Efficacy of Acetylsalicylic Acid in Preventing Maternal-Fetal Morbidity in Pregnant Women with Chronic Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **Aspirin** (acetylsalicylic acid) at a dose of 150 mg per day compared to a placebo in preventing maternal-fetal morbidity and mortality in pregnant women with chronic hypertension. This includes conditions such as preeclampsia, placental abruption, fetal growth restriction (IUGR), perinatal death, maternal death, and preterm delivery. The clinical relevance of this objective lies in its potential to reduce adverse outcomes associated with pregnancy-related hypertension, thereby improving maternal and fetal health.

Secondary objectives include:

• Comparing the preventive effect of low-dose aspirin on maternal-fetal morbidity and mortality based on the timing of treatment initiation, either before or after 15 weeks of gestation.
• Estimating the preventive effect on individual events of the main composite criterion, including the rate of superimposed preeclampsia (PE) analyzed according to specified definitions.
• Assessing the preventive effect on the severity of PE, IUGR, preterm delivery, and risks of miscarriage, fetal death, and neonatal death, as well as neonatal morbidity indicators such as neonatal intensive care unit stay, assisted ventilation over 24 hours, hyaline membrane disease, and severe intraventricular hemorrhage.
• Evaluating the potential toxicity of the active treatment, focusing on major and minor maternal hemorrhagic events.
• Analyzing patient adherence to treatment using a logbook.
• Assessing the efficacy of treatment in aspirin responders through thromboxane B2 assay.
• Constituting a biological collection associated with maternal and perinatal clinical data to evaluate the circulating angiogenic profile through systematic assay of pro and antiangiogenic factors (PlGF, sFlt-1, sEng).

The clinical trial focuses on a **vulnerable population** of pregnant women diagnosed with chronic hypertension, aiming to assess the efficacy of Aspirin in preventing maternal-fetal morbidity and mortality. The study population consists exclusively of female participants, specifically those between 10 weeks and 19 weeks + 6 days of gestation, with a **singleton pregnancy**. Participants must have chronic hypertension, regardless of whether it is currently being treated, and must be affiliated with social security. The trial does not include male subjects. The sponsor has not provided information regarding the total number of participants. All participants are required to have signed a written informed consent. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed additional details about the selection process for the trial population.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **acetylsalicylic acid** in preventing maternal-fetal morbidity and mortality in pregnant women with chronic hypertension. The trial will compare a daily dose of 150 mg of acetylsalicylic acid with a placebo. The study is expected to run from February 15, 2021, to November 15, 2026. Participants will be involved in the study for a maximum treatment period of six months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being between 10 weeks and 19 weeks + 6 days of pregnancy, having chronic hypertension, and providing informed consent. Follow-up visits will be scheduled to monitor the health of the mother and fetus, adherence to the treatment regimen, and any adverse events. The end-of-study visit will assess the primary and secondary endpoints, including the incidence of preeclampsia, placental abruption, and other maternal-fetal outcomes.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the treatment protocol, or withdraw consent. The primary endpoint is a composite morbidity-mortality criterion, while secondary endpoints include the rate of severe preeclampsia, fetal growth restriction, and neonatal morbidity. The trial will also evaluate the biological response to treatment and the psychomotor development of the child at 2 and 4 years of age.

The clinical trial involves the administration of **ACARD 150 mg**, a **gastro-resistant tablet** containing **acetylsalicylic acid** as the active substance. The pharmaceutical form is designed to resist dissolution in the stomach, ensuring the release of the active ingredient in the intestine. Each tablet contains 150 mg of acetylsalicylic acid, and the medication is administered orally. Participants in the trial are instructed to take one tablet daily, resulting in a total daily dose of 150 mg. The maximum treatment period for this medication is six months. The product is manufactured by Zakłady Farmaceutyczne Polpharma S.A., and it is authorized for use in Poland under the marketing authorization number 23375. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

The study also includes a **placebo** group, which receives an **acetylsalicylic acid placebo**. 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, with participants taking one tablet daily, similar to the active treatment group. The placebo is used to provide a comparator for evaluating the efficacy of acetylsalicylic acid in preventing maternal-fetal morbidity and mortality in pregnant women with chronic hypertension. Compliance with the placebo administration is similarly monitored to maintain the integrity of the trial results.

The efficacy of the clinical trial titled "CHASAP: Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy" will be assessed by comparing the effects of **Aspirin** (acetylsalicylic acid) at a dose of 150 mg/day with a placebo in preventing maternal-fetal morbidity and mortality. The primary endpoint is a composite morbidity-mortality criterion, which includes the occurrence of preeclampsia (early or late), birthweight below the 10th percentile, placental abruption, perinatal death, maternal death, and preterm delivery before 37 weeks of gestation.

Secondary endpoints will evaluate the rate of the composite morbidity-mortality criterion in two subgroups based on the timing of treatment initiation (before or after 15 weeks of gestation), as well as individual events of the primary endpoint. Additional secondary endpoints include the rate of severe preeclampsia, severe intrauterine growth restriction (IUGR) below the 5th percentile of birth weight, severe preterm delivery before 34 weeks of gestation, fetal loss between 10 and 21 weeks, fetal death from 22 weeks until delivery, and neonatal death within 28 days of birth. Neonatal morbidity will be assessed by factors such as stay in a neonatal intensive care unit, assisted ventilation for more than 24 hours, hyaline membrane disease, and intraventricular hemorrhages stage III or IV.

Potential treatment toxicity will be monitored by recording major maternal bleeding events, and adherence to treatment will be evaluated through a diary, examining its relationship with the efficacy of the preventive effect on the primary outcome. Biological response to the treatment will be defined by serum thromboxane B2 levels greater than 10 ng/mL. Additionally, circulating and urinary angiogenic profiles, including sFLT1 and PlGF, will be analyzed in association with maternal and fetal clinical data. Child psychomotor development and health problems will be assessed at 2 and 4 years of age.