Tacrolimus Versus Cyclosporine for Immunosuppression After Lung Transplantation
Information source: Universitätsklinikum Hamburg-Eppendorf
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Bronchiolitis Obliterans; Immunosuppression
Intervention: Tacrolimus (Drug); Cyclosporine (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: Universitätsklinikum Hamburg-Eppendorf Official(s) and/or principal investigator(s): Hermann Reichenspurner, MD, PhD, Principal Investigator, Affiliation: Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany Allan Glanville, MD, PhD, Study Chair, Affiliation: St. Vincent's Hospital, Sydney, Australia Hendrik Treede, MD, Study Chair, Affiliation: Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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
Clinical Details
Official title: Randomized, Open-label, Multi-Center Study Comparing Tacrolimus With Cyclosporin, Both Arms in Combination With Mycophenolate Mofetil and Corticosteroids for Prevention of Bronchiolitis Obliterans Syndrome in Lung Transplant Patients
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
Primary outcome: Incidence of bronchiolitis obliterans syndrome
Secondary outcome: Acute allograft rejectionPatient and graft survival Incidence and spectrum of infections Renal failure Treatment failure
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 66 Years.
Gender(s): Both.
Criteria:
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
Locations and Contacts
St. Vincent's Hospital, Sydney NSW 2010, Australia
Allgemeines Krankenhaus Wien, Wien 1090, Austria
Hospital Erasme, Bruxelles 1070, Belgium
Universitaire Ziekenhuizen, Leuven 3000, Belgium
Universitätsklinikum Essen, Essen 45147, Germany
Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany
Universitätsklinikum Jena, Jena 07740, Germany
Universitätsklinikum Kiel, Kiel 24105, Germany
Hospital Vall d`Hebron, Barcelona 08035, Spain
Hospital Reina Sofia, Cordoba 14004, Spain
Hospital Juan Canalejo, La Coruna 15006, Spain
ClÃnica Puerta de Hierro, Madrid 28035, Spain
Hospital Marques de Valdecilla, Santander 39008, Spain
Centre hospitalier universitaire vaudois, Lausanne 1011, Switzerland
Additional Information
International Society For Heart and Lung Transplantation
Related publications: Aurora P, Edwards LB, Kucheryavaya AY, Christie JD, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official pediatric lung and heart-lung transplantation report--2010. J Heart Lung Transplant. 2010 Oct;29(10):1129-41. doi: 10.1016/j.healun.2010.08.008. Reichenspurner H, Girgis RE, Robbins RC, Conte JV, Nair RV, Valentine V, Berry GJ, Morris RE, Theodore J, Reitz BA. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg. 1995 Dec;60(6):1845-53. Review. Snell GI, Boehler A, Glanville AR, McNeil K, Scott JP, Studer SM, Wallwork J, Westall G, Zamora MR, Stewart S. Eleven years on: a clinical update of key areas of the 1996 lung allograft rejection working formulation. J Heart Lung Transplant. 2007 May;26(5):423-30. Review. Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, Mallory GB, Snell GI, Yousem S. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002 Mar;21(3):297-310. Review. Hachem RR, Yusen RD, Chakinala MM, Meyers BF, Lynch JP, Aloush AA, Patterson GA, Trulock EP. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant. 2007 Oct;26(10):1012-8. Keenan RJ, Konishi H, Kawai A, Paradis IL, Nunley DR, Iacono AT, Hardesty RL, Weyant RJ, Griffith BP. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg. 1995 Sep;60(3):580-4; discussion 584-5. Treede H, Klepetko W, Reichenspurner H, Zuckermann A, Meiser B, Birsan T, Wisser W, Reichert B; Munich and Vienna Lung Transplant Group. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant. 2001 May;20(5):511-7. Zuckermann A, Reichenspurner H, Birsan T, Treede H, Deviatko E, Reichart B, Klepetko W. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg. 2003 Apr;125(4):891-900. Sarahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville A, Chaparro C, Verleden G, Gerbase MW, Venuta F, Böttcher H, Aubert JD, Levvey B, Reichenspurner H, Auterith A, Klepetko W. International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. J Thorac Cardiovasc Surg. 2004 Apr;127(4):1126-32. Vitulo P, Oggionni T, Cascina A, Arbustini E, D'Armini AM, Rinaldi M, Meloni F, Rossi A, Viganò M. Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation. J Heart Lung Transplant. 2002 Apr;21(4):435-9. McNeil K, Glanville AR, Wahlers T, Knoop C, Speich R, Mamelok RD, Maurer J, Ives J, Corris PA. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation. 2006 Apr 15;81(7):998-1003. Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, Egan T, Keshavjee S, Knoop C, Kotloff R, Martinez FJ, Nathan S, Palmer S, Patterson A, Singer L, Snell G, Studer S, Vachiery JL, Glanville AR; Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006 Jul;25(7):745-55. Shyu S, Dew MA, Pilewski JM, DeVito Dabbs AJ, Zaldonis DB, Studer SM, Crespo MM, Toyoda Y, Bermudez CA, McCurry KR. Five-year outcomes with alemtuzumab induction after lung transplantation. J Heart Lung Transplant. 2011 Jul;30(7):743-54. doi: 10.1016/j.healun.2011.01.714. Epub 2011 Mar 21.
Starting date: January 2001
Last updated: September 6, 2011
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