Clinical trial NCT02277132: The Dutch STRIDER (Sildenafil TheRapy In Dismal Prognosis Early-onset Fetal Growth Restriction)
Official title: The Dutch STRIDER (Sildenafil TheRapy In Dismal Prognosis Early-onset Fetal Growth Restriction)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Fetal Growth Restriction
Keywords: Fetal growth restriction
Sildenafil
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2014-10-28
Enrollment: 216
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Intact neonatal survival until term age
timeFrame: Term age, up to 20 weeks after randomization
Secondary outcomes:
measure: Fetal growth velocity assessed by ultrasound: abdominal circumference measurements (AC)
timeFrame: At contact moments with the patient, up to 20 weeks after randomization
measure: Age-adequate performance on the two-year Bayley scales of infant development (BSID)-III (composite cognitive score and composite motor score)
timeFrame: 2 years corrected age, up to 2 years and three months after randomization
measure: Co-incidence and severity of the maternal syndrome of pre-eclampsia / HELLP-syndrome (Hemolysis Elevated Liver enzymes Low Platelets)
timeFrame: At contact moments with the patient, up to 20 weeks after randomization
Other outcomes:
measure: Fetal ultrasound and Doppler studies: estimated fetal weight, abdominal circumference and Doppler of umbilical artery
timeFrame: At contact moments with the patients, up to 20 weeks after randomization
measure: PlGF (Placental Growth Factor) point-of-care assessment
timeFrame: At baseline
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud Medisch Centrum Nijmegen
state: Gelderland
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum
state: Limburg
city: Veldhoven
country: Netherlands
facility: Maxima Medisch Centrum
state: Noord Brabant
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
state: Noord Holland
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
state: Noord Holland
city: Zwolle
country: Netherlands
facility: Isala Klinieken
state: Overijssel
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum Rotterdam
state: Zuid Holland
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: J.W. Ganzevoort, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: K Bloemenkamp, MD PhD
role: STUDY_CHAIR
affiliation: University of British Columbia
name: P von Dadelszen, Prof
role: STUDY_CHAIR
affiliation: VU Medisch Centrum
name: C de Groot, Prof
role: STUDY_CHAIR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: M.W. de Laat, MD PhD
role: STUDY_CHAIR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: B.W. Mol, Prof
role: STUDY_CHAIR
affiliation: Perinataal Centrum MMC Veldhoven
name: M. Porath, MD PhD
role: STUDY_CHAIR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: J.A.M. van der Post, Prof
role: STUDY_CHAIR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: A. van Wassenaer, MD PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.