Clinical trial NCT04502823: Management of Fetal Growth Restriction at Term: Angiogenic Factors Versus Feto-placental Doppler
Official title: Management of Fetal Growth Restriction at Term: Angiogenic Factors Versus Feto-placental Doppler (GRAFD Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fetal Growth Retardation
Lead sponsor: Hospital Universitari Vall d'Hebron Research Institute
Sponsor class: OTHER
First posted: 2020-08-06
Enrollment: 1088
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Open randomized non-inferiority controlled trial to examine the use of angiogenic factors (instead of feto-placental Doppler) for fetal growth restriction at term to reduce the rate of labor inductions, without worsening perinatal outcomes.

Detailed description: Pregnant women with estimated fetal weight (EFW) \< 10th centile between 36+0 and 37+6 weeks of gestation (WG) will receive complete ultrasonographic assessment consisting of feto-placental Doppler, amniotic fluid measurement and biophysical profile assessment. The cases not meeting any exclusion criteria will be offered to participate in this trial. After giving their informed consent a blood sample will be drawn in all of them and they will undergo randomization into two arms.

1. Intervention arm: In women allocated to the intervention group, the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) result will be revealed to the investigators that will act according to the results of sFlt/PlGF:

   * Fetuses with sFlt-1/PlGF ≥38, elective delivery will be recommended at ≥37 weeks.
   * Fetuses with sFlt-1/PlGF \<38, weekly follow up will be recommended until delivery (at ≥40 weeks).
2. Control arm: In women allocated to the control group, the sFlt-1/PlGF result will be blinded to caregivers. Routine Doppler-based clinical care will be used to counsel women. Following the Doppler classification:

   * Fetuses with EFW below the 3rd centile or below the 10th centile accompanied by any impaired fetoplacental Doppler, elective delivery will be recommended at at ≥37 weeks.
   * Fetuses with EFW above the 3rd centile without any fetoplacental Doppler abnormality, elective delivery will be recommended at at ≥40 weeks.

In both arms, fetuses will receive weekly follow-up from randomization to delivery consisting on feto-placental Doppler sFlt-1/PlGF and CTG. If any of the following is present at any time, earlier delivery will be recommended:

* sFlt-1/PlGF ≥38 (only in the intervention group),
* absent or reverse end-diastolic flow at the umbilical artery Doppler or DV PI\>95th centile
* non-reassuring CTG
* preeclampsia
* diminished fetal movements
* biophysical profile ≤ 6 or oligohydramnios (deepest pocket \<2 cm).

Eligibility criteria: Inclusion Criteria:

1. Pregnant women ≥ 16 years of age.
2. Singleton pregnancy.
3. Ultrasonographic estimated fetal weight \<10th centile.
4. Gestational age between 36+0 and 37+6 weeks.

Exclusion Criteria:

1. Major fetal malformations or genetic disorders.
2. Fetal death.
3. Absent or reverse end-diastolic flow in umbilical artery Doppler or DV PI\>95th centile.
4. Non-reassuring cardiotocography (CTG).
5. Preeclampsia.
6. Diminished fetal movements.
7. Biophysical profile ≤ 6.
8. Oligohydramnios
9. Refusal to give informed consent.

Primary outcomes:
measure: Adverse perinatal outcomes
timeFrame: 4-6 weeks
Secondary outcomes:
measure: Rate of elective delivery
timeFrame: 4-6 weeks
measure: Rate of Cesarean delivery
timeFrame: 4-6 weeks
measure: Rate of Induction of labor
timeFrame: 4-6 weeks
measure: Rate of neonatal admission in intensive care unit
timeFrame: 4-6 weeks
measure: Time of neonatal admission in intensive care unit
timeFrame: 4-6 weeks
measure: Rate of preeclampsia
timeFrame: 4-6 weeks
measure: Rate of neonatal complications
timeFrame: 4-10 weeks
measure: Rate of maternal complications
timeFrame: 4-6 weeks
measure: Rate of perinatal complications
timeFrame: 4-6 weeks
measure: Rate of total deliveries at <37, <38, <39 and <40 weeks of gestation
timeFrame: 4-6 weeks
measure: Rate of elective deliveries at <37, <38, <39 and <40 weeks of gestation
timeFrame: 4-6 weeks
measure: Rate of newborns with birthweight <2000 and <2500 grams
timeFrame: 4-6 weeks
Other outcomes:
Locations:
city: A Coruña
country: Spain
facility: Hospital Universitario de A Coruña
city: Alicante
country: Spain
facility: Hospital General de Alicante
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'hebron
city: Cabueñes
country: Spain
facility: Hospital Universitario de Cabueñes
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
city: Girona
country: Spain
facility: Hospital Universitari Doctor Josep Trueta
city: Manresa
country: Spain
facility: Hospital Sant Joan de Deu de Manresa
city: Murcia
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llàtzer
city: Sabadell
country: Spain
facility: Consorci Corporació Sanitària Parc Taulí de Sabadell
city: Santa Cruz De Tenerife
country: Spain
facility: Hospital Universitario Nuestra Señora de Candelaria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de Valme
city: Tarragona
country: Spain
facility: Hospital Universitari Joan XXIII
city: Terrassa
country: Spain
facility: Hospital de Terrassa
city: Terrassa
country: Spain
facility: Hospital Universitari Mútua Terrassa
city: Torrejón De Ardoz
country: Spain
facility: Hospital Universitario de Torrejon
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
Study officials:
affiliation: Vall d'hebron Institut de Recerca
name: Manel Mendoza, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Garcia-Manau P, Mendoza M, Bonacina E, Martin-Alonso R, Martin L, Palacios A, Sanchez ML, Lesmes C, Hurtado I, Perez E, Tubau A, Ibanez P, Alcoz M, Valino N, Moreno E, Borrero C, Garcia E, Lopez-Quesada E, Diaz S, Broullon JR, Teixidor M, Chulilla C, Gil MM, Lopez M, Candela-Hidalgo A, Salinas-Amoros A, Moreno A, Morra F, Vaquerizo O, Soriano B, Fabre M, Gomez-Valencia E, Cuina A, Alayon N, Sainz JA, Vives A, Esteve E, Ocana V, Lopez MA, Maroto A, Carreras E. The Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) Trial to Avoid Adverse Perinatal Outcomes: Protocol for a Multicenter, Open-Label, Randomized Controlled Trial. JMIR Res Protoc. 2022 Oct 11;11(10):e37452. doi: 10.2196/37452.