Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction

Phase 3TerminatedNCT02442492

University of British Columbia21 enrolled

Overview

Early-onset placental intrauterine growth restriction (EO IUGR) is associated with a high risk of perinatal morbidity and mortality. In association with reduced circulating placental growth factor (PlGF) EO IUGR results from abnormal placentation with inadequate remodelling of the maternal uteroplacental arteries. There is no known treatment for placental IUGR. Management involves intensive fetal surveillance with delivery with evidence of serious fetal compromise. However, remote from term, delivery is associated with significant perinatal mortality and morbidity. Sildenafil vasodilates the uteroplacental vessels of IUGR-affected pregnancies and may represent a novel therapy.

STRIDER Canada is one of a consortium of STRIDER randomised controlled trials (RCTs) each of which is designed to determine whether or not maternal treatment with oral sildenafil citrate improves perinatal outcomes in pregnancies complicated by EO IUGR without increasing risks to the mother. STRIDER Canada is designed as investigator-initiated double-blind, randomised placebo-controlled trial of 90 women with a diagnosis of early-onset intrauterine growth restriction with an intention-to-treat analysis. 90 Women with affected pregnancies will be recruited and randomised to receive either sildenafil or placebo. Women reviewed in the participating fetal medicine with a diagnosis of a pregnancy affected by early-onset IUGR between 18+0 and 27+6 weeks of gestation and serum PlGF levels less than 5th percentile for gestational age will be considered for randomisation. In Canadian STRIDER, the treatment with either sildenafil or placebo (25 mg 3 times per day) will be applied from the time of randomisation until delivery, or up to 31+6 weeks of gestation whichever comes first. All patients randomly assigned to one of the treatments will be analysed together, regardless of whether or not they completed or received that treatment, on an intention to treat basis.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Gestational age from 18+0 - 27+6 weeks AND * EO IUGR, defined as 1. ultrasound (U/S) measurement of the fetal abdominal circumference (AC) \<10th percentile for gestational age and/or documented reduced fetal growth velocity complicating either a prior EO IUGR with adverse perinatal outcome or abnormal uterine artery waveform in the index pregnancy; OR 2. U/S estimate of fetal weight (EFW) \<700g AND * Serum PlGF \< 5th percentile for gestational age Exclusion Criteria: * known fetal aneuploidy * known fetal anomaly/syndrome/congenital infection confirmed at the time of enrolment * decision made to terminate pregnancy * current cocaine or vasoconstrictor use (e.g. crystal meth) (risk of acute cardiac events) * contraindication to sildenafil therapy, e.g. known significant maternal cardiac disease, left ventricular outflow tract obstruction, concomitant treatment with nitrates or previous allergy to sildenafil * known HIV positive status (due drug-drug interaction between sildenafil and antiretrovirals) * receiving peripheral alpha-blockers (e.g. prazosin) * prior participation in a STRIDER trials * pre-eclampsia or gestational hypertension diagnosed

Locations (5)

Royal Alexandra Hospital

Edmonton, Alberta, Canada

BC Women's Hospital/University of British Columbia

Vancouver, British Columbia, Canada

London Health Sciences Centre

London, Ontario, Canada

CHU Sainte-Justine

Montreal, Quebec, Canada

CHU de Quebec - Universite Laval

Québec, Quebec, Canada

Outcomes

Primary Outcomes

compare the gestational age at delivery (d) between sildenafil- and placebo-treated groups

Time frame: 6 weeks after postpartum

Secondary Outcomes

live birth

Time frame: at delivery if alive

survival to hospital discharge

Time frame: measured at the final hospital discharge (average upto 6 weeks postpartum)

intact survival (defined as survival to estimated due date (EDD) without evidence of severe central nervous system [CNS] injury [by ultrasound and/or magnetic resonance imaging (MRI)])

Time frame: measured at estimated due date (EDD)

composite non-CNS (Central Nervous System) severe morbidity (one/more of bronchopulmonary dysplasia requiring supplemental oxygen on hospital discharge, ≥grade 3 retinopathy of prematurity, or necrotising enterocolitis)

Time frame: up to 6 weeks after postpartum or final discharge which ever is sooner