Nintedanib in progressive bronchiolitis obliterans syndrome (BOS) grade 0p-1-2 in lung transplant recipients (INFINITIx-BOS): protocol of a French multicenter randomized controlled trial

BACKGROUND: Long-term survival after lung transplantation (LTx) is still hampered by the development of chronic allograft dysfunction (CLAD). Bronchiolitis obliterative syndrome (BOS), the most common phenotype of CLAD, is thought to arise from repeated injuries to graft epithelial cells, leading to fibrous scarring of small airways. Thus far, there is no approved treatment for BOS disease. Based on both animal/human studies in LTx and the demonstrated efficacy of the TKI nintedanib treatment in idiopathic pulmonary fibrosis (IPF), nintedanib is a candidate molecule capable of stopping the fibroproliferative process in BOS. Hence, the rationale to conduct a nintedanib trial in LTx recipients with BOS is based on (i) an unmet medical need due to poor survival after BOS diagnosis; (ii) the demonstrated fibrotic pathways in BOS; and (iii) the proven efficacy of nintedanib in IPF. METHODS: The INFINITIx-BOS study is an investigator-initiated, national multicentric, phase II, superiority, parallel-group, double-blind, comparative randomized clinical trial. A total of 80 recipients with progressive BOS within the prior year, at least at 6 months post-LTx, will be randomized to receive either nintedanib (150 mg bid) or placebo for a period of 6 months, in addition to maintenance immunosuppressive therapy left to their physician's discretion with 4 dedicated visits. The primary endpoint is the slope of decline over 6 months of treatment. The secondary endpoints are change in 6-min walk test, SGRQ, graft failure, SPO2, and safety events over 6 months, which will be compared between the two arms. DISCUSSION: Based on a fibrotic pattern partially shared between IPF and BOS, this randomized INFINITIx-BOS trial has the potential to demonstrate an additional strategy with nintedanib as a targeted-fibrotic pathway associated with BOS. TRIAL REGISTRATION NUMBER: NCT03283007, first posted 11 September 2017. Protocol version identifier No. 6-0, 8 September 2023.