Abstract
ObjectiveThe objective of the Dutch Sildenafil therapy in dismal prognosis early onset fetal growth restriction (STRIDER) randomised clinical trial is to assess the beneficial and harmful effects of sildenafil versus placebo on fetal and neonatal mortality in pregnant women with severe early-onset fetal growth restriction. The objective of this detailed statistical analysis plan is to minimize the risks of selective reporting and data-driven analysis.SettingThe setting is 10 tertiary care hospitals and one secondary care hospital in The Netherlands.ParticipantsThe participants will be 360 pregnant women with severe early-onset fetal growth restriction.InterventionsThe intervention is sildenafil 25 mg or placebo orally three times a day.Primary and secondary outcome measuresThe primary outcome is a composite of death or major neonatal morbidity assessed at hospital discharge. The secondary outcomes are neurodevelopmental impairment; mean scores of the Bayley III cognitive and motor assessment; the proportion of patients experiencing either preeclampsia or haemolysis, elevated liver enzymes, and low platelets syndrome; pulsatility index of uterine arteries, umbilical artery, and middle cerebral artery; birthweight; and gestational age at either delivery or intra-uterine death.ResultsA detailed statistical analysis is presented, including pre-defined exploratory outcomes and planned subgroup analyses. One interim analysis after 180 patients had completed the study was planned and a strategy to minimise the risks of type I errors due to repetitive testing is presented. During review of this manuscript the interim analysis was performed by the Data Safety Monitoring Board and early stopping of the trial was recommended. Final analyses will be conducted independently by two statistically qualified persons following the present plan.ConclusionThis pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data and updated after stopping of the trial at interim analysis.Trial registrationClinicalTrials.gov, NCT02277132. Registered on 29 September 2014.Original protocol for the study: doi:https://doi.org/10.5281/zenodo.56148
Highlights
The Dutch Sildenafil therapy in dismal prognosis earlyonset fetal growth restriction (STRIDER) randomised clinical trial is a blinded trial was recruiting patients recently, assessing the benefits and harms of sildenafil versus placebo in pregnant women with severe early-onset fetal growth restriction (FGR) and their offspring
Fetal growth restriction is a condition in which a fetus does not reach its designated growth potential and is too small for gestational age (SGA), mostly defined as either estimated fetal weight or abdominal circumference determined by ultrasound below the third percentile or gestational age below the tenth percentile
Besides the short-term randomised clinical trial and the observational study mentioned above, we identified one recently published clinical trial where 35 patients with fetal growth restriction were randomised to three groups, receiving either oral sildenafil, transdermal nitroglycerin, or oral placebo [24]
Summary
The Dutch Sildenafil therapy in dismal prognosis earlyonset fetal growth restriction (STRIDER) randomised clinical trial is a blinded trial was recruiting patients recently, assessing the benefits and harms of sildenafil versus placebo in pregnant women with severe early-onset fetal growth restriction (FGR) and their offspring. The primary outcome is mortality and morbidity of the children. Fetal growth restriction is a condition in which a fetus does not reach its designated growth potential and is too small for gestational age (SGA), mostly defined as either estimated fetal weight or abdominal circumference determined by ultrasound below the third percentile or gestational age below the tenth percentile. The predominant cause of fetal growth restriction, at early onset (< 32 weeks), is placental dysfunction with high resistance, low-flow, placental circulation, due to inadequate spiral artery remodelling early in pregnancy [2]. Depending on the gestational age at development, the fetus has a substantial risk of mortality and morbidity [3]. As the phosphodiesterase 5- (PDE5-) inhibitor sildenafil causes vasodilatation, it might improve the utero-placental circulation in fetal growth restriction resulting in improved growth and increased chances of healthy survival of the fetus [4–20]
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