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

Study Overview
=================
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.

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

Conditions
-----------------
Preeclampsia

Intervention / Treatment
-----------------
* Drug: Metformin ER
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy prolongation | 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 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 | Birth wight measured in grams | At birth | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Preeclampsia, Metformin, Preterm birth, Prolongation, Birth weight, Length of stay in neonatal care