Kidney Transplant Recipients
Conditions
Keywords
recipients of living-donor kidney allografts, antithymocyte globulin (ATG) induction, calcineurin inhibitors (CNIs), CNI withdrawal
Brief summary
The study will compare how well transplanted kidneys work and the response of people's immune systems as tacrolimus, a calcineurin inhibitor (CNI), is withdrawn. In addition, this research study will evaluate whether reducing immunosuppression can decrease some of these side effects while still preventing rejection of the kidney.
Detailed description
Kidney transplantation is a treatment option for people with kidney disease. However, there is still much to learn about how to best care for the transplanted kidney and keep it functioning for a long time. Transplant recipients take immunosuppression (anti-rejection) drugs to prevent their body from rejecting the new kidney. These drugs are used to prevent the immune system from attacking the transplanted kidney. All anti-rejection medications have unwanted side effects. The purpose of this study is to evaluate the safety of slowly removing tacrolimus, a CNI.
Interventions
DRUGTacrolimus (CNI) Withdrawal
Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus. Subjects without any clinical acute rejection (AR) in the first 6 months, without borderline or acute rejection on the 6 month biopsy, and without donor-specific antibody (DSA) at anytime, including the 6 month test will be randomized (2:1) to tacrolimus (CNI) withdrawal.
DRUGStandard Immunosuppressive Therapy
Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.
Sponsors
Clinical Trials in Organ Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Initial Enrollment/Screening: Patients who meet all of the following criteria are eligible for enrollment as study subjects: * Subject must be able to understand and provide written informed consent; * Primary living-donor (related or unrelated) kidney transplant recipients; * Peak flow-based PRAs for class I and class II \<30%(performed by local center); * Current (within 8 weeks prior to transplantation) flow-based PRAs for class I and class II \<30% (performed by local center); * No donor specific antibody by flow solid phase method on the peak PRA serum (if serum available), or on the current PRA serum (within 8 weeks prior to transplantation) performed by central core laboratory. If the sera for the peak PRA is not available, then only the current PRA serum will be tested; * Negative T-cell and B-cell crossmatch by flow cytometry (performed by local center); * Female subjects of childbearing potential must have a negative pregnancy test (urine or serum) upon study entry; * Female and male subjects with reproductive potential must agree to use FDA approved methods of birth control while participating in the study. Inclusion Criteria for Randomization: Participants who meet all of the following criteria are eligible for randomization: * No history of acute rejection episodes; * The pre-randomization protocol biopsy should confirm no rejection, including borderline rejection (based on the central pathology read); * No donor specific antibody as detected by flow solid phase method (performed by the central core laboratory).
Exclusion criteria
- Initial Enrollment/Screening: Participants who meet any of these criteria are not eligible for enrollment as study subjects: * Recipient of multiple organ transplants; * Prior history of organ transplantation; * Deceased-donor source; * Any condition that would preclude protocol biopsies; * HLA identical recipients; * Currently breast-feeding or plans to become pregnant during the timeframe of the study follow up period; * Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements; * Inability or unwillingness to comply with study protocol; * Use of investigational drugs within 4 weeks of study entry and for the duration of the study; * Recent recipient of any licensed or investigational live attenuated vaccine(s) within two months of prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Incremental IF/A Scores >2 at 24 Months Post-Randomization | IF/TA scores on protocol biopsies obtained at 24 months post-randomization will be compared to those obtained at the time of implantation for this measurement. | The investigators were not able to assess this outcome, the effect of the intervention on interstitial fibrosis/tubular atrophy (IF/TA; on a 2-year graft biopsy) due to the study's premature termination by the Data Safety Monitoring Board (DSMB) because of absence of equipoise on the basis of predetermined stopping rules. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute Rejection | 6 to 18 months post-randomization | Acute renal allograft rejection is defined as histological reading of borderline or greater determined by the local pathology laboratory. Participants suspected of having a rejection episode on the basis of clinical signs, symptoms, or on the basis of laboratory tests, had a renal ultrasound and underwent a renal transplant biopsy. Any detection of acute cellular rejection or acute humoral rejection resulted in participants in the 'Randomized to Tacrolimus Withdrawal' group to be restarted on tacrolimus and followed per the reduced follow-up schedule of events. |
| Allograft Survival Rate | 6 to 18 months post-randomization | Allograft survival is defined as participants who did not need to be re-transplanted or placed on dialysis due to the failure of their allograft transplantation during the course of this study. |
| Participant Survival Rate | 6 to 18 months post-transplantation | Number of participants who did not die within the course of this study. |
| Percentage of Participants With New Donor Specific Antibodies (DSAs) | 6 to 18 months post-randomization | Donor specific antibodies are antibodies that are directed against antigens expressed on donor organs. These antibodies can result in an immune attack on the transplanted organ, increasing risk of graft loss and/or rejection. |
| Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | 6 months post-transplantation, 24 months post-transplantation | Estimated glomerular filtration rate (eGFR) is a test to measure the level of kidney function. In this measure, the effects of tacrolimus withdrawal on long-term kidney function was assessed by comparing absolute 24 month eGFR (18 months post-randomization) and change in eGFR from 6 to 24 months (randomization to 18 months randomization). Lower numbers indicate poorer kidney function |
| Percentage of Participants in the Experimental Arm Off Tacrolimus | 18 months post-randomization | Participants in the 'Randomized to Tacrolimus Withdrawal' group were considered fully withdrawn once they no longer received any doses of tacrolimus. Participants met this endpoint if they did not resume taking tacrolimus as of 18 months post randomization with stable allograft function and without rejection of donor-specific antibodies. |
| Incremental Change in IF/TA Scores | 6 to 18 months post-transplant | This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met. |
| Measurement of Urinary Parameters Before and After Randomization | 6 months post-transplantation to 18 months post-randomization | This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met. |
| Percentage of Participants With Donor-Specific Memory Using Elispot | 6 to 18 months post-randomization | This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Transplanted, But Not Randomized These participants were enrolled into the study and received a living-donor kidney allograft transplant. Participants were given an induction therapy with rabbit antithymocyte globulin (1.5-2.0 mg/kg daily for 5 days) and treated with a regimen of mycophenolate mofetil (target dose of 1000 mg twice daily), prednisone (no less than 5 mg/day or 10 mg every other day) and tacrolimus (0.1 mg/kg twice daily, adjusted to target trough levels of 8-12 ng/ml in first 3 months post-transplant, 5-8 ng/ml thereafter). Participants were followed for up to 8 months and deemed ineligible for randomization or terminated for other reasons. | 26 |
| Randomized to Tacrolimus Withdrawal These participants were enrolled into the study and received a living-donor kidney allograft transplant. Participants were given an induction therapy with rabbit antithymocyte globulin (1.5-2.0 mg/kg daily for 5 days) and treated with a regimen of mycophenolate mofetil (target dose of 1000 mg twice daily), prednisone (no less than 5 mg/day or 10 mg every other day) and tacrolimus (0.1 mg/kg twice daily, adjusted to target trough levels of 8-12 ng/ml in first 3 months post-transplant, 5-8 ng/ml thereafter). Participants were followed for 6-8 months then randomized to tacrolimus withdrawal. Following randomization these participants had their dose of tacrolimus withdrawn gradually over three to four months, with complete withdrawal occurring no later than four months. Participants were followed up to 18 months after being randomized. | 14 |
| Randomized to Control Group Participants were given an induction therapy with rabbit antithymocyte globulin (1.5-2.0 mg/kg daily for 5 days) and treated with a regimen of mycophenolate mofetil (target dose of 1000 mg twice daily), prednisone (no less than 5 mg/day or 10 mg every other day) and tacrolimus (0.1 mg/kg twice daily, adjusted to target trough levels of 8-12 ng/ml in first 3 months post-transplant, 5-8 ng/ml thereafter). Participants were followed for 6-8 months then randomized to control group, where the continued on the pre-randomization standard care of mycophenolate mofetil, prednisone, and tacrolimus. Participants were followed up to 18 months after being randomized. | 7 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Ineligible for randomization | 0 | 14 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Screen Failure | 4 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 8 | 4 | 1 |
Baseline characteristics
| Characteristic | Randomized to Tacrolimus Withdrawal | Randomized to Control Group | Transplanted, But Not Randomized | Total |
|---|---|---|---|---|
| Age, Continuous | 46.5 years STANDARD_DEVIATION 14.4 | 44.9 years STANDARD_DEVIATION 8.5 | 54.8 years STANDARD_DEVIATION 11.6 | 50.9 years STANDARD_DEVIATION 12.7 |
| CMV status (donor, recipient) Donor missing, Recipient - | 0 participants | 0 participants | 1 participants | 1 participants |
| CMV status (donor, recipient) Donor not done, Recipient + | 0 participants | 1 participants | 0 participants | 1 participants |
| CMV status (donor, recipient) Donor -, Recipient - | 5 participants | 3 participants | 9 participants | 17 participants |
| CMV status (donor, recipient) Donor -, Recipient + | 2 participants | 2 participants | 3 participants | 7 participants |
| CMV status (donor, recipient) Donor +, Recipient - | 2 participants | 1 participants | 5 participants | 8 participants |
| CMV status (donor, recipient) Donor +, Recipient + | 5 participants | 0 participants | 8 participants | 13 participants |
| HLA mismatch | 3.4 Number of HLA marker mismatches STANDARD_DEVIATION 1.3 | 3.4 Number of HLA marker mismatches STANDARD_DEVIATION 1.3 | 3.6 Number of HLA marker mismatches STANDARD_DEVIATION 1.7 | 3.4 Number of HLA marker mismatches STANDARD_DEVIATION 1.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 7 Participants | 22 Participants | 39 Participants |
| Region of Enrollment Canada | 4 participants | 0 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 10 participants | 7 participants | 23 participants | 40 participants |
| Sex: Female, Male Female | 6 Participants | 0 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 20 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 26 | 5 / 14 | 2 / 7 |
| serious Total, serious adverse events | 2 / 26 | 4 / 14 | 0 / 7 |
Outcome results
Primary
Percentage of Participants With Incremental IF/A Scores >2 at 24 Months Post-Randomization
The investigators were not able to assess this outcome, the effect of the intervention on interstitial fibrosis/tubular atrophy (IF/TA; on a 2-year graft biopsy) due to the study's premature termination by the Data Safety Monitoring Board (DSMB) because of absence of equipoise on the basis of predetermined stopping rules.
Time frame: IF/TA scores on protocol biopsies obtained at 24 months post-randomization will be compared to those obtained at the time of implantation for this measurement.
Population: No analyses were performed due to early study closure.
Secondary
Allograft Survival Rate
Allograft survival is defined as participants who did not need to be re-transplanted or placed on dialysis due to the failure of their allograft transplantation during the course of this study.
Time frame: 6 to 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Tacrolimus Withdrawal | Allograft Survival Rate | 14 participants |
| Randomized to Control Group | Allograft Survival Rate | 7 participants |
Secondary
Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation
Estimated glomerular filtration rate (eGFR) is a test to measure the level of kidney function. In this measure, the effects of tacrolimus withdrawal on long-term kidney function was assessed by comparing absolute 24 month eGFR (18 months post-randomization) and change in eGFR from 6 to 24 months (randomization to 18 months randomization). Lower numbers indicate poorer kidney function
Time frame: 6 months post-transplantation, 24 months post-transplantation
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Randomized to Tacrolimus Withdrawal | Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | 6 Month eGFR | 56.2 mL/min | Standard Deviation 13.9 |
| Randomized to Tacrolimus Withdrawal | Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | 24 Month eGFR | 61.7 mL/min | Standard Deviation 14.8 |
| Randomized to Tacrolimus Withdrawal | Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | Change in eGFR from 6 to 24 months | 5.5 mL/min | Standard Deviation 12 |
| Randomized to Control Group | Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | 6 Month eGFR | 62.3 mL/min | Standard Deviation 15 |
| Randomized to Control Group | Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | 24 Month eGFR | 68.6 mL/min | Standard Deviation 24.1 |
| Randomized to Control Group | Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | Change in eGFR from 6 to 24 months | 6.3 mL/min | Standard Deviation 12.6 |
Secondary
Incidence of Acute Rejection
Acute renal allograft rejection is defined as histological reading of borderline or greater determined by the local pathology laboratory. Participants suspected of having a rejection episode on the basis of clinical signs, symptoms, or on the basis of laboratory tests, had a renal ultrasound and underwent a renal transplant biopsy. Any detection of acute cellular rejection or acute humoral rejection resulted in participants in the 'Randomized to Tacrolimus Withdrawal' group to be restarted on tacrolimus and followed per the reduced follow-up schedule of events.
Time frame: 6 to 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Tacrolimus Withdrawal | Incidence of Acute Rejection | 6 participants |
| Randomized to Control Group | Incidence of Acute Rejection | 0 participants |
Secondary
Incremental Change in IF/TA Scores
This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met.
Time frame: 6 to 18 months post-transplant
Population: No analyses were performed due to early study closure.
Secondary
Measurement of Urinary Parameters Before and After Randomization
This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met.
Time frame: 6 months post-transplantation to 18 months post-randomization
Population: No analyses were performed due to early study closure.
Secondary
Participant Survival Rate
Number of participants who did not die within the course of this study.
Time frame: 6 to 18 months post-transplantation
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Tacrolimus Withdrawal | Participant Survival Rate | 14 participants |
| Randomized to Control Group | Participant Survival Rate | 7 participants |
Secondary
Percentage of Participants in the Experimental Arm Off Tacrolimus
Participants in the 'Randomized to Tacrolimus Withdrawal' group were considered fully withdrawn once they no longer received any doses of tacrolimus. Participants met this endpoint if they did not resume taking tacrolimus as of 18 months post randomization with stable allograft function and without rejection of donor-specific antibodies.
Time frame: 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Tacrolimus Withdrawal | Percentage of Participants in the Experimental Arm Off Tacrolimus | 43 percentage of participants |
Secondary
Percentage of Participants With Donor-Specific Memory Using Elispot
This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met.
Time frame: 6 to 18 months post-randomization
Population: No analyses were performed due to early study closure.
Secondary
Percentage of Participants With New Donor Specific Antibodies (DSAs)
Donor specific antibodies are antibodies that are directed against antigens expressed on donor organs. These antibodies can result in an immune attack on the transplanted organ, increasing risk of graft loss and/or rejection.
Time frame: 6 to 18 months post-randomization
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Tacrolimus Withdrawal | Percentage of Participants With New Donor Specific Antibodies (DSAs) | 36 percentage of participants |
| Randomized to Control Group | Percentage of Participants With New Donor Specific Antibodies (DSAs) | 14 percentage of participants |