Abstract
Introduction
Exudative pleural effusion of an unclear aetiology remains a diagnostic challenge. Ultrasonic elastography-guided pleural biopsy (UEPB) offers a higher diagnostic yield than conventional ultrasound-guided pleural biopsy; however, its role relative to semi-rigid thoracoscopy remains unclear. This trial is designed to determine whether UEPB is non‑inferior to semi-rigid thoracoscopy in diagnostic yield when used as the initial diagnostic procedure, and to further quantify the proportion of patients in whom semi-rigid thoracoscopy could be avoided by adopting a UEPB-first diagnostic strategy.Methods and analysis
In this multicentre, open-label, parallel-group, non-inferiority, randomised controlled trial conducted at five sites in China, 420 patients with exudative pleural effusion of unknown aetiology and negative cytology will be randomly assigned 1:1 to either initial UEPB (with semi-rigid thoracoscopy reserved for non-diagnostic cases) or immediate semi-rigid thoracoscopy. The primary outcome is the overall diagnostic yield of the allocated diagnostic strategy, defined as the proportion of participants in whom a specific histopathological diagnosis is stablished through the protocol-defined biopsy procedures within the allocated diagnostic pathway. A non-inferiority margin of - 5% is applied. The secondary outcomes included diagnostic sensitivity in specific disease, procedure-related adverse events, length of hospital stay, duration of chest tube drainage, thoracoscopy avoidance rate, and direct diagnostic pathway-related medical costs.Discussion
This UPDATE-3 study will provide the evidence from a RCT directly comparing the a UEPB-first step-up diagnostic strategy with immediate semi-rigid thoracoscopy in patients with undiagnosed exudative pleural effusion. Should non-inferiority be established, UEPB will be validated as a sufficiently sensitive first-line biopsy technique. Furthermore, this trial will quantify the extent to which a UEPB-first strategy can safely decrease the necessity for semi-rigid thoracoscopy and optimize healthcare utilization. These findings could facilitate a paradigm shift towards a less invasive, step-up diagnostic pathway. Conversely, should non-inferiority not be established, the findings will reinforce the status of semi-rigid thoracoscopy as the diagnostic reference standard and elucidate the appropriate role of UEPB within the diagnostic algorithm.Trial registration
ClinicalTrials.gov (Registration ID: NCT07419620; Registration Date: 2026-02-12).