandatory notification system/ perinatal database.
Timepoint [2] 418251 0
At time of birth
Secondary outcome [3] 418252 0
Length of labour extracted from mandatory notification system/ perinatal database.
Timepoint [3] 418252 0
At time of birth
Secondary outcome [4] 418253 0
Mode of birth extracted from mandatory notification system/ perinatal database.
Timepoint [4] 418253 0
At time of birth
Secondary outcome [5] 418254 0
Estimated blood loss after birth extracted from mandatory notification system/ perinatal database.
Timepoint [5] 418254 0
Within 1 hour of birth
Secondary outcome [6] 418255 0
Shoulder dystocia extracted from mandatory notification system/ perinatal database.
Timepoint [6] 418255 0
At time of birth
Secondary outcome [7] 418256 0
Severe perineal trauma extracted from mandatory notification system/ perinatal database.
Timepoint [7] 418256 0
At time of birth
Secondary outcome [8] 418257 0
Maternal plasma melatonin levels (sub-study n= 30 participants)
Timepoint [8] 418257 0
1 hour after initial oral dose of melatonin or placebo
Secondary outcome [9] 418258 0
Neonatal APGAR (Appearance, Pulse, Grimace, Activity Respiration) scores
Timepoint [9] 418258 0
5 minutes after birth
Secondary outcome [10] 418259 0
Cord blood biomarkers (IL-1B, )
Timepoint [10] 418259 0
At time of birth
Secondary outcome [11] 418260 0
Time to first breastfeed, extracted from mandatory notification system/ perinatal database.
Timepoint [11] 418260 0
Day of birth
Secondary outcome [12] 418261 0
Baby birth weight/ birth weight centile extracted from mandatory notification system/ perinatal database.
Timepoint [12] 418261 0
At time of birth
Secondary outcome [13] 418262 0
Breastfeeding on discharge extracted from mandatory notification system/ perinatal database.
Timepoint [13] 418262 0
At day of discharge
Secondary outcome [14] 418263 0
Admission to Neonatal Intensive Care Unit, length of stay if admitted to the nursery extracted from mandatory notification system/ perinatal database if within 4 hours of birth or medical records if > 4hours post birth
Timepoint [14] 418263 0
At time of admission
Secondary outcome [15] 418264 0
Mother's total length of stay extracted from mandatory notification system/ perinatal database.
Timepoint [15] 418264 0
At time of discharge of mother
Secondary outcome [16] 418265 0
Ages and Stages Questionnaire assessing child developmental outcomes ASQ:SE-2, ASQ-3 scores
Timepoint [16] 418265 0
At child's 12 months assessment
Secondary outcome [17] 418266 0
Perinatal mortality extracted from mandatory notification system/ perinatal database.
Timepoint [17] 418266 0
Time of death
Secondary outcome [18] 418267 0
Maternal trial participation satisfaction evaluation - designed for this study
Timepoint [18] 418267 0
Within 2 weeks post discharge
Secondary outcome [19] 420841 0
Length of trial medication administration to birth extracted from mandatory notification system/ perinatal database and patient medication diary
Timepoint [19] 420841 0
Time of birth
Secondary outcome [20] 420842 0
Indication for mode of birth extracted from mandatory notification system/ perinatal database
Timepoint [20] 420842 0
At time of birth
Secondary outcome [21] 420843 0
Baby's total length of stay extracted from mandatory notification system/ perinatal database.
Timepoint [21] 420843 0
At discharge
Secondary outcome [22] 420844 0
Cord blood biomarkers ( IL-6, )
Timepoint [22] 420844 0
At time of birth
Secondary outcome [23] 420845 0
Cord blood biomarkers (IL-8, )
Timepoint [23] 420845 0
At time of birth
Secondary outcome [24] 420846 0
Cord blood biomarkers ( IL-10; )
Timepoint [24] 420846 0
At time of birth
Secondary outcome [25] 420847 0
Cord blood biomarkers (F2a-isoprostane, )
Timepoint [25] 420847 0
At time of birth
Secondary outcome [26] 420848 0
Cord blood biomarkers (advanced oxidation protein products)
Timepoint [26] 420848 0
At time of birth

Eligibility
Key inclusion criteria
Nulliparous women aged 16 years and over, with a singleton pregnancy in cephalic presentation, without clinical indication for induction, awaiting spontaneous onset of labour, not planning a scheduled birth before 41 weeks unless indicated and able to provide written informed consent to participate in the clinical trial.
Minimum age
16 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women with indications for induction of labour or caesarean section prior to 41 weeks because of medical complications; any fetal congenital abnormality or known fetal compromise that would necessitate admission to NICU after birth; any known sensitivity or adverse reaction to 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)
Allocation will occur by central randomisation by phone or computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size: Primary Outcome – Induction of Labour: Within the study site, the induction of labour rate for nulliparous women is 43%. Should antenatal melatonin be effective, we propose that a clinically relevant impact would see an overall decrease in the rate of inductions by 30%, from 43% down to 30%. Total sample size of 530 women (~265 per group) will attain 80% power to detect this clinically relevant reduction of induction rate in the melatonin group (odds ratio of 0.57) while using logistic regression analysis with adjustment for the stratification factors and other relevant covariates with an r-squared of 0.025 at alpha=0.025. This sample size is also inflated for account for a 10% loss to follow-up (Power and Sample Size Program for Windows, version 2019).
Statistical Analysis Data will be analysed on intention-to-treat basis. Logistic and binomial regression analyses will be performed on primary endpoint and other binary outcomes. Linear and/or Cox proportional hazards regression will be used to examine group differences between the continuous and time to event outcomes. Melatonin adherence will be assessed and, if applicable, supplementary analyses on the adherent subgroup and per treatment received will also be performed. All hypothesis tests will be two-sided with alpha=0.05. Data analyses will be performed using STATA statistical software (version 16).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/01/2024
Actual
25/01/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
530
Accrual to date
16
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 23931 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [2] 23932 0
Osborne Park Hospital - Stirling
Recruitment postcode(s) [1] 39424 0
6008 - Subiaco
Recruitment postcode(s) [2] 39425 0
6021 - Stirling

Funding & Sponsors
Funding source category [1] 313143 0
Government body
Name [1] 313143 0
NHMRC
Country [1] 313143 0
Australia
Funding source category [2] 313146 0
University
Name [2] 313146 0
Curtin University
Country [2] 313146 0
Australia
Funding source category [3] 313147 0
Hospital
Name [3] 313147 0
Women and Newborn Health Service
Country [3] 313147 0
Australia
Funding source category [4] 316021 0
Charities/Societies/Foundations
Name [4] 316021 0
Women and Infants Research Foundation
Country [4] 316021 0
Australia
Primary sponsor type
University
Name
Curtin University
Address
GPO Box U1987
Bentley WA 6845
Country
Australia
Secondary sponsor category [1] 314851 0
None
Name [1] 314851 0
Address [1] 314851 0
Country [1] 314851 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312386 0
King Edward Memorial Hospital Human Research Ethics Committee
Ethics committee address [1] 312386 0
Bagot Rd
Subiaco, WA 6008
Ethics committee country [1] 312386 0
Australia
Date submitted for ethics approval [1] 312386 0
05/09/2023
Approval date [1] 312386 0
03/10/2023
Ethics approval number [1] 312386 0
RGS0000006283

Summary
Brief summary
Problem: In the last 10 years, rates of induction of labour amongst first-time (nulliparous) mothers have increased by 43%, from 32% to 46%. Situated in the context of soaring medical costs, few significant improvements in perinatal outcomes have been realised in the last decade. Despite escalated investment and medical intervention, rates of stillbirths, neonatal deaths and maternal mortality remain largely unchanged. Conversely, rates of maternal and neonatal morbidity have increased, with rising rates of induction of labour, caesarean section, epidural, episiotomy, postpartum haemorrhage, maternal and neonatal birth trauma and sepsis. Evidence indicates that induction of labour in the absence of medical compromise may increase the risk for iatrogenic harm to the mother and baby.
Solution: Melatonin, a hormone released by the pineal gland, is essential for healthy spontaneous labour. Whilst it is naturally produced in the body at night, contemporary environmental impacts such as increased exposure to blue light and shorter sleep periods compete with melatonin production and release. This proposed clinical trial (randomised, double-blind, placebo-controlled trial) will test what would be a high-impact, high-value, low-cost solution aimed at potentiating spontaneous labour and reducing the rates of labour induction. This meets both the requirements for reducing unnecessary interventions while addressing some of the safety concerns about the risks associated with pregnancy extending beyond 41 weeks as outlined below. The aim is to determine if oral supplementation with 3mg melatonin from 39 weeks gestation in nulliparous women will reduce the induction of labour rates. Our unpublished consumer data indicate high acceptability and strong maternal demand for this proposed innovative approach,85% of women surveyed indicated they would be interested in participating if this exact trial were available to them.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124478 0
Dr Zoe Bradfield
Address 124478 0
Curtin University
GPO Box U1987
Bentley WA, 6845
Country 124478 0
Australia
Phone 124478 0
+61 8 9266 9484
Fax 124478 0
Email 124478 0
[email protected]
Contact person for public queries
Name 124479 0
Zoe Bradfield
Address 124479 0
Curtin University
GPO Box U1987
Bentley WA, 6845
Country 124479 0
Australia
Phone 124479 0
+61 8 9266 9484
Fax 124479 0
Email 124479 0
[email protected]
Contact person for scientific queries
Name 124480 0
Zoe Bradfield
Address 124480 0
Curtin University
GPO Box U1987
Bentley WA, 6845
Country 124480 0
Australia
Phone 124480 0
+61 8 9266 9484
Fax 124480 0
Email 124480 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?
1) analysed, aggregated data following the conclusion of the trial
2) de-identified participant data
When will data be available (start and end dates)?
We anticipate data will be available from 2028 onwards and for up to 5 years after publication.
Available to whom?
1) individuals who read the publications arising from this study which will report de-identified, analysed and aggregated data
2) editors and peer reviewers of the final manuscript
3) interested relevant parties who contact the corresponding author requesting information about the trial and associated data
Available for what types of analyses?
1) Associated documents such as protocol, PI&CF may be available to relevant parties who request access by contacting the PI
2) The de-identified raw participant data may be made available to relevant, interested parties for future use, for example for inclusion in meta-analysis or for the planning of future trials/research studies.
How or where can data be obtained?
1) analysed, aggregated data will be available via publication following the conclusion of the trial
2) access to de-identified participant data may be obtained by relevant parties who should contact the study PI Dr Zoe Bradfield [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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