The purpose of the study is to compare efficacy and safety of two different immunosuppressive regimens for prevention of bronchiolitis obliterans syndrome (BOS) (chronic lung allograft rejection)after lung transplantation: tacrolimus versus cyclosporine, both in combination with mycophenolate mofetil and steroids. The study was powered to detect a 15% reduction in BOS in tacrolimus treated patients.

Study design: open-label, randomized, comparative, multi-center, investigator driven

Lung transplantation has become a viable treatment option for selected patients with end stage lung disease and leads to prolonged survival and improved quality of life. However, despite improvements in surgical techniques, immunosuppressive therapies and long-term care, survival rates reported by the Registry of the International Society for Heart and Lung Transplantation (ISHLT) (79% 1-year and 52% 5-year) are lower than those reported for other solid organ transplants. The leading cause of death in long-term follow-up after lung transplantation is chronic allograft dysfunction due to obliterative bronchiolitis (OB) manifested by its physiological correlate the bronchiolitis obliterans syndrome (BOS). OB is thought to result from chronic rejection leading to obliteration and scarring of the terminal bronchioles which causes a significant reduction in pulmonary function parameters, most specifically the forced expiratory volume in 1 second (FEV1). In the absence of confounding variables, lung transplant recipients are considered to suffer from BOS grade ≥1 if they experience a sustained (>3 weeks) ≥ 20% decline in FEV1 from a baseline of the average of the two best FEV1 measurements obtained at least 3 weeks apart.

Most immunosuppressive regimens after lung transplantation are based on calcineurin inhibitors. The introduction of cyclosporine was responsible for the initial success of lung transplantation in the early 1980s as it allowed the use of a lower dose of corticosteroids and hence afforded superior wound healing. Its chief mechanism of action is the blockade of T-lymphocyte activation by inhibiting interleukin-2 (IL 2) synthesis. Tacrolimus is a macrolide lactone that was introduced in the 1990s and is now widely accepted as an alternative to cyclosporine. Mechanisms of action and toxicities of tacrolimus and cyclosporine are similar, and tacrolimus has proven to be at least as effective as cyclosporine in solid organ transplantation including lung transplantation. Tacrolimus is approximately 50 times more potent than cyclosporine and has proven to be an effective rescue agent for patients with either recurrent or refractory acute allograft rejection. Whether denovo tacrolimus use can reduce the incidence of BOS when compared with cyclosporine after lung transplantation remains unclear. To date there are no published adequately powered randomized controlled trials in lung transplantation which compare the efficacy and safety of the calcineurin inhibitors cyclosporine and tacrolimus for primary immunosuppression.

The investigators therefore conducted a randomized, open-label, multi-center, investigator driven trial comparing tacrolimus with cyclosporine - both arms in combination with mycophenolate mofetil (MMF) and prednisolone for the prevention of BOS in lung and heart-lung transplant recipients.

The investigators chose to partner the calcineurin inhibitor with MMF instead of azathioprine. MMF is an ester prodrug of mycophenolic acid (MPA), a potent and specific inhibitor of de novo purine synthesis which blocks the proliferation of both T and B lymphocytes. The potential superiority of MMF over its comparator azathioprine after lung transplantation has been suggested in small and nonrandomized studies. However, large randomized trials in renal and heart transplantation have demonstrated the greater efficacy of MMF for preventing acute allograft rejection when compared with azathioprine.

The study protocol was accepted by each local hospital research ethics committee. All patients provided written informed consent and were free to withdraw from the study at any time point. The trial was proposed and designed by a steering committee consisting of members of the study group, The European and Australian Investigators in Lung Transplantation (EAILTx), representing experienced lung transplant centers from Australia, Austria, Belgium, Germany, Spain and Switzerland.

The study took place at 14 experienced lung transplantation centers in 5 European countries (Austria, Belgium, Germany, Spain and Switzerland) and Australia (Appendix). Patients were screened for eligibility prior to transplantation. At the time of transplantation, randomization was performed using a centralized telephone based computer randomization tool. Patients were assigned to receive tacrolimus, MMF and corticosteroids or cyclosporine, MMF and corticosteroids and were stratified according to whether they had cystic fibrosis (CF) or not. Stratification was performed because chronic airway infection, multi-organ involvement and variable gastrointestinal absorption pose specific clinical problems in individuals with CF which may have introduced an outcome bias if there were an imbalance of CF patients between groups.

Patients were followed for 3 years. Regular visits after transplantation were scheduled at 1 and 2 weeks, at 1, 2, 3, 6, 9, and 12 months, and every 6 months thereafter. Data were entered into an electronic case report form (eCRF) and regularly monitored and checked for inconsistencies by an independent monitor who was also responsible for query management. After completion of the follow-up period source data verification was performed by independent data management specialists who visited the centers and checked patient records for completeness of data.

The study was planned and designed in 1999, the protocol written in 2000, and the first patient randomized in 2001 at which time the registration of randomized trials was not mandatory. Reporting follows the Consort statement.

From January 2001 until June 2003 a total of 265 patients from 14 centers in 6 countries were randomized and transplanted.

Inclusion Criteria:

• male or female recipients of a first heart-lung
• bilateral or single lung allograft suitable to receive triple immunosuppressive therapy with tacrolimus or cyclosporine, MMF and corticosteroids per standard guidelines
• Age range = 18-66 years
• Able to understand the purposes and risks of the study
• Female patients of child bearing age agreeing to maintain effective birth control practice during the follow-up period

Exclusion Criteria:

• need for immunosuppressive regimen other than study medication or received additional organ transplantations
• Pregnant women, nursing mothers or women unwilling to use adequate contraception
• Serologic evidence of human immunodeficiency virus, hepatitis B surface antigen or hepatitis C virus antibodies
• Panresistant infections with Burkholderia cepacia or mycobacteria during the last 12 months preceding lung transplantation
• Patients with renal insufficiency (creatinine clearance < 40 ml/min
• Patients in need of invasive ventilator devices or extracorporeal membrane oxygenation