AzTrials
AzTrials

Bronchiolitis ObliteransPhase 3EAILTXNCT01429844

Tacrolimus Versus Cyclosporine for Immunosuppression After Lung Transplantation

A Phase 3 study testing Tacrolimus and Cyclosporine in people with Bronchiolitis Obliterans and Immunosuppression, run by Universitätsklinikum Hamburg-Eppendorf at 14 sites in 6 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 66 years
Conditions the study is for
Bronchiolitis Obliterans, Immunosuppression
What is being tested?
Tacrolimus and Cyclosporine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
274 participants
Where
14 sitesin 6 countries
Study dates
Jan 2001to Aug 2010
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 66 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

14 sites in 6 countries.

14 sites in 6 countries

Spain5 sites

  • Hospital Juan Canalejo

    A Coruña, 15006

  • Hospital Vall d'Hebron

    Barcelona, 08035

  • Hospital Reina Sofia

    Córdoba, 14004

  • Clínica Puerta de Hierro

    Madrid, 28035

  • Hospital Marques de Valdecilla

    Santander, 39008

Other trials in Spain

Germany4 sites

  • Universitätsklinikum Essen

    Essen, 45147

  • Universitätsklinikum Hamburg-Eppendorf

    Hamburg, 20246

  • Universitätsklinikum Jena

    Jena, 07740

  • Universitätsklinikum Kiel

    Kiel, 24105

Other trials in Germany

Belgium2 sites

  • Hospital Erasme

    Brussels, 1070

  • Universitaire Ziekenhuizen

    Leuven, 3000

Other trials in Belgium

Australia1 site

  • St. Vincent's Hospital

    Sydney, NSW 2010

Other trials in Australia

Austria1 site

  • Allgemeines Krankenhaus Wien

    Vienna, 1090

Other trials in Austria

Switzerland1 site

  • Centre hospitalier universitaire vaudois

    Lausanne, 1011

Other trials in Switzerland

About this study

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

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

Read the 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.

Keywords
Calcineurin inhibitors, Bronchiolitis obliterans, Lung transplantation, Cyclosporine, Tacrolimus, Mycophenolate, Steroids, Chronic rejection, Acute rejection, Obliterative bronchiolitis
Medical subject headings
Bronchiolitis Obliterans

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TacrolimusDrug

    Also called FK 506, Prograf

    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.

  • CyclosporineDrug

    Also called CyA, CsA, Cyclosporine A, Sandimmune

    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.

Study groups in NCT01429844
Study groupRoleWhat they receive
TacrolimusActive comparatorTacrolimus in combination with mycophenolate mofetil and steroids for denovo immunosuppression after lung transplantation
Receives: Drug: Tacrolimus
CyclosporineActive comparatorCyclopsorine in combination with mycophenolate mofetil and steroids for denovo immunosuppression after lung transplantation
Receives: Drug: Cyclosporine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of bronchiolitis obliterans syndrome

    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.

    Measured: 3 years post transplant

Secondary outcomes (5)

  1. Acute allograft rejection

    One- and 3-year rates of acute allograft rejection determined by clinical criteria or transbronchial lung biopsy.

    Measured: 3 years post transplant

  2. Patient and graft survival

    Patient and graft survival at one and three years

    Measured: 3 years post transplant

  3. Incidence and spectrum of infections

    Incidence and spectrum (viral, bacterial, fungal)of infections after transplantation

    Measured: 3 years post transplant

  4. Renal failure

    Post operative onset of renal dysfunction (defined as a persistent increase in serum creatinine of > 2mg/dl) or dialysis dependency

    Measured: 3 years post transplant

  5. Treatment failure

    Treatment failure defined as drug discontinuation (e.g. conversion to a different immunosuppression regimen)

    Measured: 3 years post transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Sep 2011 (estimated)
  2. Study startJan 2001
  3. Primary completionOct 2007
  4. Study completionAug 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
274 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01429844
Sponsor's protocol ID
EAILTx Tac vs. CsA in LuTx
Acronym
EAILTX
Status last verified
Sep 2011
First submitted
5 Sep 2011
Last updated
7 Sep 2011
Results posted
No
Data monitoring committee
No

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. No abstract available.

    PubMed 20870167

  • 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. doi: 10.1016/0003-4975(95)00776-8.

    PubMed 8787504

  • 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. doi: 10.1016/j.healun.2007.01.040. No abstract available.

    PubMed 17449409

  • 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. doi: 10.1016/s1053-2498(02)00398-4. No abstract available.

    PubMed 11897517

  • 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. doi: 10.1016/j.healun.2007.07.027.

    PubMed 17919621

  • 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. doi: 10.1016/0003-4975(95)00407-C.

    PubMed 7545889

  • 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. doi: 10.1016/s1053-2498(01)00244-3.

    PubMed 11343977

  • 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. doi: 10.1067/mtc.2003.71.

    PubMed 12698153

  • Sarahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville A, Chaparro C, Verleden G, Gerbase MW, Venuta F, Bottcher 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. doi: 10.1016/j.jtcvs.2003.11.009.

    PubMed 15052212

  • Vitulo P, Oggionni T, Cascina A, Arbustini E, D'Armini AM, Rinaldi M, Meloni F, Rossi A, Vigano M. Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation. J Heart Lung Transplant. 2002 Apr;21(4):435-9. doi: 10.1016/s1053-2498(01)00379-5.

    PubMed 11927219

  • 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. doi: 10.1097/01.tp.0000202755.33883.61.

    PubMed 16612275

  • 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. doi: 10.1016/j.healun.2006.03.011. No abstract available.

    PubMed 16818116

  • 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.

    PubMed 21420318

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Tacrolimus and Cyclosporine in people with Bronchiolitis Obliterans and Immunosuppression, run by Universitätsklinikum Hamburg-Eppendorf at 14 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Sep 2011. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in Spain, Germany, Belgium, Australia, Austria and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of bronchiolitis obliterans syndrome (time frame: 3 years post transplant). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01429844, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Sep 2011.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in