Graft Dysfunction, Interstitial Fibrosis
Conditions
Keywords
Everolimus, Graft dysfunction, Interstitial fibrosis
Brief summary
Transition from tacrolimus based triple therapy with Mycophenolate Mofetil (MMF) and steroids in stable renal transplant patients to low intensity tacrolimus, everolimus and prednisone will be associated with improvement in Glomular Filtration Rate (GFR) and allograft fibrosis.
Interventions
DRUGEverolimus
Convert mycophenolate to everolimus with subsequent reduction in exposure to tacrolimus
OTHERStandard of Care
Tacrolimus, mycophenolate mofetil and steroids
Sponsors
Novartis
Medical University of South Carolina
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
1. At least 18 years of age and able to give informed consent. 2. Received a first or repeat cadaveric (including ECD) or living donor renal transplant. 3. Patient has stable graft function, defined as no change of greater than 40% of baseline serum creatinine and no acute rejection during the past month. 4. Currently receiving tacrolimus, mycophenolate mofetil and prednisone as their immunosuppression regimen
Exclusion criteria
1. Biopsy proven acute rejection episode that occurred within the past month. 2. Malignancy within the past 3 years, except for non-melanoma skin cancer. 3. Currently enrolled in an investigational drug trial. 4. Woman of child bearing potential not utilizing an effective form of birth control. 5. Patients with uncontrolled dyslipidemia, defined at serum fasting LDL \>200 mg/dL or serum fasting triglycerides \>500 mg/dL. 6. Patients with a spot urine protein to creatinine ratio of \> 800 mg of protein per gram of creatinine. 7. WBC \< 2,000 cells/mm3 8. Platelets \< 75,000 cells/mm3 9. Patients who have received an organ transplant other than a kidney. 10. Patients with a history of biopsy proven FSGS, MPGN, or PGN.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kidney Allograft Fibrosis Assessment | 1 year | Measure and compare the change in interstitial fibrosis (morphometric analysis of trichrome stained slides) at one-year post-transplant in patients converted to everolimus, low intensity tacrolimus and prednisone versus the standard of care tacrolimus, mycophenolate and prednisone regimen. The scale is a percentage of the tissue that demonstrates fibrosis. The scale range is 0 to 100%. The higher the percentage, the worse the fibrosis and the poorer the prognosis. A lower score (percentage) is therefore better. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Drug Reactions | 2 year | Measure and compare the incidence of significant immunosuppressant-related adverse drug reactions for each group. |
| Infection | 2 year | Compare the rates of post-transplant infections, including CMV, BK, and admissions to the hospital for infectious causes in each group. |
| Renal Function Measured by Estimated Glomerular Filtration Rate (eGFR) | 1 year | Measure and compare the estimated GFR (using the 4-variable modified MDRD equation) in patients converted to everolimus, low intensity tacrolimus and prednisone versus the standard of care tacrolimus, mycophenolate and prednisone regimen, both at one year and two years post-transplant. |
| Kidney Allograft Survival | 1 year | Compare the patient and graft survival rates at one-year post-transplant in each group. |
| Percentage of Participants Discontinuing or Modifying Immunosuppressant Use | 2 year | Measure and compare the rates of immunosuppressant discontinuation and modification for each group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Intensity Tacrolimus Low tacrolimus, everolimus, and steroids
Everolimus: Convert mycophenolate to everolimus with subsequent reduction in exposure to tacrolimus | 30 |
| Standard of Care Tacrolimus, mycophenolate mofetil and steroids
Standard of Care: Tacrolimus, mycophenolate mofetil and steroids | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Low Intensity Tacrolimus | Standard of Care | Total |
|---|---|---|---|
| Age, Continuous | 51.0 years STANDARD_DEVIATION 13.6 | 51.6 years STANDARD_DEVIATION 12.1 | 51.3 years STANDARD_DEVIATION 12.85 |
| BMI | 28.6 kg/m^2 STANDARD_DEVIATION 4.8 | 28.7 kg/m^2 STANDARD_DEVIATION 4.5 | 28.7 kg/m^2 STANDARD_DEVIATION 4.6 |
| 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 | 15 Participants | 19 Participants | 34 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 | 15 Participants | 11 Participants | 26 Participants |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 14 Participants |
| Sex: Female, Male Male | 27 Participants | 19 Participants | 46 Participants |
| Weight | 89.1 kg STANDARD_DEVIATION 17 | 84.7 kg STANDARD_DEVIATION 16.6 | 86.9 kg STANDARD_DEVIATION 16.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 11 / 30 | 6 / 30 |
| serious Total, serious adverse events | 8 / 30 | 6 / 30 |
Outcome results
Primary
Kidney Allograft Fibrosis Assessment
Measure and compare the change in interstitial fibrosis (morphometric analysis of trichrome stained slides) at one-year post-transplant in patients converted to everolimus, low intensity tacrolimus and prednisone versus the standard of care tacrolimus, mycophenolate and prednisone regimen. The scale is a percentage of the tissue that demonstrates fibrosis. The scale range is 0 to 100%. The higher the percentage, the worse the fibrosis and the poorer the prognosis. A lower score (percentage) is therefore better.
Time frame: 1 year
Population: The number of subjects analyzed for the fibrosis assessment was 15 in each group, because biopsy samples for both baseline and end of follow-up were only able to be obtained from 15 subjects per group.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Low Intensity Tacrolimus | Kidney Allograft Fibrosis Assessment | Baseline | 22.9 % of fibrosis |
| Low Intensity Tacrolimus | Kidney Allograft Fibrosis Assessment | End of Follow-up | 22.9 % of fibrosis |
| Standard of Care | Kidney Allograft Fibrosis Assessment | End of Follow-up | 27.8 % of fibrosis |
| Standard of Care | Kidney Allograft Fibrosis Assessment | Baseline | 20.8 % of fibrosis |
Secondary
Adverse Drug Reactions
Measure and compare the incidence of significant immunosuppressant-related adverse drug reactions for each group.
Time frame: 2 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Tacrolimus | Adverse Drug Reactions | 11 Participants |
| Standard of Care | Adverse Drug Reactions | 6 Participants |
Secondary
Infection
Compare the rates of post-transplant infections, including CMV, BK, and admissions to the hospital for infectious causes in each group.
Time frame: 2 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Intensity Tacrolimus | Infection | 17 percentage of subjects with infection |
| Standard of Care | Infection | 30 percentage of subjects with infection |
Secondary
Kidney Allograft Survival
Compare the patient and graft survival rates at one-year post-transplant in each group.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Intensity Tacrolimus | Kidney Allograft Survival | 100 percentage of patients graft survival |
| Standard of Care | Kidney Allograft Survival | 100 percentage of patients graft survival |
Secondary
Percentage of Participants Discontinuing or Modifying Immunosuppressant Use
Measure and compare the rates of immunosuppressant discontinuation and modification for each group.
Time frame: 2 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Intensity Tacrolimus | Percentage of Participants Discontinuing or Modifying Immunosuppressant Use | 37 percentage of participants |
| Standard of Care | Percentage of Participants Discontinuing or Modifying Immunosuppressant Use | 20 percentage of participants |
Secondary
Renal Function Measured by Estimated Glomerular Filtration Rate (eGFR)
Measure and compare the estimated GFR (using the 4-variable modified MDRD equation) in patients converted to everolimus, low intensity tacrolimus and prednisone versus the standard of care tacrolimus, mycophenolate and prednisone regimen, both at one year and two years post-transplant.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Intensity Tacrolimus | Renal Function Measured by Estimated Glomerular Filtration Rate (eGFR) | 59 mL/min/1.73 m^2 | Standard Deviation 14 |
| Standard of Care | Renal Function Measured by Estimated Glomerular Filtration Rate (eGFR) | 56 mL/min/1.73 m^2 | Standard Deviation 15 |