Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
Primary Purpose
Chronic Allograft Injury, Calcineurin Inhibitor Toxicity
Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Everolimus
Tacrolimus
Mycophenolic acid
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Allograft Injury focused on measuring CNI toxicity, CAI
Eligibility Criteria
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
- 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
Sites / Locations
- Montefiore Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Everolimus (Zortress)
Reduced dose Tacrolimus (Prograf)
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT01473732
First Posted
November 14, 2011
Last Updated
September 17, 2018
Sponsor
Montefiore Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT01473732
Brief Title
Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
Official Title
Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
Study Type
Interventional
2. Study Status
Record Verification Date
September 2018
Overall Recruitment Status
Terminated
Why Stopped
terminated after 2 patients due to difficulty in enrollment
Study Start Date
March 2012 (Actual)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
August 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Montefiore Medical Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Allograft Injury, Calcineurin Inhibitor Toxicity
Keywords
CNI toxicity, CAI
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
2 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Everolimus (Zortress)
Arm Type
Experimental
Arm Title
Reduced dose Tacrolimus (Prograf)
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
Zortress
Intervention Description
Starting dose 1.5 mg bid, target trough level 6-10 ng/ml.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Prograf
Intervention Description
Target trough level of Tacrolimus 3-5 ng/ml.
Intervention Type
Drug
Intervention Name(s)
Mycophenolic acid
Other Intervention Name(s)
Myfortic
Intervention Description
Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year.
Primary Outcome Measure Information:
Title
Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test
Description
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
10. Eligibility
Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
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
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Enver Akalin, MD
Organizational Affiliation
Montefiore Medical Center/AECOM
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
We'll reach out to this number within 24 hrs