Comparison of Sirolimus and Azathioprine in Lung Transplantation

Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen Versus Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation

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

Study Overview

• Status: Completed
• Conditions: Delayed Graft Function; Acute Graft Rejection
• Intervention / Treatment: Drug: azathioprine; Drug: sirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 181
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azathioprine; (tacrolimus,azathioprine/prednisone)	Drug: azathioprine; azathioprine 2mg/kg
Active Comparator: Sirolimus; tacrolimus/sirolimus/prednisone	Drug: sirolimus; sirolimus 2-4mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Rejection Rate at 12 Months	Raw proportion of patients that experienced acute rejection at or before 12 months.	12mos

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Rejection-free Survival at 12 Months	Kaplan-Meier estimate of proportion of patients that had not experienced acute rejection by 12 months. Acute rejection is defined as rejection at any of the following grades. Grade A0 - None With/Without Grade A1 - Minimal Grade A2 - Mild Grade A3 - Moderate	12 mos
Severity of Acute Rejection at 12 Months	Raw proportion of patients that experienced rejection at or above grade A2 by 12 months. Grade A0 - None With/Without Grade A1 - Minimal Grade A2 - Mild Grade A3 - Moderate	12 mos
Bronchiolitis Obliterans Syndrome (BOS) at 24 Months	Kaplan-Meier estimate of proportion of patients that had not experienced BOS by 24 months.	24 mos
Bronchiolitis Obliterans Syndrome (BOS) at 36 Months	Kaplan-Meier estimate of proportion of patients that had not experienced BOS by 36 months.	36 mos
Overall Survival at 12 Months	Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 12 months.	12 mos
Overall Survival at 24 Months	Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 24 months.	24 mos
Overall Survival at 36 Months	Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 36 months.	36 mos

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: Baylor College of Medicine; University of Pennsylvania; Columbia University; Astellas Pharma Inc; University of Wisconsin, Madison; University of Florida; Ochsner Health System; Loyola University
• Investigators: Principal Investigator: Edward Garrity, MD, University Of Chicago

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: May 2, 2006
• First Submitted That Met QC Criteria: May 2, 2006
• First Posted (Estimate): May 4, 2006

Study Record Updates

• Last Update Posted (Estimate): September 21, 2016
• Last Update Submitted That Met QC Criteria: September 19, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Rejection in lung transplant
• Additional Relevant MeSH Terms: Pathologic Processes; Delayed Graft Function; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Azathioprine; Sirolimus
• Other Study ID Numbers: 14467B