Renal Transplant
Conditions
Keywords
renal transplantation, kidney transplantation, renal allograft recipient, anti-rejection drugs, immunosuppression protocol, immunosuppression withdrawal
Brief summary
Belatacept is an experimental medication shown in clinical trials to have immune system suppression properties in people who have had renal (e.g., kidney) transplants. This study will determine whether a combination of anti-rejection drugs, including belatacept, can prevent the rejection of a first-time, non-human leukocyte antigen (HLA) identical renal transplant and allow patients to be safely withdrawn from anti-rejection therapy one year post-transplant.
Detailed description
Drugs that suppress the immune system have contributed to increased success of transplantation; however, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives. These drugs make patients more susceptible to infection and certain kinds of cancer. Belatacept is an experimental medication that specifically targets immune reactions against transplanted organs and has been shown to be effective in preventing kidney transplant rejection in previous clinical trials. Both thymoglobulin, an antibody, and sirolimus, an anti-rejection drug, prevent rejection by lowering the response of the immune system to the transplanted organ. This study will evaluate whether belatacept, along with thymoglobulin and sirolimus, is safe in kidney transplant patients. The study will also evaluate this regimen's potential to allow tapering and eventual discontinuation of all immunosuppressive drugs. This study will last up to 4 years. At the time of transplant, participants will begin an immunosuppressive treatment regimen consisting of thymoglobulin, sirolimus, and belatacept. Participants will receive infusions of thymoglobulin on days 1 through 4, and a combination of oral sirolimus (daily) and belatacept infusions at day 5, then weeks 2, 4, 8, and monthly for at least 2 years. Dose reduction of belatacept will occur at 12 weeks post-transplant. At Year 2, eligible participants may choose to begin drug withdrawal or continue study therapy through the end of the study. Study visits will occur weekly for the first two months, then monthly. These visits will include belatacept treatment, general medical assessments, blood and urine collection, and other assessments to determine overall health of the recipient's immune system and kidney transplant and to better understand the way the immune system works in the acceptance or rejection of organ transplants. \*\*\* IMPORTANT NOTICE: \*\*\* The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.
Interventions
DRUGBelatacept
10 mg/kg given intravenously (IV) on transplant (day 1), day 5, and at weeks 2, 4, 8 and 12, then 5 mg/kg IV every 4 weeks
DRUGSirolimus
4 mg/day (oral tablet) at transplant (day 1), then dose adjusted to maintain serum trough level of 8-12 ng/mL for at least 1 year
DRUGAnti-thymocyte globulin
1.5 mg/kg given IV daily on days 1 through 4. Subjects are premedicated with glucocorticoids, acetaminophen 650 mg by mouth, and diphenhydramine 25- 50 mg by mouth prior to each dose.
DRUGmethylprednisolone
500 mg given IV at transplant (day 1), then given 250 mg IV on day 2 and given 0.5 mg/kg IV or prednisone 0.5 mg/kg given by mouth on days 3 and 4
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Receiving first renal (e.g., kidney) transplant * Transplant is from a non-HLA-identical living donor * Willing to use acceptable forms of contraception
Exclusion criteria
* Positive for anti-human globulin (AHG) or T-cell cross-match with the donor * Receiving multiple-organ transplant * History of cancer within the 5 years prior to study entry. Patients who have certain nonmelanoma skin cancers are not excluded * Human immunodeficiency virus (HIV) infected * Hepatitis B (HBV) or C (HCV) virus infected * Other active infections * Active tuberculosis (TB) infection within the 3 years prior to study entry * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Rejection at 6-Months | 6 months post-transplant | Cumulative incidence of acute rejection\[1\] at 6 months post-transplant based on local pathology biopsy reads 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Rejection at 12-Months | 12 months post-transplant | Incidence of acute rejection\[1\] at 12 months post-transplant 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 |
| Tolerance Induction | 48 months | Time from transplantation to initiation of sirolimus withdrawal. |
| Renal Function as Measured by Glomerular Filtration Rate (GFR) at 24 Weeks | 24 weeks post-transplant | GFR utilizing clearance of iothalamate. GFR is an index of level of kidney function. A higher value means better kidney function. |
| Graft Survival at 12 Months Post-transplant | 12 months post-transplant | — |
| Time From Transplant to Acute Rejection | Transplantation until rejection occurs (participants followed up to four years post-transplantation) | Time (days) from transplant to occurrence of acute rejection\[1\] 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 |
| Proportion of Participants Requiring Antilymphocyte Therapy for Acute Rejection | Participants followed from transplantation until completion of study (up to four years post-transplantation) | Proportion of participants who experienced acute rejection\[1\] requiring antilymphocyte therapy 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 |
| Participant Survival at 12 Months Post-Transplant | 12 months post-transplant | — |
| Proportion of Participants With Wound Complications | Start of study to end of study | — |
| Proportion of Participants With Malignancies | Participants followed from transplantation until completion of study (up to four years post-transplantation) | — |
| Proportion of Participants With a Sirolimus Associated Adverse Event | Participants followed from transplantation until completion of study (up to four years post-transplantation) | — |
| Proportion of Participants With Chronic Allograft Nephropathy | Participants followed from transplantation until completion of study (up to four years post-transplantation) | — |
| Proportion of Participants With Delayed Graft Function | Participants followed from transplantation until completion of study (up to four years post-transplantation) | — |
| Proportion of Participants With Post-transplant Diabetes Mellitus | Participants followed from transplantation until completion of study (up to four years post-transplantation) | — |
| Proportion of Participants With Post-transplant Infections | Participants followed from transplantation until completion of study (up to four years post-transplantation) | Proportion of participants who experienced infections post-transplant. Participants were checked for any type of opportunistic infection at all study visits post-transplantation (up to 4 years post-transplantation) |
Countries
United States
Participant flow
Recruitment details
Two centers in the United States enrolled five recipients of non-human leukocyte antigen (HLA)-identical living-donor-related renal transplants between January 2007 and January 2009.
Pre-assignment details
At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and sign the informed consent form.
Participants by arm
| Arm | Count |
|---|---|
| Immunosuppression Withdrawal Daclizumab, antithymocyte globulin, sirolimus, or belatacept dosing with the intention of immunosuppression withdrawal | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Immunosuppression Withdrawal |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 50.4 years STANDARD_DEVIATION 5.9 |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 4 / 5 |
Outcome results
Primary
Acute Rejection at 6-Months
Cumulative incidence of acute rejection\[1\] at 6 months post-transplant based on local pathology biopsy reads 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Time frame: 6 months post-transplant
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Acute Rejection at 6-Months | 3 Participants |
Comparison: Proportion of participant's cumulative incidence of acute rejection at 24 weeks with 95% exact binomial confidence interval. Local biopsy reads were used in determining primary endpoint.95% CI: [15, 95]95% exact binomial CI of proportion
Secondary
Acute Rejection at 12-Months
Incidence of acute rejection\[1\] at 12 months post-transplant 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Time frame: 12 months post-transplant
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Acute Rejection at 12-Months | 4 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [28, 99]95% exact binomial CI of proportion
Secondary
Graft Survival at 12 Months Post-transplant
Time frame: 12 months post-transplant
Population: Intent to treat sample participants not terminating prior to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Graft Survival at 12 Months Post-transplant | 4 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [40, 100]95% exact binomial CI of proportion
Secondary
Participant Survival at 12 Months Post-Transplant
Time frame: 12 months post-transplant
Population: Intent to Treat Sample participants not terminating prior to 12 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Participant Survival at 12 Months Post-Transplant | 4 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [40, 100]95% exact binomial CI of proportion
Secondary
Proportion of Participants Requiring Antilymphocyte Therapy for Acute Rejection
Proportion of participants who experienced acute rejection\[1\] requiring antilymphocyte therapy 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants Requiring Antilymphocyte Therapy for Acute Rejection | 0 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [0, 52.2]95% exact binomial CI of proportion
Secondary
Proportion of Participants With a Sirolimus Associated Adverse Event
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With a Sirolimus Associated Adverse Event | 5 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [47.8, 100]95% exact binomial CI of proportion
Secondary
Proportion of Participants With Chronic Allograft Nephropathy
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With Chronic Allograft Nephropathy | 0 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [0, 52.2]95% exact binomial CI of proportion
Secondary
Proportion of Participants With Delayed Graft Function
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With Delayed Graft Function | 0 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [0, 52.2]95% exact binomial CI of proportion
Secondary
Proportion of Participants With Malignancies
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With Malignancies | 0 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [0, 52.2]95% exact binomial CI of proportion
Secondary
Proportion of Participants With Post-transplant Diabetes Mellitus
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With Post-transplant Diabetes Mellitus | 1 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [0.5, 71.6]95% exact binomial CI of proportion
Secondary
Proportion of Participants With Post-transplant Infections
Proportion of participants who experienced infections post-transplant. Participants were checked for any type of opportunistic infection at all study visits post-transplantation (up to 4 years post-transplantation)
Time frame: Participants followed from transplantation until completion of study (up to four years post-transplantation)
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With Post-transplant Infections | 4 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [28, 99]95% exact binomial CI of proportion
Secondary
Proportion of Participants With Wound Complications
Time frame: Start of study to end of study
Population: Intent to Treat Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Proportion of Participants With Wound Complications | 0 Participants |
Comparison: Proportion with 95% exact binomial confidence interval95% CI: [0, 52.2]95% exact binomial CI of proportion
Secondary
Renal Function as Measured by Glomerular Filtration Rate (GFR) at 24 Weeks
GFR utilizing clearance of iothalamate. GFR is an index of level of kidney function. A higher value means better kidney function.
Time frame: 24 weeks post-transplant
Population: Intent to Treat Sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Immunosuppression Withdrawal | Renal Function as Measured by Glomerular Filtration Rate (GFR) at 24 Weeks | 62.0 mL/min/1.73m^2 | Standard Deviation 8.5 |
Secondary
Time From Transplant to Acute Rejection
Time (days) from transplant to occurrence of acute rejection\[1\] 1. Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater\[2\] 2. Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999
Time frame: Transplantation until rejection occurs (participants followed up to four years post-transplantation)
Population: Intent to treat sample participants with rejection
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Immunosuppression Withdrawal | Time From Transplant to Acute Rejection | 15 Days | Full Range 95.4 |
Secondary
Tolerance Induction
Time from transplantation to initiation of sirolimus withdrawal.
Time frame: 48 months
Population: Intent to treat sample that initiated sirolimus withdrawal
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immunosuppression Withdrawal | Tolerance Induction | 391 Days |