A randomised controlled trial of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction

INTERVENTION: Trade Name: Sildenafil Product Name: Sildenafil Pharmaceutical Form: Capsule INN or Proposed INN: sildenafil CAS Number: 171599‐83‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 75‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Early onset intrauterine growth restriction ; MedDRA version: 17.1 Level: LLT Classification code 10022819 Term: Intrauterine growth retardation System Organ Class: 100000004868 Therapeutic area: Body processes [G] ‐ Reproductive physiologi cal processes [G08] PRIMARY OUTCOME: Main Objective: The overarching aim is to determine whether maternal treatment of oral sildenafil citrate improves perinatal outcomes in pregnancies complicated by severe early‐onset IUGR without increasing risks to the mother. ; ; This study has a specific objective to evaluate the clinical efficacy of sildenafil i.e. its ability to lead to a delay of a clinical indication for delivery on fetal grounds by at least one week. The other specific objective is to add to our understanding of the mechanism of action of sildenafil by monitoring changes in the maternal, utero‐placental and fetal circulation. Primary end point(s): Primary outcome is average prolongation of pregnancy for one week (i.e. one week difference in the mean randomisation to birth interval). Secondary Objective: i) to investigate impact on fetal growth and fetal well‐being by comparing differential effect on the vascular resistance in the uterine arteries, umbilical, fetal middle cerebral artery and fetal ductus venosus and differences in birth weight centiles in infants treated in‐utero with sildenafil and placebo.; ii) to examine, through collaboration with an international consortium, the hypothesis that sildenafil therapy compared to placebo therapy increases the rate of infant survival free of major handicap.; iii) to report frequency of adverse and serious adverse events associated with sildenafil use. ; iv) to investigate the impact on maternal cardiovascular parameters by measurements of maternal heart rate and peripheral blood pressure before and one hour following administration of study medication, 48‐72 hours later and once after delivery.; v)to elucidate the precise mechanism and location of action of sildenafil Timepoint(s) of evaluation of this end point: Randomisation: ; Gestational age is determined by early pregnancy dating ultrasound examination and recorded at the point of randomisation (days.; Delivery: ; Gestational age at birth (days). 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 Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) no F.1.2.1 Number of subjects for this age range 112 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0 SECONDARY OUTCOME: Secondary end point(s): i) Fetal outcomes ‐ estimated fetal weight, abdominal circumference growth velocity,serial measurements of Doppler pulsatility index in the umbilical artery, middle cerebral artery and ductusvenosus and uterine arteries, serial measurements of short term variability of the fetal heart rate.; ; ii) Infant outcomes ‐ gestational age at birth, survival at discharge, birth weight centile, length of admission on the neonatal intensive care unit, oxygen dependency at day 28 and 36 weeks corrected age, necrotising enterocolitis, retinopathy of prematurity, significant (grade III/IV) cerebral haemorrhage detected by cerebral ultrasound, number of doses of surfactant, ventilator days, supplemental oxygen days, number of days of full feeds.; ; iii) Maternal outcomes ‐ mode of delivery, standardised blood pressure and pulse monitoring during treatment, pre‐eclampsia, postpartum haemorrhage, recording of the side effects eg headaches, facial flushing Timepoint(s) of evaluation of this end point: Fetal Outcomes: ; All assessments will be conducted at baseline amd weekly thereafter until birth. ; ; Infant Outcomes: ; All assessements to be conducted at birth and daily until hospital discharge; ; Maternal outcomes: ; Assessment will be conducted during and directly after birth and on hospital discharge