Statin Intervention for Severe Early-Onset Placental Insufficiency. (STATIN-PRE Trial)

Official title

Statin Intervention for Severe Early-Onset Placental Insufficiency: A Randomized Controlled Trial Assessing Daily Administration as a Treatment Strategy (STATIN-PRE Trial)

Overview

In pregnancies with placental insufficiency, the only available treatment is close monitoring to determine the point at which the risks of preterm birth for the baby are lower than the risks of continuing the pregnancy. Therefore, safely prolonging pregnancy is the current management goal for this condition. Statins, such as pravastatin, are approved and marketed drugs used to prevent cardiovascular disease. Recent studies suggest that statins may help treat pregnancy complications and prolong pregnancy, thereby avoiding extreme prematurity and improving long-term health outcomes for both mother and baby. Previous clinical trials have shown the ability of statins to stabilize angiogenic factors, thus reducing obstetric complications associated with placental insufficiency. In 2015, a study reported that pravastatin was effective in stabilizing blood pressure and reducing proteinuria associated with preeclampsia. More recently, in 2020, it was demonstrated that in pregnant women with fetal growth restriction treated with pravastatin, the sFlt-1/PlGF ratio was lower than in untreated women, indicating a slower progression of placental insufficiency. This study proposes administering a daily dose of 40 mg of pravastatin between 24 and 29.6 weeks of gestation to mothers diagnosed with preeclampsia and/or fetal growth restriction. One group of women will receive the medication, while another group will receive a visually identical but inactive pill (a placebo), allowing us to determine whether any observed improvement in pregnancy is attributable to the medication. Assignment to the treatment or placebo group will be random, and neither the mothers nor the healthcare professionals caring for them will know which group they are in. The investigators also aim to examine whether this intervention during pregnancy protects the cardiovascular system. For this reason, the investigators will assess both the mother and the baby six months after birth using an ultrasound of the heart and blood vessels, and the investigators will also perform a blood test on the mothers. Additionally, the investigators want to explore the needs and expectations of women who experience these complications during pregnancy and postpartum, so that their stories can guide us in finding answers and solutions that are as personalized as possible to the real needs of families. After the visit at six months postpartum, yhe investigators will follow up with annual phone calls over the next four years to check on the participants' health and their baby's. During each call, the investigators will review the participant's health status and talk about how the participant is feeling. All of this will help us ensure that the treatment does not cause any long-term issues and will improve future care for other mothers and babies. A total of 154 pregnant women are expected to be included in order to meet the study's objectives.

Detailed description

Preeclampsia (PE) and intrauterine growth restriction (IUGR) arise as clinical manifestations of placental insufficiency. While significant strides have been made in the prevention of PE over the past decade, resulting in a noteworthy decline in its prevalence, both PE and IUGR persist as prominent contributors to peripartum morbidity, major causes of prematurity, and sources of neonatal complications and mortality. In severe instances of PE, the potential for serious complications extends throughout pregnancy and the postpartum period, and both entities have implications on long-term maternal and children cardiovascular risks in later life.

Despite the efforts to generate successful therapeutic strategies aimed to prolong pregnancy and attenuate prematurity-related morbidity, presently, the only effective cure is timely delivery, and pharmacological therapy aims to mitigate tertiary complications such as eclampsia or severe hypertension. PE and IUGR are considered orphan diseases by the European Medicines Agency. Therefore, there is an urgent need to investigate novel drugs aimed to improve maternal and neonatal outcomes and mitigate long term sequels. Between 24 and 28 weeks of pregnancy, every day of prolongation of the pregnancy is followed by a 1-2% reduction of neonatal mortality or severe morbidity.

HMG-CoA reductase inhibitors (HMG-CoA-RI), beyond their lipid-lowering effects, have been shown to improve endothelial function, placental perfusion, have anti-inflammatory and anti-oxidant effects, and up-regulation of angiogenesis with their "pleiotropic effects". These HMG-CoA-RI related beneficial properties suggest their potential protective potential during the acute phase of placental insufficiency and subsequent protection on cardiovascular maternal and fetal programming.

It is our WORKING HYPOTHESIS that 40 mgr of oral administration of pravastatin daily will prolong duration of pregnancy and will provide cardioprotection and additional benefits to both mother and neonates to that afforded by conventional management of PE and IUGR.

FIRST AIM: To assess that daily 40 mgr of oral administration of pravastatin in pregnant individuals with PE and/or IUGR between 24.0 and 29.6 weeks of gestation will prolong duration of pregnancy compared to conventional management.

SECOND AIM: Determine whether pravastatin improve cardiac function, placental perfusion, angiogenesis, total antioxidant status (TAS) and lipid profile during pregnancy and after pregnancy in both mothers and neonates in the intervention group compared to controls.

THIRD AIM: To evaluate changes in genetic expression profile in human tissues after treatment with novel statins' therapy.

FOURTH AIM: To include women's needs and expectations about PE, IUGR and preterm birth and future heath in order to improve the success of the translation into real changes in women and infant health.

Interventions

• Drug Pravastatin 40 mg
  This study proposes administering a daily dose of 40 mg of pravastatin between 24 and 29.6 weeks of gestation to mothers diagnosed with preeclampsia and/or fetal growth restriction.
• Other Placebo
  A visually identical but inactive pill (a placebo),

Primary outcome measures

• Days of prolongation of pregnancy between inclusion and delivery. [Time frame: From date of randomization until the date of delivery, assesed up to 10 weeks]

Secondary outcome measures (12)

• Maternal pregnancy-related morbidity composite score [Time frame: At delivery]
• Preterm birth before 34 weeks of gestation [Time frame: At delivery]
• Birth weight [Time frame: At delivery]
• Neonatal acidosis [Time frame: At delivery]
• Perinatal mortality [Time frame: from 22 weeks of gestation to 28 days post-partum]
• Days in the neonatal intensive care [Time frame: From date of delivery until the date of discharge of the neonatal intensive care or date of death from any cause, whichever came first, assessed up to 3 months]
• Neonatal morbidity [Time frame: At delivery]
• Maternal/ fetal cardiac function [Time frame: at inclusion, at delivery and at 6 months after delivery]
• Biomarkers in maternal blood [Time frame: at the time of diagnosis and delivery]
• Biomarkers in umbilical cord blood [Time frame: At delivery]
• Concentrations in plasma/serum [Time frame: Since inlcusion until 6 months after delivery]
• Increased cardiovascular risk by blood preassure measurement, echocardiographic assessment, global longitudinal strain, carotid-ntima-media thickness, Ophtalmic artery Doppler evaluation, IBERLIFERISK score. [Time frame: 6 months after delivery]

Eligibility criteria

Inclusion criteria

• Singleton fetus.
• Between 24+0 to 29+6 weeks of gestation at the inclusion.
• Early-onset severe PE: women with a diagnosis of severe-preterm PE who are candidates for expectant management and have no clinical indication for immediate delivery, based on the clinical assessments of the attending doctors.

And/or

• IUGR: Diagnosis of early onset IUGR according to the SMFM classification with umbilical artery Doppler with absent/reversed diastolic flow; or estimated fetal weight <10th percentile plus pulsatility index (PI) of umbilical artery Doppler >95th percentil.
• Able to give informed consent.

Exclusion criteria

• Established maternal or fetal compromise that necessitated immediate delivery
• Abnormal karyotype, structural abnormalities, or congenital infections.
• Treatment with pravastatin or other statins prior to inclusion.
• Lactose intolerance

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Supportive care

Study locations

Spain · 2 centers

• Hospital de la Santa Creu i de Sant Pau — Barcelona
• Hospital Clínic de Barcelona — Barcelona

Identifiers

NCT: NCT07098975 · IIBSP-PRE-2024-198

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗