Antibody-mediated Rejection, Lung Transplant Rejection
Conditions
Keywords
donor-specific HLA antibodies, lung transplantation
Brief summary
This is a pilot randomized controlled trial examining the feasibility of conducting a large scale randomized controlled trial of belatacept-based immunosuppression in lung transplantation. This pilot study will enroll 40 lung transplant recipients and randomize them to belatacept-based immunosuppression or standard of care. The primary endpoint of the study is the development of donor-specific HLA antibodies after transplantation. All study participants will be followed for a minimum of 12 months after transplantation.
Detailed description
Lung transplantation is the ultimate treatment for patients with advanced lung disease. However, long-term outcomes remain disappointing and the median survival after transplantation is approximately 5.5 years. Beyond the first year after transplantation, chronic lung allograft dysfunction is the leading cause of death. The exact mechanisms that lead to chronic lung allograft dysfunction are unclear, but the development of donor-specific HLA antibodies is an independent risk factor. In fact, studies have consistently identified the development of donor-specific HLA antibodies as a significant and independent risk factor for chronic lung allograft dysfunction and mortality after transplantation. Belatacept is a CTLA4-Ig fusion protein that binds CD80 and CD86 thereby blocking CD28 co-stimulatory signals. Belatacept has been extensively studied in kidney transplantation. In a long-term study, patients treated with Belatacept had better survival than those treated with Cyclosporine. Importantly, Belatacept-treated patients were significantly less likely to develop donor-specific HLA antibodies than Cyclosporine-treated patients. Nonetheless, Belatacept has not been formally evaluated after lung transplantation. The investigators hypothesize that Belatacept-based immunosuppression would result in a lower incidence of donor-specific HLA antibodies and that this would result in better chronic lung allograft dysfunction-free survival after transplantation. Before conducting a large scale randomized controlled trial to test this hypothesis, the investigators plan to conduct the current pilot randomized controlled trial to examine the feasibility of conducting the large scale randomized controlled trial. The investigators plan to enroll and randomize 40 lung transplant recipients at 2 sites. All recipients will be treated with anti-thymocyte globulin for induction immunosuppression. Those randomized to standard of care immunosuppression will be treated with Tacrolimus, Mycophenolate mofetil, and prednisone. Those randomized to Belatacept-based immunosuppression will be treated with Belatacept, Tacrolimus, and prednisone for the first 89 days; on day 90, Mycophenolate mofetil will be substituted for Tacrolimus and patients will be continued on Belatacept, Mycophenolate mofetil, and prednisone for the remainder of year 1 after transplantation. Patients in both groups will be monitored closely for episodes of acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection with surveillance bronchoscopy and transbronchial lung biopsies on days 28, 84, 112, 168, 252, and 365 (± 7 days) as part of the sites' routine clinical protocols. In addition, patients will be monitored for the development of donor-specific HLA antibodies with routine blood tests on on days 10 (± 3 days), 28, 56, 84, 112, 168, 252, and 365 (± 7 days). The primary endpoint of the study is a composite of the development of donor-specific HLA antibodies, re-transplantation, and death. Secondary endpoints include acute cellular rejection, lymphocytic bronchiolitis, antibody-mediated rejection, chronic lung allograft dysfunction, survival, cytomegalovirus infection, bacterial infection, community-acquired respiratory viral infection, chronic kidney disease stage 3, malignancy, hypertension, diabetes, and hypercholesterolemia.
Interventions
DRUGBelatacept
Belatacept will be dosed at 10 mg/kg of actual body weight on days 0, 7, 14, 28, 56, and 84 then at 5 mg/kg on day 112 and every 28 days through day 364 (i.e., on days 140, 168, 196, 224, 252, 280, 308, 336, and 364)
DRUGTacrolimus
Tacrolimus will be dosed enterally or sublingually within 48 hours of transplantation and the dose will be adjusted to target a trough blood level of 8-15 ng/ml
DRUGATG
Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation
DRUGMycophenolate Mofetil
Mycophenolate mofetil will be dosed at 1000 mg twice daily (or if the enteric coated formulation is used, this will be dosed at 720 mg twice daily. In the standard of care arm, mycophenolate mofetil will be initiated on day 0 after transplantation, whereas in the belatacept-based immunosuppression arm, mycophenolate mofetil will be initiated on day 90 after transplantation
DRUGMethylprednisolone
Methylprednisolone 500 mg will be given intravenously before perfusion of the allograft during the transplant procedure, then methylprednisolone 0.5 mg/kg will be given intravenously twice daily for 6 total doses
DRUGPrednisone
Prednisone will be dosed at 0.5 mg/kg orally daily through day 14, then 0.2 mg/kg orally daily through day 30, then 0.1 mg/kg daily through day 180, then 5 mg daily through day 365
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Bristol-Myers Squibb
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Investigators examining lung biopsy results and blood for the development of donor-specific HLA antibodies will be blinded to study participants' treatment arm assignment.
Intervention model description
Study participants will be randomized to 1 of 2 arms: Belatacept-based immunosuppression or standard of care immunosuppression
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Provided written informed consent for study participation * Underwent single or bilateral lung transplantation * Negative urine pregnancy test for women of child bearing potential and willingness to use highly-effective contraception
Exclusion criteria
* Requiring invasive mechanical ventilation immediately before transplantation * Requiring extracorporeal life support (ECLS) (i.e., ECMO) immediately before transplantation * Received treatment to deplete HLA antibodies before transplantation to improve the possibility of transplantation * Having DSA immediately before transplantation (i.e., positive virtual crossmatch) * Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung) * Pregnant or breast-feeding * Active infection with Hepatitis B or C virus * Active infection with human immunodeficiency virus (HIV) * Chronic infection with Burkholderia cepacia complex before transplantation * Epstein Barr Virus (EBV) seronegative status * Participation in another interventional clinical trial * Allograft dysfunction requiring ECMO support after transplantation * Delayed chest closure after transplantation * Severe coagulopathy and significant bleeding in the opinion of the PI * Any condition that in the opinion of the site PI introduces undue risk by participating in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Donor-specific HLA Antibodies, Re-transplantation, or Death | 365 days | The Outcome Measure is a composite primary endpoint of the development of donor-specific HLA antibodies, re-transplantation, or death. Testing for donor-specifc HLA antibodies was performed at study-specified time points using the single antigen bead assay at the study core lab. Donor-specific HLA antibodies were defined as reactivity with a mean fluorescence intensity (MFI) ≥ 2,000. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at 2 centers (Washington University in St. Louis and Houston Methodist Hospital) between 12/2019 and 5/2021.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Tacrolimus + Mycophenolate mofetil + prednisone from day 0 through day 365
Tacrolimus: Tacrolimus will be dosed enterally or sublingually within 48 hours of transplantation and the dose will be adjusted to target a trough blood level of 8-15 ng/ml
ATG: Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation
Mycophenolate Mofetil: Mycophenolate mofetil will be dosed at 1000 mg twice daily (or if the enteric coated formulation is used, this will be dosed at 720 mg twice daily. In the standard of care arm, mycophenolate mofetil will be initiated on day 0 after transplantation, whereas in the belatacept-based immunosuppression arm, mycophenolate mofetil will be initiated on day 90 after transplantation
Methylprednisolone: Methylprednisolone 500 mg will be given intravenously before perfusion of the allograft during the transplant procedure, then methylprednisolone 0.5 mg/kg will be given intravenously twice daily for 6 total doses
Prednisone: Prednisone will be dosed at 0.5 mg/kg orally daily through day 14, then 0.2 mg/kg orally daily through day 30, then 0.1 mg/kg daily through day 180, then 5 mg daily through day 365 | 14 |
| Belatacept-based Immunosuppression Belatacept + Tacrolimus + prednisone from day 0 through day 89, then Belatacept + Mycophenolate mofetil + prednisone from day 90 through day 365
Belatacept: Belatacept will be dosed at 10 mg/kg of actual body weight on days 0, 7, 14, 28, 56, and 84 then at 5 mg/kg on day 112 and every 28 days through day 364 (i.e., on days 140, 168, 196, 224, 252, 280, 308, 336, and 364)
ATG: Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation
Mycophenolate Mofetil: Mycophenolate mofetil will be dosed at 1000 mg twice daily (or if the enteric coated formulation is used, this will be dosed at 720 mg twice daily. In the standard of care arm, mycophenolate mofetil will be initiated on day 0 after transplantation, whereas in the belatacept-based immunosuppression arm, mycophenolate mofetil will be initiated on day 90 after transplantation
Methylprednisolone: Methylprednisolone 500 mg will be given intravenously before perfusion of the allograft during the transplant procedure, then methylprednisolone 0.5 mg/kg will be given intravenously twice daily for 6 total doses
Prednisone: Prednisone will be dosed at 0.5 mg/kg orally daily through day 14, then 0.2 mg/kg orally daily through day 30, then 0.1 mg/kg daily through day 180, then 5 mg daily through day 365 | 13 |
| Total | 27 |
Baseline characteristics
| Characteristic | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 11.8 | 57.8 years STANDARD_DEVIATION 7.5 | 58.7 years STANDARD_DEVIATION 9.8 |
| Diagnosis COPD | 0 Participants | 4 Participants | 4 Participants |
| Diagnosis Interstitial Lung Disease | 8 Participants | 7 Participants | 15 Participants |
| Diagnosis Other | 4 Participants | 2 Participants | 6 Participants |
| Diagnosis Pulmonary Arterial Hypertension | 2 Participants | 0 Participants | 2 Participants |
| Operation Bilateral lung transplant | 11 Participants | 12 Participants | 23 Participants |
| Operation Single lung transplant | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 12 Participants | 24 Participants |
| Region of Enrollment United States | 14 participants | 13 participants | 27 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 5 / 13 |
| other Total, other adverse events | 12 / 14 | 13 / 13 |
| serious Total, serious adverse events | 10 / 14 | 10 / 13 |
Outcome results
Primary
Donor-specific HLA Antibodies, Re-transplantation, or Death
The Outcome Measure is a composite primary endpoint of the development of donor-specific HLA antibodies, re-transplantation, or death. Testing for donor-specifc HLA antibodies was performed at study-specified time points using the single antigen bead assay at the study core lab. Donor-specific HLA antibodies were defined as reactivity with a mean fluorescence intensity (MFI) ≥ 2,000.
Time frame: 365 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care | Donor-specific HLA Antibodies, Re-transplantation, or Death | Death | 0 participants |
| Standard of Care | Donor-specific HLA Antibodies, Re-transplantation, or Death | Donor-specific HLA antibodies | 3 participants |
| Standard of Care | Donor-specific HLA Antibodies, Re-transplantation, or Death | Re-transplantation | 0 participants |
| Belatacept-based Immunosuppression | Donor-specific HLA Antibodies, Re-transplantation, or Death | Death | 5 participants |
| Belatacept-based Immunosuppression | Donor-specific HLA Antibodies, Re-transplantation, or Death | Donor-specific HLA antibodies | 3 participants |
| Belatacept-based Immunosuppression | Donor-specific HLA Antibodies, Re-transplantation, or Death | Re-transplantation | 0 participants |