ANZCTR - Registration

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

ACTRN12615000319572

Ethics application status

Approved

Date submitted

24/03/2015

Date registered

9/04/2015

Date last updated

30/07/2019

Date data sharing statement initially provided

26/11/2018

Date results information initially provided

30/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Does sildenafil reduce the risk of fetal distress in labour?

Scientific title

Investigating if Sildenafil Citrate (50mg PO 8hrly) administration in labour reduces the rates of emergency operative delivery for fetal distress and improves fetal and uteroplacental blood flow on Dopper ultrasound in term (37-42 weeks), singleton, appropriately grown pregnancies

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1167-5821

Trial acronym

RIDSTRESS

Linked study record

Health condition

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

Intrapartum fetal hypoxia

Condition category

Condition code

Reproductive Health and Childbirth

Normal pregnancy

Reproductive Health and Childbirth

Fetal medicine and complications of pregnancy

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will be randomised to either placebo orally 8 hourly (maximum three doses in 24 hours) or sildenafil citrate 50mg orally 8 hourly (maximum 150mg in 24 hours).

Only women at term (37-42 weeks of pregnancy) are eligible. Participants will be randomised when delivery is anticipated within 72 hours and dosing regimen commenced when transferred to birth suite for management of labour. Doses will be administered intrapartum in labour ward by medical and midwifery staff under supervision and unused drug tablets will be returned and disposed of in adherence with hospital policy.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Prevention

Comparator / control treatment

placebo (capsulated, no active ingredients) taken orally 8 hourly for up to three doses maximum in 24 hours.

Control group

Placebo

Outcomes

Primary outcome [1]

To ascertain if the use of sildenafil citrate in labour is associated with a reduction in the incidence of intrapartum fetal compromise requiring emergency delivery. For the purposes of this study emergency delivery is defined as either caesarean section or instrumental vaginal delivery where the primary indication for delivery is concern for fetal wellbeing (non-reassuring fetal status).

Timepoint [1]

Until delivery of the baby.

Primary outcome [2]

To ascertain if sildenafil is associated with improved fetal and uteroplacental blood flow on Doppler ultrasound

Timepoint [2]

Within four hours of first dose of sildenafil citrate/placebo

Secondary outcome [1]

To ascertain if sildenafil is associated with an improvement in neonatal outcomes as defined by a composite neonatal outcome score (admission to neonatal intensive care unit, APGAR <7 at 5 minutes, cord pH<7.1 or lactate >6mmol/L, neonatal encephalopathy).

Timepoint [1]

To neonatal discharge from hospital

Secondary outcome [2]

To ascertain if sildenafil citrate is associated with a reduction in intrapartum fetal heart rate abnormalities (as demonstrated and interpreted from cardiotocograph) or meconium stained liquor.

Timepoint [2]

Until delivery of the baby.

Secondary outcome [3]

To ascertain if sildenafil citrate is associated with a reduction in the need for intrapartum fetal blood sampling. This data is collected from the clinical notes where performance of fetal blood sampling is documented.

Timepoint [3]

Until delivery of the baby.

Secondary outcome [4]

To establish the extent to which sildenafil citrate crosses the placenta into the fetal circulation by measuring umbilical cord blood levels of sildenafil citrate or its active metabolite (N-Desmethyl-Sildenafil). Plasma samples will be sent to the BioNotus GCV laboratory in Belgium for assay.

Timepoint [4]

From time of delivery to within 2 hours of birth. This window is the timeframe in which cord blood can be obtained. Samples will be immediately sent to the local hospital laboratory to be processed and stored at -80degrees Celsius prior to all samples being sent to the laboratory in Belgium for SC assay at the end of the study period for batch processing.

Eligibility

Key inclusion criteria

*Aged between 18-50 who are able to give informed consent
*Singleton pregnancy at 37-42 weeks gestation
*Appropriately grown fetus without any structural, chromosomal or genetic abnormality.
*Admitted in spontaneous labour (cervical dilatation <4cm) or prior to induction of labour
*Planning a vaginal delivery

Minimum age

18 Years

Maximum age

50 Years

Sex

Females

Can healthy volunteers participate?

Yes

Key exclusion criteria

*Women <18 years old
*Those unable to give informed consent
*Women with pre-existing heart disorders, stroke, hypotension or hypertension, retinitis pigmentosa, kidney or liver abnormalities, sickle cell anaemia, stomach ulcers or any other bleeding disorder.
*Women on any anti-hypertensive medication.

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)

Pregnant women at term (37-42 weeks) will be recruited from the Pregnancy Assessment and Observation Unit, Antenatal clinic or Antenatal Wards at the Mater Mothers’ Hospital, Raymond Terrace, Brisbane, QLD, Australia.
Women with singleton pregnancies who are admitted in early labour (<4cm dilated) with regular uterine contractions OR women prior to induction of labour will be approached to participate in this study. The aim is to recruit women who have had apparently “normal” low risk pregnancies who will deliver within 72 hours of recruitment.
Participants will be given the Participant Information sheet and encouraged to ask question. Participants will then be required to sign a consent form.
Information about the maternal age, ethnicity, parity, booking blood pressure, gestation at onset of labour, body mass index, history of smoking, pre-existing maternal medical disorders, history of previous fetal growth restriction, stillbirth or neonatal death will be recorded on a pro-forma sheet.
At recruitment, all participants will have an ultrasound scan to measured fetal biparietal diameter, head circumference, abdominal circumference and femur length thereby allowing an estimated fetal weight to be calculated. Doppler assessment of several fetal vessels and cardiac function as well as maternal uterine Doppler indices and vessel diameters (Pulsatility index, Resistance index and maximum velocity) will be recorded. The amniotic fluid index will also be measured. The entire ultrasound assessment should not take longer than 30-40 mins. In addition these women will have a blood sample (10ml) taken for measurement of placental growth factor (PlGF) levels.
After the ultrasound, the participant will be computer randomised to either Sildenafil or placebo. The first dose of sildenafil or placebo will be administered when the woman is transferred to the Birth Suite for management of labour. The dose of Sildenafil will be 50mg taken orally every 8 hours for a maximum of 24 hours (total dose 150mg. ie 3 doses only). Both the active drug and the placebo will be provided by the Pharmacy department at the Mater Mothers’ Hospital in sealed opaque envelopes in sequential order of computer generated randomisation. Allocation will be concealed. Following the first dose of either Sildenafil or placebo a repeat ultrasound scan will be performed within 2-4 hours to assess fetal cardiac function and blood flow in various fetal vessels (umbilical artery, middle cerebral artery and ductus venosus) as well as the maternal uterine arteries. The second scan should not take longer than 20 mins to perform.
Clinicians managing the pregnancy will be blinded as to the results of the ultrasound scan and the blood tests to ensure that the care these women receive is not influenced by the results. After delivery, case notes for all participants will be reviewed, and intra-partum and neonatal outcomes collected.

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
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

This is a double blinded, randomised controlled trial (Phase II trial). The sample size calculation was based on our previous data which showed that the incidence of emergency operative delivery (caesarean section or instrumental vaginal delivery) for fetal compromise was approximately 18.9%. If sildenafil was successful in halving the rate of caesarean section in this cohort to 9.5%, a total sample size of 288 women per group (>90% power, alpha of 0.05) would be required. Assuming a 10% drop out rate, a sample of 320 women per group should be sufficient to adequately address the research objectives.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/06/2015

Actual

29/09/2015

Date of last participant enrolment

Anticipated

1/01/2019

Actual

3/01/2019

Date of last data collection

Anticipated

Actual

21/02/2019

Sample size

Target

640

Accrual to date

Final

300

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Mater Mother's Hospital - South Brisbane

Recruitment postcode(s) [1]

4101 - South Brisbane

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Mater Research Translating Research Into Practice (TRIP)

Address [1]

Aubigny Place
Raymond Tce
South Brisbane QLD 4101

Country [1]

Australia

Primary sponsor type

Hospital

Name

Mater Health Service

Address

Aubigny Place
Raymond Tce
South Brisbane QLD 4101

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Prof Sailesh Kumar

Address [1]

Mater Medical Research Institute (MMRI)
Aubigny Place
Raymond Tce
South Brisbane QLD 4101

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Mater Health Services Human Research Ethics Committee

Ethics committee address [1]

Aubigny Place
Raymond Tce
South Brisbane QLD 4101

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

13/03/2015

Approval date [1]

21/05/2015

Ethics approval number [1]

15/MHS/33

Summary

Brief summary

Labour is perhaps the most hazardous time in pregnancy for the fetus. Uterine contractions can contribute to more than a halving of blood flow to the uterus and placenta and this in turn may lead to fetal distress. In most pregnancies, the placental blood supply and function is adequate but it may not be sufficient to tolerate the extra demands of labour. Up to 63% of babies who become distressed and suffer oxygen deprivation in labour have no prior risk factors. Furthermore, events in labour account for as many as 20% of cases of cerebral palsy in term infants. Recent research demonstrates that the changes in blood flow to the fetus can be detected by ultrasound and that these changes are highly predictive of identifying fetuses at risk of becoming distressed in labour, as well as reliably excluding those that were not at risk.
With this in mind, investigating ways to preserve and promote the blood supply and in turn, the oxygenation to the fetus has the potential to significantly change intrapartum care. Sildenafil is a vasodilator (opens blood vessels) and based on previous research may play a role in enhancing blood flow to the fetus.
This clinical trial will investigate if having sildenafil in labour improves the blood flow to the fetus and reduces the need for emergency operative delivery (either caesarean section or operative vaginal birth) for fetal distress.

Trial website

Trial related presentations / publications

Dunn L, Flenady V, Kumar S. Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double-blind randomised control trial. Journal of translational medicine. 2016 Dec;14(1):15.

Public notes

Contacts

Principal investigator

Name

Prof Sailesh Kumar

Address

Mater Medical Research Institute (MMRI)
Aubigny Place
Raymond Terrace
South Brisbane, QLD, 4101

Country

Australia

Phone

+61731638111

Fax

[email protected]

Contact person for public queries

Name

Prof Sailesh Kumar

Address

Mater Medical Research Institute (MMRI)
Aubigny Place
Raymond Terrace
South Brisbane, QLD, 4101

Country

Australia

Phone

+61731638111

Fax

[email protected]

Contact person for scientific queries

Name

Prof Sailesh Kumar

Address

Mater Medical Research Institute (MMRI)
Aubigny Place
Raymond Terrace
South Brisbane, QLD, 4101

Country

Australia

Phone

+61731638111

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?

All of the de-identified individual participant data collected during the trial will be made available to other researchers

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

All of the de-identified individual participant data collected during the trial will be made available to other researchers beginning 3 months and ending 10 years after article publication. Data will only be made available to researchers who provide research ethics approval and an appropriate research proposal.

Available to whom?

approved researchers, assessed on individual request basis

Available for what types of analyses?

IPD meta-analysis

How or where can data be obtained?

Requests should be directed to Professor Sailesh Kumar ([email protected]).

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
376	Study protocol					368057-(Uploaded-26-07-2019-11-10-41)-Study-related document.docx

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	Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): A double-blind randomised control trial.	2016	https://dx.doi.org/10.1186/s12967-016-0769-0
Embase	Safety and efficacy of sildenafil citrate to reduce operative birth for intrapartum fetal compromise at term: a phase 2 randomized controlled trial.	2020	https://dx.doi.org/10.1016/j.ajog.2020.01.025
Embase	Neurodevelopmental outcomes in infants following intrapartum maternal oral sildenafil citrate treatment.	2021	https://dx.doi.org/10.1016/j.ajog.2020.10.036
Embase	PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia.	2023	https://dx.doi.org/10.3389/fphar.2023.1068153

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

Trial Review

Documents added manually

Documents added automatically