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terminated after 2 patients due to difficulty in enrollment
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Everolimus (Zortress) | Experimental |
| |
| Reduced dose Tacrolimus (Prograf) | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus | Drug | Starting dose 1.5 mg bid, target trough level 6-10 ng/ml. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, One year |
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Inclusion Criteria:
All patients with biopsy proven pure chronic allograft injury due to CNI toxicity.
Exclusion Criteria:
24 hour urine protein or spot urine protein/creatinine ratio > 500 mg/day
Estimated glomerular filtration rate (eGFR) < 30 ml/min by modification of Diet in Renal Disease( MDRD) or 24 hour urine collection
Patients with Donor-specific antibody (DSA) by Luminex (mean fluorescence intensity values > 1,000)
Recipients of multiple organ transplants or ABO-incompatible allograft
Current panel reactive antibody (PRA) greater than 30 percent
Graft loss at randomization
Pregnant women
Previous history of acute rejection
Previous history of allergy or intolerance to Zortress or Myfortic
Platelet count less than 100,000
White Blood Cell (WBC) less than 3,000
Hb less than 9 g/dL or Htc less than 30%
Biopsy findings of
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| Name | Affiliation | Role |
|---|---|---|
| Enver Akalin, MD | Montefiore Medical Center/AECOM | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montefiore Medical Center | The Bronx | New York | 10467 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
We did not analyze the data due to no patient enrolled in reduced dose prograf group and 2 patients enrolled in everolimus group did not complete the study due to death and adverse event
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Reduced Dose Prograf+ Mycophenolic Acid(Myfortic) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Baseline, One year |
|
The only two patients enrolled in everolimus group did not complete the study due to events leading to death and one due to proteinuria. The first participant was enrolled in March of 2012 and the study was terminated in August 2012.
The two patients enrolled in everolimus group did not complete the study due to events leading to death and one due to proteinuria discontinued everolimus and switched to tacrolimus. The death occurred two months after enrollment. The proteinuria event occurred fours months after enrollment. No patient enrolled in reduced tacrolimus dose group and due to difficulty in enrollment the study is terminated. No data was analyzed for any participant.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| proteinuria | Renal and urinary disorders | Systematic Assessment | proteinuria |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Enver Akalin, Medical Director Kidney Transplant | Montefiore Medical Center | 718-920-4815 | eakalin@montefiore.org |
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| ID | Term |
|---|---|
| D000068338 | Everolimus |
| D016559 | Tacrolimus |
| D009173 | Mycophenolic Acid |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002208 |
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| Tacrolimus | Drug | Target trough level of Tacrolimus 3-5 ng/ml. |
|
|
| Mycophenolic acid | Drug | Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year. |
|
|
Tacrolimus: Target trough level of Tacrolimus 3-5 ng/ml. Myfortic Min. 360 mg bid and Max. 720 mg bid Both for one year. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
Tacrolimus: Target trough level of Tacrolimus 3-5 ng/ml. Myfortic Min. 360 mg bid and Max. 720 mg bid Both for one year.
|
| 1 |
| 2 |
| 2 |
| 2 |
| 0 |
| 2 |
| EG001 | 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 | 0 | 0 | 0 | 0 | 0 |
| Small bowel obstruction leading to death | Gastrointestinal disorders | Non-systematic Assessment | Small bowel obstruction lead to sepsis which lead to death |
|
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| Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |