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

• Sponsor: University of British Columbia
• Information provided by (Responsible Party): Kenneth Lim, University of British Columbia

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Intrauterine Growth Restriction (IUGR); Fetal Growth Restriction (FGR)	Drug: Sildenafil; Drug: Placebo	Phase 2; Phase 3

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	21 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	STRIDER Canada: A Randomized Controlled Trial of Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction (Canada)
Actual Study Start Date :	January 2017
Actual Primary Completion Date :	July 2018
Actual Study Completion Date :	April 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. compare the gestational age at delivery (d) between sildenafil- and placebo-treated groups [ Time Frame: 6 weeks after postpartum ]

Secondary Outcome Measures :

1. live birth [ Time Frame: at delivery if alive ]
2. survival to hospital discharge [ Time Frame: measured at the final hospital discharge (average upto 6 weeks postpartum) ]
3. 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) ]
4. 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 ]

Other Outcome Measures:

1. Maternal - symptomatic hypotension [ Time Frame: up to 6 weeks after postpartum or final discharge which ever is sooner ]
2. Maternal - pre-eclampsia [ Time Frame: from randomisation to delivery (expected to be assessed weekly) ]
3. Maternal - mode of delivery [ Time Frame: At delivery ]
4. Maternal - haemorrhage requiring transfusion [ Time Frame: At delivery ]
5. Maternal - maternal plasma PlGF. [ Time Frame: from randomisation to delivery (expected to be assessed weekly) ]
6. Maternal - uterine artery Doppler indices [ Time Frame: from randomisation to delivery (expected to be done weekly) ]
7. Perinatal - fetal growth velocity [ Time Frame: from randomisation to delivery (expected to be done weekly) ]
8. Perinatal - fetal Doppler [ Time Frame: from randomisation to delivery (expected to be done weekly) ]
9. Perinatal - amniotic fluid [ Time Frame: At randomisation, if done ]
10. Perinatal - fetal heart indices [ Time Frame: rom randomisation to delivery (expected to be done weekly) ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

University of British Columbia

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Kenneth Lim, Study Principal Investigator, University of British Columbia
ClinicalTrials.gov Identifier:	NCT02442492 History of Changes
Other Study ID Numbers:	H15-00899
First Posted:	May 13, 2015
Last Update Posted:	May 7, 2019
Last Verified:	May 2019

Keywords provided by Kenneth Lim, University of British Columbia:

sildenafil; IUGR; FGR; STRIDER

Additional relevant MeSH terms:

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Fetal Growth Retardation; Fetal Diseases; Pregnancy Complications; Growth Disorders; Pathologic Processes; Sildenafil Citrate	Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents