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

NCT02277132 | Terminated Phase 2 DMC

• 1 other identifier: 80-83600-98-20081
• Study Type: interventional
• Target: 216
• Locations: 1 country
• Sites: 10

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.

Conditions

Fetal Growth Restriction

Keywords

Fetal growth restriction; Sildenafil

Outcome Measures

Primary Outcomes (1)

• Intact neonatal survival until term age

  Term age, up to 20 weeks after randomization

Secondary Outcomes (3)

• Fetal growth velocity assessed by ultrasound: abdominal circumference measurements (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 Outcomes (2)

• 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

• PlGF (Placental Growth Factor) point-of-care assessment

  At baseline

Study Arms (2)

Sildenafil

ACTIVE COMPARATOR

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

Drug: Sildenafil

Placebo

PLACEBO COMPARATOR

Placebo tablets three times daily orally from randomization until delivery

Drug: Placebo

Interventions

Sildenafil DRUG

Sildenafil 25 mg three times daily orally from randomization until delivery

Also known as: Viagra

Sildenafil

Placebo DRUG

Placebo tablets three times daily orally from randomization until delivery

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (10)

Radboud Medisch Centrum Nijmegen

Nijmegen, Gelderland, 6525GA, Netherlands

Location

Maastricht Universitair Medisch Centrum

Maastricht, Limburg, 6202AZ, Netherlands

Location

Maxima Medisch Centrum

Veldhoven, North Brabant, 5504 DB, Netherlands

Location

Vrije Universiteit Medisch Centrum

Amsterdam, North Holland, 1081HV, Netherlands

Location

Academisch Medisch Centrum

Amsterdam, North Holland, 1105AZ, Netherlands

Location

Isala Klinieken

Zwolle, Overijssel, 8025 AB, Netherlands

Location

Leids Universitair Medisch Centrum

Leiden, South Holland, 2333ZA, Netherlands

Location

Erasmus Medisch Centrum Rotterdam

Rotterdam, South Holland, 3015CE, Netherlands

Location

Universitair Medisch Centrum Groningen

Groningen, 9713GZ, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584CX, Netherlands

Location

Related Publications (3)

• 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.

  PMID: 32585017 DERIVED

• 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.

  PMID: 30635020 DERIVED

• 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.

  PMID: 29282009 DERIVED

MeSH Terms

Conditions

Fetal Growth Retardation

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Fetal Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Growth Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• J.W. Ganzevoort, MD PhD

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

  PRINCIPAL INVESTIGATOR

• 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)

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: J.W. Ganzevoort MD PhD

Study Record Dates

• First Submitted: September 29, 2014
• First Posted: October 28, 2014
• Study Start: January 1, 2015
• Primary Completion: July 19, 2018
• Study Completion: July 19, 2018
• Last Updated: July 26, 2018

Record last verified: 2018-07

Locations

NL (10)