Fetal Growth RetardationearlyGRAFDNCT05284474
Management of Early-onset Fetal Growth Restriction: Angiogenic Factors Versus Feto-placental Doppler
A study testing soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) in people with Fetal Growth Retardation and Preeclampsia, run by Hospital Universitari Vall d'Hebron Research Institute at 27 sites in Spain.
Trial summary
This is a multicentre, open-label, randomized controlled trial. A total of 340 singleton pregnancies with an EFW ≤10th percentile between 26+0 and 31+6 weeks will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Fetal Growth Retardation, Preeclampsia, Placenta Diseases
- What is being tested?
- soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 340 participants
- Where
- 27 sitesSpain
- Study dates
- 3 Jun 2024to 30 Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Pregnant women of at least 18 years old
- Singleton pregnancy
- Ultrasonographic EFW ≤10th percentile between 26+0 and 31+6 weeks of gestation
- Gestational age confirmed by fetal crown-rump length measurement during the first trimester scan (from 11+0 to 13+6 weeks of gestation) or by in vitro fertilization dates.
Who cannot join
- Major fetal malformations or genetic disorders
- Fetal death
- Refusal to give informed consent
- Stage IV FGR
Trial locations and contacts
27 sites in 1 country. Contact the study team or a site near you to ask about taking part.
27 sites in 1 country
Spain27 sites
Complejo Hospitalario Universitario de A Coruña
A Coruña
Nuria Valiño, nuvalino@gmail.com
Hospital Universitario General de Alicante
Alicante
Ana Palacios, ana.palacios.marques@gmail.com
Hospital Universitari Germans Trias i Pujol
Badalona
Ivan Hurtado, ivan.hurtado85@gmail.com
Vall d'hebron Barcelona Hospital Campus
Barcelona, 08035
Manel Mendoza, MD, PhD, 934893000 ext. 3085, manel.mendoza@vallhebron.cat
Hospital de la Santa Creu i Sant Pau
Barcelona
Johana Ullmo, jullmo@santpau.cat
Hospital Universitari Dexeus
Barcelona
Pilar Prats, pilpra@dexeus.com
Hospital Universitario Puerta del Mar
Cadiz
Maria Angeles Anaya, manaya2404@gmail.com
Hospital General Universitario de Elche
Elche
Ada Harrington, ada.herrington@gmail.com
Hospital Universitario de Getafe
Getafe
Elena Pintado, elenapintadoparedes@gmail.com
Hospital Universitario de Cabueñes
Gijón
Esther Perez, estherpcarbajo@hotmail.com
Hospital Universitari de Girona Doctor Josep Trueta
Girona
Alexandra Bonmatí, abonmatis.girona.ics@gencat.cat
Hospital Universitario San Cecilio
Granada
Maria del Carmen Jimenez, mcarmenjimenezhernandez@gmail.com
Hospital Universitario de Jerez de la Frontera
Jerez de la Frontera
Cristina Romero, CRGARRI@GMAIL.COM
Hospital Materno Infantil de Gran Canaria
Las Palmas de Gran Canaria
Laura Molero, laura.molerosala@gmail.com
Hospital Universitari Arnau de Vilanova
Lleida
Sandra Borderia, sb.rabassa@gmail.com
Hospital Clínico San Carlos
Madrid
Ricardo Saviron, ricardo.saviron@salud.madrid.org
Hospital Universitari Son Espases
Palma de Mallorca
Maria Vila, mariavilacortes@gmail.com
Hospital Universitari Son Llàtzer
Palma de Mallorca
Beatriz Soriano, bea180680@gmail.com
Corporació Sanitària Parc Taulí
Sabadell
Anna Moreno, annmorenoba@gmail.com
Hospital Universitario de Canarias
Santa Cruz de Tenerife
Merecedes Hernandez, mercedes021281@hotmail.com
Hospital Universitario Virgen de Valme
Seville
Carlota Borrero, carlotaborrero@gmail.com
Virgen Macarena
Seville
Eva Carmona, evam.carmona.sspa@juntadeandalucia.es
Hospital Universitario Joan XXIII de Tarragona
Tarragona
Monica Lopez, monicalopez4099@gmail.com
Consorci Sanitari de Terrassa
Terrassa
Angels Vives, vivesangels@gmail.com
Hospital Universitari Mútua Terrassa
Terrassa
Eva Lopez, evalq@hotmail.com
Hospital Universitario de Torrejón
Torrejón de Ardoz
Raquel Martin, MD, raqmaral@gmail.com
Hospital Clínico Universitario Lozano Blesa
Zaragoza
Patricia Ibañez, patribanez@hotmail.com
About this study
Official title: Management of Early-onset Fetal Growth Restriction: Angiogenic Factors Versus Feto-placental Doppler (Early GRAFD)
This is a multicentre, open-label, randomized controlled trial. A total of 340 singleton pregnancies with an EFW ≤10th percentile between 26+0 and 31+6 weeks will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, different soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) cutoffs will be incorporated to the current protocol to adjust the frequency of ultrasounds and to plan elective delivery.
- Conditions
- Fetal Growth Retardation, Preeclampsia, Placenta Diseases
- Being tested
- soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)
- Keywords
- fetal growth restriction, small for gestational age, PlGF, sFlt-1, Doppler
- Medical subject headings
- Fetal Growth Retardation, Pre-Eclampsia, Placenta Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)Diagnostic test
soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) will be incorporated to the management of early-onset small fetuses (estimated fetal weight ≤10th percentile)
| Study group | Role | What they receive |
|---|---|---|
| Control | No intervention | Small fetuses will be classified into 5 severity stages and managed as follows: * SGA: Estimated fetal weight (EFW) between p3 and p10 with normal Dopplers. Ultrasound/2 weeks, elective vaginal delivery at ≥39-40 weeks. * Stage I: EFW ≤p3 p or EFW p3-10 + UA PI >p95 and/or UtA PI >p95, and, at ≥32 weeks, CPR and/or MCA PI <p5, in 2 occasions >12 hours apart. Ultrasound weekly, elective vaginal delivery at ≥37 weeks. * Stage II: AEDF UA in 2 occasions >12 hours apart. Ultrasound every 48-72h, elective Cesarean delivery at ≥34 weeks. * Stage III: DV PI > p95 (or absent DV "a" wave) or reversed end-diastolic UA >50% of cycles, in both cases in two occasions > 6 hours apart. Ultrasound every 24-48h, elective Cesarean delivery at ≥30 weeks. * Stage IV: reversed DV "a" wave in two occasions > 6 hours apart. Elective Cesarean delivery at ≥26 weeks. |
| Study | Experimental | Doppler protocol (as in controls) + sFlt-1/PlGF ratio cutoffs will be incorporated as follows:
* <38: Ultrasound biweekly in stage I FGR and every four weeks in SGA. In both cases delivery at ≥39-40 weeks.
* 38-110: In stage I FGR and SGA ultrasound weekly. Delivery at ≥37 weeks.
* >110: In stage I FGR and SGA ultrasound weekly. Delivery at ≥36 weeks.
* >110 and concurrent preeclampsia: In stage I FGR and SGA ultrasound every 48h-72h. Delivery at ≥34 weeks.
* >201: Ultrasound every 48-72h, delivery at ≥34+0 weeks. If concurrent preeclampsia, delivery at ≥32+0 weeks.
* >655: Ultrasound every 48-72h, delivery at ≥32+0 weeks. If concurrent preeclampsia, delivery at ≥30+0 weeks.
* >1000: In cases with concurrent PE, delivery at ≥29+0 weeks. Receives: Diagnostic Test: soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fetal and Neonatal complications
stillbirth, neonatal death, artery cord pH ≤7.0, respiratory distress syndrome, required invasive ventilatory support, grade III or IV intraventricular hemorrhage, neonatal sepsis, necrotizing enterocolitis, neonatal seizures, pneumonia, meningitis, broncopulmonary dysplasia, hypoxic ischemic encephalopathy, Apgar score <7 at 5 minutes, or elective delivery at <28 weeks of gestation.
Measured: During pregnancy and up to 28 days after delivery
Composite adverse maternal outcome
Progression to PE with severity features; progression to hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (LDH >600 IU/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and the platelet count less than 100 X 109/L); eclampsia, stroke, hepatic hematoma or rupture; oliguria (urine output of <400 mL during 24 hours, or need for treatment with furosemide to maintain urine output at >400 mL for 24 hours); cardiovascular dysfunction (need for inotropic support, left ventricle failure, or myocardial infarction); placental abruption; maternal death; maternal admission to intensive care unit >48 hours, and/or requirement for blood transfusion.
Measured: During pregnancy and up to 28 days after delivery
Secondary outcomes (3)
Maternal perceived stress
Mean and sd or median and IQR of the score obtained in the perceived stress scale in each group
Measured: At inclusion and 4 weeks later
Other perinatal outcomes
transient tachypnea, non-invasive ventilatory support, hypoglycemia, neonatal jaundice (treated with phototherapy), rate of elective deliveries < 30 weeks, <34 weeks and < 37 weeks for FGR and/or PE, birthweight <3 rd and <10th percentiles, mode of delivery (vaginal, instrumental vaginal delivery and Cesarean), rate of Cesarean delivery for abnormal CTG, median maternal stay in ICU, median neonatal stay in N-ICU, maternal corticosteroids (single dose, complete course), prenatal magnesium sulfate (at least 4h) for preterm delivery.
Measured: During pregnancy and up to 28 days after delivery
Number of ultrasounds per participant
Mean and sd or median and IQR in each group
Measured: During pregnancy (before and after 37 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2022
- Study start3 Jun 2024 (estimated)
- Primary completion1 Sep 2026 (estimated)
- Study completion30 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Fetal Growth RetardationStudies of the same condition, open and under way.
- More trials run by Hospital Universitari Vall d'Hebron Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 340 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Instituto de Salud Carlos III, Roche Diagnostics GmbH
- Responsible party
- Sponsor
- Investigators
- Manel Mendoza, MD, PhD, Principal investigator, Vall d'Hebron Institute Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05284474
- Sponsor's protocol ID
- PR(AMI)113/2022
- Acronym
- earlyGRAFD
- Status last verified
- May 2024
- First submitted
- 13 Feb 2022
- Last updated
- 4 Jun 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 4 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Management of Early-onset Fetal Growth Restriction: Angiogenic Factors Versus Feto-placental Doppler (Early GRAFD)
- ClinicalTrials.gov ID
- NCT05284474
- Acronym / sponsor ID
- earlyGRAFD / PR(AMI)113/2022
- Conditions
- Fetal Growth Retardation, Preeclampsia, Placenta Diseases
- Keywords
- fetal growth restriction, small for gestational age, PlGF, sFlt-1, Doppler
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 340 participants (estimated)
- Lead sponsor
- Hospital Universitari Vall d'Hebron Research InstituteUniversity, hospital or other
- Collaborators
- Instituto de Salud Carlos III, Roche Diagnostics GmbH
- Study start
- 3 Jun 2024 (estimated)
- Primary completion
- 1 Sep 2026 (estimated)
- Study completion
- 30 Dec 2026 (estimated)
- First posted
- 17 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a multicentre, open-label, randomized controlled trial. A total of 340 singleton pregnancies with an EFW ≤10th percentile between 26+0 and 31+6 weeks will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, different soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) cutoffs will be incorporated to the current protocol to adjust the frequency of ultrasounds and to plan elective delivery.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control | No intervention | –Small fetuses will be classified into 5 severity stages and managed as follows: * SGA: Estimated fetal weight (EFW) between p3 and p10 with normal Dopplers. Ultrasound/2 weeks, elective vaginal delivery at ≥39-40 weeks. * Stage I: EFW ≤p3 p or EFW p3-10 + UA PI >p95 and/or UtA PI >p95, and, at ≥32 weeks, CPR and/or MCA PI <p5, in 2 occasions >12 hours apart. Ultrasound weekly, elective vaginal delivery at ≥37 weeks. * Stage II: AEDF UA in 2 occasions >12 hours apart. Ultrasound every 48-72h, elective Cesarean delivery at ≥34 weeks. * Stage III: DV PI > p95 (or absent DV "a" wave) or reversed end-diastolic UA >50% of cycles, in both cases in two occasions > 6 hours apart. Ultrasound every 24-48h, elective Cesarean delivery at ≥30 weeks. * Stage IV: reversed DV "a" wave in two occasions > 6 hours apart. Elective Cesarean delivery at ≥26 weeks. |
| Study | Experimental | Diagnostic Test: soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)Doppler protocol (as in controls) + sFlt-1/PlGF ratio cutoffs will be incorporated as follows: * <38: Ultrasound biweekly in stage I FGR and every four weeks in SGA. In both cases delivery at ≥39-40 weeks. * 38-110: In stage I FGR and SGA ultrasound weekly. Delivery at ≥37 weeks. * >110: In stage I FGR and SGA ultrasound weekly. Delivery at ≥36 weeks. * >110 and concurrent preeclampsia: In stage I FGR and SGA ultrasound every 48h-72h. Delivery at ≥34 weeks. * >201: Ultrasound every 48-72h, delivery at ≥34+0 weeks. If concurrent preeclampsia, delivery at ≥32+0 weeks. * >655: Ultrasound every 48-72h, delivery at ≥32+0 weeks. If concurrent preeclampsia, delivery at ≥30+0 weeks. * >1000: In cases with concurrent PE, delivery at ≥29+0 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Pregnant women of at least 18 years old
- Singleton pregnancy
- Ultrasonographic EFW ≤10th percentile between 26+0 and 31+6 weeks of gestation
- Gestational age confirmed by fetal crown-rump length measurement during the first trimester scan (from 11+0 to 13+6 weeks of gestation) or by in vitro fertilization dates.
Key exclusion criteria (4 listed)
- Major fetal malformations or genetic disorders
- Fetal death
- Refusal to give informed consent
- Stage IV FGR
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) will be incorporated to the management of early-onset small fetuses (estimated fetal weight ≤10th percentile) | Diagnostic test | Study |
Primary outcome
Fetal and Neonatal complications
Time frame: During pregnancy and up to 28 days after delivery
stillbirth, neonatal death, artery cord pH ≤7.0, respiratory distress syndrome, required invasive ventilatory support, grade III or IV intraventricular hemorrhage, neonatal sepsis, necrotizing enterocolitis, neonatal seizures, pneumonia, meningitis, broncopulmonary dysplasia, hypoxic ischemic encephalopathy, Apgar score <7 at 5 minutes, or elective delivery at <28 weeks of gestation.
Composite adverse maternal outcome
Time frame: During pregnancy and up to 28 days after delivery
Progression to PE with severity features; progression to hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (LDH >600 IU/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and the platelet count less than 100 X 109/L); eclampsia, stroke, hepatic hematoma or rupture; oliguria (urine output of <400 mL during 24 hours, or need for treatment with furosemide to maintain urine output at >400 mL for 24 hours); cardiovascular dysfunction (need for inotropic support, left ventricle failure, or myocardial infarction); placental abruption; maternal death; maternal admission to intensive care unit >48 hours, and/or requirement for blood transfusion.
3 secondary outcomes
Maternal perceived stress
Time frame: At inclusion and 4 weeks later
Other perinatal outcomes
Time frame: During pregnancy and up to 28 days after delivery
Number of ultrasounds per participant
Time frame: During pregnancy (before and after 37 weeks)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jun 2024.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Manel Mendoza, MD, PhD principal investigator
Vall d'Hebron Institute Research
27 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) in people with Fetal Growth Retardation and Preeclampsia, run by Hospital Universitari Vall d'Hebron Research Institute at 27 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 4 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 27 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Manel Mendoza, MD, PhD (+34934893000 ext. 3085, manel.mendoza@vallhebron.cat), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fetal and Neonatal complications (time frame: During pregnancy and up to 28 days after delivery). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jun 2024.