Clinical Study on the Prevention of High-Risk Pulmonary Nodule Progression With Yifei Sanjie Pill: Protocol for a Multicenter Randomized Controlled Trial.

Background: High-risk subsolid pulmonary nodules, especially mixed ground-glass nodules, can represent precancerous or early-stage lung adenocarcinoma spectrum lesions. Standard management relies mainly on risk stratification, repeated thin-slice computed tomography, and invasive diagnosis or surgery when progression suggests malignancy. Safe adjunctive pharmacologic options to reduce nodule progression remain limited. Yifei Sanjie Pill (YFSJ) is an 8-herb traditional Chinese medicine formula that has been previously studied as an adjunctive treatment for non-small cell lung cancer. However, its effect on high-risk pulmonary nodules-a distinct clinical condition-has not yet been investigated. Objective: This protocol describes a multicenter randomized trial evaluating the efficacy, safety, and exploratory mechanisms of YFSJ for preventing high-risk pulmonary nodule progression. Methods: Adults aged 18 to 80 years with single or multiple mixed ground-glass nodules measuring ≤8 mm will be randomized in a 1:1 ratio to receive YFSJ optimized formula granules or matched placebo granules, 2 packets twice daily for 6 months. Both groups will receive guideline-based computed tomography surveillance and any clinically indicated standard diagnostic or therapeutic care. The primary outcome is the 2-year pulmonary nodule progression rate, defined as an increase in the lesion's longest diameter of ≥2 mm, an increase in the solid component of ≥1 mm, or the appearance of a new solid component. Secondary outcomes include lung cancer detection rate, surgery rate, 6-month nodule size and volume change, artificial intelligence-based malignancy risk index, traditional Chinese medicine symptom score, Hospital Anxiety and Depression Scale (HADS) score, Pittsburgh Sleep Quality Index (PSQI) score, safety indicators, and exploratory plasma biomarkers. The primary analysis will use the full analysis set, Kaplan-Meier estimates, log-rank testing, and Cox regression adjusted for center and key covariates; repeated outcomes will be analyzed using mixed-effects models. Results: The study was funded in 2022 and approved by the Research Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (K-2022-131-XZ-01). Recruitment started in June 2023 and was scheduled for completion in December 2025. As of April 2026, a total of 589 participants have completed randomization. The final 2-year follow-up is scheduled for December 2027. Database lock and primary analysis are planned for early 2028, and submission of the first results is expected in spring or summer 2028. Conclusions: This trial will determine whether adding YFSJ to guideline-based surveillance can reduce high-risk pulmonary nodule progression and provide mechanistic evidence for integrative early lung cancer prevention.