Failing Renal Allograft
Conditions
Keywords
Kidney transplant
Brief summary
The purpose of this study is to test the safety and effectiveness of belatacept (Nulojix®) in preventing antibody formation in patients with chronic failing kidney transplants. This study is a randomized study of first-time kidney transplant patients who have worsening kidney function and biopsy proven grade 2 or 3 interstitial fibrosis/tubular atrophy (IF/TA). Patients must be eligible to get a second transplant. They must have completed or be actively undergoing evaluation for re-listing for a second transplant. Patients will be randomized to either convert to belatacept or continue on calcineurin inhibitor-based therapy.
Detailed description
The purpose of this study is to test the safety and effectiveness of the medicine belatacept (Nulojix®) in preventing antibodies from forming in people with a failing kidney transplant. Kidney transplant patients take immunosuppression medicines to prevent kidney rejection. When a kidney transplant begins to fail, the immunosuppression medicines are slowly weaned. Once dialysis is started, the immunosuppressant medicines are usually stopped. After immunosuppression is stopped, some people form antibodies. Antibodies are proteins that the immune system makes to protect against harmful foreign substances like bacteria, viruses, or foreign tissues, like a transplant. High levels of antibodies can make it harder to find a kidney donor for that person. Participants will be randomized into one of the two treatment groups. One group will continue taking their current immunosuppression medicines. The people in the treatment group will be switched to belatacept (Nulojix®). Belatacept (Nulojix®) is an immunosuppression medicine that is approved by the U.S. Food and Drug Administration (the FDA) to prevent rejection in kidney transplant. Participants will stop taking calcineurin inhibitors (either cyclosporine or tacrolimus) or sirolimus but will keep taking other immunosuppression medicines like Cellcept (MMF) or azathioprine (Imuran) and prednisone. These medicines will be slowly weaned and will be stopped if the participant has to start dialysis. Participants will continue taking belatacept (Nulojix®), even while on dialysis. The study team will test both groups to see how many people in each group develop antibodies.
Interventions
DRUGBelatacept
Belatacept, dosing 10mg/kg- day 0, 2 weeks, 1 month, 2 months, 3 months; subsequent doses 5mg/kg monthly through duration of trial or until retransplantation, whichever is first.
DRUGCalcineurin inhibitor therapy
Upon enrollment, wean calcineurin inhibitor (CNI) to target tacrolimus trough of 3-5 nanogram/milliliter (ng/ml)or equivalent cyclosporine trough. Upon initiation of hemodialysis, discontinue CNI therapy over 5 days.
DRUGMycophenolate mofetil
Continue current dose at enrollment. Upon initiation of dialysis, decrease dose by half, then discontinue 2 weeks later
DRUGprednisone
Begin steroid withdrawal one month after initiation of dialysis, with monthly reduction in dose by half, with plans to discontinue prednisone by 3 months after initiation of dialysis
Sponsors
Bristol-Myers Squibb
Andrew B Adams
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Signed written informed consent * Kidney transplant recipient (human leukocyte antigen (HLA) non-identical donor) who now has impaired renal allograft function with: * Estimated glomerular filtration rate (GFR) \< 35 with a decline in GFR of \> 10% in the 12 months prior to enrollment and must have biopsy proven grade II or III interstitial fibrosis/tubular atrophy (IF/TA) OR * Estimated GFR persistently \< 20 ml/min over the 6 month period prior to enrollment absent other causes for graft dysfunction, and deemed to have a failing allograft by the patient's transplant nephrologist * On a maintenance immunosuppressive regimen that includes calcineurin inhibitor (CNI)(tacrolimus or cyclosporine) or sirolimus and at least * MMF of a dose of at least 1 gm/day or comparable dose of azathioprine OR * Prednisone at a dose of at least 5 mg/day * Men and women, ages 18 to 70, inclusive
Exclusion criteria
* Women of childbearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study drug. * Women who are pregnant or breastfeeding. * Women with a positive pregnancy test. * Sexually active fertile men not using effective birth control if their partners are WOCBP. * Subjects who are Epstein-Barr Virus (EBV) seronegative. * Subjects with any prior solid organ (e.g., heart, liver, pancreas) or cell (e.g., islet, bone marrow) transplant other than a renal allograft. Exception may be made for recipient of a simultaneous kidney-pancreas transplant who had previously experienced graft loss of the pancreas allograft due to thrombosis or rejection. * Subjects with presence of donor specific antibody at the time of enrollment * Subjects who have a recent history (within 1 yr) of biopsy proven acute rejection \> Banff grade Ia * Subjects who have a living donor identified for re-transplant within 3 months * Subjects with a history of post-transplant lymphoproliferative disease (PTLD) * Subjects at risk for tuberculosis (TB) * Subjects with a history of cancer within the past 3 years, other than non-melanoma skin cancer(s) * Subjects with a positive BK virus serum polymerase chain reaction (PCR) \> 20,000 copies at the time of enrollment OR history of biopsy-proven BK nephropathy within the year prior to enrollment. * Subjects with a mammogram that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations * Subjects who have difficult intravenous access or other reasons that would likely preclude the ability to receive long-term intravenous infusions * Hypersensitivity to any medications that will be used in the protocol * Subjects who have used any investigational drug within the 30 days prior to anticipated enrollment * Subjects currently receiving belatacept as part of their maintenance immunosuppressive regimen * Prisoners, or subjects who are involuntarily incarcerated. * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Donor-specific Antibody Formation | Month 36 | The number of participants in each group with donor-specific antibody formation at 36 months following randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glomerular Filtration Rate (GFR) | Baseline up to Month 24 | The glomerular filtration rate (GFR) assesses kidney function. GFR uses values for serum creatinine (SCr) measured in mg/dL, age in years, blood urea nitrogen (BUN) measures in mg/dL, and serum albumin (Alb) measured in g/dL. GFR is calculated as 170 x (SCr/0.95)\^(-0.999) x (Age)\^(-0.176) x (0.762 if the patient is female) x (1.180 if the patient is black) x (BUN)\^(-0.170) x (Alb)\^(0.318). A value of 90 or above is considered normal while values between 15 and 29 indicate severely decreased kidney function and values below 15 indicate kidney failure. The GFR in participants who do not require dialysis will be followed for two years. |
| Time to Initiation of Dialysis | Up to Year 2 | Time to dialysis is measured as the time of randomization to initiation of dialysis. Participants already requiring dialysis at the time of enrollment were excluded from this endpoint analysis. |
| Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline up to Month 36 | The presence of anti-HLA Class I and Class II alloantibodies is categorized as being negative (absent for both classes of alloantibodies), positive for Class I, positive for Class II, and positive for both Class I and Class II alloantibodies. |
| Number of Infectious Complications | Baseline up to Month 36 | The number of infections complications occurring among study participants is presented here. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Emory University Hospital and the Emory Clinic in Atlanta, Georgia. Enrollment began August 2013 and all follow up was complete by December 12, 2019.
Participants by arm
| Arm | Count |
|---|---|
| Belatacept Treatment Group Participants with a failing kidney or failed kidney transplant receiving belatacept therapy | 6 |
| Control Group Participants with a failing kidney transplant continuing their current immunosuppression and once allograft failed discontinuing immunosuppression | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Kidney transplant | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Control Group | Total | Belatacept Treatment Group |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 12 Participants | 5 Participants |
| Age, Continuous | 45.69 years STANDARD_DEVIATION 14.99 | 51.31 years STANDARD_DEVIATION 12.83 | 56.12 years STANDARD_DEVIATION 9.12 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 7 Participants | 13 Participants | 6 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 7 |
| other Total, other adverse events | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 4 / 6 | 5 / 7 |
Outcome results
Primary
Number of Participants With Donor-specific Antibody Formation
The number of participants in each group with donor-specific antibody formation at 36 months following randomization.
Time frame: Month 36
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Treatment Group | Number of Participants With Donor-specific Antibody Formation | 3 Participants |
| Control Group | Number of Participants With Donor-specific Antibody Formation | 4 Participants |
Secondary
Glomerular Filtration Rate (GFR)
The glomerular filtration rate (GFR) assesses kidney function. GFR uses values for serum creatinine (SCr) measured in mg/dL, age in years, blood urea nitrogen (BUN) measures in mg/dL, and serum albumin (Alb) measured in g/dL. GFR is calculated as 170 x (SCr/0.95)\^(-0.999) x (Age)\^(-0.176) x (0.762 if the patient is female) x (1.180 if the patient is black) x (BUN)\^(-0.170) x (Alb)\^(0.318). A value of 90 or above is considered normal while values between 15 and 29 indicate severely decreased kidney function and values below 15 indicate kidney failure. The GFR in participants who do not require dialysis will be followed for two years.
Time frame: Baseline up to Month 24
Population: Participants requiring dialysis, either at the time of enrollment or initiating dialysis during the study, are not included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 18 | 7 mL/min/1.73 m^2 | Standard Deviation 0 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Baseline | 14.25 mL/min/1.73 m^2 | Standard Deviation 7.8 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 1 | 14.25 mL/min/1.73 m^2 | Standard Deviation 8.06 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 3 | 16.33 mL/min/1.73 m^2 | Standard Deviation 1.53 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 6 | 14.67 mL/min/1.73 m^2 | Standard Deviation 1.15 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 9 | 14.67 mL/min/1.73 m^2 | Standard Deviation 3.06 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 12 | 13.67 mL/min/1.73 m^2 | Standard Deviation 2.89 |
| Belatacept Treatment Group | Glomerular Filtration Rate (GFR) | Month 2 | 19.33 mL/min/1.73 m^2 | Standard Deviation 4.93 |
| Control Group | Glomerular Filtration Rate (GFR) | Month 2 | 10.5 mL/min/1.73 m^2 | Standard Deviation 4.95 |
| Control Group | Glomerular Filtration Rate (GFR) | Month 6 | 14.5 mL/min/1.73 m^2 | Standard Deviation 6.36 |
| Control Group | Glomerular Filtration Rate (GFR) | Month 3 | 16.5 mL/min/1.73 m^2 | Standard Deviation 4.95 |
| Control Group | Glomerular Filtration Rate (GFR) | Baseline | 14.5 mL/min/1.73 m^2 | Standard Deviation 0.71 |
| Control Group | Glomerular Filtration Rate (GFR) | Month 9 | 13.5 mL/min/1.73 m^2 | Standard Deviation 10.61 |
| Control Group | Glomerular Filtration Rate (GFR) | Month 1 | 11 mL/min/1.73 m^2 | Standard Deviation 1.41 |
| Control Group | Glomerular Filtration Rate (GFR) | Month 12 | 20 mL/min/1.73 m^2 | Standard Deviation 0 |
Secondary
Number of Infectious Complications
The number of infections complications occurring among study participants is presented here.
Time frame: Baseline up to Month 36
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Belatacept Treatment Group | Number of Infectious Complications | 12 complications |
| Control Group | Number of Infectious Complications | 18 complications |
Secondary
Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies
The presence of anti-HLA Class I and Class II alloantibodies is categorized as being negative (absent for both classes of alloantibodies), positive for Class I, positive for Class II, and positive for both Class I and Class II alloantibodies.
Time frame: Baseline up to Month 36
Population: This analysis includes participants remaining in the study at the indicated study visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Negative | 1 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Negative | 6 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Positive Class I | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Negative | 4 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Positive Class II | 2 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Positive Class I | 1 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Positive Class I and II | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Positive Class II | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Negative | 1 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Positive Class II | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Positive Class I | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Positive Class I | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Positive Class II | 2 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Positive Class I and II | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Positive Class I and II | 0 Participants |
| Belatacept Treatment Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Positive Class I and II | 0 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Positive Class I and II | 1 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Negative | 2 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Positive Class I | 2 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Positive Class II | 0 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Positive Class I and II | 0 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Positive Class I | 4 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Positive Class II | 3 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 12 - Positive Class I and II | 3 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Negative | 1 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Positive Class I | 2 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Positive Class II | 1 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 24 - Positive Class I and II | 1 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Negative | 1 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Positive Class I | 2 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Month 36 - Positive Class II | 1 Participants |
| Control Group | Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies | Baseline - Negative | 5 Participants |
Secondary
Time to Initiation of Dialysis
Time to dialysis is measured as the time of randomization to initiation of dialysis. Participants already requiring dialysis at the time of enrollment were excluded from this endpoint analysis.
Time frame: Up to Year 2
Population: This analysis includes participants who initiated dialysis during the course of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belatacept Treatment Group | Time to Initiation of Dialysis | 11.75 months | Standard Deviation 7.46 |
| Control Group | Time to Initiation of Dialysis | 10.5 months | Standard Deviation 2.12 |