Clinical trial NCT02442492: Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction
Official title: STRIDER Canada: A Randomized Controlled Trial of Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction (Canada)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Intrauterine Growth Restriction (IUGR)
Fetal Growth Restriction (FGR)
Keywords: sildenafil
IUGR
FGR
STRIDER
Lead sponsor: University of British Columbia
Sponsor class: OTHER
First posted: 2015-05-13
Enrollment: 21
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: compare the gestational age at delivery (d) between sildenafil- and placebo-treated groups
timeFrame: 6 weeks after postpartum
Secondary outcomes:
measure: live birth
timeFrame: at delivery if alive
measure: survival to hospital discharge
timeFrame: measured at the final hospital discharge (average upto 6 weeks postpartum)
measure: 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)])
timeFrame: measured at estimated due date (EDD)
measure: 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)
timeFrame: up to 6 weeks after postpartum or final discharge which ever is sooner
Other outcomes:
measure: Maternal - symptomatic hypotension
timeFrame: up to 6 weeks after postpartum or final discharge which ever is sooner
measure: Maternal - pre-eclampsia
timeFrame: from randomisation to delivery (expected to be assessed weekly)
measure: Maternal - mode of delivery
timeFrame: At delivery
measure: Maternal - haemorrhage requiring transfusion
timeFrame: At delivery
measure: Maternal - maternal plasma PlGF.
timeFrame: from randomisation to delivery (expected to be assessed weekly)
measure: Maternal - uterine artery Doppler indices
timeFrame: from randomisation to delivery (expected to be done weekly)
measure: Perinatal - fetal growth velocity
timeFrame: from randomisation to delivery (expected to be done weekly)
measure: Perinatal - fetal Doppler
timeFrame: from randomisation to delivery (expected to be done weekly)
measure: Perinatal - amniotic fluid
timeFrame: At randomisation, if done
measure: Perinatal - fetal heart indices
timeFrame: rom randomisation to delivery (expected to be done weekly)
Locations:
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Vancouver
country: Canada
facility: BC Women's Hospital/University of British Columbia
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Quebec - Universite Laval
state: Quebec
Study officials:
affiliation: University of British Columbia
name: Peter von Dadelszen, BMedSc, MBChB, DipObst, DPhil,
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia
name: Kenneth Lim, MD FRCSC
role: PRINCIPAL_INVESTIGATOR
References:
citation: von Dadelszen P, Audibert F, Bujold E, Bone JN, Sandhu A, Li J, Kariya C, Chung Y, Lee T, Au K, Skoll MA, Vidler M, Magee LA, Piedboeuf B, Baker PN, Lalji S, Lim KI. Halting the Canadian STRIDER randomised controlled trial of sildenafil for severe, early-onset fetal growth restriction: ethical, methodological, and pragmatic considerations. BMC Res Notes. 2022 Jul 7;15(1):244. doi: 10.1186/s13104-022-06107-y.
citation: Pels A, Kenny LC, Alfirevic Z, Baker PN, von Dadelszen P, Gluud C, Kariya CT, Mol BW, Papageorghiou AT, van Wassenaer-Leemhuis AG, Ganzevoort W, Groom KM; international STRIDER Consortium. STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials. BMC Pregnancy Childbirth. 2017 Dec 28;17(1):440. doi: 10.1186/s12884-017-1594-z.