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Results of interim analysis
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| Name | Class |
|---|---|
| ZonMw: The Netherlands Organisation for Health Research and Development | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sildenafil | Active Comparator | Sildenafil 25 mg tablets three times daily orally from randomization until delivery |
|
| Placebo | Placebo Comparator | Placebo tablets three times daily orally from randomization until delivery |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sildenafil | Drug | Sildenafil 25 mg three times daily orally from randomization until delivery |
|
| Measure | Description | Time Frame |
|---|---|---|
| Intact neonatal survival until term age | Term age, up to 20 weeks after randomization |
| 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) |
| 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 |
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)
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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) |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Radboud Medisch Centrum Nijmegen | Nijmegen | Gelderland | 6525GA | Netherlands | ||
| Maastricht Universitair Medisch Centrum |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32585017 | Derived | 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. | |
| 30635020 |
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| Placebo | Drug | Placebo tablets three times daily orally from randomization until delivery |
|
| 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 |
| PlGF (Placental Growth Factor) point-of-care assessment | If possible in designated clinic | At baseline |
| Maastricht |
| Limburg |
| 6202AZ |
| Netherlands |
| Maxima Medisch Centrum | Veldhoven | North Brabant | 5504 DB | Netherlands |
| Vrije Universiteit Medisch Centrum | Amsterdam | North Holland | 1081HV | Netherlands |
| Academisch Medisch Centrum | Amsterdam | North Holland | 1105AZ | Netherlands |
| Isala Klinieken | Zwolle | Overijssel | 8025 AB | Netherlands |
| Leids Universitair Medisch Centrum | Leiden | South Holland | 2333ZA | Netherlands |
| Erasmus Medisch Centrum Rotterdam | Rotterdam | South Holland | 3015CE | Netherlands |
| Universitair Medisch Centrum Groningen | Groningen | 9713GZ | Netherlands |
| Universitair Medisch Centrum Utrecht | Utrecht | 3584CX | Netherlands |
| 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. |
| 29282009 | 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. |
| ID | Term |
|---|---|
| D005317 | Fetal Growth Retardation |
| ID | Term |
|---|---|
| D005315 | Fetal Diseases |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006130 | Growth Disorders |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000068677 | Sildenafil Citrate |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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