Clinical trial NCT06452498: Preeclampsia Intervention Netherlands
Official title: Metformin for the Prolongation of Pregnancy in Preterm Preeclampsia
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
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
Keywords: Preterm Preeclampsia
Metformin
RCT
Placebo
Gestational Prolongation
Treatment
Pregnancy
Multicenter
Preterm
HELLP Syndrome
Hypertensive disorders of pregnancy
Preeclampsia
Randomized controlled trial
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2024-06-11
Enrollment: 180
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-arm trial with intervention arm (metformin) and comparator arm (placebo), aside from usual care for all patients.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of days between randomization and delivery
timeFrame: Time between randomization and delivery (up to 37 weeks of gestation)
Secondary outcomes:
measure: Number of participants reaching a composite maternal adverse outcome
timeFrame: Randomization till 90 days postpartum (unless otherwise specified)
measure: Number of participants reaching a composite fetal adverse outcome
timeFrame: Randomization till delivery (up to 37 weeks of gestation)
measure: Number of participants reaching a composite neonatal adverse outcome
timeFrame: Birth till 90 days after birth (unless otherwise specified)
Other outcomes:
measure: Maternal individual exploratory outcomes
timeFrame: Randomization till 90 days postpartum (unless otherwise specified)
measure: Fetal individual exploratory outcomes
timeFrame: Randomization till 90 days postpartum (unless otherwise specified)
measure: Neonatal individual exploratory outcomes
timeFrame: Randomization till 90 days postpartum (unless otherwise specified)
measure: Mean neonatal birthweight
timeFrame: Within the first 24 hours after birth
measure: Median neonatal length of stay in any neonatal nursery, including NICU
timeFrame: Birth till 90 days postpartum
measure: Incremental cost-effectiveness ratios (ICERs; exploratory)
timeFrame: Start of pregnancy till 90 days postpartum
measure: Rate of diarrhea, nausea/vomiting, abdominal pain, headache (all based on PHASE-20 questionnaire), lactic acidosis, and hypoglycemia (individually)
timeFrame: Randomization till delivery (up to 37 weeks of gestation)
measure: Score on PROMIS Anxiety 8a Short Form
timeFrame: Randomization till 90 days postpartum
measure: Score on EPDS
timeFrame: Randomization till 90 days postpartum
measure: Score on Rosenberg Self-Esteem Scale
timeFrame: Randomization till 90 days postpartum
measure: Score on City Birth Trauma Scale
timeFrame: Randomization till 90 days postpartum
Locations:
Study officials:
affiliation: Amsterdam UMC
name: R.C. Painter, Prof, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: