PI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia
NCT ID: NCT06033131
Last Updated: 2025-04-09
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
294 participants
INTERVENTIONAL
2024-01-19
2029-07-31
Brief Summary
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Detailed Description
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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 Sweden, 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 Swedish setting. Follow up of mothers and children will be carried out two years post partum.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Metformin ER
Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
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.
Placebo
1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
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.
Interventions
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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.
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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 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
18 Years
FEMALE
No
Sponsors
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The Swedish Research Council
OTHER_GOV
Lina Bergman
OTHER
Responsible Party
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Lina Bergman
Senior consultant, Associate Professor
Principal Investigators
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Lina Bergman, Associate professor
Role: PRINCIPAL_INVESTIGATOR
Sahlgrenska University Hospital
Locations
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Falu Lasarett
Falun, , Sweden
Sahlgrenska University Hospital
Gothenburg, , Sweden
Linköping University Hospital
Linköping, , Sweden
Skåne University Hospital
Lund, , Sweden
Skåne University Hospital
Malmo, , Sweden
Karolinska University Hospital Huddinge
Stockholm, , Sweden
Karolinska University Hospital Solna
Stockholm, , Sweden
Danderyd Hospital
Stockholm, , Sweden
Uppsala University Hospital
Uppsala, , Sweden
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
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.
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.
Other Identifiers
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EU Trial nr: 2022-502707-2-00
Identifier Type: -
Identifier Source: org_study_id
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