A Phase 3 interventional study of Metformin Hydrochloride and Placebo in Pre-Eclampsia Onset Less Than 37 Weeks, Pre-Eclampsia and Pre-Eclampsia; Complicating Pregnancy, sponsored by Amsterdam UMC. Not yet recruiting. Open to female participants aged 18 Years to 50 Years. Per ClinicalTrials.gov, last updated 2024-06-11.
Sponsored by Amsterdam UMC · Phase 3, Interventional, and Treatment
The goal of this study is to find out if pregnant individuals with preterm preeclampsia (PE) who are treated with metformin can stay pregnant for longer, and if this is safe(r) for the mother and child. Preterm PE affects about 1 in 100 pregnant individuals in the Netherlands. Signs of preterm PE can be high blood pressure and protein in the urine in the second half of pregnancy (but before 32-34 weeks of pregnancy). Other symptoms can develop, such as problems with blood clotting and how well the blood cells, liver, lungs, and brain work. The disease can lead to serious complications for both the mother and child. The only way to cure preterm PE is to make sure the child is born, and many times, children have to be delivered (very) early (before 37 weeks). Children born (very) early can suffer from infections, breathing difficulties, and problems in their development.
Metformin is a medicine used to treat high blood sugar during and outside of pregnancy. In a previous study in South Africa, women with preterm PE that used metformin were able to safely remain pregnant for an extra week. Similarly, the main goal of the Preeclampsia Intervention NetherLands (PI-NL) study is to see if patients with preterm PE in the Netherlands that use metformin can remain pregnant for a longer time than patients taking a placebo. A placebo is a look-a-like capsule that contains no active ingredients. Researchers, the treating medical team, and participants will not know which participant gets which treatment. In addition, all participants will receive the standard care that all preterm PE patients get.
Preterm preeclampsia (PE) is a severe hypertensive disorder of pregnancy and a major cause of maternal and perinatal morbidity and mortality. Currently, the only treatment to halt disease progression is delivery of the dysfunctional placenta and thereby the child. This often happens prematurely. Being able to safely (for mother and child) extend pregnancy, even by a few days, is expected to reduce the short- and long-term risks associated with (severe) prematurity. Preclinical and recent clinical evidence presents metformin, a drug commonly used to treat diabetes in and outside of pregnancy, as a promising treatment candidate for preterm PE. Metformin might reduce inflammation, oxidative stress, and anti-angiogenesis, and improve endothelial function. In a recent South African trial, use of metformin was associated with a safe median 7.6 day prolongation of pregnancy in women with preterm PE, compared to placebo. There was a nonsignificant increase in the neonatal birthweight and a decrease in the length of stay in any neonatal nursery. Metformin did not lead to any serious adverse events.
The goal of this multicenter, triple-blind, randomized placebo-controlled trial is to investigate whether metformin can safely prolong gestation in patients with preterm PE in the Dutch population. Secondary outcomes include composite adverse maternal, fetal, and neonatal outcomes. Cost-effectiveness of the treatment will be evaluated.
903 studies on the registry are indexed under Pre-Eclampsia; 240 are open to participants now.
This study's planned enrollment of 180 is above the median of 110 across 478 interventional studies indexed under Pre-Eclampsia.
Browse Pre-Eclampsia studies →Amsterdam UMC is the lead sponsor of 10 studies on the registry; 9 are open to participants now.
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All of the following:
Exclusion Criteria
Any of the following:
Metformin 3000 mg divided by three daily doses (3 times 2 capsules of 500 mg; following a step-up schedule) from randomization till delivery, aside from usual preterm preeclampsia care.
Drug: Metformin Hydrochloride
Placebo, divided by three daily doses (3 times 2 capsules; following a step-up schedule) from randomization till delivery, aside from usual preterm preeclampsia care.
Drug: Placebo
Metformin Hydrochloride encapsulated immediate-release tablet of 500 mg, backfilled with cellulose.
Also known as: Metformin, Metformin HCl
Capsule filled with cellulose.
Number of days between randomization and delivery
Prolongation of gestation
Time frame: Time between randomization and delivery (up to 37 weeks of gestation)
Number of participants reaching a composite maternal adverse outcome
Combined endpoint of maternal death (during pregnancy or within 42 days postpartum), eclampsia, pulmonary edema, severe renal impairment, cerebrovascular accident, placental abruption, and/or liver hematoma or rupture.
Time frame: Randomization till 90 days postpartum (unless otherwise specified)
Number of participants reaching a composite fetal adverse outcome
Combined endpoint of intrauterine fetal demise, suboptimal fetal condition based on CTG, and fetal growth restriction.
Time frame: Randomization till delivery (up to 37 weeks of gestation)
Number of participants reaching a composite neonatal adverse outcome
Combined endpoint of neonatal death (within 28 days after birth), grade 3 or 4 intraventricular hemorrhage, retinopathy of prematurity requiring treatment, necrotizing enterocolitis (grade II or higher), bronchopulmonary dysplasia, neonatal sepsis, and cystic periventricular leukomalacia (grade II or higher)
Time frame: Birth till 90 days after birth (unless otherwise specified)
Maternal individual exploratory outcomes
Number of participants experiencing each of the following: maternal death, cerebrovascular event, eclampsia, cortical blindness, pulmonary edema, AKI, liver hematoma/rupture, placental abruption, retinal detachment, postpartum hemorrhage, HELLP syndrome, severe elevated liver enzymes, low platelets, left ventricular heart failure, PRES, DIC, thromboembolic disease, need for dialysis due to renal failure, admission to high or ICU, need for intubation and mechanical ventilation
Time frame: Randomization till 90 days postpartum (unless otherwise specified)
Fetal individual exploratory outcomes
Number of participants experiencing each of the following: intrauterine or intrapartum fetal death, reversed end diastolic flow in umbilical artery on at least 2 occasions, redistribution in the middle cerebral artery, absent or reversed a-wave in ductus venosus, suboptimal fetal condition based on CTG.
Time frame: Randomization till 90 days postpartum (unless otherwise specified)
Neonatal individual exploratory outcomes
Number of participants experiencing each of the following: neonatal death within 28 days after birth, neonatal death between 29 and 90 days after birth, growth restriction at birth, Apgar score \< 7 at 5 min, umbilical artery pH \< 7.10, neonatal hypoglycemia, neonatal seizures, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of the premature, pulmonary insufficiency of the preterm infant, bronchopulmonary dysplasia, cystic periventricular leukomalacia, patent ductus arteriosus, persistent pulmonary hypertension, surfactant use within 72 hours after birth, need for respiratory support, admission to NICU.
Time frame: Randomization till 90 days postpartum (unless otherwise specified)
Mean neonatal birthweight
In grams
Time frame: Within the first 24 hours after birth
Median neonatal length of stay in any neonatal nursery, including NICU
In days
Time frame: Birth till 90 days postpartum
Incremental cost-effectiveness ratios (ICERs; exploratory)
Determined through length of maternal stay in hospital (and specifically ICU), neonatal length of stay in hospital (and specifically NICU), other health care utilization (based on iMCQ questionnaire, maternal and neonatal use of medication during pregnancy and after birth), loss of productivity (measured with iPCQ questionnaire), quality-of-life (score on EQ-5D-5L).
Time frame: Start of pregnancy till 90 days postpartum
Rate of diarrhea, nausea/vomiting, abdominal pain, headache (all based on PHASE-20 questionnaire), lactic acidosis, and hypoglycemia (individually)
Tolerability and safety of metformin
Time frame: Randomization till delivery (up to 37 weeks of gestation)
Score on PROMIS Anxiety 8a Short Form
Maternal anxiety
Time frame: Randomization till 90 days postpartum
Score on EPDS
Maternal depressive symptoms
Time frame: Randomization till 90 days postpartum
Score on Rosenberg Self-Esteem Scale
Maternal self-esteem
Time frame: Randomization till 90 days postpartum
Score on City Birth Trauma Scale
Child-related PTSD
Time frame: Randomization till 90 days postpartum
No study locations are listed for this record.
Plan to share: Yes — The investigators plan to collaborate with researchers doing similar Preeclampsia Intervention (PI) trials.
Supporting information: Study protocol, Statistical analysis plan, Clinical study report, Analytic code
No publications or documents are linked to this record.
Start is estimated for Aug 2024; primary completion for Apr 2028, 44 months later.
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This study is not yet recruiting, as verified in Jun 2024. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Metformin
Amsterdam UMC