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

• ClinicalTrials.gov Identifier: NCT02277132
• Recruitment Status: Terminated
• First Posted: October 28, 2014
• Last Update Posted: July 26, 2018
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborator: ZonMw: The Netherlands Organisation for Health Research and Development
• Information provided by (Responsible Party): Wessel Ganzevoort, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Fetal Growth Restriction	Drug: Sildenafil; Drug: Placebo	Phase 2; Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 216 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Dutch STRIDER (Sildenafil TheRapy In Dismal Prognosis Early-onset Fetal Growth Restriction)
• Study Start Date: January 2015
• Actual Primary Completion Date: July 19, 2018
• Actual Study Completion Date: July 19, 2018

Arms and Interventions

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 Name: 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

Outcome Measures

Primary Outcome Measures :

1. Intact neonatal survival until term age [ Time Frame: Term age, up to 20 weeks after randomization ]

Secondary Outcome Measures :

1. Fetal growth velocity assessed by ultrasound: abdominal circumference measurements (AC) [ Time Frame: At contact moments with the patient, up to 20 weeks after randomization ]
   Average daily increase in ultrasound-estimated AC
2. Age-adequate performance on the two-year Bayley scales of infant development (BSID)-III (composite cognitive score and composite motor score) [ Time Frame: 2 years corrected age, up to 2 years and three months after randomization ]
3. Co-incidence and severity of the maternal syndrome of pre-eclampsia / HELLP-syndrome (Hemolysis Elevated Liver enzymes Low Platelets) [ Time Frame: At contact moments with the patient, up to 20 weeks after randomization ]

Other Outcome Measures:

1. Fetal ultrasound and Doppler studies: estimated fetal weight, abdominal circumference and Doppler of umbilical artery [ Time Frame: 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.
2. PlGF (Placental Growth Factor) point-of-care assessment [ Time Frame: At baseline ]
   If possible in designated clinic

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Netherlands

Radboud Medisch Centrum Nijmegen

Nijmegen, Gelderland, Netherlands, 6525GA

Maastricht Universitair Medisch Centrum

Maastricht, Limburg, Netherlands, 6202AZ

Maxima Medisch Centrum

Veldhoven, Noord Brabant, Netherlands, 5504 DB

Vrije Universiteit Medisch Centrum

Amsterdam, Noord Holland, Netherlands, 1081HV

Academisch Medisch Centrum

Amsterdam, Noord Holland, Netherlands, 1105AZ

Isala Klinieken

Zwolle, Overijssel, Netherlands, 8025 AB

Leids Universitair Medisch Centrum

Leiden, Zuid Holland, Netherlands, 2333ZA

Erasmus Medisch Centrum Rotterdam

Rotterdam, Zuid Holland, Netherlands, 3015CE

Universitair Medisch Centrum Groningen

Groningen, Netherlands, 9713GZ

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands, 3584CX

Sponsors and Collaborators

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

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)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Wessel Ganzevoort, J.W. Ganzevoort MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• ClinicalTrials.gov Identifier: NCT02277132
• Other Study ID Numbers: 80-83600-98-20081
• First Posted: October 28, 2014
• Last Update Posted: July 26, 2018
• Last Verified: July 2018

Keywords provided by Wessel Ganzevoort, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Fetal growth restriction; Sildenafil

Additional relevant MeSH terms:

Fetal Growth Retardation; Fetal Diseases; Pregnancy Complications; Growth Disorders; Pathologic Processes; Sildenafil Citrate; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents