Repertaxin in Prevention of Primary Graft Dysfunction After Lung Transplantation

A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of Repertaxin in the Prevention of Primary Graft Dysfunction After Lung Transplantation

The chemokine CXCL8 plays a key role in the recruitment and activation of polymorphonuclear neutrophils in post-ischemia reperfusion injury after solid organ transplantation. Repertaxin is a novel, specific inhibitor of CXCL8. This study is configured to explore the safety and efficacy of repertaxin in preventing the primary graft dysfunction (PGD) after lung transplantation.

Lung transplantation has become a standard therapy for patients with end-stage lung disease. Within last decades, donor management, organ preservation, immunosuppressive regimens and control of infectious complications have been substantially improved. In addition, the operative techniques of transplantation procedures have been developed to an international standard of high quality. However, despite these refinements, significant reperfusion injury occurs in up to 10-20% of lung transplant recipients as the consequence of unavoidable processes of procurement, preservation and restoring blood flow. This clinical condition, recently termed primary graft dysfunction (PGD), remains an important problem after lung transplantation, and still represents the single biggest cause of early morbidity and mortality for lung recipients. In addition, there is some evidence to suggest a relationship between reperfusion injury, acute rejection, and the subsequent development of chronic graft dysfunction. In post-ischemia reperfusion, restoration of the blood supply (reperfusion) after prolonged tissue ischemia is associated with an inflammatory reaction characterized by massive polymorphonuclear neutrophil infiltration into the reperfused tissue. The infiltrating inflammatory cells can perpetuate the initial inflammatory reaction and induce further injuries. The importance of CXCL8 in lung tissue during the ischemic time and after reperfusion has been clearly demonstrated. The current standard of care in preventing this clinical condition focuses on prevention by way of surgical techniques in the procurement, storage and implantation of graft lungs. The efficacy of repertaxin in preventing polymorphonuclear neutrophil infiltration and tissue damage in rat models of kidney transplantation and lung transplantation, as well as the safety shown in human phase 1 studies, provide the rationale for a clinical study aimed at evaluating the effect of repertaxin in preventing PGD after lung transplantation.

Inclusion Criteria: Patients accepted and listed for transplantation due to irreversible, progressive disabling, end-stage pulmonary disease Body weight 30 - 95 kg, inclusive (i.e. up to 95.99 kg) Planned isolated (single and bi-lateral) lung transplant from a non-living donor with brain death Normal renal function at the time of transplant Patient willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations Patient given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. Exclusion Criteria: Recipients of an intended multiple organ transplant, including heart-lung and liver-lung transplantation Recipients of a lung from a living lobar donor Recipients of a lung from a non-heart beating donor Re-do lung transplantation Recipients requiring mechanical ventilation at the time of transplant Recipients with extra-respiratory tract site of infection Recipients with hepatic dysfunction at the time of transplant Hypersensitivity to ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID) Hypersensitivity to medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib Patients simultaneously participating in any other studies involving a study drug to be administered concomitantly with the Investigational Product and/or a study drug intended to prevent ischemia/reperfusion injury Planned use of anti-CD3 monoclonal antibody (Orthoclone OKT3) or alemtuzumab (Campath) induction immunosuppression Planned use of sirolimus in the first three months after transplantation Pregnant or breast-feeding women