Evaluation of Acetylsalicylic Acid Versus Placebo for Preeclampsia Prevention in Twin Pregnancies: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **low-dose aspirin** on the incidence of preterm **preeclampsia** with delivery before 37 weeks' gestation. This is clinically relevant as preeclampsia is a significant cause of maternal and neonatal morbidity and mortality, and early intervention could potentially improve outcomes in twin pregnancies.

Secondary objectives include determining the effect of low-dose aspirin on various outcomes stratified by chorionicity:

• Incidence of delivery with preeclampsia at <32 weeks, <34 weeks, <37 weeks, and at any gestation.
• Incidence of severe preeclampsia features, including stroke, eclampsia, severe hypertension, respiratory failure, myocardial ischemia, pulmonary edema, hepatic dysfunction, acute kidney injury, and other severe complications.
• Incidence of gestational hypertension.
• Incidence of birth at <32 weeks, <34 weeks, and <37 weeks, whether spontaneous or iatrogenic for preeclampsia, gestational hypertension, fetal growth restriction, or other reasons.
• Incidence of death of one or both twins before hospital discharge, including miscarriage, stillbirth, or neonatal death at various gestational ages.
• Incidence of birthweight below the 3rd, 5th, and 10th percentiles for gestational age.
• Incidence of placental abruption at various gestational ages.
• Incidence of postpartum hemorrhage, defined as blood loss ≥1 L within the first 24 hours after birth.
• Incidence of neonatal morbidity and therapy, including neonatal intensive care unit admission and ventilation requirements.
• Length of stay in the neonatal intensive care unit.

The clinical trial involves a total of **627 participants** who are exclusively female, as the study focuses on **preeclampsia** in pregnancy. The study population comprises women aged over 18 years with either DCDA or MCDA twin pregnancies, and both fetuses must be alive at 11+2 to 13+6 weeks of gestation. Participants were selected based on these criteria, and informed and written consent was obtained. The trial does not include male subjects, and the population is considered vulnerable due to the nature of the condition being studied. Lifestyle factors such as diet and physical activity are not specified in the available data. The primary objective of the trial is to assess the impact of low-dose aspirin on the incidence of preterm preeclampsia with delivery before 37 weeks of gestation.

The clinical trial is designed to evaluate the effect of low-dose **aspirin** on the incidence of preterm **preeclampsia** in women with twin pregnancies. This is a multicenter, randomized, double-blind, placebo-controlled trial. Participants will be randomly assigned to receive either aspirin 75mg gastro-resistant tablets or a placebo. The trial is expected to run from December 16, 2022, to January 30, 2026, with a maximum treatment period of 174 days for each participant.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, DCDA or MCDA twin pregnancies, and both live fetuses at 11+2 to 13+6 weeks of gestation. Informed and written consent is required. Following the screening, participants will attend regular follow-up visits to monitor health status and adherence to the treatment regimen. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of reducing preterm preeclampsia incidence with delivery before 37 weeks' gestation.

Participant involvement is expected to last up to 174 days, depending on individual circumstances. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial's methodology ensures rigorous data collection and analysis to achieve its primary objective, contributing valuable insights into the prevention of preeclampsia in twin pregnancies.

The clinical trial involves the administration of **Aspirin 75mg Gastro-resistant Tablets** as the experimental medication. The active substance in this formulation is **acetylsalicylic acid**, which is chemically derived. The pharmaceutical form of the medication is a gastro-resistant tablet, designed to prevent the release of the active ingredient in the stomach, thereby minimizing gastric irritation. The tablets are administered orally. The dosage is set at 75 mg per tablet, with a maximum daily dose of 150 mg. The treatment period extends up to 174 days. The product is manufactured by Bristol Laboratories Limited and holds the marketing authorization number PL 17907/0157. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** control group. The placebo is manufactured using Prosolv® Easytab SR (JRS Pharma) and Acryl-EZE Aqueous Enteric coating solution (Colorcon). The placebo is designed to mimic the appearance and administration route of the active treatment, ensuring the double-blind nature of the trial. The placebo is administered orally in the same frequency and form as the active treatment, maintaining consistency in the administration process. Participant compliance with the placebo regimen is similarly monitored to ensure the integrity of the trial results.

The efficacy of the clinical trial titled "Aspirin versus placebo in twin pregnancies for preeclampsia prevention: A multicentre, randomised, double-blind, placebo-controlled trial (ASPRE-T)" will be assessed by evaluating the primary endpoint. The primary endpoint is to determine if the prophylactic use of low-dose **aspirin** from the first trimester of pregnancy in women with twin pregnancies can reduce the incidence of preeclampsia (PE) with delivery before 37 weeks' gestation. The trial aims to measure the effect of low-dose aspirin on the incidence of preterm preeclampsia, with delivery occurring before 37 weeks of gestation. The assessment will involve comparing the incidence rates of preterm preeclampsia between the aspirin and placebo groups. The trial is designed to be multicentre, randomised, double-blind, and placebo-controlled, ensuring rigorous evaluation of the efficacy of low-dose aspirin in preventing preeclampsia in twin pregnancies.