Efficacy and Safety of Aspirin and Lansoprazole for Prevention of Preterm Birth in High-Risk Pregnant Women: A Biomarker-Enriched Trial

This protocol describes a seamless Phase II/III, randomized, double-blind clinical trial evaluating the efficacy and safety of daily low-dose aspirin (81 mg) plus lansoprazole (30 mg) in pregnant individuals at high risk for preterm birth when compared to existing standard of care, identified through biomarker-enriched screening. Participants will be enrolled between 12-16+6 weeks' gestation and followed through delivery and postpartum. The primary objective is to determine whether the investigational combination reduces the incidence of preterm birth before 37 weeks of gestation compared with placebo.

This study is a seamless Phase II/III, randomized, double-blind, biomarker-enriched clinical trial designed to evaluate the efficacy and safety of low-dose aspirin (81 mg daily) combined with lansoprazole (30 mg daily) for the prevention of preterm birth in pregnant individuals at high risk for spontaneous preterm delivery. Participants are enrolled early in pregnancy, between 12+0 and 16+6 weeks' gestation, and followed through delivery and a 6-week postpartum period. Preterm birth remains a leading cause of neonatal morbidity and mortality, yet effective pharmacologic prevention strategies are limited, particularly following the withdrawal of 17-hydroxyprogesterone caproate. This trial addresses a critical unmet need by testing a repurposed, scalable, and globally accessible drug combination, guided by precision-medicine risk stratification rather than broad, unselected treatment. Eligible participants are pregnant individuals aged 18 to 45 years with a singleton gestation who meet clinical high-risk criteria for preterm birth, such as a history of prior spontaneous preterm birth, cervical insufficiency, or short cervical length. All consented participants undergo biomarker screening, including a validated serum protein serological signature and/or a digital-twin immune profiling approach, to identify those at highest biological risk. Only participants who test biomarker-positive are eligible for randomization, ensuring an enriched population most likely to benefit from intervention. Approximately 670 biomarker-positive participants will be randomized in a 1:1 ratio to one of two study arms: (1) daily aspirin plus lansoprazole in addition to standard obstetric care, or (2) standard obstetric care alone. Investigational therapy begins immediately after randomization and continues until delivery unless discontinued for safety or clinical indications. Standard obstetric care may include cervical length surveillance, vaginal progesterone, cerclage, and other guideline-based interventions, but excludes routine aspirin or proton pump inhibitor use unless clinically required outside the protocol. The primary endpoint is the incidence of preterm birth before 37 weeks' gestation. Key secondary endpoints include preterm birth before 34 weeks, gestational age at delivery, hypertensive disorders of pregnancy, fetal growth restriction, neonatal morbidity, NICU admission, and perinatal mortality. Safety outcomes focus on maternal bleeding, gastrointestinal events, laboratory abnormalities, and serious maternal or neonatal adverse events. The study also evaluates treatment-biomarker interactions, longitudinal changes in immune and protein signatures, and concordance between predicted and observed treatment response. The trial incorporates a group-sequential design with a pre-specified interim analysis during the Phase II portion to evaluate safety, biomarker performance, and conditional power, enabling a seamless transition to Phase III if criteria are met. Randomization is stratified by study site, prior preterm birth history, and biomarker category. Bias is minimized through centralized randomization, double blinding, standardized outcome definitions, intention-to-treat analysis, and oversight by an independent Data and Safety Monitoring Board (DSMB). Conducted across multiple academic medical centers with expertise in maternal-fetal medicine, this study is designed not only to determine whether aspirin plus lansoprazole can reduce preterm birth, but also to generate high-quality evidence supporting a precision-guided preventive strategy. If successful, the trial has the potential to redefine pharmacologic prevention of preterm birth using safe, inexpensive, and widely available medications tailored to biologic risk.