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

Phase 2

Terminated

• Conditions: Fetal Growth Restriction
• Interventions: Drug: Sildenafil; Drug: Placebo

• Registration Number: NCT02277132
• Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-09-29
• Study First Submitted QC: 2014-10-26
• Study First Posted: 2014-10-28
• Study Start: 2015-01
• Status Verified: 2018-07
• Primary Completion: 2018-07-19
• Study Completion: 2018-07-19
• Last Update Submitted: 2018-07-24
• Last Update Posted: 2018-07-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Female
• Target Recruitment: 216

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sildenafil	Sildenafil	Sildenafil 25 mg tablets three times daily orally from randomization until delivery
Placebo	Placebo	Placebo tablets three times daily orally from randomization until delivery

Primary Outcome Measures

Name	Time	Method
Intact neonatal survival until term age	Term age, up to 20 weeks after randomization

Secondary Outcome Measures

Name	Time	Method
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
Fetal growth velocity assessed by ultrasound: abdominal circumference measurements (AC)	At contact moments with the patient, up to 20 weeks after randomization	Average daily increase in ultrasound-estimated AC
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

Trial Locations

Locations (10)

Maastricht Universitair Medisch Centrum; 🇳🇱 Maastricht, Limburg, Netherlands

Academisch Medisch Centrum; 🇳🇱 Amsterdam, Noord Holland, Netherlands

Isala Klinieken; 🇳🇱 Zwolle, Overijssel, Netherlands

Leids Universitair Medisch Centrum; 🇳🇱 Leiden, Zuid Holland, Netherlands

Universitair Medisch Centrum Groningen; 🇳🇱 Groningen, Netherlands

Universitair Medisch Centrum Utrecht; 🇳🇱 Utrecht, Netherlands

Erasmus Medisch Centrum Rotterdam; 🇳🇱 Rotterdam, Zuid Holland, Netherlands

Vrije Universiteit Medisch Centrum; 🇳🇱 Amsterdam, Noord Holland, Netherlands

Maxima Medisch Centrum; 🇳🇱 Veldhoven, Noord Brabant, Netherlands

Radboud Medisch Centrum Nijmegen; 🇳🇱 Nijmegen, Gelderland, Netherlands