End Stage Renal Failure With Renal Transplant
Conditions
Keywords
transplant, kidney, renal disease
Brief summary
The immune system is the body's defense against infection and other disease. After transplantation, the body sees the new organ as foreign and tries to destroy or reject it. Immunosuppressive medications help to prevent the immune system from attacking a transplanted organ. The primary purpose of this study is to investigate the impact of two maintenance immunosuppressive regimens. Subjects who enroll in this study will be randomly selected to have tacrolimus and everolimus (group 1) or tacrolimus and mycophenolate mofetil (group 2) as their immunosuppression medication. This study will enroll adult patients who are scheduled to receive a kidney transplant. The study is designed to understand the mechanisms of Everolimus in regards to kidney function in transplant recipients. The investigators hypothesis is that decreased exposure to Tacrolimus to the immune system will then translate in better renal allograft function.
Detailed description
Immunosuppressive therapy with the calcineurin inhibitors (CNI) Cyclosporine (CsA) and Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically, although extensively and effectively used for kidney transplantation and other solid organ transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of post-transplant renal dysfunction and it is characterized by an irreversible and progressive tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and arterioles. Furthermore, this class of medications is associated also, by blocking Interleukin-2 (IL2) production, with negative impact on regulatory T cells (T-Regs) generation (an important subpopulation of T helper cells that has been associated with positive immunomodulation and donor specific hypo responsiveness). In renal transplant recipients, complete avoidance of calcineurin inhibitors from the time of renal transplant surgery has been associated with increased incidence of acute cellular rejection, and the combination of mammalian target of rapamycin (mTOR) inhibitors with full dose CNI has been shown to be synergistically nephrotoxic and it has been associated with poor graft outcome. CNI conversion to mTOR inhibitors, at different time point post-transplant, has been tested with promising results, by different investigators and by the investigators group. The investigators have shown that in a Prednisone-free immunosuppression, conversion from Tacrolimus to mTor inhibitors at different time point post transplant is safe, it is not associated with an increased risk of acute rejection and more importantly it is associated with an a persistent increase of regulatory T cells (Data presented at the American Transplant Congress (ATC) 09 and 2010) Recently the A2309 study allowed Everolimus to be FDA approved. The A2309 was a study designed to combined reduced dose Cyclosporine+Everolimus. Interesting the reduced exposure to Cyclosporine was not associated with an increase rate of albumin-creatinine ratio (ACR) and renal allograft function was well maintained compared to the control group. The A2309 opens then an important question regarding the mechanism(s) that can explain the efficacy of a low dose CNI with an mTOR inhibitor in preventing acute allograft rejection. The present proposal is designed to understand the mechanisms of the synergistic effect(s) of low dose CNI and mTOR inhibitors (Everolimus) in controlling allo-reactive T and B cells while expanding T-Regs. The investigators hypothesis based in published data and from their laboratory (see preliminary data-Supportive documents), is that mTOR inhibitors allow expansion of T-Regs and low exposure of CNI is sufficient to control allo-reactive T cells. Decrease exposure to CNI and concomitant increase of T-Regs will then translate in better renal allograft function and histology.
Interventions
DRUGGroup 2: Tacrolimus with Everolimus.
From day 5 on, the starting dose of Everolimus (0.75 mg bid) will be increased if the trough level is \< 3 ng/mL, or reduced if the trough level is \> 8 ng/mL. Tacrolimus will be initiated according to our practice. In this treatment arm, the Tacrolimus dose will be adjusted from day 3 on, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be 3 ng/mL to 6 ng/mL. After month 6, the Tacrolimus dose should be adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. MMF dose will be initiated as 1 g b.i.d. (2 g/day). Adjustments should be made for adverse events including but not limited to gastrointestinal intolerance and a decrease in white blood cell (WBC).
DRUGTacrolimus with MMF
Standard dose Tacrolimus and MMF. This will follow standard of care procedures at Northwestern Memorial Hospital's Comprehensive Transplant Center. MMF trough or area under the concentration time curve (AUC) shall not be used to adjust dosing. In this group, Tacrolimus will be initiated according to our practice. The Tacrolimus dose will be adjusted from day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 10 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be reduced to 6 ng/mL to 8 ng/mL. After month 6, the target level of Tacrolimus will be reduced to 4 ng/mL to 8 ng/mL.
Sponsors
Novartis
Northwestern University
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
1. Subjects should be adults between 18 and 70 years of age 2. Subjects can be either gender or of any ethnic background 3. Subjects should be single organ recipients (kidney only) 4. Subjects must be able to understand the protocol and provide informed consent. 5. Recipient of living donor kidney transplants 6. Panel reactive antibody (PRA) \< 20%
Exclusion criteria
1. Subjects with End Stage Renal Disease (ESRD) secondary to primary focal segmental glomerulonephritis (FSGS). 2. Inability to fully understand the purpose of the study and the inability to sign the informed consent 3. Subjects with a significant or active infection 4. Subjects who are pregnant or nursing females 5. Subjects with a history of severe hyperlipidemia not controlled with statins, patients with Cholesterol \> 400mg/dl 6. Subjects with a platelet count \< 100,000mm3, WBC \< 2,000mm3 (or clinical practice) 7. Subjects, who, due to the existence of a surgical, medical or psychiatric condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment into this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in T Cell & B Cell Generation | Baseline, 3 months, and 12 months post-transplant | Evaluate the change in regulatory T cell generation and review the relationship of the newly generated T cells with their function in the two maintenance immunosuppressive regimens at baseline, 3 and 12 months post-transplant. |
| Change in Glomerular Filtration Rate (GFR) | 3 months, 6 months, and 12 months post-transplant | Evaluate the change in graft function (as measured by GFR) at 12 months post-transplant from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Survival | baseline - 24 months post transplant | The number of patients who were alive at 2 years post transplant |
| Renal Allograft Survival | 12 months post-transplant | The number of subjects with renal allograft survival. |
| Acute Rejection | 12 months post transplant | Number of subjects who experience acute rejection of the renal allograft. |
Countries
United States
Participant flow
Recruitment details
Donor participants were considered to be enrolled but were not part of our outcome analysis because their participation was only on the basis of providing blood for testing the immune system of the recipients.
Pre-assignment details
Donor participants were considered to be enrolled but were not part of our outcome analysis because their participation was only on the basis of providing blood for testing the immune system of the recipients.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Tacrolimus With MMF. This group will receive a standard dose Tacrolimus and MMF. This will follow standard of care protocol at Northwestern Memorial Hospital's Comprehensive Transplant Center.
Tacrolimus with MMF: Standard dose Tacrolimus and MMF. This will follow standard of care procedures at Northwestern Memorial Hospital's Comprehensive Transplant Center. MMF trough or area under the concentration time curve (AUC) shall not be used to adjust dosing. In this group, Tacrolimus will be initiated according to our practice. The Tacrolimus dose will be adjusted from day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 10 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be reduced to 6 ng/mL to 8 ng/mL. After month 6, the target level of Tacrolimus will be reduced to 4 ng/mL to 8 ng/mL. | 20 |
| Group 2: Tacrolimus With Everolimus This group will receive a low dose Tacrolimus with concentration controlled Everolimus
Group 2: Tacrolimus with Everolimus.: From day 5 on, the starting dose of Everolimus (0.75 mg bid) will be increased if the trough level is \< 3 ng/mL, or reduced if the trough level is \> 8 ng/mL. Tacrolimus will be initiated according to our practice. In this treatment arm, the Tacrolimus dose will be adjusted from day 3 on, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be 3 ng/mL to 6 ng/mL. After month 6, the Tacrolimus dose should be adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. MMF dose will be initiated as 1 g b.i.d. (2 g/day). Adjustments should be made for adverse events including but not limited to gastrointestinal intolerance and a decrease in white blood cell (WBC). | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Group 2: Tacrolimus With Everolimus | Group 1: Tacrolimus With MMF. | Total |
|---|---|---|---|
| Age, Continuous | 48.3 years STANDARD_DEVIATION 16 | 48.4 years STANDARD_DEVIATION 13 | 48.4 years STANDARD_DEVIATION 14.5 |
| Cause of End Stage Renal Disease Diabetes | 5 Participants | 10 Participants | 15 Participants |
| Cause of End Stage Renal Disease Hypertension | 6 Participants | 5 Participants | 11 Participants |
| Cause of End Stage Renal Disease Lupus | 1 Participants | 1 Participants | 2 Participants |
| Cause of End Stage Renal Disease Polycystic Kidney Disease | 3 Participants | 1 Participants | 4 Participants |
| Cause of End Stage Renal Disease Unknown | 5 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 20 Participants | 20 Participants | 40 Participants |
| Induction Therapy History Alemtuzumab | 19 Participants | 20 Participants | 39 Participants |
| Induction Therapy History IL-2 Receptor Antagonist | 1 Participants | 0 Participants | 1 Participants |
| Pre-Emptive Transplant (Prior to Dialysis) | 6 Participants | 7 Participants | 13 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 | 11 Participants | 7 Participants | 18 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 | 9 Participants | 13 Participants | 22 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 13 Participants | 16 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 6 / 20 | 8 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Glomerular Filtration Rate (GFR)
Evaluate the change in graft function (as measured by GFR) at 12 months post-transplant from baseline.
Time frame: 3 months, 6 months, and 12 months post-transplant
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Tacrolimus With MMF. | Change in Glomerular Filtration Rate (GFR) | 3 months | 63 ml/minutes per 1.73 meters^2 | Standard Deviation 19 |
| Group 1: Tacrolimus With MMF. | Change in Glomerular Filtration Rate (GFR) | 6 months | 64 ml/minutes per 1.73 meters^2 | Standard Deviation 19 |
| Group 1: Tacrolimus With MMF. | Change in Glomerular Filtration Rate (GFR) | 12 months | 65 ml/minutes per 1.73 meters^2 | Standard Deviation 20 |
| Group 2: Tacrolimus With Everolimus | Change in Glomerular Filtration Rate (GFR) | 3 months | 66 ml/minutes per 1.73 meters^2 | Standard Deviation 22 |
| Group 2: Tacrolimus With Everolimus | Change in Glomerular Filtration Rate (GFR) | 6 months | 64 ml/minutes per 1.73 meters^2 | Standard Deviation 24 |
| Group 2: Tacrolimus With Everolimus | Change in Glomerular Filtration Rate (GFR) | 12 months | 72 ml/minutes per 1.73 meters^2 | Standard Deviation 21 |
Primary
Change in T Cell & B Cell Generation
Evaluate the change in regulatory T cell generation and review the relationship of the newly generated T cells with their function in the two maintenance immunosuppressive regimens at baseline, 3 and 12 months post-transplant.
Time frame: Baseline, 3 months, and 12 months post-transplant
Population: The percentage of Treg cells in peripheral blood is shown below per group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Tacrolimus With MMF. | Change in T Cell & B Cell Generation | Baseline | 1.05 Mean % of Treg cells in peripheral blood | Standard Deviation 0.17 |
| Group 1: Tacrolimus With MMF. | Change in T Cell & B Cell Generation | 3 Months | 0.8 Mean % of Treg cells in peripheral blood | Standard Deviation 0.19 |
| Group 1: Tacrolimus With MMF. | Change in T Cell & B Cell Generation | 12 Months | 0.81 Mean % of Treg cells in peripheral blood | Standard Deviation 0.1 |
| Group 2: Tacrolimus With Everolimus | Change in T Cell & B Cell Generation | Baseline | 0.93 Mean % of Treg cells in peripheral blood | Standard Deviation 0.13 |
| Group 2: Tacrolimus With Everolimus | Change in T Cell & B Cell Generation | 3 Months | 1.12 Mean % of Treg cells in peripheral blood | Standard Deviation 0.13 |
| Group 2: Tacrolimus With Everolimus | Change in T Cell & B Cell Generation | 12 Months | 1.18 Mean % of Treg cells in peripheral blood | Standard Deviation 0.13 |
Secondary
Acute Rejection
Number of subjects who experience acute rejection of the renal allograft.
Time frame: 12 months post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Tacrolimus With MMF. | Acute Rejection | 4 Participants |
| Group 2: Tacrolimus With Everolimus | Acute Rejection | 0 Participants |
Secondary
Patient Survival
The number of patients who were alive at 2 years post transplant
Time frame: baseline - 24 months post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Tacrolimus With MMF. | Patient Survival | 20 Participants |
| Group 2: Tacrolimus With Everolimus | Patient Survival | 20 Participants |
Secondary
Renal Allograft Survival
The number of subjects with renal allograft survival.
Time frame: 12 months post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Tacrolimus With MMF. | Renal Allograft Survival | 20 Participants |
| Group 2: Tacrolimus With Everolimus | Renal Allograft Survival | 20 Participants |