Acute Graft Rejection, Delayed Graft Function
Conditions
Keywords
Rejection in lung transplant
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.
Interventions
DRUGazathioprine
azathioprine 2mg/kg
DRUGsirolimus
sirolimus 2-4mg daily
Sponsors
Astellas Pharma Inc
Loyola University
University of Florida
University of Pennsylvania
Baylor College of Medicine
Ochsner Health System
Columbia University
University of Wisconsin, Madison
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Rejection Rate at 12 Months | 12mos | Raw proportion of patients that experienced acute rejection at or before 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of Acute Rejection at 12 Months | 12 mos | 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 |
| Bronchiolitis Obliterans Syndrome (BOS) at 24 Months | 24 mos | Kaplan-Meier estimate of proportion of patients that had not experienced BOS by 24 months. |
| Bronchiolitis Obliterans Syndrome (BOS) at 36 Months | 36 mos | Kaplan-Meier estimate of proportion of patients that had not experienced BOS by 36 months. |
| Acute Rejection-free Survival at 12 Months | 12 mos | 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 |
| Overall Survival at 24 Months | 24 mos | Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 24 months. |
| Overall Survival at 36 Months | 36 mos | Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 36 months. |
| Overall Survival at 12 Months | 12 mos | Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 12 months. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azathioprine (tacrolimus,azathioprine/prednisone) | 94 |
| Sirolimus tacrolimus/sirolimus/prednisone | 87 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 36 | 44 |
| Overall Study | Death | 9 | 6 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Azathioprine | Sirolimus | Total |
|---|---|---|---|
| Age, Continuous | 58 years | 57 years | 57 years |
| Sex: Female, Male Female | 40 Participants | 34 Participants | 74 Participants |
| Sex: Female, Male Male | 54 Participants | 53 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 94 / 94 | 87 / 87 |
| serious Total, serious adverse events | 32 / 94 | 47 / 87 |
Outcome results
Primary
Acute Rejection Rate at 12 Months
Raw proportion of patients that experienced acute rejection at or before 12 months.
Time frame: 12mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Acute Rejection Rate at 12 Months | 48 percentage of participants |
| Sirolimus | Acute Rejection Rate at 12 Months | 39 percentage of participants |
Secondary
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
Time frame: 12 mos
Population: The analysis population included patients who underwent at least one transbronchial biopsy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Acute Rejection-free Survival at 12 Months | 56 percentage of participants |
| Sirolimus | Acute Rejection-free Survival at 12 Months | 58 percentage of participants |
Secondary
Bronchiolitis Obliterans Syndrome (BOS) at 24 Months
Kaplan-Meier estimate of proportion of patients that had not experienced BOS by 24 months.
Time frame: 24 mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Bronchiolitis Obliterans Syndrome (BOS) at 24 Months | 81 percentage of participants |
| Sirolimus | Bronchiolitis Obliterans Syndrome (BOS) at 24 Months | 78 percentage of participants |
Secondary
Bronchiolitis Obliterans Syndrome (BOS) at 36 Months
Kaplan-Meier estimate of proportion of patients that had not experienced BOS by 36 months.
Time frame: 36 mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Bronchiolitis Obliterans Syndrome (BOS) at 36 Months | 76 percentage of participants |
| Sirolimus | Bronchiolitis Obliterans Syndrome (BOS) at 36 Months | 72 percentage of participants |
Secondary
Overall Survival at 12 Months
Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 12 months.
Time frame: 12 mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Overall Survival at 12 Months | 97 percentage of participants |
| Sirolimus | Overall Survival at 12 Months | 97 percentage of participants |
Secondary
Overall Survival at 24 Months
Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 24 months.
Time frame: 24 mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Overall Survival at 24 Months | 89 percentage of participants |
| Sirolimus | Overall Survival at 24 Months | 94 percentage of participants |
Secondary
Overall Survival at 36 Months
Kaplan-Meier estimate of proportion of patients that survived to (i.e., had not died by) 36 months.
Time frame: 36 mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Overall Survival at 36 Months | 84 percentage of participants |
| Sirolimus | Overall Survival at 36 Months | 87 percentage of participants |
Secondary
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
Time frame: 12 mos
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azathioprine | Severity of Acute Rejection at 12 Months | 24 percentage of participants |
| Sirolimus | Severity of Acute Rejection at 12 Months | 18 percentage of participants |