PI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia

NCT06033131 | Recruiting Phase 3 DMC

• 1 other identifier: EU Trial nr: 2022-502707-2-00
• Study Type: interventional
• Target: 294
• Locations: 3 countries
• Sites: 17

Brief Summary

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.

Conditions

Preeclampsia

Keywords

Preeclampsia; Metformin; Preterm birth; Prolongation; Birth weight; Length of stay in neonatal care

Outcome Measures

Primary Outcomes (1)

• Pregnancy prolongation

  Length of pregnancy from diagnosis of preeclampsia to delivery

  From randomisation to delivery, measured in days and hours, up to 105 days

Secondary Outcomes (2)

• Time for neonatal care

  From birth to discharge from neonatal care, measured in days and hours, up to 126 days

• Neonatal birth weight

  At birth

Study Arms (2)

Metformin ER

ACTIVE COMPARATOR

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

Drug: Metformin ER

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Metformin ER DRUG

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.

Also known as: Glucophage SR 500 mg prolonged release tablets

Metformin ER

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Lina Bergman: lead
• The Swedish Research Council: collaborator

Study Sites (17)

Helsinki University Hospital

Helsinki, 00290, Finland

NOT YET RECRUITING

Tampere University Hospital

Tampere, 33520, Finland

RECRUITING

Akershus University Hospital

Lørenskog, N-1474, Norway

NOT YET RECRUITING

Oslo University Hospital

Oslo, 0372, Norway

NOT YET RECRUITING

Södra Älvsborgs Hospital

Borås, 50455, Sweden

RECRUITING

Falu Lasarett

Falun, 79129, Sweden

RECRUITING

Sahlgrenska University Hospital

Gothenburg, 416 85, Sweden

RECRUITING

Linköping University Hospital

Linköping, 581 85, Sweden

RECRUITING

Skåne University Hospital

Lund, 221 85, Sweden

RECRUITING

Skåne University Hospital

Malmö, 205 02, Sweden

RECRUITING

Karolinska University Hospital Huddinge

Stockholm, 14157, Sweden

RECRUITING

Karolinska University Hospital Solna

Stockholm, 17176, Sweden

RECRUITING

Danderyd Hospital

Stockholm, 182 88, Sweden

RECRUITING

Norra Älvsborgs County Hospital

Trollhättan, 461 74, Sweden

RECRUITING

Norrland´s University Hospital

Umeå, 901 85, Sweden

RECRUITING

Uppsala University Hospital

Uppsala, 75237, Sweden

RECRUITING

Västmanlands Hospital Västerås

Västerås, 72335, Sweden

NOT YET RECRUITING

Related Publications (6)

• Chappell LC, Cluver CA, Kingdom J, Tong S. Pre-eclampsia. Lancet. 2021 Jul 24;398(10297):341-354. doi: 10.1016/S0140-6736(20)32335-7. Epub 2021 May 27.

  PMID: 34051884 BACKGROUND

• Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2013 Sep;170(1):1-7. doi: 10.1016/j.ejogrb.2013.05.005. Epub 2013 Jun 7.

  PMID: 23746796 BACKGROUND

• Cluver CA, Hiscock R, Decloedt EH, Hall DR, Schell S, Mol BW, Brownfoot F, Kaitu'u-Lino TJ, Walker SP, Tong S. Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial. BMJ. 2021 Sep 22;374:n2103. doi: 10.1136/bmj.n2103.

  PMID: 34551918 BACKGROUND

• Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, Senadheera S, Illanes SE, Kaitu'u-Lino TJ, Tong S. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol. 2016 Mar;214(3):356.e1-356.e15. doi: 10.1016/j.ajog.2015.12.019. Epub 2015 Dec 22.

  PMID: 26721779 BACKGROUND

• Hu J, Zhang J, Zhu B. Protective effect of metformin on a rat model of lipopolysaccharide-induced preeclampsia. Fundam Clin Pharmacol. 2019 Dec;33(6):649-658. doi: 10.1111/fcp.12501. Epub 2019 Aug 13.

  PMID: 31334867 BACKGROUND

• Wang F, Cao G, Yi W, Li L, Cao X. Effect of Metformin on a Preeclampsia-Like Mouse Model Induced by High-Fat Diet. Biomed Res Int. 2019 Dec 7;2019:6547019. doi: 10.1155/2019/6547019. eCollection 2019.

  PMID: 31886236 BACKGROUND

MeSH Terms

Conditions

Pre-Eclampsia; Premature Birth; Birth Weight

Interventions

Metformin

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Lina Bergman, Associate professor

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lina Bergman, Associate Professor

CONTACT

0046-3134307; lina.bergman@obgyn.gu.se

Pia Gudmundsson, PhD

CONTACT

0046-313434327; pia.gudmundsson@obgyn.gu.se

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Senior consultant, Associate Professor

Study Record Dates

• First Submitted: August 28, 2023
• First Posted: September 13, 2023
• Study Start: January 19, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

SE (13); NO (2); FI (2)