Lung Transplant Clinical Trial Network (LT-CTN)

This Lung Transplant Clinical Trials Network (LT-CTN) CTOT-CA consortium includes twelve of the high-volume, research-oriented adult and pediatric lung transplant programs in North America. Long-term survival for lung recipients is limited by chronic lung allograft dysfunction (CLAD), the final manifestation of chronic lung rejection. CLAD is not effectively prevented by posttransplant immunosuppression, as over 50% of lung recipients develop CLAD within five years. Evidence suggests upregulation of inflammatory cytokines in the allograft contributes to CLAD through innate immunity and allorecognition-driven adaptive immune responses. We previously showed posttransplant acute rejection (AR), lymphocytic bronchiolitis (LB), organizing pneumonia (OP), or acute lung injury (ALI), increase CLAD risk and are associated with elevations of Types I & II cytokines in the lung fluid. Because these cytokines share signaling through the Janus Kinase (JAK) family, blocking the JAK signaling modulator Rho-associated protein kinase 2 (ROCK2) could be an effective strategy to limit inflammatory cytokine responses and prevent CLAD. Studies in bone marrow recipients with graft vs. host disease showed clinical benefit with the oral selective ROCK2 inhibitor belumosudil, including in patients with the pulmonary manifestation of bronchiolitis obliterans syndrome, the most common presentation of CLAD. Thus, we hypothesize that adding belumosudil to standard posttransplant immunosuppression will reduce inflammatory cytokine signaling, diminish innate and adaptive immune responses, and prevent CLAD. To test this, we will complete the BLOCK-CLAD (Belumosudil to Block CLAD in High-Risk Lung Transplant Recipients: a randomized, multicenter, double-blind placebo-controlled trial) study, randomizing 234 bilateral lung recipients at higher CLAD risk (i.e. evidence of AR, LB, OP, or ALI) to belumosudil or placebo. Enrollment will occur over two years with participants having one to three years of follow-up. We will conduct mechanistic studies to determine how innate and adaptive responses that contribute to CLAD are mitigated by belumosudil. Our investigator team brings longstanding collaboration and a depth of experience, including leading the adult CTOT-20 and -22 and pediatric CTOTC-03, -05, -08, and -11 studies. When completed, BLOCK-CLAD has potential to transform clinical practice, improve lung recipient outcomes, and expand immunosuppression paradigms after solid organ transplantation.