Tacrolimus Versus Cyclosporine for Immunosuppression After Lung Transplantation
Condition: Bronchiolitis Obliterans; Immunosuppression
MeSH terms: Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis Obliterans Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      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
    

Detailed description: 
      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.
    

Intervention name(s): Tacrolimus; Cyclosporine
Intervention type(s): Drug; Drug
Intervention description(s): Tacrolimus therapy was started immediately after transplantation with a continuous intravenous infusion of 0.01-0.03 mg/kg/d. After extubation, the mode of delivery was switched to oral administration (b.i.d.) with doses of 0.05-0.3 mg/kg/d. Tacrolimus doses were adjusted to trough levels. Target C0 (trough) levels were 10-15 ng/ml for the first 3 months after transplantation and 8-12 ng/ml thereafter with dose adjustments according to patient outcome.; Cyclosporine therapy was started immediately after transplantation with a continuous intravenous infusion of 1-3 mg/kg/d. After extubation the mode of delivery was switched to oral administration (b.i.d. or t.i.d.) with doses of 4-18 mg/kg/d. Cyclosporine doses were adjusted to C0 or C2 levels according to local practice. Target trough levels were 200 - 300 ng/ml for the first 3 months after transplantation and 150 - 200 ng/ml thereafter.
Other intervention name(s): FK 506; Prograf; CyA; CsA; Cyclosporine A; Sandimmune
Intervention MeSH terms: Cyclosporine; Tacrolimus; Cyclosporins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Calcineurin inhibitors; Bronchiolitis obliterans; Lung transplantation; Cyclosporine; Tacrolimus; Mycophenolate; Steroids; Chronic rejection; Acute rejection; Obliterative bronchiolitis