PreeclampsiaPhase 3PI4NCT06033131
PI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia
A Phase 3 study testing Metformin ER in people with Preeclampsia, run by Lina Bergman at 18 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Preeclampsia
- What is being tested?
- Metformin ER
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 294 participants
- Where
- 18 sitesin 3 countries
- Study dates
- 19 Jan 2024to 31 Dec 2029
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
18 sites in 3 countries. Contact the study team or a site near you to ask about taking part.
18 sites in 3 countries
Sweden14 sites, 14 recruiting
- Recruiting
Södra Älvsborgs Hospital
Borås, 50455
Stina Berver, 0046-336163281, stina.berver@vgregion.se
Lina Bergman, Associate Professor
- Recruiting
Falu Lasarett
Falun, 79129
Susanne Hesselman, PhD, 0046-23492351, susanne.hesselman@regiondalarna.se
- Recruiting
Sahlgrenska University Hospital
Gothenburg, 416 85
Lina Bergman, Associate professor, 0046-3134307, lina.bergman@obgyn.gu.se
Pia Gudmundsson, PhD, pia.gudmundsson@obgyn.gu.se
- Recruiting
Linköping University Hospital
Linköping, 581 85
Caroline Lilliecreutz, Associate professor, 0046-101034909, caroline.lilliecreutz@liu.se
Marie Blomberg, Professor, marie.blomberg@regionostergotland.se
- Recruiting
Skåne University Hospital
Lund, 221 85
Simon Timpka, Associate professor, 0046-46171000, simon.timpka@med.lu.se
Emma von Wowern, PhD, 004640336809, emma.von_wowern@med.lu.se
- Recruiting
Skåne University Hospital
Malmö, 205 02
Simon Timpka, Ass Prof, 0046-46171000, simon.timpka@med.lu.se
- Recruiting
Skaraborg Hospital
Skövde, 549 49
Emelie Ottosson, Senior consultant, +46-73729 98 70, emelie.ottosson@vgregion.se
- Recruiting
Karolinska University Hospital Huddinge
Stockholm, 14157
Anna Sandström, Associate Professor, 0046-739829820, anna.sandstrom@ki.se
Ängla Mantel, Associate Professor, angla.mantel@ki.se
- Recruiting
Karolinska University Hospital Solna
Stockholm, 17176
Anna Sandström, Associate Professor, 0046-739829820, anna.sandstrom@ki.se
Ängla Mantel, Associate Professor, angla.mantel@ki.se
- Recruiting
Danderyd Hospital
Stockholm, 182 88
Sophia Hugo Aronzon, PhD student, 0046-72-582 21 57, hugo.aronzon@regionstockholm.se
- Recruiting
Norra Älvsborgs County Hospital
Trollhättan, 461 74
Carina Bejlum, 0046-104350000, carina.bejlum@vgregion.se
Lina Bergman, Associate Professor
- Recruiting
Norrland´s University Hospital
Umeå, 901 85
Marie-Therese Vinnars, PhD, 0046-739426777, marie-therese.vinnars@umu.se
Marie-Therese Vinnars, PhD
- Recruiting
Uppsala University Hospital
Uppsala, 75237
Linda Lindström, PhD, 0046-186115729, linda.lindstrom@uu.se
- Recruiting
Västmanlands Hospital Västerås
Västerås, 72335
Merit Kullinger, 0046-21173155, merit.kullinger@regionvastmanland.se
Linda Lindström, PhD
Finland2 sites, 2 recruiting
- Recruiting
Helsinki University Hospital
Helsinki, 00290
Pia Villa, Associate Professor, 00358-405389779, pia.villa@helsinki.fi
Pia Villa, Associate Professor
- Recruiting
Tampere University Hospital
Tampere, 33520
Hannele Laivuori, Professor, 00358-504154871, hannele.laivuori@tuni.fi
Hannele Laivuori, Professor
Norway2 sites, 2 recruiting
- Recruiting
Akershus University Hospital
Lørenskog, N-1474
Camilla Haavaldsen, PhD, 0047-95763946, Marit.Camilla.Haavaldsen@ahus.no
Camilla Haavaldsen, PhD
- Recruiting
Oslo University Hospital
Oslo, 0372
Trond Michelsen, Professor, 0047-23072619, trmi1@ous-hf.no
Ingvil Krarup Sørbye, Professor
About this study
Official title: 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.
Read the 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.
- Conditions
- Preeclampsia
- Being tested
- Metformin ER, Placebo
- Keywords
- Preeclampsia, Metformin, Preterm birth, Prolongation, Birth weight, Length of stay in neonatal care
- Medical subject headings
- Pre-Eclampsia, Premature Birth, Birth Weight
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin ERDrug
Also called Glucophage SR 500 mg prolonged release tablets
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Metformin ER |
| Placebo | Placebo comparator | 1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pregnancy prolongation
Length of pregnancy from diagnosis of preeclampsia to delivery
Measured: From randomisation to delivery, measured in days and hours, up to 105 days
Secondary outcomes (2)
Time for neonatal care
Time for neonatal care from birth to discharge
Measured: From birth to discharge from neonatal care, measured in days and hours, up to 126 days
Neonatal birth weight
Birth wight measured in grams
Measured: At birth
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2023
- Study start19 Jan 2024
- Primary completion31 Dec 2027 (estimated)
- Study completion31 Dec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for PreeclampsiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 294 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Lina Bergman
- Sponsor type
- University, hospital or other
- Collaborators
- The Swedish Research Council
- Responsible party
- Sponsor-investigator, Lina Bergman, Sahlgrenska University Hospital
- Investigators
- Lina Bergman, Associate professor, Principal investigator, Sahlgrenska University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06033131
- Sponsor's protocol ID
- EU Trial nr: 2022-502707-2-00
- Acronym
- PI4
- Status last verified
- Aug 2026
- First submitted
- 28 Aug 2023
- Last updated
- 28 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 34051884Abalos 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.
PubMed 23746796Cluver 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.
PubMed 34551918Brownfoot 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.
PubMed 26721779Hu 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.
PubMed 31334867Wang 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.
PubMed 31886236