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Pre-eclampsie Interventie Nederland (PI-NL)

2 november 2026 bijgewerkt door: Dr Rebecca C. Painter, Amsterdam UMC

Metformine voor de verlenging van de zwangerschap bij premature pre-eclampsie

The goal of this study is to find out if pregnant individuals with preterm preeclampsia (PE) who are treated with metformin can stay pregnant for longer, and if this is safe(r) for the mother and child. Preterm PE affects about 1 in 100 pregnant individuals in the Netherlands. Signs of preterm PE can be high blood pressure and protein in the urine in the second half of pregnancy (but before 32-34 weeks of pregnancy). Other symptoms can develop, such as problems with blood clotting and how well the blood cells, liver, lungs, and brain work. The disease can lead to serious complications for both the mother and child. The only way to cure preterm PE is to make sure the child is born, and many times, children have to be delivered (very) early (before 37 weeks). Children born (very) early can suffer from infections, breathing difficulties, and problems in their development.

Metformin is a medicine used to treat high blood sugar during and outside of pregnancy. In a previous study in South Africa, women with preterm PE that used metformin were able to safely remain pregnant for an extra week. Similarly, the main goal of the Preeclampsia Intervention NetherLands (PI-NL) study is to see if patients with preterm PE in the Netherlands that use metformin can remain pregnant for a longer time than patients taking a placebo. A placebo is a look-a-like capsule that contains no active ingredients. Researchers, the treating medical team, and participants will not know which participant gets which treatment. In addition, all participants will receive the standard care that all preterm PE patients get.

Studie Overzicht

Toestand

Werving

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

Preterm preeclampsia (PE) is a severe hypertensive disorder of pregnancy and a major cause of maternal and perinatal morbidity and mortality. Currently, the only treatment to halt disease progression is delivery of the dysfunctional placenta and thereby the child. This often happens prematurely. Being able to safely (for mother and child) extend pregnancy, even by a few days, is expected to reduce the short- and long-term risks associated with (severe) prematurity. Preclinical and recent clinical evidence presents metformin, a drug commonly used to treat diabetes in and outside of pregnancy, as a promising treatment candidate for preterm PE. Metformin might reduce inflammation, oxidative stress, and anti-angiogenesis, and improve endothelial function. In a recent South African trial, use of metformin was associated with a safe median 7.6 day prolongation of pregnancy in women with preterm PE, compared to placebo. There was a nonsignificant increase in the neonatal birthweight and a decrease in the length of stay in any neonatal nursery. Metformin did not lead to any serious adverse events.

The goal of this multicenter, triple-blind, randomized placebo-controlled trial is to investigate whether metformin can safely prolong gestation in patients with preterm PE in the Dutch population. Secondary outcomes include composite adverse maternal, fetal, and neonatal outcomes. Cost-effectiveness of the treatment will be evaluated.

Studietype

Ingrijpend

Inschrijving (Geschat)

180

Fase

  • Fase 3

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Studie Locaties

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

18 jaar tot 50 jaar (Volwassen)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Vrouw

Beschrijving

Inclusion Criteria

All of the following:

  • Aged 18 years or older
  • Singleton pregnancy
  • Gestational age between 23+0 and 31+6 weeks
  • A diagnosis of preterm preeclampsia, defined according to modified International Society for the Study of Hypertension in Pregnancy (ISSHP) classification, including only those who have proteinuria (≥300 mg of protein in a 24-hour urine specimen or a protein-creatinine-ratio >50 in a single urine sample)
  • Estimated fetal weight >400 grams
  • No clear indication (maternal or fetal) or intention, by both the treating multidisciplinary team and the patient after counseling, to immediately deliver (or directly after corticosteroid administration) or to terminate the pregnancy otherwise.
  • Ability to understand English or Dutch
  • Ability and willingness to provide written informed consent

Exclusion Criteria

Any of the following:

  • Current use of metformin or a clinical indication for the use of metformin
  • A decision for immediate delivery (including cases where corticosteroids are administered with planned delivery directly after completion of treatment) or termination of pregnancy (e.g., due to disease severity in the patient combined with a dismal prognosis for the fetus), as made by the treating multidisciplinary team and the parent(s)
  • Contraindication(s) for the use of metformin (e.g., severe renal insufficiency, acute metabolic acidosis, severe liver insufficiency)
  • Use of drugs that might interact with metformin
  • Suspicion of a major fetal anomaly and/or chromosomal abnormality
  • Unable or unwilling to (completely) understand or provide informed consent, due to language, culture, or other barriers

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: Gerandomiseerd
  • Interventioneel model: Parallelle opdracht
  • Masker: Verviervoudigen

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Metformin

Metformin 3000 mg divided by three daily doses (3 times 2 capsules of 500 mg; following a step-up schedule) from randomization till delivery, aside from usual preterm preeclampsia care.
Geneesmiddel: Metformin Hydrochloride

Metformin Hydrochloride encapsulated immediate-release tablet of 500 mg, backfilled with cellulose.

Andere namen:
  • Metformine
  • Metformine HCl
Placebo-vergelijker: Placebo

Placebo, divided by three daily doses (3 times 2 capsules; following a step-up schedule) from randomization till delivery, aside from usual preterm preeclampsia care.
Geneesmiddel: Placebo

Capsule filled with cellulose.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Number of days between randomization and delivery
Tijdsspanne: Time between randomization and delivery (up to 37 weeks of gestation)

Prolongation of gestation
Time between randomization and delivery (up to 37 weeks of gestation)

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Number of participants reaching a composite maternal adverse outcome
Tijdsspanne: Randomization till 90 days postpartum (unless otherwise specified)

Combined endpoint of maternal death (during pregnancy or within 42 days postpartum), eclampsia, pulmonary edema, severe renal impairment, cerebrovascular accident, placental abruption, and/or liver hematoma or rupture.
Randomization till 90 days postpartum (unless otherwise specified)
Number of participants reaching a composite fetal adverse outcome
Tijdsspanne: Randomization till delivery (up to 37 weeks of gestation)

Combined endpoint of intrauterine fetal demise, suboptimal fetal condition based on CTG, and fetal growth restriction.
Randomization till delivery (up to 37 weeks of gestation)
Number of participants reaching a composite neonatal adverse outcome
Tijdsspanne: Birth till 90 days after birth (unless otherwise specified)

Combined endpoint of neonatal death (within 28 days after birth), grade 3 or 4 intraventricular hemorrhage, retinopathy of prematurity requiring treatment, necrotizing enterocolitis (grade II or higher), bronchopulmonary dysplasia, neonatal sepsis, and cystic periventricular leukomalacia (grade II or higher)
Birth till 90 days after birth (unless otherwise specified)

Andere uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Maternal individual exploratory outcomes
Tijdsspanne: Randomization till 90 days postpartum (unless otherwise specified)

Number of participants experiencing each of the following: maternal death, cerebrovascular event, eclampsia, cortical blindness, pulmonary edema, AKI, liver hematoma/rupture, placental abruption, retinal detachment, postpartum hemorrhage, HELLP syndrome, severe elevated liver enzymes, low platelets, left ventricular heart failure, PRES, DIC, thromboembolic disease, need for dialysis due to renal failure, admission to high or ICU, need for intubation and mechanical ventilation
Randomization till 90 days postpartum (unless otherwise specified)
Fetal individual exploratory outcomes
Tijdsspanne: Randomization till 90 days postpartum (unless otherwise specified)

Number of participants experiencing each of the following: intrauterine or intrapartum fetal death, reversed end diastolic flow in umbilical artery on at least 2 occasions, redistribution in the middle cerebral artery, absent or reversed a-wave in ductus venosus, suboptimal fetal condition based on CTG.
Randomization till 90 days postpartum (unless otherwise specified)
Neonatal individual exploratory outcomes
Tijdsspanne: Randomization till 90 days postpartum (unless otherwise specified)

Number of participants experiencing each of the following: neonatal death within 28 days after birth, neonatal death between 29 and 90 days after birth, growth restriction at birth, Apgar score < 7 at 5 min, umbilical artery pH < 7.10, neonatal hypoglycemia, neonatal seizures, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of the premature, pulmonary insufficiency of the preterm infant, bronchopulmonary dysplasia, cystic periventricular leukomalacia, patent ductus arteriosus, persistent pulmonary hypertension, surfactant use within 72 hours after birth, need for respiratory support, admission to NICU.
Randomization till 90 days postpartum (unless otherwise specified)
Mean neonatal birthweight
Tijdsspanne: Within the first 24 hours after birth

In grams
Within the first 24 hours after birth
Median neonatal length of stay in any neonatal nursery, including NICU
Tijdsspanne: Birth till 90 days postpartum

In days
Birth till 90 days postpartum
Incremental cost-effectiveness ratios (ICERs; exploratory)
Tijdsspanne: Start of pregnancy till 90 days postpartum

Determined through length of maternal stay in hospital (and specifically ICU), neonatal length of stay in hospital (and specifically NICU), other health care utilization (based on iMCQ questionnaire, maternal and neonatal use of medication during pregnancy and after birth), loss of productivity (measured with iPCQ questionnaire), quality-of-life (score on EQ-5D-5L).
Start of pregnancy till 90 days postpartum
Rate of diarrhea, nausea/vomiting, abdominal pain, headache (all based on PHASE-20 questionnaire), lactic acidosis, and hypoglycemia (individually)
Tijdsspanne: Randomization till delivery (up to 37 weeks of gestation)

Tolerability and safety of metformin
Randomization till delivery (up to 37 weeks of gestation)
Score on PROMIS Anxiety 8a Short Form
Tijdsspanne: Randomization till 90 days postpartum

Maternal anxiety
Randomization till 90 days postpartum
Score on EPDS
Tijdsspanne: Randomization till 90 days postpartum

Maternal depressive symptoms
Randomization till 90 days postpartum
Score on Rosenberg Self-Esteem Scale
Tijdsspanne: Randomization till 90 days postpartum

Maternal self-esteem
Randomization till 90 days postpartum
Score on City Birth Trauma Scale
Tijdsspanne: Randomization till 90 days postpartum

Childbirth-related PTSD
Randomization till 90 days postpartum

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Amsterdam UMC

Medewerkers

ZonMw: The Netherlands Organisation for Health Research and Development

Onderzoekers

  • Hoofdonderzoeker: R.C. Painter, Prof, MD, PhD, Amsterdam UMC

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

19 september 2025

Primaire voltooiing (Geschat)

19 maart 2029

Studie voltooiing (Geschat)

19 juni 2029

Studieregistratiedata

Eerst ingediend

31 mei 2024

Eerst ingediend dat voldeed aan de QC-criteria

5 juni 2024

Eerst geplaatst (Werkelijk)

11 juni 2024

Updates van studierecords

Laatste update geplaatst (Werkelijk)

4 november 2026

Laatste update ingediend die voldeed aan QC-criteria

2 november 2026

Laatst geverifieerd

1 november 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • PI-NL trial
  • 2023-510382-10-00 (Ctis)
  • 2023 (Subsidie/contract van de Amerikaanse NIH)

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

JA

Beschrijving IPD-plan

The investigators plan to collaborate with researchers of the international Preeclampsia Intervention (PI) trials.

IPD-tijdsbestek voor delen

T.b.d.

IPD-toegangscriteria voor delen

The results of the IPD will be published in a peer-reviewed journal.

IPD delen Ondersteunend informatietype

  • LEERPROTOCOOL
  • SAP
  • ANALYTIC_CODE
  • MVO

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

product vervaardigd in en geëxporteerd uit de V.S.

Nee

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