STRIDER NZAus Trial Information

STRIDER NZAus - Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction

Recruitment for STRIDER NZAUs WAS COMPLETED IN MARCH 2017

DATA ANALYSIS TO COMMENCE IN OCTOBER 2017

 

STRIDER NZAus Childhood Outcome Study

Currently follow up visits are undertaken at 2.5 years’ corrected age (+/- 6 months) to determine if any benefit (or harm) of antenatal sildenafil therapy seen in the newborn period is sustained, or develops, through childhood. All surviving children are assessed on survival free of neurosensory impairment, defined as the absence of cerebral palsy, deafness, blindness, cognitive delay and motor delay.

Additional funding has been secured from the following funders: Cure Kids, the Neurological Foundation of NZ, AMRF, RANZCOG Mercia Barnes Trust, the Maurice and Phyllis Paykel Trust and the University of Auckland FMHS.

Objective

Severe, early-onset intrauterine growth restriction (IUGR) due to utero-placental insufficiency is associated with a high risk of perinatal morbidity with long-lasting sequelae and mortality. Utero-placental insufficiency is the result of abnormal formation and function of the placenta (placentation) with inadequate remodelling of the maternal spiral (utero-placental) arteries. There is currently no therapy available proven to be of benefit for IUGR other than premature birth when a fetus becomes compromised. Animal and preclinical studies suggest the drug, sildenafil citrate, may improve uteroplacental blood flow, fetal growth, and meaningful neonatal outcomes. The objective of the STRIDER NZAus trial is to evaluate the effective of sildenafil compared to placebo on fetal growth in-utero measured by assessment of abdominal circumference growth velocity.

The results of STRIDER NZAus will be used in pre-planned individual patient data analyses with four other international STRIDER trials underway in the UK, the Netherlands, Ireland and Canada. By international collaboration these studies will be able to effectively assess whether the antenatal use of sildenafil in early-onset fetal growth restriction has a positive effect on healthy perinatal survival.

STRIDER NZAus includes several sub-studies including placental and myometrial vascular physiology studies (Auckland centre only) and a neonatal cardiac and body composition outcome study. Planning for longer term follow-up of surviving infants is underway.

Study Design

STRIDER NZAus is a bi-national multicentre double blind randomised placebo controlled trial.

Study Population

Women with a singleton pregnancy between 22 and 30 weeks gestation with severe fetal growth restriction.

Intervention

Sildenafil 25mg or matching placebo tablet orally three times daily from recruitment to 32 weeks gestation, delivery of fetal demise (whichever occurs first).

Outcome Measures

Primary outcome:

An increase in fetal growth velocity. Fetal growth velocity will be determined by abdominal circumference growth velocity. Mean daily increase in abdominal circumference (calculated as a proportion to that expected if AC were on 50th centile for gestational age) pre and post treatment will be compared.

Secondary outcomes include:

• Additional measures of fetal growth and wellbeing: mean absolute change in abdominal circumference (mm) per day, mean birthweight and mean birthweight centile, amniotic fluid index, deepest vertical amniotic fluid pocket and short term variability measured by computerised cardiotocography.
• Changes in uteroplacental, umbilical and fetal Doppler waveform studies.
• Maternal symptomatic hypotension, headaches, flushing and pre-eclampsia.
• Randomisation-to-delivery interval, gestational age at delivery, mode of delivery and postpartum haemorrhage requiring transfusion.
• Measures of neonatal outcome; rates of intrauterine death, live-births, survival to hospital discharge, major morbidity including chronic lung disease requiring ambulatory oxygen therapy on hospital discharge, intraventricular haemorrhage grade 3-4, ≥grade 3 retinopathy of prematurity, necrotising enterocolitis, number of doses of surfactant, ventilator days, supplemental oxygen days and number of days to full feeds.
• Any adverse or serious adverse events

Data/Power Analysis

Assuming 50% (placebo-treated) vs 80% (sildenafil-treated) increased post-randomisation abdominal circumfernece growth velocity, with an α of 0.05, two sided, the trial will have 90% power to detect this difference if 58 women are randomised per group. Allowing for a 5% drop-out rate, the total sample size required is 122 women.

Data will be analysed on an intention-to-treat basis. Demographic and other baseline data will be summarised by study treatment groups. For continuous outcomes, t-test, linear regression and mixed model for repeated measures method will be used where appropriate. For categorical outcomes, Fisher’s exact test, logistic regression and generalised linear mixed effects model will be used where appropriate. Two sided-p-values less than 0.05 will be used to determine statistical significance and all confidence intervals will be reported at a two sided 95% level.

Commencement Date

March 2014

Investigators and Primary Contacts

Chief Investigator: Katie Groom, University of Auckland, k.groom@auckland.ac.nz

Clinical Trial Manager: Laura Mackay, University of Auckland, laura.mackay@auckland.ac.nz

Australia New Zealand Clinical Trials Registry (ANZCTR) Trial Registry Number

ACTRN12612000584831

Funding

Health Research Council of NZ (HRC) and Cure Kids NZ