Kidney Transplantation
Conditions
Keywords
Kidney Transplantation, Immunosuppressive Agents
Brief summary
This study is designed to optimize calcineurin immunosuppressive regimens and evaluate immunological and non-immunological markers that may explain mechanistic differences in these agents and their effects.
Detailed description
One of the major challenges in transplantation over the past two decades has been managing long-term renal function. Serum creatinine is the most commonly used serum marker of renal function. However serum creatinine is insensitive for detecting small decreases in glomerular filtration rate (GFR). Another marker for renal function is cystatin C. Dharnidharka et al concluded that cystatin C is superior to serum creatinine as a marker of kidney function since cystatin C was a more sensitive marker than serum creatinine for detecting decreases in GFR. Pirsch et al reported that tacrolimus-treated patients had a lower incidence of severe acute rejection and better lipid profiles than cyclosporine-treated patients. Cardiovascular disease is the primary cause of premature death in renal and other transplant recipients. Current immunosuppressive protocols often elevate cardiovascular disease risk factors such as hypertension, hyperlipidemia, obesity and diabetes. This study is designed to optimize calcineurin immunosuppressive regimens to ensure the best possible long-term outcomes after renal transplantation.
Interventions
DRUGcyclosporine
Maintain on cyclosporine at target trough level of 50-250 ng/mL.
Convert to Prograf at target trough levels of 3.0-5.9 ng/mL (Arm 2) or target trough levels of 6.0-8.9 ng/mL (Arm 3).
Sponsors
Astellas Pharma US, Inc.
East Carolina University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patient is the recipient of a cadervic or living donor renal transplant. * Patient was 18 years of age at time of transplant. * Patient is at least 6 months post-transplant. * Patient has been on a cyclosporine-based immunosuppressive regimen since the transplant. * Patient has a functioning allograft and a Cockcroft/Gault estimate of creatinine clearance \>or= 35 mL/min within four weeks prior to randomization. * Patient or legal guardian has signed and dated an Institutional Review Board (IRB) approved informed consent document and is willing and able to follow study procedures. * Females are not pregnant and agree to practice effective birth control while receiving immunosuppressant medication.
Exclusion criteria
* Patient is the recipient of a solid organ transplant other than the kidney. * Patient experienced biopsy-confirmed, acute rejection, (Banff 97 criteria)within 3 months before randomization that required treatment, which is defined as antilymphocyte therapy, corticosteroids, or an increase in the number or dose of immunosuppressant medication. * Patient has recurrence of primary renal disease, or de novo renal disease. * Patient has a urine protein of \> 1.5g/24 hours or two successive urinalyses sent to and reported by the laboratory indicating albuminuria greater than 2+ within 6 months prior to enrollment. * Patient has an estimated creatinine clearance \< 35 mL/min calculated using Cockcroft/Gault formula within four weeks prior to randomization. * Patient has changed adjunctive immunosuppressant therapy within one month if randomization. * Patient is pregnant or lactating. * Patient is a known carrier of any of the HIV viruses. * Patient has a known or suspected malignancy (except for treated squamous or basal cell skin cancers) \< 5 years before randomization or a history of post-transplant lymphoproliferative disease (PTLD). * Patient has a known hypersensitivity to tacrolimus, or any of the excipients of the drug.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Renal Function in Patients Converted From Cyclosporine to Prograf | 3 years |
| Optimal Dose of Calcineurin Inhibitor in Long-term Maintenance Kidney Transplant Patients | 3 years |
| Change in Risk Factors for Cardiovascular Morbidity and Chronic Graft Dysfunction as Evidenced by Blood Levels of Homocysteine | 3 years |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Remaining on CsA Patients remained on CSA and were not converted to TAC. | 21 |
| Reduced TAC Patients converted from CsA to TAC with trough concentrations 3.0-5.9 ng/mL | 20 |
| Standard TAC Patients were converted from CsA to TAC with trough concentrations of 6.0-8.9 ng/mL | 22 |
| Total | 63 |
Baseline characteristics
| Characteristic | Reduced TAC | Standard TAC | Remaining on CsA | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 8 Participants | 8 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 14 Participants | 13 Participants | 43 Participants |
| Age, Continuous | 58.57 years STANDARD_DEVIATION 12.023 | 59.14 years STANDARD_DEVIATION 10.011 | 57.65 years STANDARD_DEVIATION 12.036 | 58.48 years STANDARD_DEVIATION 11.196 |
| Region of Enrollment United States | 20 participants | 22 participants | 21 participants | 63 participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 15 Participants | 44 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 | 11 / 21 | 14 / 20 | 14 / 22 |
| serious Total, serious adverse events | 0 / 21 | 2 / 20 | 1 / 22 |
Outcome results
Primary
Change in Risk Factors for Cardiovascular Morbidity and Chronic Graft Dysfunction as Evidenced by Blood Levels of Homocysteine
Time frame: 3 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Remaining on CsA | Change in Risk Factors for Cardiovascular Morbidity and Chronic Graft Dysfunction as Evidenced by Blood Levels of Homocysteine | 4.75 ng/dL | Standard Deviation 0.82 |
| Reduced TAC | Change in Risk Factors for Cardiovascular Morbidity and Chronic Graft Dysfunction as Evidenced by Blood Levels of Homocysteine | 4.72 ng/dL | Standard Deviation 0.52 |
| Standard TAC | Change in Risk Factors for Cardiovascular Morbidity and Chronic Graft Dysfunction as Evidenced by Blood Levels of Homocysteine | 4.89 ng/dL | Standard Deviation 0.33 |
Primary
Optimal Dose of Calcineurin Inhibitor in Long-term Maintenance Kidney Transplant Patients
Time frame: 3 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remaining on CsA | Optimal Dose of Calcineurin Inhibitor in Long-term Maintenance Kidney Transplant Patients | 130.2 ng/dL | Standard Deviation 54.94 |
| Reduced TAC | Optimal Dose of Calcineurin Inhibitor in Long-term Maintenance Kidney Transplant Patients | 5.24 ng/dL | Standard Deviation 2.06 |
| Standard TAC | Optimal Dose of Calcineurin Inhibitor in Long-term Maintenance Kidney Transplant Patients | 6.90 ng/dL | Standard Deviation 2.06 |
Primary
Renal Function in Patients Converted From Cyclosporine to Prograf
Time frame: 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Remaining on CsA | Renal Function in Patients Converted From Cyclosporine to Prograf | 0.05 Change in serum creatinine (mg/dL) |
| Reduced TAC | Renal Function in Patients Converted From Cyclosporine to Prograf | 0 Change in serum creatinine (mg/dL) |
| Standard TAC | Renal Function in Patients Converted From Cyclosporine to Prograf | 0.10 Change in serum creatinine (mg/dL) |