Back to resultsPI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia (PI4)
Primary Purpose
Preeclampsia
Status
Not yet recruiting
Phase
Phase 3
Locations
Sweden
Study Type
Interventional
Intervention
Metformin ER
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Preeclampsia focused on measuring Preeclampsia, Metformin, Preterm birth, Prolongation, Birth weight, Length of stay in neonatal care
Eligibility Criteria
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 Concomitant medications that are not compatible with metformin such as glyburide, furosemide or cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) 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
Sites / Locations
- Falu Lasarett
- Sahlgrenska University Hospital
- Malmö University Hospital
- Karolinska University Hospital Huddinge
- Karolinska University Hospital Solna
- Uppsala University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Metformin ER
Placebo
Arm Description
Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
Outcomes
Primary Outcome Measures
Pregnancy prolongation
Length of pregnancy from diagnosis of preeclampsia to delivery
Secondary Outcome Measures
Time for neonatal care
Time for neonatal care from birth to discharge
Neonatal birth weight
Birth wight measured in grams
Full Information
NCT ID
NCT06033131
First Posted
August 28, 2023
Last Updated
September 10, 2023
Sponsor
Lina Bergman
Collaborators
The Swedish Research Council
1. Study Identification
Unique Protocol Identification Number
NCT06033131
Brief Title
PI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia
Acronym
PI4
Official Title
Preeclampsia Intervention 4 - A Triple Blind Phase III Randomised Controlled Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
November 1, 2023 (Anticipated)
Primary Completion Date
July 31, 2027 (Anticipated)
Study Completion Date
October 31, 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lina Bergman
Collaborators
The Swedish Research Council
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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 Swedish setting.
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 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Preeclampsia
Keywords
Preeclampsia, Metformin, Preterm birth, Prolongation, Birth weight, Length of stay in neonatal care
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
294 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Metformin ER
Arm Type
Active Comparator
Arm Description
Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
Intervention Type
Drug
Intervention Name(s)
Metformin ER
Other Intervention Name(s)
Glucophage SR 500 mg prolonged release tablets
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Pregnancy prolongation
Description
Length of pregnancy from diagnosis of preeclampsia to delivery
Time Frame
From randomisation to delivery, measured in days and hours, up to 105 days
Secondary Outcome Measure Information:
Title
Time for neonatal care
Description
Time for neonatal care from birth to discharge
Time Frame
From birth to discharge from neonatal care, measured in days and hours, up to 126 days
Title
Neonatal birth weight
Description
Birth wight measured in grams
Time Frame
At birth
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Concomitant medications that are not compatible with metformin such as glyburide, furosemide or cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin)
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lina Bergman, Associate Pr
Phone
+463134307
Email
lina.bergman@obgyn.gu.se
First Name & Middle Initial & Last Name or Official Title & Degree
Pia Gudmundsson, PhD
Email
pia.gudmundsson@obgyn.gu.se
Facility Information:
Facility Name
Falu Lasarett
City
Falun
ZIP/Postal Code
79129
Country
Sweden
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Susanne Hesselman, PhD
Phone
004623492351
Email
susanne.hesselman@regiondalarna.se
Facility Name
Sahlgrenska University Hospital
City
Gothenburg
ZIP/Postal Code
416 85
Country
Sweden
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lina Bergman, Associate professor
Phone
+463134307
Email
lina.bergman@obgyn.gu.se
First Name & Middle Initial & Last Name & Degree
Pia Gudmundsson, PhD
Email
pia.gudmundsson@obgyn.gu.se
Facility Name
Malmö University Hospital
City
Malmö
ZIP/Postal Code
21428
Country
Sweden
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Simon Timpka, associate Professor
Phone
0046462220000
Email
simon.timpka@med.lu.se
Facility Name
Karolinska University Hospital Huddinge
City
Stockholm
ZIP/Postal Code
14157
Country
Sweden
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna Sandström, Associate Professor
Phone
0046739829820
Email
anna.sandstrom@ki.se
Facility Name
Karolinska University Hospital Solna
City
Stockholm
ZIP/Postal Code
17176
Country
Sweden
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna Sandström, Associate Professor
Phone
0046739829820
Email
anna.sandstrom@ki.se
Facility Name
Uppsala University Hospital
City
Uppsala
ZIP/Postal Code
75237
Country
Sweden
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna-Karin Wikström, Professor
Phone
0046184710000
Email
anna-karin.wikstrom@kbu.uu.se
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
We plan to share data with similar ongoing or planned trials in South Africa and The Netherlands.
Citations:
PubMed Identifier
34051884
Citation
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.
Results Reference
background
PubMed Identifier
23746796
Citation
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.
Results Reference
background
PubMed Identifier
34551918
Citation
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.
Results Reference
background
PubMed Identifier
26721779
Citation
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.
Results Reference
background
PubMed Identifier
31334867
Citation
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.
Results Reference
background
PubMed Identifier
31886236
Citation
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.
Results Reference
background
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PI4 - A Trial Assessing Metformin to Prolong Gestation in Preterm Preeclampsia
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