Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction (STRIDERCan)

STRIDER Canada: A Randomized Controlled Trial of Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction (Canada)

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.

Study Overview

• Status: Terminated
• Conditions: Intrauterine Growth Restriction (IUGR); Fetal Growth Restriction (FGR)
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V7H3N1
      • BC Women's Hospital/University of British Columbia
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
  • Quebec
    • Montréal, Quebec, Canada, H3T 1C5
      • CHU Sainte-Justine
    • Quebec City, Quebec, Canada, G2N 0B2
      • CHU de Québec - Université Laval

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sildenafil; Sildenafil 25 mg tablets three times daily orally from randomization until delivery or 31+6 weeks of gestational age, whichever is sooner.	Drug: Sildenafil; Sildenafil 25 mg tablets three times daily orally from randomization until delivery or 31+6 weeks of gestational age, whichever is sooner.
Placebo Comparator: Placebo; Placebo 25 mg tablets three times daily orally from randomization until delivery or 31+6 weeks of gestational age, whichever is sooner.	Drug: Placebo; Placebo 25 mg tablets three times daily orally from randomization until delivery or 31+6 weeks of gestational age, whichever is sooner.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
compare the gestational age at delivery (d) between sildenafil- and placebo-treated groups	6 weeks after postpartum

Secondary Outcome Measures

Outcome Measure	Time Frame
live birth	at delivery if alive
survival to hospital discharge	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)])	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)	up to 6 weeks after postpartum or final discharge which ever is sooner

Other Outcome Measures

Outcome Measure	Time Frame
Maternal - symptomatic hypotension	up to 6 weeks after postpartum or final discharge which ever is sooner
Maternal - pre-eclampsia	from randomisation to delivery (expected to be assessed weekly)
Maternal - mode of delivery	At delivery
Maternal - haemorrhage requiring transfusion	At delivery
Maternal - maternal plasma PlGF.	from randomisation to delivery (expected to be assessed weekly)
Maternal - uterine artery Doppler indices	from randomisation to delivery (expected to be done weekly)
Perinatal - fetal growth velocity	from randomisation to delivery (expected to be done weekly)
Perinatal - fetal Doppler	from randomisation to delivery (expected to be done weekly)
Perinatal - amniotic fluid	At randomisation, if done
Perinatal - fetal heart indices	rom randomisation to delivery (expected to be done weekly)

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Peter von Dadelszen, BMedSc, MBChB, DipObst, DPhil,, University of British Columbia; Principal Investigator: Kenneth Lim, MD FRCSC, University of British Columbia

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: May 5, 2015
• First Submitted That Met QC Criteria: May 8, 2015
• First Posted (Estimate): May 13, 2015

Study Record Updates

• Last Update Posted (Actual): February 11, 2020
• Last Update Submitted That Met QC Criteria: February 7, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: sildenafil; IUGR; FGR; STRIDER
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Fetal Growth Retardation; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: H15-00899