Clinical trial NCT00321906: Comparison of Sirolimus and Azathioprine in Lung Transplantation
Official title: Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen Versus Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Delayed Graft Function
Acute Graft Rejection
Keywords: Rejection in lung transplant
Lead sponsor: University of Chicago
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
name: Loyola University
name: University of Florida
name: University of Pennsylvania
name: Baylor College of Medicine
name: Ochsner Health System
name: Columbia University
name: University of Wisconsin, Madison
First posted: 2006-05-04
Enrollment: 181
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to compare the safety and effectiveness of two different anti-rejection drug regimens.

Detailed description: This multicenter prospective, randomized controlled clinical trial compared the open label use of sirolimus with that of azathioprine in a tacrolimus-based immunosuppression regimen. Eligible patients were identified during a 90-day screening period immediately after transplantation and randomized via a computer-generated scheme. Patient randomization was stratified according to center and rejection status in the first 90 days after transplantation. All patients received IL-2 receptor antagonist induction therapy, tacrolimus, azathioprine, and corticosteroids until 90 days after transplantation. At 90 days after transplantation, patients were randomized at a 1:1 ratio to either continue azathioprine or change from azathioprine to sirolimus.

The dosing and levels of immunosuppressive medications were standardized for all patients included in this study. Tacrolimus was dosed at 0.04 mg/kg twice daily with target trough levels between 5 and 15 ng/ml, azathioprine was administered at 2 mg/kg daily with dose adjustments for leukopenia, sirolimus was initially dosed at 2 mg/day with target trough levels between 5 and 15 ng/ml, and prednisone was tapered to not more than 10 mg/day by 3 months after transplantation. All patients received induction therapy with either daclizumab or basiliximab as per the product package insert.

In addition, prophylactic antimicrobials were standardized among the participating sites. All patients with either donor and/or recipient cytomegalovirus (CMV)-positive serostatus received either intravenous ganciclovir or oral valganciclovir for a total of 90 days. Lung transplant recipients who were negative for both donor and recipient CMV serostatus received valacyclovir for 90 days. Antifungal prophylaxis was determined by each site. Pneumocystis jiroveci prophylaxis was continued throughout the study. Lipid-lowering medications were recommended according to the National Cholesterol Education Program guidelines.

Eligibility criteria: Inclusion Criteria:

* Lung transplant recipients between the age of 18 and 65 years of age.
* Females who are capable of becoming pregnant must have a negative pregnancy test prior to consent. (Females of childbearing potential must be using a medically acceptable method of birth control for the duration of the study.)
* All patients must be able to give written informed consent.

Exclusion Criteria:

* White blood cell count (WBC) \< 4.0/mm3
* Platelet count \< 100,000/mm3
* Severe hypercholesterolemia (\> 350 mg/dl) or hypertriglyceridemia (\> 500 mg/dl)
* Uncontrolled systemic infection at the time of consent.
* Previous organ transplant
* Treatment with a drug within the last 30 days that has not received regulatory approval at the time of study entry or for the duration of the study (3 years).
* Use of maintenance immunosuppression other than daclizumab, tacrolimus, azathioprine, or prednisone prior to randomization.

Primary outcomes:
measure: Acute Rejection Rate at 12 Months
timeFrame: 12mos
Secondary outcomes:
measure: Acute Rejection-free Survival at 12 Months
timeFrame: 12 mos
measure: Severity of Acute Rejection at 12 Months
timeFrame: 12 mos
measure: Bronchiolitis Obliterans Syndrome (BOS) at 24 Months
timeFrame: 24 mos
measure: Bronchiolitis Obliterans Syndrome (BOS) at 36 Months
timeFrame: 36 mos
measure: Overall Survival at 12 Months
timeFrame: 12 mos
measure: Overall Survival at 24 Months
timeFrame: 24 mos
measure: Overall Survival at 36 Months
timeFrame: 36 mos
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
Study officials:
affiliation: University of Chicago
name: Edward Garrity, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bhorade S, Ahya VN, Baz MA, Valentine VG, Arcasoy SM, Love RB, Seethamraju H, Alex CG, Bag R, Deoliveira NC, Husain A, Vigneswaran WT, Charbeneau J, Krishnan JA, Durazo-Arvizu R, Norwick L, Garrity E. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. Am J Respir Crit Care Med. 2011 Feb 1;183(3):379-87. doi: 10.1164/rccm.201005-0775OC. Epub 2010 Sep 10.
citation: Bhorade SM, Husain AN, Liao C, Li LC, Ahya VN, Baz MA, Valentine VG, Love RB, Seethamraju H, Alex CG, Bag R, DeOliveira NC, Vigneswaran WT, Garrity ER, Arcasoy SM. Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation. Chest. 2013 Jun;143(6):1717-1724. doi: 10.1378/chest.12-2107.