Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction

ISRCTN	ISRCTN39133303
DOI	https://doi.org/10.1186/ISRCTN39133303
Clinical Trials Information System (CTIS)	2013-005398-32
Protocol serial number	16986
Sponsor	Liverpool Women's NHS Foundation Trust (UK)
Funder	NIHR Evaluation, Trials and Studies Coordinating Centre (UK); Grant Codes: 12/62/109

Submission date: 31/07/2014
Registration date: 31/07/2014
Last edited: 03/09/2018

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Pregnancy and Childbirth

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Failure to thrive before birth, also known as intrauterine fetal growth restriction (IUGR), can occur due to a variety of causes. However, the main problem is when fetal growth slows down, or stops altogether, because of a poorly functioning placenta. In a healthy pregnancy, placental cells (trophoblasts) invade the lining (endothelium) of the mothers uterine blood vessels. Normally, this trophoblast invasion should be complete early in pregnancy to enable maternal blood to flow easily to the developing placenta. In IUGR pregnancies, the trophoblast invasion is less effective and this leads to damage of the developing placenta and abnormally slow fetal growth. The earlier this occurs, the more difficult and challenging the treatment options are, including very early preterm birth by caesarean section. Extremely premature babies with low birth weight may suffer from long-term complications. Not only is their early life more traumatic, but there is also increasing evidence that the impact of being within a less nourishing uterus environment persists beyond infancy into adulthood. Fetal growth restriction has been linked with an increased risk of a wide variety of adult diseases which include heart disease and diabetes. Sildenafil citrate (Viagra®) causes the blood vessels supplying the uterus and placenta to relax. This relaxation increases blood flow through the placenta and leads to improved fetal weight gain. Sildenafil has been found to be safe in both pregnant and non-pregnant women and has been used for many years for the treatment of newborns with lung disease. These features suggest that it has the potential to offer a unique treatment for IUGR - a currently untreatable fetal disease.

Who can participate?
Women whose unborn children are failing to thrive due to the poor blood supply to the placenta.

What does the study involve?
Once the patient has agreed to take part and signed the consent form, they will be given medication to take (by mouth) three times a day, from the time they start the study until they reach 32 weeks pregnancy or the baby is born. The patient wont know whether they are taking sildenafil or the placebo (dummy), and neither will the doctor or pharmacist. In addition to the patients regular ultrasound scans the patient will have extra blood tests and more detailed monitoring of their blood pressure. This will be carried out by the hospital doctors or research midwives. Detailed blood pressure monitoring will involve placing a Velcro cuff on the patients wrist and arm. In some hospitals as part of the study extra monitoring of the patients heart will be carried out. This will depend on the hospital having the appropriate equipment. Heart monitoring is a painless, non-invasive procedure where four stickers are placed on the skin of the patients chest to record the signal from the heart very similar to routine ECG heart monitoring done in the GP practices. The research team will try to complete these tests during the patients stay in the hospital or during the patients regular hospital appointments, if the patient is monitored from home. Appointments may take a little longer than normal to complete. Patients will also be asked to donate their placenta after the baby is born to study in the laboratory; the placenta is no longer required by the baby and is normally disposed of after birth. If the patient wishes to keep the placenta, it will not be collected.

What are the possible benefits and risks of participating?
We hope that the results of the study overall will show us whether sildenafil helps pregnancies affected by severe IUGR. If our results show it does, we will be able to use this knowledge to improve the care for affected women and their babies. It is possible that sildenafil may not work in the way we intended. This is also very important so we can focus our future efforts on other possible treatments, but they will be tested in the same way we are testing sildenafil. Blood sampling will be carried out by someone who is skilled in taking blood. The patient may have some bruising at the site of blood collection, but this will go after a few days. The studies of sildenafil in animals, non-pregnant adults, pregnant women and unborn babies have not shown harmful effects. Like all medicines, it is not possible to say that sildenafil is 100% safe, but based on what is known it is unlikely that the use of sildenafil in pregnancy will harm the patient or the baby. We know that people receiving sildenafil can have some short-lasting side effects like headache, flushing, blurred vision and indigestion. Sildenafil can cross the placenta and babies may be at risk for some of these side effects which are not permanent. At present we do not know whether these side effects are relevant to a fetus or how they compare to any discomfort experienced by a baby with IUGR. Sildenafil has been used in pregnant women and premature babies previously but none of these side effects have been reported in babies. The long-term consequences, positive or negative, of exposure to sildenafil before birth are not known. This is why we plan to follow the babies after they are born. We will stop the trial medication at 32 weeks and babies born before 32 weeks will not be given the study medication after birth. We do not know the effects of stopping sildenafil that has been given to a fetus, but we will monitor all pregnancies that continue beyond 32 weeks and examine carefully any babies born before 32 weeks.

Where is the study run from?
The study will be carried out in the following 18 large maternity units in England:
1. Liverpool Women's NHS Foundation Trust
2. St. Marys Hospital Manchester
3. University Hospital of North Staffordshire
4. St Georges Hospital
5. Heartlands Hospital, Heart of England NHS Foundation Trust
6. Leicester Royal Infirmary
7. Royal Victoria Infirmary
8. St. Michaels Hospital, University Hospitals Bristol NHS Foundation Trust
9. Birmingham Women's NHS Foundation Trust
10. Queen's Medical Centre (QMC) Nottingham University Hospitals NHS Trust
11. UCL, University College London
12. Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary
13. Norfolk and Norwich University Hospital NHS Foundation Trust
14. John Radcliffe Women's Centre, Oxford University Hospital NHS Trust
15. The Jessop Wing, Sheffield Teaching Hospitals NHS Foundation Trust
16. Maternal Fetal Medicine MRC Centre for Reproductive Health
17. Kings College Hospital NHS Foundation Trust
18. Guys and St Thomas Hospital NHS Foundation Trust

When is the study starting and how long is it expected to run for?
The study starts in August 2014 and will run for two years.

Who is funding the study?
National Institute for Health Research (NIHR), UK.

Who is the main contact?
Miss Sarah Quinby
s.quinby@liverpool.ac.uk

Contact information

Miss Sarah Quinby
Scientific

Liverpool CR-UK Centre - Waterhouse Building
1-3 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Email	s.quinby@liverpool.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Treatment
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	A randomised controlled trial of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction
Study acronym	STRIDER
Study objectives	The STRIDER trial aims to determine whether maternal treatment of oral sildenafil citrate improves perinatal outcomes in pregnancies complicated by severe early-onset IUGR without increasing risk to mother. Failure to thrive before birth (intrauterine growth restriction (IUGR)) can occur due to a variety of causes such as fetal chromosomal or structural abnormalities. However, the main management issues occur when fetal growth slows down, or stops altogether, because of poorly functioning placenta. In a healthy pregnancy, placental cells invade the lining of the maternal uterine blood vessels. Women whose unborn children are failing to thrive due to poor blood supply to the placenta will be invited to participate. The trial will be conducted in large maternity units across England. During a 24 month period, all women carrying a fetus diagnosed with severe IUGR before 30+0 weeks of pregnancy will be invited to participate. It is anticipated that around 50% of eligible women will agree to participate and 112 women will be given either oral sildenafil or matching placebo tablets until delivery, or 32+0 weeks of pregnancy, whichever comes first. It is expected that babies exposed to sildenafil will be delivered one week later compared to those exposed to placebo. This one week increase in maturity is clinically very important.
Ethics approval(s)	14/NE/0011; First MREC approval date 20/03/2014
Health condition(s) or problem(s) studied	Topic: Reproductive health and childbirth; Subtopic: Reproductive Health and Childb (all Subtopics); Disease: Reproductive Health & Childbirth
Intervention	Participants are randomised to two arms: Arm A: Sildenafil tablets 25 mg three times per day from baseline until delivery 31+6 weeks gestation, whichever comes first Arm B: Placebo tablets 25 mg three times per day from baseline until delivery 31+6 weeks gestation, whichever comes first Follow-up length: 12 month(s)
Intervention type	Other
Primary outcome measure(s)	Difference in length of gestation (days): The primary outcome will be average prolongation of pregnancy for one week i.e. one week difference between two randomised groups in the mean randomisation to birth interval. Gestational age will be determined by early pregnancy dating ultrasound examination. The primary outcome was chosen as a surrogate for long-term morbidity as it has been shown that gestational age at birth remains the most powerful predictor of intact survival in early-onset IUGR cohorts. Recently published data from the 2006 English cohort of babies born between 22 and 26 weeks gestation showed a step increase in survivors without major morbidity ranging from 15% at 23 weeks to 50% at 26 weeks.
Key secondary outcome measure(s)	Fetal outcomes: 1. Abdominal circumference growth velocity defined as increase of abdominal circumference in mm per day 2. Changes in gestational age adjusted Doppler measurements expressed as pulsatility index in the umbilical artery, middle cerebral artery and ductus venosus and uterine arteries 3. Changes in short-term variability of the fetal heart rate recorded by transabdominal cardiotococography Infant outcomes include: 1. Gestational age at birth (days) 2. Survival to discharge 3. Birth weight centile 4. Length of admission on the Neonatal Intensive Care Unit (days) 5. Bronchopulmonary dysplasia requiring oxygen 36 weeks corrected age 6. Necostising enterocolotos (requiring surgery) 7. Retinopathy of prematurity (requiring treatment such as laser, grade 2/3 or more) 8. Severe central nervous system injury (detected by ultrasound and or MRI) periventricular leucomalacia grade II or more, intracerebral haemorrhage or more or hydrocephalus 9. Confirmed sepsis by positive blood culture 10. Patent ductus arteriosus needing medical or surgical treatment 11. Need for inotropes or vasopressors 12. Number of doses of surfactant 13. Ventilator days 14. Supplemental oxygen days 15. Number of days to full feeds Maternal safety monitoring including: 1. Mode of delivery 2. Standardised blood pressure and pulse monitoring during treatment 3. Pre-eclampsia 4. Postpartum haemorrhage 5. Recording of the side effects e.g. headache, facial flushing 6. In-patient postnatal stay
Completion date	31/07/2016

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Female
Target sample size at registration	112
Key inclusion criteria	1. Women with singleton pregnancy and fetus diagnosed with severe, early onset intrauterine growth restriction (IUGR) between 22+0 and 29+6 weeks of gestation and clinical decision to manage pregnancy expectantly. 2. IUGR is defined as estimated fetal weight or abdominal circumference <10th centile and absent or reversed end diastolic velocity Doppler in the umbilical artery. 3. 16 years of age or older 4. Consent to take part in the trial
Key exclusion criteria	1. Multiple pregnancy 2. Known or suspected structural or chromosomal fetal abnormality 3. Maternal illness (e.g., pre-eclampsia) that is expected to require delivery for maternal reasons within the next 72 hours 4. Maternal wish not to have active management of the pregnancy, or to have pregnancy termination weeks 5. Inability to give informed consent 6. Cocaine use 7. Contraindication to sildenafil therapy, e.g., known maternal cardiac disease, left ventricular outflow tract obstruction, concomitant treatment with nitrates or previous allergy to sildenafil
Date of first enrolment	01/08/2014
Date of final enrolment	31/07/2016

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

Liverpool CR-UK Centre - Waterhouse Building

Liverpool
L69 3GL
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/02/2018		Yes	No
Protocol article	protocol	11/03/2014		Yes	No
Protocol article	protocol	28/12/2017		Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

03/09/2018: Internal review.
24/07/2018: Publication references added.