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Preeklampsi-intervensjon Nederland (PI-NL)

2. november 2026 oppdatert av: Dr Rebecca C. Painter, Amsterdam UMC

Metformin for forlengelse av svangerskapet ved preterm preeklampsi

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.

Studieoversikt

Status

Rekruttering

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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

Intervensjonell

Registrering (Antatt)

180

Fase

  • Fase 3

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiekontakt

Studer Kontakt Backup

Studiesteder

  • Nederland
      • Amsterdam, Nederland
        • Rekruttering
        • Amsterdam UMC
        • Ta kontakt med:

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 50 år (Voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Hunn

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Behandling
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Firemannsrom

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: 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.
Legemiddel: Metformin Hydrochloride

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

Andre navn:
  • Metformin
  • Metformin HCl
Placebo komparator: 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.
Legemiddel: Placebo

Capsule filled with cellulose.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Number of days between randomization and delivery
Tidsramme: 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)

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Number of participants reaching a composite maternal adverse outcome
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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)

Andre resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Maternal individual exploratory outcomes
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: Birth till 90 days postpartum

In days
Birth till 90 days postpartum
Incremental cost-effectiveness ratios (ICERs; exploratory)
Tidsramme: 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)
Tidsramme: 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
Tidsramme: Randomization till 90 days postpartum

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

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

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

Childbirth-related PTSD
Randomization till 90 days postpartum

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Amsterdam UMC

Samarbeidspartnere

ZonMw: The Netherlands Organisation for Health Research and Development

Etterforskere

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

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

19. september 2025

Primær fullføring (Antatt)

19. mars 2029

Studiet fullført (Antatt)

19. juni 2029

Datoer for studieregistrering

Først innsendt

31. mai 2024

Først innsendt som oppfylte QC-kriteriene

5. juni 2024

Først lagt ut (Faktiske)

11. juni 2024

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

4. november 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

2. november 2026

Sist bekreftet

1. november 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • PI-NL trial
  • 2023-510382-10-00 (Ctis)
  • 2023 (U.S. NIH-stipend/kontrakt)

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

JA

IPD-planbeskrivelse

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

IPD-delingstidsramme

T.b.d.

Tilgangskriterier for IPD-deling

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

IPD-deling Støtteinformasjonstype

  • STUDY_PROTOCOL
  • SEVJE
  • ANALYTIC_CODE
  • CSR

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

produkt produsert i og eksportert fra USA

Nei

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