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

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Status and phase: Terminated; Phase 3; Phase 2

Conditions: Fetal Growth Restriction

Treatments: Drug: Sildenafil; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02277132

80-83600-98-20081

Details and patient eligibility

About

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.

Enrollment: 216 patients

Sex: Female

Ages: 18 to 50 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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216 participants in 2 patient groups, including a placebo group

Sildenafil

Active Comparator group

Description:

Sildenafil 25 mg tablets three times daily orally from randomization until delivery

Treatment:

Drug: Sildenafil

Placebo

Placebo Comparator group

Description:

Placebo tablets three times daily orally from randomization until delivery

Treatment:

Drug: Placebo