BackgroundTransbronchial biopsy is a common bronchoscopic procedure that is traditionally performed with forceps. However, its diagnostic capability is limited by small specimen size and crush artifact. A 1.1 mm cryoprobe was developed to overcome these limitations utilizing rapid, controlled, freezing to retrieve larger specimens which are extractable through the bronchoscope's working channel. Whether this improves diagnostic yield remains uncertain. The 1.1 mm cryoprobe has not been directly compared to standard capacity forceps in a prospective, randomized fashion.MethodsThis multicenter randomized controlled trial evaluates whether transbronchial biopsy with a 1.1 mm cryoprobe yields superior diagnostic yield compared to standard capacity forceps in adults undergoing transbronchial biopsy for diffuse parenchymal lung disease, parenchymal pulmonary lesions, or lung allografts. Participants will be randomized 1:1 to either biopsy tool, stratified by indication. Primary outcomes include indication-specific and overall diagnostic yield, adjudicated by centralized pathology review. Secondary outcomes include histologic quality metrics and complication rates. This trial is individually powered for each indication-specific primary outcome, and can detect an 11.3% difference in overall diagnostic yield with 250 participants per arm.DiscussionThis trial will provide high-quality evidence to guide transbronchial biopsy tool selection to maximize diagnostic yield. Results of this trial may yield practice changing data for the evaluation of patients with diffuse parenchymal lung disease, parenchymal pulmonary lesions, and lung allografts. Unique design features include the use of a centralized histopathology core to minimize bias and interobserver variability and a pragmatic design to facilitate integration into clinical workflows and optimize recruitment.