Tacrolimus Versus Cyclosporine for Immunosuppression After Lung Transplantation - Full Text View

Purpose

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

Condition	Intervention	Phase
Bronchiolitis Obliterans Immunosuppression	Drug: Tacrolimus Drug: Cyclosporine	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
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

Resource links provided by NLM:

MedlinePlus related topics: Lung Transplantation

Drug Information available for: Mycophenolic acid Mycophenolate sodium Cyclosporine Tacrolimus Mycophenolate mofetil hydrochloride Mycophenolate mofetil

U.S. FDA Resources

Further study details as provided by Universitätsklinikum Hamburg-Eppendorf:

Primary Outcome Measures:

Incidence of bronchiolitis obliterans syndrome [ Time Frame: 3 years post transplant ] [ Designated as safety issue: No ]
The incidence of patients with bronchiolitis obliterans syndrome (BOS), defined as a sustained fall (for >1 month) in maximum FEV1 of 20% or more (compared to baseline) over three years post transplant.

Secondary Outcome Measures:

Acute allograft rejection [ Time Frame: 3 years post transplant ] [ Designated as safety issue: No ]
One- and 3-year rates of acute allograft rejection determined by clinical criteria or transbronchial lung biopsy.
Patient and graft survival [ Time Frame: 3 years post transplant ] [ Designated as safety issue: No ]
Patient and graft survival at one and three years
Incidence and spectrum of infections [ Time Frame: 3 years post transplant ] [ Designated as safety issue: Yes ]
Incidence and spectrum (viral, bacterial, fungal)of infections after transplantation
Renal failure [ Time Frame: 3 years post transplant ] [ Designated as safety issue: Yes ]
Post operative onset of renal dysfunction (defined as a persistent increase in serum creatinine of > 2mg/dl) or dialysis dependency
Treatment failure [ Time Frame: 3 years post transplant ] [ Designated as safety issue: No ]
Treatment failure defined as drug discontinuation (e.g. conversion to a different immunosuppression regimen)

Enrollment:	274
Study Start Date:	January 2001
Study Completion Date:	August 2010
Primary Completion Date:	October 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Tacrolimus Tacrolimus in combination with mycophenolate mofetil and steroids for denovo immunosuppression after lung transplantation	Drug: Tacrolimus 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. Other Names: FK 506 Prograf
Active Comparator: Cyclosporine Cyclopsorine in combination with mycophenolate mofetil and steroids for denovo immunosuppression after lung transplantation	Drug: Cyclosporine 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 Names: CyA CsA Cyclosporine A Sandimmune

Arms

Assigned Interventions

Active Comparator: Tacrolimus

Tacrolimus in combination with mycophenolate mofetil and steroids for denovo immunosuppression after lung transplantation

Drug: Tacrolimus

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.

Other Names:

FK 506
Prograf

Active Comparator: Cyclosporine

Cyclopsorine in combination with mycophenolate mofetil and steroids for denovo immunosuppression after lung transplantation

Drug: Cyclosporine

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 Names:

CyA
CsA
Cyclosporine A
Sandimmune

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 66 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01429844

Locations

Australia
St. Vincent's Hospital
Sydney, Australia, NSW 2010
Austria
Allgemeines Krankenhaus Wien
Wien, Austria, 1090
Belgium
Hospital Erasme
Bruxelles, Belgium, 1070
Universitaire Ziekenhuizen
Leuven, Belgium, 3000
Germany
Universitätsklinikum Essen
Essen, Germany, 45147
Universitätsklinikum Hamburg-Eppendorf
Hamburg, Germany, 20246
Universitätsklinikum Jena
Jena, Germany, 07740
Universitätsklinikum Kiel
Kiel, Germany, 24105
Spain
Hospital Vall d`Hebron
Barcelona, Spain, 08035
Hospital Reina Sofia
Cordoba, Spain, 14004
Hospital Juan Canalejo
La Coruna, Spain, 15006
Clínica Puerta de Hierro
Madrid, Spain, 28035
Hospital Marques de Valdecilla
Santander, Spain, 39008
Switzerland
Centre hospitalier universitaire vaudois
Lausanne, Switzerland, 1011

Sponsors and Collaborators

Universitätsklinikum Hamburg-Eppendorf

Investigators

Principal Investigator:	Hermann Reichenspurner, MD, PhD	Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany
Study Chair:	Allan Glanville, MD, PhD	St. Vincent's Hospital, Sydney, Australia
Study Chair:	Hendrik Treede, MD	Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

More Information

Additional Information:

International Society For Heart and Lung Transplantation This link exits the ClinicalTrials.gov site

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. No abstract available.

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. No abstract available.

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. No abstract available.

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. No abstract available.

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. Epub 2011 Mar 21.

Responsible Party:	Prof. Dr. Hermann Reichenspurner, Prof. Dr. med. Hermann Reichenspurner, PhD, Universitätsklinikum Hamburg-Eppendorf
ClinicalTrials.gov Identifier:	NCT01429844 History of Changes
Other Study ID Numbers:	EAILTx Tac vs. CsA in LuTx
Study First Received:	September 5, 2011
Last Updated:	September 6, 2011
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Universitätsklinikum Hamburg-Eppendorf:

Calcineurin inhibitors
Bronchiolitis obliterans
Lung transplantation
Cyclosporine
Tacrolimus

Mycophenolate
Steroids
Chronic rejection
Acute rejection
Obliterative bronchiolitis

Additional relevant MeSH terms:

Bronchiolitis Obliterans
Bronchiolitis
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
Cyclosporins
Cyclosporine
Mycophenolic Acid
Mycophenolate mofetil
Tacrolimus

Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on May 23, 2013

Tacrolimus Versus Cyclosporine for Immunosuppression After Lung Transplantation (EAILTX)