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

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.

Study Overview

• Status: Terminated
• Conditions: Fetal Growth Restriction
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713GZ
    • Universitair Medisch Centrum Groningen
  • Utrecht, Netherlands, 3584CX
    • Universitair Medisch Centrum Utrecht
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Radboud Medisch Centrum Nijmegen
  • Limburg
    • Maastricht, Limburg, Netherlands, 6202AZ
      • Maastricht Universitair Medisch Centrum
  • Noord Brabant
    • Veldhoven, Noord Brabant, Netherlands, 5504 DB
      • Máxima Medisch Centrum
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1081HV
      • Vrije Universiteit Medisch Centrum
    • Amsterdam, Noord Holland, Netherlands, 1105AZ
      • Academisch Medisch Centrum
  • Overijssel
    • Zwolle, Overijssel, Netherlands, 8025 AB
      • Isala Klinieken
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333ZA
      • Leids Universitair Medisch Centrum
    • Rotterdam, Zuid Holland, Netherlands, 3015CE
      • Erasmus Medisch Centrum Rotterdam

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Sildenafil; Sildenafil 25 mg tablets three times daily orally from randomization until delivery	Drug: Sildenafil; Sildenafil 25 mg three times daily orally from randomization until delivery; Other Names: Viagra
PLACEBO_COMPARATOR: Placebo; Placebo tablets three times daily orally from randomization until delivery	Drug: Placebo; Placebo tablets three times daily orally from randomization until delivery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: J.W. Ganzevoort, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Study Chair: K Bloemenkamp, MD PhD, Leiden University Medical Center; Study Chair: P von Dadelszen, Prof, University of British Columbia; Study Chair: C de Groot, Prof, VU Medisch Centrum; Study Chair: M.W. de Laat, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Study Chair: B.W. Mol, Prof, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Study Chair: M. Porath, MD PhD, Perinataal Centrum MMC Veldhoven; Study Chair: J.A.M. van der Post, Prof, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Study Chair: A. van Wassenaer, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Pels A, Derks J, Elvan-Taspinar A, van Drongelen J, de Boer M, Duvekot H, van Laar J, van Eyck J, Al-Nasiry S, Sueters M, Post M, Onland W, van Wassenaer-Leemhuis A, Naaktgeboren C, Jakobsen JC, Gluud C, Duijnhoven RG, Lely T, Gordijn S, Ganzevoort W; Dutch STRIDER Trial Group. Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial. JAMA Netw Open. 2020 Jun 1;3(6):e205323. doi: 10.1001/jamanetworkopen.2020.5323.
• Pels A, Jakobsen JC, Ganzevoort W, Naaktgeboren CA, Onland W, van Wassenaer-Leemhuis AG, Gluud C. 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. Trials. 2019 Jan 11;20(1):42. doi: 10.1186/s13063-018-3136-z.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (ACTUAL): July 19, 2018
• Study Completion (ACTUAL): July 19, 2018

Study Registration Dates

• First Submitted: September 29, 2014
• First Submitted That Met QC Criteria: October 26, 2014
• First Posted (ESTIMATE): October 28, 2014

Study Record Updates

• Last Update Posted (ACTUAL): July 26, 2018
• Last Update Submitted That Met QC Criteria: July 24, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Sildenafil; Fetal growth restriction
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Fetal Growth Retardation; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 80-83600-98-20081