Preeclampsia Intervention Netherlands

NCT ID: NCT06452498

Last Updated: 2024-06-11

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 180 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-08-31
• Study Completion Date: 2028-07-31

Brief Summary

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.

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.

Conditions

Pre-Eclampsia Onset Less Than 37 Weeks; Pre-Eclampsia; Pre-Eclampsia; Complicating Pregnancy; Pre-Eclampsia as Antepartum Condition; Pre-eclampsia or Eclampsia With Pre-existing Hypertension; Pre-Eclampsia; Affecting Fetus; HELLP Syndrome Complicating Pregnancy; HELLP Syndrome; HELLP

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Metformin Hydrochloride

Intervention Type: DRUG

Metformin Hydrochloride encapsulated immediate-release tablet of 500 mg, backfilled with cellulose.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Capsule filled with cellulose.

Interventions

Metformin Hydrochloride

Metformin Hydrochloride encapsulated immediate-release tablet of 500 mg, backfilled with cellulose.

Intervention Type: DRUG

Placebo

Capsule filled with cellulose.

Intervention Type: DRUG

Other Intervention Names

Metformin; Metformin HCl

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Amsterdam UMC

OTHER

Sponsor Role: lead

Responsible Party

Dr Rebecca C. Painter

Prof. dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

R.C. Painter, Prof, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC

Central Contacts

M. Khelil, MD

Role: CONTACT

PI_NL@amsterdamumc.nl

+31 20 566 9111

R.C. Painter, Prof, MD, PhD

Role: CONTACT

PI_NL@amsterdamumc.nl

+31 20 566 9111

Other Identifiers

2023-510382-10-00

Identifier Type: CTIS

Identifier Source: secondary_id

PI-NL trial

Identifier Type: -

Identifier Source: org_study_id