A Phase 2 interventional study of Belatacept and Tacrolimus in Lung Transplant Rejection and Antibody-mediated Rejection, sponsored by Washington University School of Medicine. Completed at 2 sites in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2022-11-25.
Sponsored by Washington University School of Medicine · Phase 2, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Tacrolimus + Mycophenolate mofetil + prednisone from day 0 through day 365
Drug: Tacrolimus · Drug: ATG · Drug: Mycophenolate Mofetil · Drug: Methylprednisolone · Drug: Prednisone
Belatacept + Tacrolimus + prednisone from day 0 through day 89, then Belatacept + Mycophenolate mofetil + prednisone from day 90 through day 365
Drug: Belatacept · Drug: ATG · Drug: Mycophenolate Mofetil · Drug: Methylprednisolone · Drug: Prednisone
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)
Also known as: Nulojix
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
Also known as: Prograf
Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation
Also known as: Thymoglobulin
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
Also known as: Cellcept, Myfortic
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
Also known as: Solumedrol
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
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
Participants were recruited at 2 centers (Washington University in St. Louis and Houston Methodist Hospital) between 12/2019 and 5/2021.
| Milestone | Standard of Care | Belatacept-based Immunosuppression |
|---|---|---|
| Started | 14 | 13 |
| Completed | 14 | 13 |
| Not completed | 0 | 0 |
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.
| participants | Standard of Care | Belatacept-based Immunosuppression |
|---|---|---|
| Death | 0 | 5 |
| Donor-specific HLA antibodies | 3 | 3 |
| Re-transplantation | 0 | 0 |
Collected over Adverse events were collected over 14 months after randomization. However, not all participants have completed 14 months of follow-up at this time.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Standard of Care | 0/14 (0%) | 10/14 (71.4%) | 12/14 (85.7%) |
| Belatacept-based Immunosuppression | 5/13 (38.5%) | 10/13 (76.9%) | 13/13 (100%) |
| Event | Standard of Care | Belatacept-based Immunosuppression |
|---|---|---|
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 4/14 | 6/13 |
| COVID-19 infectionInfections and infestations | 3/14 | 2/13 |
| Venous ThromboembolismVascular disorders | 0/14 | 2/13 |
| Cytomegalovirus infectionInfections and infestations | 1/14 | 2/13 |
| Nausea and vomitingGastrointestinal disorders | 0/14 | 2/13 |
| Atrial fibrillationCardiac disorders | 2/14 | 0/13 |
| Acute kidney injuryRenal and urinary disorders | 2/14 | 0/13 |
| Surgical site infectionInfections and infestations | 1/14 | 1/13 |
| PneumoniaInfections and infestations | 0/14 | 1/13 |
| HeadacheNervous system disorders | 0/14 | 1/13 |
| Event | Standard of Care | Belatacept-based Immunosuppression |
|---|---|---|
| AnemiaBlood and lymphatic system disorders | 8/14 | 9/13 |
| Positive bronchoscopy cultureInfections and infestations | 9/14 | 8/13 |
| Acute cellular rejectionImmune system disorders | 7/14 | 3/13 |
| Electrolyte abnormalityRenal and urinary disorders | 7/14 | 5/13 |
| Atrial fibrillationCardiac disorders | 3/14 | 6/13 |
| ThrombocytopeniaBlood and lymphatic system disorders | 6/14 | 5/13 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 0/14 | 5/13 |
| Ischemic mucosal airway injuryRespiratory, thoracic and mediastinal disorders | 5/14 | 4/13 |
| NauseaGastrointestinal disorders | 4/14 | 4/13 |
| Acute kidney injuryRenal and urinary disorders | 0/14 | 4/13 |
| Age, Continuous(years) | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| Mean | 59.5 ± 11.8 | 57.8 ± 7.5 | 58.7 ± 9.8 |
| Sex: Female, Male(Participants) | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| Female | 5 | 4 | 9 |
| Male | 9 | 9 | 18 |
| Race (NIH/OMB)(Participants) | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 2 | 1 | 3 |
| White | 12 | 12 | 24 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| United States | 14 | 13 | 27 |
| Diagnosis(Participants) | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| Interstitial Lung Disease | 8 | 7 | 15 |
| COPD | 0 | 4 | 4 |
| Pulmonary Arterial Hypertension | 2 | 0 | 2 |
| Other | 4 | 2 | 6 |
| Operation(Participants) | Standard of Care | Belatacept-based Immunosuppression | Total |
|---|---|---|---|
| Bilateral lung transplant | 11 | 12 | 23 |
| Single lung transplant | 3 | 1 | 4 |
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Washington University School of Medicine