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Trial registered on ANZCTR

Registration number

ACTRN12613000476730

Ethics application status

Approved

Date submitted

16/04/2013

Date registered

30/04/2013

Date last updated

2/06/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

A pilot study of antenatal maternally administered melatonin to decrease the level of oxidative stress in human pregnancies affected by preeclampsia (PAMPR Trial).

Scientific title

A pilot study of antenatal maternally administered melatonin in human pregnancies affected by preterm preeclampsia to prolong pregnancy.

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1141-9792

Trial acronym

PAMPR

Linked study record

Health condition

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

Preeclampsia

Condition category

Condition code

Reproductive Health and Childbirth

Fetal medicine and complications of pregnancy

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Oral melatonin sustained release tablet 10mg administered three-times-daily. Duration is from recruitment to delivery. Adherence will be monitored through utilisation of hospital inpatient drug prescription charts for the entire duration of the trial.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Nil. We will measure outcome data pre- and post-treatment.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Interval in days from diagnosis with preeclampsia to delivery.

Timepoint [1]

From diagnosis to delivery.

Secondary outcome [1]

Biomarkers of oxidative stress including: Malondialdehyde (serum), 8-iosprostane (serum), Total antioxidant capacity (serum), Superoxide dismutase (serum), Melatonin (serum), Haeme oxygenase (PAXgene).

Timepoint [1]

At recruitment and then up to every 3 days till delivery and postpartum at 6 weeks.

Secondary outcome [2]

Biomarkers of preeclampsia including: Soluble fms-like tyrosine kinase-1 (serum/urine), Soluble endoglin (serum), Activin (serum), Placental growth factor (serum), Vascular endothelial growth factor (serum), Highly sensitive C-reactive protein (serum), von Willebrand Factor (serum), Neutrophil Elastase (serum), Platelet function tests (plasma), Leukocyte function tests (plasma).

Timepoint [2]

At recruitment and then up to every 3 days till delivery and postpartum at 6 weeks.

Secondary outcome [3]

Severity of preeclampsia as indicated by: Maternal blood pressure, Level of proteinuria, Haemoglobin & platelet count, Liver-transminases, Renal function, Composite of preeclamptic symptoms: oedema, headache, visual disturbance, epigastric or left upper-quadrant pain.

Timepoint [3]

At recruitment and then up to every 3 days till delivery and postpartum at 6 weeks.

Secondary outcome [4]

Maternal morbidity as indicated by: Serum creatinine equal to or >120micmol/L, Proteinuria equal to or >5g/24h, Signs of left ventricular failure (pulmonary oedema, oxygen sats <95%), Hypertension equal to or >170/110mmHg despite anti-hypertensive treatment, Disseminated intravascular coagulation and/or platelets <50x10^9, Eclampsia, Cerebrovascular event, Liver transaminase equal to or >500IU/L.

Timepoint [4]

At recruitment and then up to every 3 days till delivery and postpartum at 6 weeks.

Secondary outcome [5]

Ultrasound and Doppler measurements including: Maternal brachial artery Doppler studies, Maternal uterine artery Doppler studies, Fetal Morphology, Biometry, Amniotic fluid indices, Placental location & abnormalities, Fetal characteristics: heart rate, tone, breathing, movements, Doppler velocimetry: umbilical artery, middle cerebral artery & ductus venosus.

Timepoint [5]

At recruitment and then up to every 3 days till delivery.

Secondary outcome [6]

Pregnancy end-points including: Gestation at birth, Mode of birth, Labour induction methods, Labour augmentation, Analgesia/anaesthesia utilized in labour, Duration of membrane rupture to birth, Group B streptococcus infection, Placental histology, Duration of labour stages, Presence of meconium liquor, Placental weight, Placental abnormalities, Cord insertion, Cord lactates: artery & vein, Intrapartum lactates, Abnormal cardiotocogram (CTG).

Timepoint [6]

Various points during pregnancy.

Secondary outcome [7]

Neonatal outcomes: Sex, Neonatal Apgar score at 1, 5, 10 minutes, Weight at birth, Length, Head circumference, Composite neonatal outcome (admission to NICU, duration of admission, need & duration of respiratory support, intraventricular haemorrhage, necrotising enterocolitis, abnormal neurology, mortality prior to discharge).

Timepoint [7]

At delivery and during postnatal admission.

Secondary outcome [8]

Use of anti-hypertensives and/or magnesium sulfate.

Timepoint [8]

During whole period of recruitment.

Secondary outcome [9]

Level of melatonin in the cord blood at delivery relative to maternal levels.

Timepoint [9]

At delivery.

Secondary outcome [10]

Serious adverse events and reactions as assessed clinically by the Obstetric clinician attending the patient and Principal Investigator.

Melatonin has an excellent biosafety profile, but like any other medicine can have adverse reactions. As referenced by MIMS, these are considered to be uncommon side effects of melatonin (i.e., likely to occur in fewer than 1 in 100 patients):
Irritability, nervousness, restlessness insomnia, abnormal dreams, anxiety, migraine, lethargy, psychomotor hyperactivity (restlessness associated with increased activity), dizziness, somnolence (tiredness), high blood pressure, (upper) abdominal pain, indigestion, mouth ulceration, dry mouth, hyperbilirubinaemia (changes in the composition of your blood which could cause yellowing of the skin or eyes ( jaundice), inflammation of the skin (dermatitis, night sweats, pruritis (itching), rash, dry skin, pain in extremities, menopausal symptoms, asthenia (feeling of weakness), chest pain, excretion of glucose in urine, excess proteins in the urine, abnormal liver function and weight increase.

The following events are considered to be rare (i.e., likely to occur in fewer than 1 in 1,000 patients):
Shingles, reduced number of white blood cells in the blood, decreased number of platelets in the blood, high level of fatty molecules in the blood, severe chest pain due to angina, feeling your heartbeat (palpitations). low serum calcium levels in the blood, low sodium levels in the blood, altered mood, aggression, agitation, crying, stress symptoms, disorientation, early morning awakening, increased sex drive, depressed mood, depression, loss of consciousness or fainting, memory impairment, disturbance in attention, dreamy state, restless legs syndrome, poor quality sleep, ‘pins and needles’ feeling (paresthesia) reduced visual acuity (visual impairment), blurred vision, watery eyes, dizziness when standing or sitting, vertigo, hot flushes, gastro-oesophageal reflux, gastrointestinal disorder, blistering in the mouth, tongue luceration, gastrointestinal upset, vomiting, abnormal bowel sounds, flatulence (wind), salivary hypersecretion (excess saliva production), halitosis (bad breath), abdominal discomfort, gastric disorder, inflammation of the stomach lining, eczema, erythema (skin rash), hand dermatitis, psoriasis, pruritic rash (itchy rash), nail disorder, arthritis, muscle spasms, neck pain, night cramps, increased duration of erection, inflammation of the prostate gland, tiredness, pain, thirst, passing large volumes or urine, presence of red blood cells in the urine, urination during the night, increased liver enzymes, abnormal blood electrolytes and abnormal laboratory tests.

Timepoint [10]

From recruitment till 6 weeks postpartum.

Eligibility

Key inclusion criteria

1. Be at least 18 years of age.
2. Be between 24+0 weeks’ and 35+6 weeks’ gestation.
3. Have a singleton pregnancy.
4. Have a diagnosis of Preeclampsia.
5. Be considered capable of safely continuing the pregnancy for 48 hours or more, as determined by the attending clinician.
6. Obstetrician and neonatologist believe the fetus is likely to be viable.
7. No major anomalies evident on the mid-trimester morphology scan. Any anomaly should be assessed by the Principal Investigator and discussed with the Trial Supervisor, following classification of the anomaly according to the ICD10 codes. All major anomalies will be excluded, but minor anomalies, subject to agreement between the PI and Trial Supervisor will be included.
8. Be capable of understanding the information provided, with use of an interpreter if required.
9. Give written informed consent.

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

1. Eclampsia.
2. Current use of melatonin.
3. Contraindications to melatonin use including:
a. Hypersensitivity to melatonin or any of its derivatives.
4. Imminent transfer to a non-trial centre due to unavailability of neonatal beds.
5. Significant uncertainty regarding gestational age.
6. Women to be treated as an outpatient.
7. Use of any of the following medications:
a. Fluvoxamine.
b. 5- or 8-Methoxypsoralen.
c. Cimetidine.
d. Quinolones and other CYP1A2 inhibitors.
e. Carbamazepine, rifampicin and other CYP1A2 inducers.
f. Zaleplon, zolpidem, zopiclone and other non-benzodiazepine hypnotics.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

The PAMPR trial will be introduced to potential trial participants with sensitivity. The PI, research midwife or other authorized investigator will give the potential participant an information sheet about the trial and answer any questions she or her relatives may have. Once confirmation of a diagnosis of preeclampsia and eligibility for PAMPR has been obtained, the women can be considered for consent to the PAMPR trial.

Maternal and fetal assessments combined with the results of blood tests will determine whether immediate delivery is essential for the survival and wellbeing of mother and baby. If the attending clinician considers delivery within 48 hours as probable, the mother is not eligible for inclusion to the PAMPR trial. Absolute criteria for immediate delivery are not specified in this protocol and remain the responsibility of the attending clinician.

Where delivery within 48 hours is considered unlikely, the women can be approached for consent to the PAMPR trial. Ideally there should be a period of 24 hours for the women to consider whether she wishes to take part in the trial. However, it is considered clinically important to initiate treatment as soon as possible after the diagnosis of preeclampsia, therefore consent should be sought at the earliest opportunity, provided the investigator is reassured that the woman has fully understood the requirements of the trial.

Following admission to the hospital the trial medication will be written on the patient drug chart and administered through usual prescribing practices.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

N/A.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Phase 1

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The length of gestation post recruitment will be analysed using a T-test.

The biomarkers will be analysed using a repeated measures analysis in SPSS, including the baseline value as a covariate. For the primary analysis the treatment effect will be considered constant over time, secondary analyses will examine the possibility of a trend over time. Plots of mean score over time will be shown for clarification.

Initially, the treatment effect will be assumed to be constant over time, but if time by treatment interaction is shown to be important by including this parameter in the model (the conventional level of p=0.05 will be used here) then further investigation into effects at differing time points will be made by analysing the least-square means as above. Plots of mean score over time will be shown for clarification.

All other continuous measures (clinical measures, etc) will be considered in the same manner as above (adjusting by baseline value if available). Dichotomous outcomes (mortality, etc) will be presented as risk ratios, with a corresponding chi-squared test performed.

Apart from baseline value, no adjustments for covariates will be made in the first instance in any of the investigations. Treatment estimates will only be adjusted when subgroups are explored. Interaction between treatment and subgroup variables will be examined in a similar fashion as above by including the relevant parameters in the model. This will be done in turn for each subgroup variable and adjusted estimates presented.

All tests are 2-sided and results will be presented as a point estimate along with 95% confidence intervals. All analyses will be conducted by the PI and statistician at Monash University.

This study is a proof-of-principle phase 1 trial and as such a power calculation has not been performed to calculate sample size. The purpose of this trial is to determine appropriate outcome measures that can be used to calculate power for a future phase 2 randomised controlled trial for the same intervention.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

6/05/2013

Actual

26/08/2013

Date of last participant enrolment

Anticipated

Actual

17/01/2016

Date of last data collection

Anticipated

Actual

1/09/2016

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [2]

Jessie McPherson Private Hospital - Clayton

Recruitment postcode(s) [1]

3168 - Clayton

Funding & Sponsors

Funding source category [1]

University

Name [1]

Monash University

Address [1]

Department of Obstetrics & Gynaecology
Level 5, 246 Clayton Rd
Clayton Vic 3168

Country [1]

Australia

Primary sponsor type

Hospital

Name

Monash Health Research Directorate

Address

Monash Health
Level 4, 246 Clayton Rd
Clayton Vic 3168

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health HREC

Ethics committee address [1]

Level 4, 246 Clayton Rd
Clayton Vic 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/03/2013

Approval date [1]

02/04/2013

Ethics approval number [1]

13076B

Summary

Brief summary

This research project will investigate whether the hormone, Melatonin, is a useful treatment for oxidative stress in pregnancies affected by preeclampsia. Preeclampsia is one of the most common diseases in pregnancy and is potentially very dangerous for both mother and baby.

Oxidative stress in preeclampsia occurs when a pregnant mother and the baby in the womb are exposed to certain noxious chemicals produced by the placenta. Oxidative stress can cause serious damage to the mother and baby, including premature birth, brain damage and even death.

Melatonin is a strong antioxidant and is been used to effectively treat oxidative stress in pre-clinical trials. It has also been studied intensively in both animals and humans and has shown to be very safe.

In this trial, we hope to use melatonin to reduce the damage caused by oxidative stress during pregnancies affected by preeclampsia. To do this, we will give mothers diagnosed with preeclampsia melatonin (10mg) tablets three times a day. We will measure levels of oxidative stress before, during and after treatment in the mother's blood, as well as in blood from the placenta after birth. Other non-invasive measurements of mother and baby health will also be measured including the outcome of their pregnancies. This will give us an indication whether melatonin is helping to protect the unborn baby from oxidative stress.

Participation in this project will be undertaken during the normal care of a woman with preeclampsia admitted to hospital. She will be cared for in the usual way with best practice and there will be regular blood samples twice per week as is normally done. Ultrasound scans to check the health of the baby will be done at least weekly. Samples will be taken from the maternal blood or from material that would normally be discarded. No samples will be obtained directly from the baby.

If this project is successful, it will potentially give us the very first and only treatment for preeclampsia.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Sebastian Hobson

Address

Department of Obstetrics & Gynaecology
Level 5, Monash Medical Centre
246 Clayton Road
Clayton Vic 3168

Country

Australia

Phone

+613 9594 5145

Fax

[email protected]

Contact person for public queries

Name

Dr Sebastian Hobson

Address

Department of Obstetrics & Gynaecology
Level 5, Monash Medical Centre
246 Clayton Road
Clayton Vic 3168

Country

Australia

Phone

+613 9594 5145

Fax

[email protected]

Contact person for scientific queries

Name

Dr Sebastian Hobson

Address

Department of Obstetrics & Gynaecology
Level 5, Monash Medical Centre
246 Clayton Road
Clayton Vic 3168

Country

Australia

Phone

+613 9594 5145

Fax

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Melatonin improves endothelial function in vitro and prolongs pregnancy in women with early-onset preeclampsia.	2018	https://dx.doi.org/10.1111/jpi.12508
Embase	Novel Therapy for the Treatment of Early-Onset Preeclampsia.	2017	https://dx.doi.org/10.1097/GRF.0000000000000249
Dimensions AI	Phase I pilot clinical trial of antenatal maternally administered melatonin to decrease the level of oxidative stress in human pregnancies affected by pre-eclampsia (PAMPR): study protocol	2013	https://doi.org/10.1136/bmjopen-2013-003788

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically