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PI4 - Studie hodnotící metformin k prodloužení těhotenství u předčasné preeklampsie (PI4)

23. září 2026 aktualizováno: Lina Bergman

Preeklampsie Intervence 4 – Trojitě slepá randomizovaná kontrolovaná studie III. fáze hodnotící metformin k prodloužení těhotenství u předčasné preeklampsie

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.

Přehled studie

Postavení

Nábor

Podmínky

Intervence / Léčba

Detailní popis

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.

Typ studie

Intervenční

Zápis (Odhadovaný)

294

Fáze

  • Fáze 3

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní kontakt

Studijní záloha kontaktů

Studijní místa

  • Finsko
      • Helsinki, Finsko, 00290
        • Nábor
        • Helsinki University Hospital
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Pia Villa, Associate Professor
      • Tampere, Finsko, 33520
        • Nábor
        • Tampere University Hospital
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Hannele Laivuori, Professor
  • Norsko
      • Lørenskog, Norsko, N-1474
        • Nábor
        • Akershus University Hospital
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Camilla Haavaldsen, PhD
      • Oslo, Norsko, 0372
        • Nábor
        • Oslo University Hospital
        • Kontakt:
          • Trond Michelsen, Professor
          • Telefonní číslo: 0047-23072619
          • E-mail: trmi1@ous-hf.no
        • Vrchní vyšetřovatel:
          • Ingvil Krarup Sørbye, Professor
  • Švédsko
      • Borås, Švédsko, 50455
        • Nábor
        • Södra Älvsborgs Hospital
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Lina Bergman, Associate Professor
      • Falun, Švédsko, 79129
      • Gothenburg, Švédsko, 416 85
      • Linköping, Švédsko, 581 85
      • Lund, Švédsko, 221 85
        • Nábor
        • Skåne University Hospital
        • Kontakt:
        • Kontakt:
      • Malmö, Švédsko, 205 02
        • Nábor
        • Skåne University Hospital
        • Kontakt:
      • Skövde, Švédsko, 549 49
        • Nábor
        • Skaraborg Hospital
        • Kontakt:
      • Stockholm, Švédsko, 17176
        • Nábor
        • Karolinska University Hospital Solna
        • Kontakt:
          • Anna Sandström, Associate Professor
          • Telefonní číslo: 0046-739829820
          • E-mail: anna.sandstrom@ki.se
        • Kontakt:
      • Stockholm, Švédsko, 182 88
      • Stockholm, Švédsko, 14157
        • Nábor
        • Karolinska University Hospital Huddinge
        • Kontakt:
          • Anna Sandström, Associate Professor
          • Telefonní číslo: 0046-739829820
          • E-mail: anna.sandstrom@ki.se
        • Kontakt:
      • Trollhättan, Švédsko, 461 74
        • Nábor
        • Norra Älvsborgs County Hospital
        • Vrchní vyšetřovatel:
          • Lina Bergman, Associate Professor
        • Kontakt:
      • Umeå, Švédsko, 901 85
        • Nábor
        • Norrland´s University Hospital
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Marie-Therese Vinnars, PhD
      • Uppsala, Švédsko, 75237
        • Nábor
        • Uppsala University Hospital
        • Kontakt:
      • Västerås, Švédsko, 72335
        • Nábor
        • Västmanlands Hospital Västerås
        • Kontakt:
        • Vrchní vyšetřovatel:
          • Linda Lindström, PhD

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let a starší (Dospělý, Starší dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Ženský

Popis

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

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: Randomizované
  • Intervenční model: Paralelní přiřazení
  • Maskování: Trojnásobný

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Aktivní komparátor: Metformin ER

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

Ostatní jména:
  • Glucophage SR 500 mg tablety s prodlouženým uvolňováním
Komparátor placeba: Placebo

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

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Pregnancy prolongation
Časové okno: 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

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Time for neonatal care
Časové okno: 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
Časové okno: At birth

Birth wight measured in grams
At birth

Další výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Occurrence of maternal death
Časové okno: Registered from inclusion to two month post partum

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

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

Occurrence of renal dialysis
Registered from inclusion to two month post partum
Occurrence of renal failure
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: At birth

Occurrence of caesarean section
At birth
Occurrence of major postpartum hemorrhage
Časové okno: At birth

Occurrence of major postpartum hemorrhage (>1000 ml)
At birth
Occurrence of thromboembolic disease
Časové okno: 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
Časové okno: Registered from birth to hospital discharge

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

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

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

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

Occurrence of neonatal death
From inclusion to two month post partum
Occurrence of growth restriction at birth
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: Registered from birth to two month post partum

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

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

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

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

Breastfeeding initiation (measured by unvalidated breastfeeding questionnaire with no score)
From birth to two month postpartum
Depressive symptoms
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

Lina Bergman

Spolupracovníci

The Swedish Research Council

Vyšetřovatelé

  • Vrchní vyšetřovatel: Lina Bergman, Associate professor, Sahlgrenska University Hospital

Publikace a užitečné odkazy

Osoba odpovědná za zadávání informací o studiu tyto publikace poskytuje dobrovolně. Mohou se týkat čehokoli, co souvisí se studiem.

Obecné publikace

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia (Aktuální)

19. ledna 2024

Primární dokončení (Odhadovaný)

31. prosince 2027

Dokončení studie (Odhadovaný)

31. prosince 2029

Termíny zápisu do studia

První předloženo

28. srpna 2023

První předloženo, které splnilo kritéria kontroly kvality

10. září 2023

První zveřejněno (Aktuální)

13. září 2023

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

28. září 2026

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

23. září 2026

Naposledy ověřeno

1. srpna 2026

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • EU Trial nr: 2022-502707-2-00

Plán pro data jednotlivých účastníků (IPD)

Plánujete sdílet data jednotlivých účastníků (IPD)?

ANO

Popis plánu IPD

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.

Informace o lécích a zařízeních, studijní dokumenty

Studuje lékový produkt regulovaný americkým FDA

Ne

Studuje produkt zařízení regulovaný americkým úřadem FDA

Ne

produkt vyrobený a vyvážený z USA

Ne

Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .

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