Preeclampsia Intervention Netherlands (PI-NL)

Metformin for the Prolongation of Pregnancy in Preterm Preeclampsia

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pre-Eclampsia; HELLP Syndrome; Pre-eclampsia or Eclampsia With Pre-existing Hypertension; HELLP; Pre-Eclampsia; Complicating Pregnancy; Pre-Eclampsia Onset Less Than 37 Weeks; Pre-Eclampsia as Antepartum Condition; Pre-Eclampsia; Affecting Fetus; HELLP Syndrome Complicating Pregnancy
• Intervention / Treatment: Drug: Metformin Hydrochloride; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: M. Khelil, MD; Phone Number: +31 20 566 9111; Email: PI_NL@amsterdamumc.nl
• Study Contact Backup: Name: R.C. Painter, Prof, MD, PhD; Phone Number: +31 20 566 9111; Email: PI_NL@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

All of the following:

• Aged 18 years or older
• Singleton pregnancy
• Gestational age between 23+0 and 31+6 weeks
• A diagnosis of preterm preeclampsia, defined according to modified International Society for the Study of Hypertension in Pregnancy (ISSHP) classification, including only those who have proteinuria (≥300 mg of protein in a 24-hour urine specimen or a protein-creatinine-ratio >50 in a single urine sample)
• Estimated fetal weight >400 grams
• No clear indication (maternal or fetal) or intention, by both the treating multidisciplinary team and the patient after counseling, to immediately deliver (or directly after corticosteroid administration) or to terminate the pregnancy otherwise.
• Ability to understand English or Dutch
• Ability and willingness to provide written informed consent

Exclusion Criteria

Any of the following:

• Current use of metformin or a clinical indication for the use of metformin
• A decision for immediate delivery (including cases where corticosteroids are administered with planned delivery directly after completion of treatment) or termination of pregnancy (e.g., due to disease severity in the patient combined with a dismal prognosis for the fetus), as made by the treating multidisciplinary team and the parent(s)
• Contraindication(s) for the use of metformin (e.g., severe renal insufficiency, acute metabolic acidosis, severe liver insufficiency)
• Use of drugs that might interact with metformin
• Suspicion of a major fetal anomaly and/or chromosomal abnormality
• Unable or unwilling to (completely) understand or provide informed consent, due to language, culture, or other barriers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; 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; Metformin Hydrochloride encapsulated immediate-release tablet of 500 mg, backfilled with cellulose.; Other Names: Metformin; Metformin HCl
Placebo Comparator: Placebo; 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; Capsule filled with cellulose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days between randomization and delivery	Prolongation of gestation	Time between randomization and delivery (up to 37 weeks of gestation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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)	Birth till 90 days after birth (unless otherwise specified)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	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.	Randomization till 90 days postpartum (unless otherwise specified)
Mean neonatal birthweight	In grams	Within the first 24 hours after birth
Median neonatal length of stay in any neonatal nursery, including NICU	In days	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).	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	Randomization till delivery (up to 37 weeks of gestation)
Score on PROMIS Anxiety 8a Short Form	Maternal anxiety	Randomization till 90 days postpartum
Score on EPDS	Maternal depressive symptoms	Randomization till 90 days postpartum
Score on Rosenberg Self-Esteem Scale	Maternal self-esteem	Randomization till 90 days postpartum
Score on City Birth Trauma Scale	Child-related PTSD	Randomization till 90 days postpartum

Collaborators and Investigators

• Sponsor: Amsterdam UMC
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: R.C. Painter, Prof, MD, PhD, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: May 31, 2024
• First Submitted That Met QC Criteria: June 5, 2024
• First Posted (Actual): June 11, 2024

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: June 5, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Treatment; Pregnancy; Randomized controlled trial; Metformin; RCT; Placebo; Preeclampsia; Multicenter; Preterm; HELLP Syndrome; Hypertensive disorders of pregnancy; Preterm Preeclampsia; Gestational Prolongation
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Hypertension, Pregnancy-Induced; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Syndrome; Eclampsia; Pre-Eclampsia; Pregnancy Complications; HELLP Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: PI-NL trial; 2023-510382-10-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators plan to collaborate with researchers doing similar Preeclampsia Intervention (PI) trials.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• 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