ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616000311459

Ethics application status

Approved

Date submitted

3/03/2016

Date registered

9/03/2016

Date last updated

21/01/2022

Date data sharing statement initially provided

5/04/2019

Date results information initially provided

21/01/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

Melatonin to improve induction of labour: a double blind, randomised, placebo controlled trial.

Scientific title

A double blind, randomised, placebo controlled trial to evaluate the effect of Melatonin as an adjuvant agent at Induction of labour on the rate of induction of labour failure in healthy, pregnant women undergoing cervical ripening prior to induction of labour for prolonged pregnancy

Secondary ID [1]

NIL

Universal Trial Number (UTN)

U1111-1195-3515

Trial acronym

MILO

Linked study record

Health condition

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

Failed Induction of Labour

Condition category

Condition code

Reproductive Health and Childbirth

Childbirth and postnatal care

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The intervention for this trial is:: melatonin (10mg) prolonged release (Circadin), oral tablet.

We propose to administer the trial intervention (melatonin 10mg prolonged release) or a comparator, a placebo, oral tablet.

There are TWO trial tablet administration regimens.

The trial tablet administration regimen will be determined by the method of cervical ripening/labour induction, the tablet administration regimens are as follows:

For those women who are having a cervical balloon catheter and/or vaginal Dinoprostone PGE 2 (e.g Cervadil or Prostin) as the initial method of labour induction:

1) The first dose of the tablets will be given at the time of the initial cervical balloon catheter or vaginal Dinoprostone PGE 2 insertion
2) The second dose of tablets will be given after the membranes ('waters') are broken and only when the oxytocin intravenous infusion (IVI) is started (within 30 minutes)
3) Six hours after the second dose, if birth has not yet occurred, a third dose of tablets will be given
4) Six hours after the third dose, if birth has not yet occurred, a fourth and final dose of tablets will be given.
For this group of participants, if birth occurs at any time between the first and fourth dose, administration of the trial tablets will immediately cease.

For those women who are just having amniotomy as the initial method of labour induction:

1) The first dose of the trial tablets will be given after the amniotomy procedure and only when the oxytocin intravenous infusion (IVI) is started (within 30 minutes)
2) Six hours later, if birth has not occurred, a second dose of tablets will be given
3) Six hours after the second dose, if birth has not yet occurred, a third and final dose of tablets will be given.
For this group of participants, if birth occurs at any time between the first and third dose, administration of the trial tablets will immediately cease.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Prevention

Comparator / control treatment

The intervention for this trial is:: melatonin (10mg) prolonged release (Circadin), oral tablet.

We propose to administer the trial intervention (melatonin 10mg prolonged release) or a comparator, a placebo, oral tablet.

There are TWO trial tablet administration regimens.

The trial tablet administration regimen will be determined by the method of cervical ripening/labour induction, the tablet administration regimens are as follows:

For those women who are having a cervical balloon catheter and/or vaginal Dinoprostone PGE 2 (e.g Cervadil or Prostin) as the initial method of labour induction:

1) The first dose of the tablets will be given at the time of the initial cervical balloon catheter or vaginal Dinoprostone PGE 2 insertion
2) The second dose of tablets will be given after the membranes ('waters') are broken and only when the oxytocin intravenous infusion (IVI) is started (within 30 minutes)
3) Six hours after the second dose, if birth has not yet occurred, a third dose of tablets will be given
4) Six hours after the third dose, if birth has not yet occurred, a fourth and final dose of tablets will be given
For this group of participants, if birth occurs at any time between the first and fourth dose, administration of the trial tablets will immediately cease.

For those women who are just having amniotomy as the initial method of labour induction:

1) The first dose of the trial tablets will be given after the amniotomy procedure and only when the oxytocin intravenous infusion (IVI) is started (within 30 minutes)
2) Six hours later, if birth has not occurred, a second dose of tablets will be given
3) Six hours after the second dose, if birth has not yet occurred, a third and final dose of tablets will be given.
For this group of participants, if birth occurs at any time between the first and third dose, administration of the trial tablets will immediately cease.

Control group

Placebo

Outcomes

Primary outcome [1]

Caesarean Section as per standard clinical definition from the woman's medical records.

Timepoint [1]

The birth of the baby.

Secondary outcome [1]

Length of all labour stages: first, second and third (hours/minutes), as recorded in the maternal, medical records.

Timepoint [1]

Retrospective data extraction from medical records, undertaken following birth and complete explosion of the placenta and associated membranes,

Secondary outcome [2]

Epidural (yes/no) as recorded in the maternal medical records.

Timepoint [2]

Induction commencement until birth of baby

Secondary outcome [3]

Estimated blood loss (EBL) in milliliters (mLs), as recorded in the maternal medical records.

Timepoint [3]

From birth of the baby until 24 hours postpartum.

Secondary outcome [4]

Apgar score at 5 minutes, as recorded in the maternal/infant's medical records.

Timepoint [4]

Baby at five minutes of age

Secondary outcome [5]

Admission to the Neonatal Intensive Care Unit (NICU)/Neonatal Unit, as recorded in the maternal/infant's medical records.

Timepoint [5]

From birth of baby to discharge of baby

Secondary outcome [6]

Indication for caesarean section where relevant

Timepoint [6]

Assessed from the maternal medical records, following the birth of the baby.

Secondary outcome [7]

Total volume of intravenous oxytocin administered for the induction of labour, measured in international units (IU), as recorded in the maternal medical records.

Timepoint [7]

Commencement of oxytocin intravenous infusion (IVI) for the induction of labour until cessation of the oxytocin IVI following birth.

Secondary outcome [8]

Uterine hyperstimulation with fetal heart rate changes, as recorded in the maternal medical records (including cardiotocography/CTG recordings).

Timepoint [8]

From administration of the first dose of the trial intervention (10mg melatonin or placebo tablet), until birth.

Secondary outcome [9]

Vaginal birth (yes/no) within 24 hours of commencement of the induction procedure, as recorded in the maternal medical records.

Timepoint [9]

From commencement of the induction procedure, until the time of birth.

Secondary outcome [10]

The induction commencement to birth interval, duration (hours/minutes), as recorded in the maternal medical records.

Timepoint [10]

From the commencement of the labour induction procedure, until birth.

Secondary outcome [11]

Rate of unassisted vaginal birth or instrumental vaginal birth (forceps or vacuum extraction) within 24 hours of induction commencement.

Timepoint [11]

The birth of the baby.

Secondary outcome [12]

Participant satisfaction with labour experience.
Participant satisfaction will be determined by asking women if they were satisfied with their labour (yes/no) and via a visual analogue scale (VAS)

Timepoint [12]

Postnatal period prior to hospital discharge (0-4 days postpartum).

Secondary outcome [13]

Participant serum melatonin levels.

Timepoint [13]

Participant (maternal) venous blood samples will be collected at three time points:
1) Prior to commencement of the oxytocin intravenous infusion (IVI) and second dose of trial tablet(s) (melatonin 10mg prolonged release or placebo).
2) Three hours following the administration of the second dose of trial tablet(s) (melatonin 10mg prolonged release or placebo).
3) A third and final participant blood sample will be collected following birth (15 minutes, or less).

Secondary outcome [14]

Umbilical cord blood melatonin level (venous sample).

Timepoint [14]

Following birth (15 minutes, or less)

Eligibility

Key inclusion criteria

Pregnant women, parity: 0 (nulliparous) or up to para 3 (multiparous), who currently have a singleton, cephalic presentation undergoing induction of labour for prolonged pregnancy with a low Bishop score (a score of cervical ripeness) of 5 or less.
Methods of cervical ripening/labour induction to include: cervical balloon catheter e.g. Foley, Cook, Atad and/or a Dinoprostone PGE 2 vaginal pessary e.g. Cervadil or Prostin or women who are only having an amniotomy as the initial method of labour induction.
Intact membranes. No known significant maternal or obstetric medical condition that would affect melatonin pharmacokinetics or maternal safety. The woman must be able to provide written informed consent to participate in the clinical trial

Minimum age

18 Years

Maximum age

49 Years

Sex

Females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Non-reassuring fetal status (e.g. diminished or no fetal movements, non-reassuring CTG, known lethal fetal congenital anomalies or abnormal karyotype, fetal growth restriction (FGR) 10th centile or less, with Doppler changes), a clinical decision indicative of a low threshold for caesarean section, contraindication to a cervical ripening balloon catheter (as per Monash Health CPG IOL Cervical Ripening balloon catheter procedure. Prompt Doc No: SNH0003541 v3.0), known allergy or sensitivity to melatonin or any of the excipients in its formulation, unwillingness or inability to follow the procedures outlined in the PI&CF, mentally, cognitively or legally incapacitated or unable to provide informed consent, co-recruitment/participation in another clinical trial where there is pharmaceutical or herbal or nutritional intervention (such trial interventions would also include: multi-vitamins, minerals, complementary and alternative medicines), currently taking a medication known to influence melatonin pharmacokinetics or bioavailability.

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)

Methods used to generate the sequence in which subjects will be randomised (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- Caesarean section: Within our health service, 37% of term nulliparous women who were induced had an intrapartum caesarean section compared to 17% of term nulliparous women who labour spontaneously (Data derived from Monash Health Birthing Outcomes System 2009-2015). A clinically relevant decrease in caesarean births, should melatonin supplementation at induction of labour be effective, would be an absolute reduction of 10% in the caesarean rate from 37% to 27%. This is aligned with the Healthy people 2020 targets, an initiative of the American Federal Government that recommends a 10% reduction in caesarean rates. To detect a 10% decrease in the rate of caesarean birth (37% down to 27%) with 80% power (two-tailed, p<0.05) we will need to recruit 361 women to each arm, with a resultant total cohort of n=722.

Statistical Analysis: All analyses will be performed using intention-to-treat and per- protocol if relevant. All data will be assessed for normality. Characteristics of the two groups will be tabulated and compared using the appropriate statistical test (chi2, independent t-test, Mann-Whitney test). Differences in the primary outcome will be assessed by logistic regression adjusting for confounders/baseline imbalances between groups. Differences in the secondary outcomes will be assessed using the appropriate regression method adjusting for confounders/baseline imbalances between groups. The costs will be calculated separately for each mother/infant pair. The data will be assessed for normality and then compared between the melatonin and control arm using the appropriate statistical test. A p value of <0.05 will be considered statistically significant and all analyses will be undertaken using StataCorp 12 (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP.)

Recruitment

Recruitment status

Stopped early

Data analysis

Data collected is being analysed

Reason for early stopping/withdrawal

Lack of funding/staff/facilities
Participant recruitment difficulties
Other reasons/comments

Other reasons

COVID pandemic has impacted the total number of women who were able to be recruited over previous two years. Funding has now ended therefore unfortunately the trial must be stopped early.

Date of first participant enrolment

Anticipated

6/11/2017

Actual

28/03/2019

Date of last participant enrolment

Anticipated

Actual

14/08/2021

Date of last data collection

Anticipated

Actual

14/08/2021

Sample size

Target

722

Accrual to date

Final

187

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Recruitment postcode(s) [1]

3168 - Clayton

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Hudson Institute of Medical Research

Address [1]

27 - 31 Wright Street, Clayton VIC 3168

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

National Health and Medical Research Council (NHMRC)

Address [2]

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

Country [2]

Australia

Primary sponsor type

Hospital

Name

Monash Health

Address

Monash Health
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

No longer applicable

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health HREC

Ethics committee address [1]

246 Clayton Rd, Clayton VIC 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/04/2017

Approval date [1]

19/06/2017

Ethics approval number [1]

Monash Health HREC: RES-17-0000-168A

Summary

Brief summary

Induction of labour is a common obstetric intervention that 1 in 4 women will experience. The ultimate goal of induction of labour is to achieve a vaginal birth, however in almost 40% of first time mothers it fails. The outcome of a failed induction, a caesarean delivery is associated with vast range of adverse effects, both short and long term for the mother and her baby. In this application we propose that a simple and inexpensive intervention will increase the success of induction of labour. Lessons from successful spontaneous births tell us that labour occurs more frequently, and is shorter with less intervention when it occurs at night. The driver of this is thought to be the endogenous hormone, melatonin. Melatonin is synthesised by the placenta. Healthy pregnant women have higher concentrations of melatonin compared to non-pregnant women. Melatonin levels also increase with gestation, peaking during labour and then falling rapidly after delivery. The biological reason for an altered melatonin cycle in pregnancy is unclear. However, the myometrium of the pregnant uterus expresses melatonin receptors and these receptors have been shown to be up-regulated in labouring compared to non-labouring women. Intriguingly, both melatonin and oxytocin activate the same signalling pathway that results in uterine contractions. Specifically, melatonin treatment of myometrium increases it’s sensitivity, enhances oxytocin-induced contractions and improves myometrium cell communication and synchronization. Taken together this suggests an important role of melatonin in the onset and progress of labour. We therefore hypothesise that supplementing women undergoing induction of labour with melatonin will improve the success rate of induction of labour. We will undertake a double-blinded randomised controlled trial of melatonin supplementation to improve the success of induction of labour in healthy first time mothers.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Miranda Davies-Tuck

Address

Hudson Institute of Medical Research
27-31 Wright St, Clayton VIC 3168

Country

Australia

Phone

+61 3 9902 4700

Fax

[email protected]

Contact person for public queries

Name

Dr Miranda Davies-Tuck

Address

Department of Obstetrics and Gynaecology, Monash University and Monash Health, Level 5, Block B, Monash Medical Centre 246 Clayton Road, Clayton, Victoria 3168. Australia.

Country

Australia

Phone

+61 3 8572 2700

Fax

+613 959 46811

[email protected]

Contact person for scientific queries

Name

Dr Miranda Davies

Address

Department of Obstetrics and Gynaecology, Monash University Level 5, Block B Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168. Australia

Country

Australia

Phone

+61 3 8572 2700

Fax

[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) The aggregated data will be shared through publication in a peer reviewed journal following completion of the trial
2) All de-identified participant data.

When will data be available (start and end dates)?

We hope to have the final data set available from (approx) June 2023 for analysis. Once the data analysis has been completed a manuscript will be prepared for submission to a peer reviewed journal.

Available to whom?

1) The editors and peer reviewers of the final manuscript
2) Interested parties who contact the senior author requesting more information about the trial and its associated data
3) Those individuals who read the journal where the manuscript has been accepted for
publication are able to see the de-identified, aggregated data

Available for what types of analyses?

1) Associated documents such as protocol, PI&CF may be available by contacting the senior author.
2) The participant de-identified raw data may be made available to 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?

The data will be shared either through publication in a peer reviewed journal or by those parties
who are interested, emailing the senior author directly to seek more information about the trial.

What supporting documents are/will be available?

Doc. No.	Type	Email	Other Details
3853	Informed consent form	[email protected]
3854	Study protocol	[email protected]
3855	Ethical approval	[email protected]	Requests for trial documentation can be made in wr... [More Details]

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Trial Review

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