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

Sponsor

Lina Bergman (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06033131

Collaborator

The Swedish Research Council (Other)

294

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Preeclampsia	Drug: Metformin ER Drug: Placebo	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

294 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Nov 1, 2023

Anticipated Primary Completion Date :

Jul 31, 2027

Anticipated Study Completion Date :

Oct 31, 2027

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Pregnancy prolongation [From randomisation to delivery, measured in days and hours, up to 105 days]
Length of pregnancy from diagnosis of preeclampsia to delivery

Secondary Outcome Measures

Time for neonatal care [From birth to discharge from neonatal care, measured in days and hours, up to 126 days]
Time for neonatal care from birth to discharge
Neonatal birth weight [At birth]
Birth wight measured in grams

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Falu Lasarett	Falun	Sweden	79129
2	Sahlgrenska University Hospital	Gothenburg	Sweden	416 85
3	Malmö University Hospital	Malmö	Sweden	21428
4	Karolinska University Hospital Huddinge	Stockholm	Sweden	14157
5	Karolinska University Hospital Solna	Stockholm	Sweden	17176
6	Uppsala University Hospital	Uppsala	Sweden	75237