The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617001515381
Ethics application status
Approved
Date submitted
16/10/2017
Date registered
30/10/2017
Date last updated
16/01/2019
Date data sharing statement initially provided
16/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised controlled trial of antenatal melatonin supplementation in fetal growth restriction for fetal neuroprotection.
Scientific title
A double-blind, randomized, parallel-group, placebo controlled trial to assess the impact of maternal antenatal melatonin supplementation on early childhood neurodevelopmental outcomes in the setting of severe preterm fetal growth restriction.
Secondary ID [1] 293120 0
None
Universal Trial Number (UTN)
The Universal Trial Number (UTN) is U1111-1203-6718
Trial acronym
The Protect Me Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fetal Growth Restriction (FGR) 305074 0
Fetal Neuroprotection 305075 0
Condition category
Condition code
Reproductive Health and Childbirth 304392 304392 0 0
Fetal medicine and complications of pregnancy
Neurological 304393 304393 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention for this trial is: melatonin (10mg)
-the dose administered, 10mg three times daily (tds)
- the duration of administration: from the time of recruitment to the trial until birth
- the mode of administration: oral tablet
Intervention code [1] 299370 0
Prevention
Comparator / control treatment
The comparator for this trial is: a placebo tablet, the placebo will be have an identical presentation to the intervention (melatonin 10mg) tablet, thus the intervention and comparator will be indistinguishable from each other
-administered: three times daily (tds)
- the duration of administration: from the time of recruitment to the trial until birth
- the mode of administration: oral tablet
Control group
Placebo

Outcomes
Primary outcome [1] 303637 0
To compare neurodevelopmental outcomes between groups using the Bayley Scales of Infant and Toddler Development III (Bayley-III).
Timepoint [1] 303637 0
The Bayley Scales of Infant and Toddler Development III (Bayley-III) will be undertaken when the child is 2 years corrected age.
Secondary outcome [1] 339726 0
Safety and tolerability of melatonin.

The safety and tolerability of melatonin will be assessed though:

1) The participant completing a project specific, intervention administration and side effects diary, which has been prepared for use in the trial. The participant will record the date and time the intervention (tablet) was taken and then record how it subsequently made them feel, if anything. Any recorded side effects will be compared to those side effects named in the product information leaflet for melatonin. Such side effects would include: drowsiness, abdominal cramps, gastro intestinal disturbance, flushing and migraine.

2) The collection of participant venous blood samples and the measurement of: full blood count (FBE) (red blood cells, white blood cells and platelets). In addition to monitoring kidney function though the measurement of urea and electrolytes (U&Es), creatinine and urate, and also liver function, ascertained though liver function tests (LFTs) (ALT, bilirubin and albumin).
Timepoint [1] 339726 0
1) The participant will keep a project specific, intervention administration and side effects diary. The diary will be maintained, from the time of recruitment to the trial when administration of the trial intervention commences, until the time of birth, when the administration of the trial intervention ceases.

2) Participant venous blood samples will be collected at these time points: prior to the intervention being administered and thereafter (at least) fortnightly until birth, and then following birth (ideally, 20 minutes, or less) and finally, one week post birth.
Secondary outcome [2] 340000 0
To measure the in-utero effects of participant melatonin administration upon the growth trajectory of the fetus.
Timepoint [2] 340000 0
The growth trajectory of the fetus will be measured through the undertaking of participant abdominal ultrasound. The ultrasound(s) will take place at these time points: from time of the participant's recruitment to the trial (prior to the administration of the trial intervention), and once administration of the trial intervention has begun, thereafter (at least), fortnightly until birth has taken place.
Secondary outcome [3] 340001 0
To measure the effects of participant melatonin administration upon amniotic fluid index (AFI) and fetal wellbeing.
Timepoint [3] 340001 0
Fetal surveillance will be assessed using doppler waveform analysis. The doppler waveform analysis will take place at these time points: from time of recruitment to the trial (prior to the administration of the trial intervention), and once administration of the trial intervention has begun, thereafter (at least) weekly until birth has taken place.

Eligibility
Key inclusion criteria
1) Women, with a singleton pregnancy
2) Severe fetal growth restriction (FGR), defined as:
Estimated fetal weight equal to, or less than, 3rd centile for gestational age according to charts from Mikolajczyk et al (2011) or an estimated fetal weight that is less than the 10th centile (Mikolajcyk et al 2011) in combination with at least one abnormal fetoplacental doppler study, these being:
- Uterine artery (raised pulsatility index equal to, or more than, 95th centile)
- Umbilical artery (pulsatility index equal to, or more than, 95th centile or absent/reversed end-diastolic flow)
- Ductus venosus (abnormal A wave and/or pulsatility index equal to, or more than, 95th centile)
3) Gestation: (confirmed) 23+0 to 31+6 weeks’
4) Age: 18 years or more
5) Understands English

Reference: Mikolajczyk, R.T., et al., A global reference for fetal-weight and birthweight percentiles. Lancet, 2011. 377 (9780): pp. 1855-61
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1) A fetus with a known chromosomal, major structural anomaly or non-placental cause of fetal growth restriction
2) Pregnancies requiring immediate delivery (eg absent A wave in ductus venosus, preterminal CTG or biophysical profile)
3) Co-recruitment in another clinical trial where a pharmaceutical product or nutritional supplement is the trial intervention.

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)
Central randomisation service by phone/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation 1::1 determined through the use of an online randomisation service

The 292 participants will be stratified by gestational age:
23+0 to 27+6
28+0 to 31+6
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
N/A
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Outcome measures between the melatonin treatment and placebo groups will be analysed on an intention to treat basis. GMA, ITSEA and BSID-III scores will be compared between groups using parametric or non-parametric testing, depending on their distribution. Simple regression analyses will be performed to explore relationships with functional outcomes, as previously reported.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9185 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 17835 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 297746 0
University
Name [1] 297746 0
Monash University
Address [1] 297746 0
Department of Obstetrics and Gynaecology, Monash University
Level 5, Block B, Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country [1] 297746 0
Australia
Funding source category [2] 297753 0
Other Collaborative groups
Name [2] 297753 0
Monash Partners
Address [2] 297753 0
PO Box 315
Prahran
Victoria 3181
Country [2] 297753 0
Australia
Primary sponsor type
Hospital
Name
Monash Health
Address
Monash Health
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country
Australia
Secondary sponsor category [1] 296789 0
None
Name [1] 296789 0
N/A
Address [1] 296789 0
N/A
Country [1] 296789 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298809 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 298809 0
Monash Health
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Ethics committee country [1] 298809 0
Australia
Date submitted for ethics approval [1] 298809 0
18/10/2017
Approval date [1] 298809 0
13/02/2018
Ethics approval number [1] 298809 0
Monash Health HREC ID: 17-0000-583A

Summary
Brief summary
During pregnancy, fetal growth restriction (FGR) is a recognised causal pathway to neurodevelopmental injury, which manifests, following birth, as cognitive and behavioural impairment as well as cerebral palsy. Currently, antenatal care is focused on detecting FGR and assessment of fetal wellbeing to guide timing of delivery. This approach seeks to maximize gestational age at birth to minimise the risks of prematurity, while delivering the fetus in time to minimise the likelihood of stillbirth. However, no therapies exist that can maximize fetal wellbeing in the setting of FGR and minimise the frequency of antenatally acquired brain injury. This double-blind RCT seeks to recruit n=292 women with FGR pregnancies to determine if antenatal maternal Melatonin administration can PROTECT the fetal brain and lead to improved neurodevelopmental outcomes.
Trial website
None
Trial related presentations / publications
Wilkinson, D., Shepherd, E. and Wallace, E.M. Melatonin for women in pregnancy for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD010527. DOI: 10.1002/14651858.CD010527.pub2.

Miller, S. L., Yawno, T., Alers, N. O., Castillo-Melendez, M., Supramaniam, V. G., VanZyl, N., Sabaretnam, T., Loose, J. M., Drummond, G. R., Walker, D. W., Jenkin, G. and Wallace, E. M. (2014), Antenatal antioxidant treatment with melatonin to decrease newborn neurodevelopmental deficits and brain injury caused by fetal growth restriction. J. Pineal Res., 56: 283–294. doi:10.1111/jpi.12121
Public notes
None

Contacts
Principal investigator
Name 78294 0
Dr Kirsten R. Palmer
Address 78294 0
Department of Obstetrics and Gynaecology, Monash University
Monash Medical Centre
Level 5, Block B,
246 Clayton Road
Clayton
Victoria 3168
Country 78294 0
Australia
Phone 78294 0
+61 3 9594 6666
Fax 78294 0
+61 3 9594 6389
Email 78294 0
kirsten.palmer@monash.edu
Contact person for public queries
Name 78295 0
Ms Joanne C. Mockler
Address 78295 0
Department of Obstetrics and Gynaecology, Monash University
Monash Medical Centre
Level 5, Block B,
246 Clayton Road
Clayton
Victoria 3168
Country 78295 0
Australia
Phone 78295 0
+61 3 8572 2840
Fax 78295 0
+61 3 9594 6811
Email 78295 0
joanne.mockler@monash.edu
Contact person for scientific queries
Name 78296 0
Dr Kirsten R. Palmer
Address 78296 0
Department of Obstetrics and Gynaecology, Monash University
Monash Medical Centre
Level 5, Block B,
246 Clayton Road
Clayton
Victoria 3168
Country 78296 0
Australia
Phone 78296 0
+61 3 9594 6666
Fax 78296 0
+61 3 9594 6389
Email 78296 0
kirsten.palmer@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The data will be shared through publication in a peer reviewed journal following completion of
the trial.
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
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?
The raw data will not available for external analysis. Associated documents such as protocol,
PI&CF may be available by contacting the senior author. The senior author will determine who
has access to documentation and data associated with this trial.
By what mechanism will data be made available?
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?
Study protocol
Informed consent form
Ethical approval
Attachments/websites
Type [1] 1071 0
Study protocol
URL/details/comments [1] 1071 0
At the end of 2018, the trial protocol manuscript was submitted to a journal for their consideration of its publication.
Attachment [1] 1071 0
Summary results
Not applicable