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

April 28, 2026 updated by: Lina Bergman

Preeclampsia Intervention 4 - A Triple Blind Phase III Randomised Controlled Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

294

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Finland
      • Helsinki, Finland, 00290
        • Not yet recruiting
        • Helsinki University Hospital
        • Contact:
        • Principal Investigator:
          • Pia Villa, Associate Professor
      • Tampere, Finland, 33520
        • Recruiting
        • Tampere University Hospital
        • Contact:
        • Principal Investigator:
          • Hannele Laivuori, Professor
  • Norway
      • Lørenskog, Norway, N-1474
        • Not yet recruiting
        • Akershus University Hospital
        • Contact:
        • Principal Investigator:
          • Camilla Haavaldsen, PhD
      • Oslo, Norway, 0372
        • Not yet recruiting
        • Oslo University Hospital
        • Contact:
          • Trond Michelsen, Professor
          • Phone Number: 0047-23072619
          • Email: trmi1@ous-hf.no
        • Principal Investigator:
          • Ingvil Krarup Sørbye, Professor
  • Sweden
      • Borås, Sweden, 50455
        • Recruiting
        • Södra Älvsborgs Hospital
        • Contact:
        • Principal Investigator:
          • Lina Bergman, Associate Professor
      • Falun, Sweden, 79129
      • Gothenburg, Sweden, 416 85
      • Linköping, Sweden, 581 85
      • Lund, Sweden, 221 85
      • Malmö, Sweden, 205 02
        • Recruiting
        • Skane University Hospital
        • Contact:
      • Stockholm, Sweden, 17176
        • Recruiting
        • Karolinska University Hospital Solna
        • Contact:
        • Contact:
      • Stockholm, Sweden, 182 88
      • Stockholm, Sweden, 14157
        • Recruiting
        • Karolinska University Hospital Huddinge
        • Contact:
        • Contact:
      • Trollhättan, Sweden, 461 74
        • Recruiting
        • Norra Älvsborgs County Hospital
        • Principal Investigator:
          • Lina Bergman, Associate Professor
        • Contact:
      • Umeå, Sweden, 901 85
        • Recruiting
        • Norrland´s University Hospital
        • Contact:
        • Principal Investigator:
          • Marie-Therese Vinnars, PhD
      • Uppsala, Sweden, 75237
        • Recruiting
        • Uppsala University Hospital
        • Contact:
      • Västerås, Sweden, 72335
        • Not yet recruiting
        • Västmanlands Hospital Västerås
        • Contact:
        • Principal Investigator:
          • Linda Lindström, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Metformin ER
Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
Drug: 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.
Other Names:
  • Glucophage SR 500 mg prolonged release tablets
Placebo Comparator: Placebo
1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pregnancy prolongation
Time Frame: 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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time for neonatal care
Time Frame: 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
Time Frame: At birth
Birth wight measured in grams
At birth

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Lina Bergman

Collaborators

The Swedish Research Council

Investigators

  • Principal Investigator: Lina Bergman, Associate professor, Sahlgrenska University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 19, 2024

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2029

Study Registration Dates

First Submitted

August 28, 2023

First Submitted That Met QC Criteria

September 10, 2023

First Posted (Actual)

September 13, 2023

Study Record Updates

Last Update Posted (Actual)

May 4, 2026

Last Update Submitted That Met QC Criteria

April 28, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EU Trial nr: 2022-502707-2-00

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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