Trial Review

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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
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] 288688 0
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 297900 0
Condition category
Condition code
Reproductive Health and Childbirth 298064 298064 0 0
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] 294111 0
Treatment: Drugs
Intervention code [2] 294128 0
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] 297584 0
Caesarean Section as per standard clinical definition from the woman's medical records.
Timepoint [1] 297584 0
The birth of the baby.
Secondary outcome [1] 321486 0
Length of all labour stages: first, second and third (hours/minutes), as recorded in the maternal, medical records.
Timepoint [1] 321486 0
Retrospective data extraction from medical records, undertaken following birth and complete explosion of the placenta and associated membranes,
Secondary outcome [2] 321560 0
Epidural (yes/no) as recorded in the maternal medical records.
Timepoint [2] 321560 0
Induction commencement until birth of baby
Secondary outcome [3] 321561 0
Estimated blood loss (EBL) in milliliters (mLs), as recorded in the maternal medical records.
Timepoint [3] 321561 0
From birth of the baby until 24 hours postpartum.
Secondary outcome [4] 321562 0
Apgar score at 5 minutes, as recorded in the maternal/infant's medical records.
Timepoint [4] 321562 0
Baby at five minutes of age
Secondary outcome [5] 321563 0
Admission to the Neonatal Intensive Care Unit (NICU)/Neonatal Unit, as recorded in the maternal/infant's medical records.
Timepoint [5] 321563 0
From birth of baby to discharge of baby
Secondary outcome [6] 321564 0
Indication for caesarean section where relevant
Timepoint [6] 321564 0
Assessed from the maternal medical records, following the birth of the baby.
Secondary outcome [7] 321594 0
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] 321594 0
Commencement of oxytocin intravenous infusion (IVI) for the induction of labour until cessation of the oxytocin IVI following birth.
Secondary outcome [8] 323326 0
Uterine hyperstimulation with fetal heart rate changes, as recorded in the maternal medical records (including cardiotocography/CTG recordings).
Timepoint [8] 323326 0
From administration of the first dose of the trial intervention (10mg melatonin or placebo tablet), until birth.
Secondary outcome [9] 323327 0
Vaginal birth (yes/no) within 24 hours of commencement of the induction procedure, as recorded in the maternal medical records.
Timepoint [9] 323327 0
From commencement of the induction procedure, until the time of birth.
Secondary outcome [10] 323328 0
The induction commencement to birth interval, duration (hours/minutes), as recorded in the maternal medical records.
Timepoint [10] 323328 0
From the commencement of the labour induction procedure, until birth.
Secondary outcome [11] 334505 0
Rate of unassisted vaginal birth or instrumental vaginal birth (forceps or vacuum extraction) within 24 hours of induction commencement.
Timepoint [11] 334505 0
The birth of the baby.
Secondary outcome [12] 334506 0
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] 334506 0
Postnatal period prior to hospital discharge (0-4 days postpartum).
Secondary outcome [13] 334507 0
Participant serum melatonin levels.
Timepoint [13] 334507 0
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] 334508 0
Umbilical cord blood melatonin level (venous sample).
Timepoint [14] 334508 0
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] 5712 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 13197 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 293046 0
Charities/Societies/Foundations
Name [1] 293046 0
Hudson Institute of Medical Research
Country [1] 293046 0
Australia
Funding source category [2] 296363 0
Government body
Name [2] 296363 0
National Health and Medical Research Council (NHMRC)
Country [2] 296363 0
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] 291824 0
None
Name [1] 291824 0
Address [1] 291824 0
No longer applicable
Country [1] 291824 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294555 0
Monash Health HREC
Ethics committee address [1] 294555 0
Ethics committee country [1] 294555 0
Australia
Date submitted for ethics approval [1] 294555 0
06/04/2017
Approval date [1] 294555 0
19/06/2017
Ethics approval number [1] 294555 0
Monash Health HREC: RES-17-0000-168A

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64126 0
Dr Miranda Davies-Tuck
Address 64126 0
Hudson Institute of Medical Research
27-31 Wright St, Clayton VIC 3168
Country 64126 0
Australia
Phone 64126 0
+61 3 9902 4700
Fax 64126 0
Email 64126 0
[email protected]
Contact person for public queries
Name 64127 0
Miranda Davies-Tuck
Address 64127 0
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 64127 0
Australia
Phone 64127 0
+61 3 8572 2700
Fax 64127 0
+613 959 46811
Email 64127 0
[email protected]
Contact person for scientific queries
Name 64128 0
Miranda Davies
Address 64128 0
Department of Obstetrics and Gynaecology, Monash University Level 5, Block B Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168. Australia
Country 64128 0
Australia
Phone 64128 0
+61 3 8572 2700
Fax 64128 0
Email 64128 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) 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.TypeCitationLinkEmailOther DetailsAttachment
3853Informed consent form  [email protected]
3854Study protocol  [email protected]
3855Ethical approval  [email protected] Requests for trial documentation can be made in wr... [More Details]



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