Calcineurin Inhibitor Toxicity, Chronic Allograft Injury
Conditions
Keywords
CNI toxicity, CAI
Brief summary
The purpose of this study is to find out how well the current drug regimen (including low Prograf dose and Myfortic, which is usually recommended to prevent any further deterioration in the kidney function) works and how safe it is when compared to a combination of Zortress and Myfortic in patients with chronic kidney injury associated with Prograf or Neoral use.
Detailed description
Specific Aim 1: To investigate allograft and peripheral blood cell gene expression patterns of patients with CAI by using Affymetrix microarrays. Hypothesis 1: Gene expression patterns of patients with biopsy findings suggesting calcineurin inhibitor (CNI) toxicity without significant tubulointerstitial infiltrates or transplant glomerulopathy might demonstrate upregulation of genes related to tissue injury, fibrosis, and extracellular matrix deposition without upregulation of genes related to alloimmune response, such as, T and/or B lymphocyte activation markers, surface receptors, co-stimulation molecules, adhesion molecules, cytokines, and chemokines comparing to patients with significant tubulointerstitial infiltrates and/or transplant glomerulopathy that might show upregulation of genes related to alloimmune response, such as, T and/or B lymphocyte activation markers, surface receptors, co-stimulation molecules, adhesion molecules, cytokines, and chemokines. Specific Aim 2: The effect of everolimus (Zortress)/ mycophenolate sodium (EC-MPS, myfortic®) treatment on allograft and peripheral gene expression patterns. Hypothesis 2: Everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) treatment attenuates the progression of CAI due to CNI toxicity by downregulating the expression of genes related to fibrosis, such as, transforming growth factor-β, thrombospondin 1, and platelet derived growth factor-C. Specific Aim 3: To document the clinical outcomes of everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) in patients with CAI due to CNI toxicity Hypothesis 3: Everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) can attenuate the progression of CAI due to CNI toxicity and may improve the creatinine clearance.
Interventions
DRUGEverolimus
Starting dose 1.5 mg bid, target trough level 6-10 ng/ml.
DRUGTacrolimus
Target trough level of Tacrolimus 3-5 ng/ml.
DRUGMycophenolic acid
Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year.
Sponsors
Montefiore Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
All patients with biopsy proven pure chronic allograft injury due to CNI toxicity.
Exclusion criteria
1. 24 hour urine protein or spot urine protein/creatinine ratio \> 500 mg/day 2. Estimated glomerular filtration rate (eGFR) \< 30 ml/min by modification of Diet in Renal Disease( MDRD) or 24 hour urine collection 3. Patients with Donor-specific antibody (DSA) by Luminex (mean fluorescence intensity values \> 1,000) 4. Recipients of multiple organ transplants or ABO-incompatible allograft 5. Current panel reactive antibody (PRA) greater than 30 percent 6. Graft loss at randomization 7. Pregnant women 8. Previous history of acute rejection 9. Previous history of allergy or intolerance to Zortress or Myfortic 10. Platelet count less than 100,000 11. White Blood Cell (WBC) less than 3,000 12. Hb less than 9 g/dL or Htc less than 30% 13. Biopsy findings of * Chronic antibody mediated rejection * Acute rejection * Positive C4d staining * Interstitial infiltrates more than 25% of the area * Transplant glomerulopathy * Recurrent or de novo glomerular disease * Polyoma nephropathy or positive simian virus 40 (SV40) staining
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test | Baseline, One year | Estimated glomerular filtration rate (eGFR) indicates kidney function. Normal eGFR value for healthy is 80-120ml/min. For transplants, it is expected to be 60-80 ml/min. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Everolimus (Zortress)+ Mycophenolic Acid(Myfortic) Everolimus: Starting dose 1.5 mg bid, target trough level 6-10 ng/ml. Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Both for one year. | 2 |
| Reduced Dose Prograf+ Mycophenolic Acid(Myfortic) Tacrolimus: Target trough level of Tacrolimus 3-5 ng/ml. Myfortic Min. 360 mg bid and Max. 720 mg bid Both for one year. | 0 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Everolimus (Zortress)+ Mycophenolic Acid(Myfortic) |
|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 2 | 63 years STANDARD_DEVIATION 2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 0 / 0 |
| other Total, other adverse events | 0 / 2 | 0 / 0 |
| serious Total, serious adverse events | 2 / 2 | 0 / 0 |
Outcome results
Primary
Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test
Estimated glomerular filtration rate (eGFR) indicates kidney function. Normal eGFR value for healthy is 80-120ml/min. For transplants, it is expected to be 60-80 ml/min.
Time frame: Baseline, One year
Population: The only two patients enrolled did not reach the one year mark; they did not complete the study so there was no data to analyze.