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PI4 - Et forsøk som vurderer metformin for å forlenge svangerskapet ved prematur svangerskapsforgiftning (PI4)

23. september 2026 oppdatert av: Lina Bergman

Preeklampsi intervensjon 4 - En trippelblind fase III randomisert kontrollert studie som vurderer metformin for å forlenge svangerskapet ved prematur preeklampsi

Preterm preeclampsia is a severe condition for both the mother and the fetus. Currently, the only treatment available to stop disease progression is termination/delivery of the fetus and placenta. Therefore, preterm preeclampsia carries the highest rates of neonatal morbidity and mortality due to iatrogenic preterm birth. There is evidence suggesting metformin, a drug commonly used to treat diabetes in and outside pregnancy, may be able to counter the pathophysiology of preeclampsia, raising the possibility that it could be used to treat the condition. This multi centre double blind randomised controlled trial aims to investigate if metformin can prolong gestation, lower neonatal length of stay and increase birthweight in a Nordic setting.

Studieoversikt

Status

Rekruttering

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

Preeclampsia is globally responsible for 60,000 maternal deaths per year, and far greater numbers of fetal losses. Preterm preeclampsia is a severe variant with the highest rates of neonatal morbidity and mortality due to iatrogenic preterm birth (clinicians are forced to deliver the baby preterm for maternal or fetal health reasons).

There is preclinical evidence suggesting metformin, a drug commonly used to treat diabetes in and outside pregnancy, may be able to counter the pathophysiology of preeclampsia, raising the possibility that it could be used to treat the condition.

Previous research from the Preeclampsia Intervention 2 trial (PI2) show that metformin was able to delay delivery in early preterm preeclampsia. Metformin extended release (ER) was associated with a median 7.6-day prolongation of pregnancy (geometric mean ratio (GMR) 1.39 (95% CI 0.99 to 1.96) P=0.057).Trends towards increased birthweight (mean difference 110gm (95%CI -80 to 300), a decreased length of stay at the neonatal intensive care unit (median difference 5.0 days less; GMR 0.86, 95% CI 0.62 to 1.2) and a shorter period of admission in any neonatal ward (median difference 12.0 days less; GMR 0.82, 95% CI 0.57 to 1.18) in the metformin ER group were found. Importantly, while gastrointestinal side effects were common, no serious adverse events related to trial medications were observed.

The PI 2 trial has shown that metformin may be a disease modifying treatment for preterm preeclampsia. The trial is being repeated in a larger scale in the PI3 trial in South Africa to also assess neonatal outcomes. In the Nordic countries, the demographics of the population are different and expectant management of preeclampsia allows for the women to reach 37 weeks of gestation as opposed to 34 weeks of gestation in the PI2 trial. This trial aims to investigate if metformin can prolong gestation, lower neonatal length of stay and increase birthweight in a Nordic setting. Follow up of mothers and children will be carried out two years post partum.

Studietype

Intervensjonell

Registrering (Antatt)

294

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

  • Finland
      • Helsinki, Finland, 00290
        • Rekruttering
        • Helsinki University Hospital
        • Ta kontakt med:
        • Hovedetterforsker:
          • Pia Villa, Associate Professor
      • Tampere, Finland, 33520
        • Rekruttering
        • Tampere University Hospital
        • Ta kontakt med:
        • Hovedetterforsker:
          • Hannele Laivuori, Professor
  • Norge
      • Lørenskog, Norge, N-1474
        • Rekruttering
        • Akershus University Hospital
        • Ta kontakt med:
        • Hovedetterforsker:
          • Camilla Haavaldsen, PhD
      • Oslo, Norge, 0372
        • Rekruttering
        • Oslo University Hospital
        • Ta kontakt med:
          • Trond Michelsen, Professor
          • Telefonnummer: 0047-23072619
          • E-post: trmi1@ous-hf.no
        • Hovedetterforsker:
          • Ingvil Krarup Sørbye, Professor
  • Sverige
      • Borås, Sverige, 50455
        • Rekruttering
        • Södra Älvsborgs Hospital
        • Ta kontakt med:
        • Hovedetterforsker:
          • Lina Bergman, Associate Professor
      • Falun, Sverige, 79129
      • Gothenburg, Sverige, 416 85
      • Linköping, Sverige, 581 85
      • Lund, Sverige, 221 85
        • Rekruttering
        • Skåne University Hospital
        • Ta kontakt med:
        • Ta kontakt med:
      • Malmö, Sverige, 205 02
        • Rekruttering
        • Skåne University Hospital
        • Ta kontakt med:
      • Skövde, Sverige, 549 49
        • Rekruttering
        • Skaraborg Hospital
        • Ta kontakt med:
      • Stockholm, Sverige, 17176
        • Rekruttering
        • Karolinska University Hospital Solna
        • Ta kontakt med:
        • Ta kontakt med:
      • Stockholm, Sverige, 182 88
      • Stockholm, Sverige, 14157
        • Rekruttering
        • Karolinska University Hospital Huddinge
        • Ta kontakt med:
        • Ta kontakt med:
      • Trollhättan, Sverige, 461 74
        • Rekruttering
        • Norra Älvsborgs County Hospital
        • Hovedetterforsker:
          • Lina Bergman, Associate Professor
        • Ta kontakt med:
      • Umeå, Sverige, 901 85
        • Rekruttering
        • Norrland´s University Hospital
        • Ta kontakt med:
        • Hovedetterforsker:
          • Marie-Therese Vinnars, PhD
      • Uppsala, Sverige, 75237
        • Rekruttering
        • Uppsala University Hospital
        • Ta kontakt med:
      • Västerås, Sverige, 72335
        • Rekruttering
        • Västmanlands Hospital Västerås
        • Ta kontakt med:
        • Hovedetterforsker:
          • Linda Lindström, PhD

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 og eldre (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Hunn

Beskrivelse

Inclusion Criteria:

  • A diagnosis of preeclampsia (defined as hypertension in combination with significant proteinuria (albumin/creatinine ratio >8 mg/mmol, protein/creatinine ratio>30 mg/mmol or >2+ protein on a urinary dipstick) has been made by the attending clinician
  • The managing clinicians have made the assessment to proceed with expectant management.
  • The subject has given written consent to participate in the study.
  • The woman must be 18 years of age or older
  • The gestational age is between 22+0 weeks to 33+6 weeks with a viable fetus
  • The woman carries a singleton pregnancy

Exclusion Criteria:

  • Contraindications to treatment with metformin as outlined in SmPC
  • Contraindications for expectant management of preeclampsia such as an immediate indication for delivery according to SFOG guidelines for preeclampsia (https://www.sfog.se/media/338533/pe-riktlinje-230214.pdf).
  • Type 1 Diabetes Mellitus
  • Current use of metformin
  • Known or suspected allergies against metformin
  • Reluctance or language difficulties that result in difficulty understanding the meaning of study participation
  • Unable to understand the informed consent process
  • Previous participation in the study
  • Established fetal compromise that necessitates imminent delivery (including planned delivery after 48 hours of corticosteroid treatment). This will be decided by the clinical team before expectant management is offered to the patient.
  • Suspicion of a major known fetal anomaly or malformation.
  • Renal disease or dysfunction, suggested by a creatinine level greater than or equal to 125 µmol/L or rapidly declining renal function
  • Known acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • Not suitable for inclusion by the opinion of the investigator

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: Trippel

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Aktiv komparator: Metformin ER

Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
Legemiddel: Metformin ER

Metformin ER, one gram three times daily taken orally. Once the participants have been recruited, they will start by taking one 500 mg tablet three times a day. If well tolerated it will be increased day two to a maximum of two tablets three times a day. Treatment will continue until delivery. If there are side effects that are not tolerable, the dose will be decreased and the participant will remain blinded. Each participant will keep a treatment diary and number of tablets taken will be documented by the participant or hospital staff. The study will not alter or interfere with treatment or care routinely given for preterm preeclampsia.

Andre navn:
  • Glucophage SR 500 mg depottabletter
Placebo komparator: Placebo

1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
Legemiddel: Placebo

Placebo, two tablets three times daily taken orally. Once the participants have been recruited, they will start by taking one tablet three times a day. If well tolerated it will be increased day two to a maximum of two tablets three times a day. Treatment will continue until delivery. If there are side effects that are not tolerable, the dose will be decreased and the participant will remain blinded. Each participant will keep a treatment diary and number of tablets taken will be documented by the participant or hospital staff. The study will not alter or interfere with treatment or care routinely given for preterm preeclampsia.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Pregnancy prolongation
Tidsramme: From randomisation to delivery, measured in days and hours, up to 105 days

Length of pregnancy from diagnosis of preeclampsia to delivery
From randomisation to delivery, measured in days and hours, up to 105 days

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Time for neonatal care
Tidsramme: From birth to discharge from neonatal care, measured in days and hours, up to 126 days

Time for neonatal care from birth to discharge
From birth to discharge from neonatal care, measured in days and hours, up to 126 days
Neonatal birth weight
Tidsramme: At birth

Birth wight measured in grams
At birth

Andre resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Occurrence of maternal death
Tidsramme: Registered from inclusion to two month post partum

Occurrence of maternal death
Registered from inclusion to two month post partum
Occurrence of Eclampsia
Tidsramme: Registered from inclusion to two month post partum

Occurrence of Eclampsia
Registered from inclusion to two month post partum
Occurrence of Cerebral vascular event
Tidsramme: Registered from inclusion to two month post partum

Occurrence of Cerebral vascular event
Registered from inclusion to two month post partum
Occurrence of posterior reversible encephalopathy syndrome
Tidsramme: Registered from inclusion to two month post partum

Occurrence of posterior reversible encephalopathy syndrome
Registered from inclusion to two month post partum
Occurrence of pulmonary edema
Tidsramme: Registered from inclusion to two month post partum

Occurrence of pulmonary edema
Registered from inclusion to two month post partum
Occurrence of left ventricular failure
Tidsramme: Registered from inclusion to two month post partum

Occurrence of left ventricular failure
Registered from inclusion to two month post partum
Occurrence of renal dialysis
Tidsramme: Registered from inclusion to two month post partum

Occurrence of renal dialysis
Registered from inclusion to two month post partum
Occurrence of renal failure
Tidsramme: Registered from inclusion to two month post partum

Occurrence of renal failure:≥ 90 µmol/L or no urinary output for 6 hours
Registered from inclusion to two month post partum
Occurrence of elevated liver transaminases
Tidsramme: Registered from inclusion to two month post partum

Occurrence of elevated liver transaminases: ALT or AST ≥ 2 times highest normal value (ALAT >1.5 µkat/L and ASAT > 1.2 µkat/L)
Registered from inclusion to two month post partum
Occurrence of HELLP syndrome
Tidsramme: Registered from inclusion to two month post partum

Occurrence of HELLP (Haemolysis, elevated liver enzymes and low platelets) syndrome
Registered from inclusion to two month post partum
Occurrence of thrombocytopenia
Tidsramme: Registered from inclusion to two month post partum

Occurrence of thrombocytopenia (platelets <100 X 109/L)
Registered from inclusion to two month post partum
Occurrence of liver haematoma or rupture
Tidsramme: Registered from inclusion to two month post partum

Occurrence of liver haematoma or rupture
Registered from inclusion to two month post partum
Occurrence of admission to an intensive care unit
Tidsramme: Registered from inclusion to two month post partum

Occurrence of admission to an intensive care unit
Registered from inclusion to two month post partum
Occurrence of severe hypertension
Tidsramme: Registered from inclusion to two month post partum

Occurrence of severe hypertension (BP>160/110 mm Hg)
Registered from inclusion to two month post partum
Occurrence of disseminated intravascular coagulation
Tidsramme: Registered from inclusion to two month post partum

Occurrence of disseminated intravascular coagulation
Registered from inclusion to two month post partum
Occurrence of caesarean section
Tidsramme: At birth

Occurrence of caesarean section
At birth
Occurrence of major postpartum hemorrhage
Tidsramme: At birth

Occurrence of major postpartum hemorrhage (>1000 ml)
At birth
Occurrence of thromboembolic disease
Tidsramme: Registered from inclusion to two month post partum

Occurrence of thromboembolic disease: deep venous thrombosis or pulmonary embolism
Registered from inclusion to two month post partum
Duration of maternal postpartum hospital stay
Tidsramme: Registered from birth to hospital discharge

Duration of maternal postpartum hospital stay (days)
Registered from birth to hospital discharge
Number of antihypertensive drugs
Tidsramme: At discharge

Number of antihypertensive drugs at discharge after delivery
At discharge
Duration of antihypertensive medication
Tidsramme: From inclusion to two month postpartum

Duration of antihypertensive medication (days)
From inclusion to two month postpartum
Occurrence of intrauterine fetal demise
Tidsramme: From inclusion to birth

Occurrence of intrauterine fetal demise
From inclusion to birth
Occurrence of neonatal death
Tidsramme: From inclusion to two month post partum

Occurrence of neonatal death
From inclusion to two month post partum
Occurrence of growth restriction at birth
Tidsramme: At birth

Occurrence of growth restriction at birth (less than 2 standard deviations from median weight from Swedish birth weight growth curves).
At birth
Occurrence of grade 3 or 4 intraventricular hemorrhage
Tidsramme: Registered from birth to two month post partum

Occurrence of grade 3 or 4 intraventricular hemorrhage
Registered from birth to two month post partum
Occurrence of necrotizing enterocolitis
Tidsramme: Registered from birth to two month post partum

Occurrence of necrotizing enterocolitis
Registered from birth to two month post partum
Occurrence of reversed a-wave in the ductus venosus
Tidsramme: Registered from birth to two month post partum

Occurrence of reversed a-wave in the ductus venosus
Registered from birth to two month post partum
Occurrence of persistent reversed flow in the umbilical artery
Tidsramme: Registered from inclusion to birth

Occurrence of persistent reversed flow in the umbilical artery
Registered from inclusion to birth
Occurrence of redistribution in the middle cerebral artery
Tidsramme: Registered from birth to two month post partum

Occurrence of redistribution in the middle cerebral artery
Registered from birth to two month post partum
Occurrence of low APGAR score
Tidsramme: At birth

Occurrence of low APGAR score, defined as less than 4 at 5 minutes
At birth
Occurrence of umbilical artery pH below 7.1
Tidsramme: At birth

Occurrence of umbilical artery pH below 7.1
At birth
Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilatione outcome
Tidsramme: Registered from birth to two month post partum

Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilation; continuous positive airway pressure (CPAP) support or high flow nasal oxygen
Registered from birth to two month post partum
Occurrence of grade III/IV hyaline membrane disease
Tidsramme: Registered from birth to two month post partum

Occurrence of grade III/IV hyaline membrane disease
Registered from birth to two month post partum
Occurrence of surfactant use
Tidsramme: Registered from birth to two month post partum

Occurrence of surfactant use
Registered from birth to two month post partum
Occurrence of retinopathy of prematurity
Tidsramme: Registered from birth to two month post partum

Occurrence of retinopathy of prematurity
Registered from birth to two month post partum
Occurrence of neonatal sepsis
Tidsramme: Registered from birth to two month post partum

Occurrence of neonatal sepsis
Registered from birth to two month post partum
Tolerability and safety
Tidsramme: From inclusion to birth

Severity of nausea measured by PHASE-20 Severity of vomiting measured by PHASE-20 Severity of diarrhoea measured by PHASE-20 Severity of headache measured by PHASE-20
From inclusion to birth
Tolerability and safety
Tidsramme: From inclusion to birth

Occurrence of lactic acidosis (blood pH< 7.35 or blood lactate> 5 mM)
From inclusion to birth
Tolerability and safety
Tidsramme: From inclusion to birth

Drug adherence (measured by treatment diary)
From inclusion to birth
Pre-eclampsia-related biomarkers
Tidsramme: From inclusion to two years post partum

Concentrations of Soluble Fms-like tyrosine kinase-1 Concentrations of Placental growth factor Concentrations of Soluble endoglin
From inclusion to two years post partum
Gut and vaginal microbiome composition
Tidsramme: From inclusion to two years post partum

Omics-based analysis of the microbiome
From inclusion to two years post partum
Breastfeeding initiation
Tidsramme: From birth to two month postpartum

Breastfeeding initiation (measured by unvalidated breastfeeding questionnaire with no score)
From birth to two month postpartum
Depressive symptoms
Tidsramme: From inclusion to two years post partum

Depressive symptoms (measured by the Edinburgh Postnatal Depression Scale; 0-30, with higher scores indicating higher self-esteem)
From inclusion to two years post partum
Self-esteem
Tidsramme: From inclusion to two years post partum

Self-esteem (measured by The Rosenberg Self-Esteem Scale; 0-30, higher scores indicating higher self-esteem)
From inclusion to two years post partum
Perceived stress
Tidsramme: From inclusion to two years postpartum

Perceived stress (measured by the 10-item Perceived Stress Scale; 0-40, with higher scores indicating greater perceived stress)
From inclusion to two years postpartum
Breastfeeding self-efficacy
Tidsramme: From birth to two month postpartum

Breastfeeding self-efficacy (measured by the Breastfeeding Self-Efficacy Scale-Short Form; 14-70, higher score= greater breastfeeding self-efficacy)
From birth to two month postpartum
Health-related quality of life
Tidsramme: From inclusion to two years post partum

Health-related quality of life (measured using the EQ-5D-5L (the official name) and reported as the EQ-5D-5L index value and the EQ VAS [0-100]). EQ-5D-5L index values will be derived using country-specific value sets where available; higher index values indicate better health-related quality of life. The EQ VAS ranges from 0 to 100, with higher scores indicating better self-rated health)
From inclusion to two years post partum
Parental-infant bonding
Tidsramme: From birth to two month post partum

Parental-infant bonding (measured by the Postpartum Bonding Questionnaire; 0-125, higher score= greater impairment/difficulties in parent-infant bonding)
From birth to two month post partum
Health economic outcomes
Tidsramme: From birth to two years post partum

Cost-effectiveness short-term: direct healthcare costs (based on drug and healthcare use) for mother and child from enrolment until discharge, will be compared to incremental effects measured as prolongation of gestation

Cost-effectiveness long-term: societal costs (based on drug and healthcare use, and social insurance transactions) for mother and child from enrolment until two years postpartum, will be compared to incremental effects measured as prolongation of gestation and health-related quality of life
From birth to two years post partum
Risk of autism spectrum disorder
Tidsramme: At two years corrected age

Risk of autism spectrum disorder (evaluated by the Modified Checklist for Autism in Toddlers, Revised (M-CHAT/R); 20 questions resulting in score 0-20 where 0-2 indicates no risk, 3-7 moderate risk and 8-20 high risk for autism).
At two years corrected age
Cognitive development of the child
Tidsramme: At two years corrected age

Developmental screening (based on parental questionnaire Ages and Stages Questionnaire, Third Edition 24-months (ASQ-3);questions covering five key developmental domains; communication, gross motor, fine motor, problem-solving and personal-social skills; answers scored from 0-60 with age-specific cut-off levels at -2 and -1SD indicating clear or suspect developmental delay)
At two years corrected age
Cognitive development of the child
Tidsramme: At two years corrected age

Comprehensive developmental assessment (evaluated by the Bayley Scales of Infant Development-4 (BSID-4), with main scores for motor, language and cognitive function. Results expressed as age-corrected developmental scores in each domain with clear developmental delay at scores < 70 (-2SD) and suspect developmental delay at scores < 85 (-1SD).
At two years corrected age

Samarbeidspartnere og etterforskere

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

Sponsor

Lina Bergman

Samarbeidspartnere

The Swedish Research Council

Etterforskere

  • Hovedetterforsker: Lina Bergman, Associate professor, Sahlgrenska University Hospital

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Generelle publikasjoner

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. januar 2024

Primær fullføring (Antatt)

31. desember 2027

Studiet fullført (Antatt)

31. desember 2029

Datoer for studieregistrering

Først innsendt

28. august 2023

Først innsendt som oppfylte QC-kriteriene

10. september 2023

Først lagt ut (Faktiske)

13. september 2023

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

28. september 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

23. september 2026

Sist bekreftet

1. august 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • EU Trial nr: 2022-502707-2-00

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

JA

IPD-planbeskrivelse

Metadata and statistical code will be published in public repositories upon release of the trial's primary results. Deidentified data may be shared upon reasonable request following a written application including a research proposal and ethical approval, in accordance with applicable ethical and legal requirements.

We plan to share data with similar ongoing or planned trials in South Africa and The Netherlands.

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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