The Dutch STRIDER (Sildenafil TheRapy In Dismal Prognosis Early-onset Fetal Growth Restriction)

Study Overview
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Brief Summary
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Rationale: Severe, early-onset fetal growth restriction (FGR) due to placental insufficiency is associated with a high risk of perinatal morbidity with long-lasting sequelae and mortality. Placental insufficiency is the result of abnormal formation and function of the placenta (placentation) with inadequate remodelling of the maternal spiral (uteroplacental) arteries. There is currently no therapy available with demonstrated effectiveness. Evidence suggests Sildenafil citrate improves uteroplacental blood flow, growth, and meaningful outcomes. Objective: To evaluate the effectiveness of sildenafil (versus placebo) in achieving healthy perinatal survival. Study design: Multicenter nationwide randomized placebo-controlled clinical trial. Study population: Women with a singleton pregnancy between 20 and 30 weeks with severe fetal growth restriction of likely placental origin, and with estimated significant likelihood of perinatal death. Intervention: Sildenafil 25mg or placebo tablet orally three times daily. Main study parameters/endpoints: Perinatal healthy survival, i.e. survival without severe neonatal morbidity at term age. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Taking tablets three times daily. No additional ultrasounds, other than standard clinical protocol, one extra blood sample at inclusion. No risks anticipated, unexpected medication-associated risks can't be excluded on beforehand.

Official Title
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The Dutch STRIDER (Sildenafil TheRapy In Dismal Prognosis Early-onset Fetal Growth Restriction)

Conditions
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Fetal Growth Restriction

Intervention / Treatment
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* Drug: Sildenafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria ((I OR II) AND III): At 20+0-27+6 weeks: an ultrasound measurement of the fetal abdominal circumference (AC) <3rd percentile for gestational age or an ultrasound estimate of fetal weight (EFW) <5th percentile OR At 28+0-29+6 weeks: an ultrasound estimate of fetal weight (EFW) <700 grams using Hadlock C formula AND Likely placental origin defined by (a AND/OR b AND/OR c AND/OR d) The presence of uterine artery notching Abnormal flow velocity patterns of the umbilical artery or middle cerebral artery Maternal hypertensive disorders Low PlGF in point-of-care assessment Exclusion Criteria: Plan to terminate pregnancy for maternal or fetal indication within days Known multiple pregnancy Identified congenital anomalies or congenital infection Maternal age at eligibility <18 years Cocaine use Current use of sildenafil Current use of cyp3A5 inhibitors: amiodaron, azitromycine, ciclosporine, claritromycine, diltiazem, erytromycine, fluconazol, itraconazol, ketoconazol, verapamil, voriconazol. Recent myocardial infarction or stroke

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sildenafil<br>Sildenafil 25 mg tablets three times daily orally from randomization until delivery | Drug: Sildenafil<br>* Sildenafil 25 mg three times daily orally from randomization until delivery<br>* Other names: Viagra;|
| Placebo Comparator: Placebo<br>Placebo tablets three times daily orally from randomization until delivery | Drug: Placebo<br>* Placebo tablets three times daily orally from randomization until delivery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intact neonatal survival until term age |  | Term age, up to 20 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fetal growth velocity assessed by ultrasound: abdominal circumference measurements (AC) | Average daily increase in ultrasound-estimated AC | At contact moments with the patient, up to 20 weeks after randomization | 
| Age-adequate performance on the two-year Bayley scales of infant development (BSID)-III (composite cognitive score and composite motor score) |  | 2 years corrected age, up to 2 years and three months after randomization | 
| Co-incidence and severity of the maternal syndrome of pre-eclampsia / HELLP-syndrome (Hemolysis Elevated Liver enzymes Low Platelets) |  | At contact moments with the patient, up to 20 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fetal growth restriction, Sildenafil