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

Conditions

Fetal Growth Restriction

Keywords

Fetal growth restriction, Sildenafil

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.

Anouk Pels, Jan Derks, Ayten Elvan‐Taşpınar, J. van Drongelen, Marjon A. de Boer et al. (21 authors)

JAMA Network Open2020-06-17114 citations

10.1001/jamanetworkopen.2020.5323

Detailed statistical analysis plan for the Dutch STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset fetal growth Restriction) randomised clinical trial on sildenafil versus placebo for pregnant women with severe early onset fetal growth restriction.

Pels A, Jakobsen JC, Ganzevoort W, Naaktgeboren CA, Onland W, van Wassenaer-Leemhuis AG, Gluud C.

2019-01-118 citations

10.1186/s13063-018-3136-z

STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials.

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.

2017-12-2835 citations

10.1186/s12884-017-1594-z

Interventions

DRUGSildenafil

Sildenafil 25 mg three times daily orally from randomization until delivery

DRUGPlacebo

Placebo tablets three times daily orally from randomization until delivery

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 50 Years

Healthy volunteers

No

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

Design outcomes

Primary

Measure	Time frame
Intact neonatal survival until term age	Term age, up to 20 weeks after randomization

Secondary

Measure	Time frame	Description
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	—
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	—

Other

Measure	Time frame	Description
Fetal ultrasound and Doppler studies: estimated fetal weight, abdominal circumference and Doppler of umbilical artery	At contact moments with the patients, up to 20 weeks after randomization	Umbilical artery, middle cerebral artery, ductus venosus and aortic isthmus Doppler indices; fetal biometry; amniotic fluid index; deepest vertical amniotic fluid pocket.
PlGF (Placental Growth Factor) point-of-care assessment	At baseline	If possible in designated clinic

Countries

Netherlands

Outcome results

None listed