Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
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Purpose
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.
| Condition | Intervention |
|---|---|
|
Chronic Allograft Injury Calcineurin Inhibitor Toxicity |
Drug: Everolimus Drug: Tacrolimus |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity |
- EFFICACY AND SAFETY ASSESMENT [ Time Frame: One year ] [ Designated as safety issue: Yes ]
Patients will be evaluated in terms of acute rejection episodes, graft loss, death, infection episodes, malignancies and graft function at each clinic visit.
Study will be terminated in these circumstances:
- Acute rejection rate > 30%
- Serious infection rate > 50%
- > 50% progression of kidney dysfunction in one third of patients by eGFR
| Estimated Enrollment: | 30 |
| Study Start Date: | November 2011 |
| Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: Everolimus (Zortress)+ Mycophenolic acid(Myfortic) |
Drug: 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.
|
| Active Comparator: Reduced dose Prograf+ Mycophenolic acid(Myfortic) |
Drug: Tacrolimus
Target trough level of Tacrolimus 3-5 ng/ml. Myfortic Min. 360 mg bid and Max. 720 mg bid Both for one year.
|
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.
Eligibility| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
- eGFR < 30 ml/min by MDRD or 24 hour urine collection
- Patients with DSAs by Luminex (mean fluorescence intensity values > 1,000)
- Recipients of multiple organ transplants or ABO-incompatible allograft
- Current 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
- 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 SV40 staining
Contacts and Locations| United States, New York | |
| Montefiore Medical Center | |
| Bronx, New York, United States, 10467 | |
| Principal Investigator: | Enver Akalin, MD | Montefiore Medical Center/AECOM |
More Information
No publications provided
| Responsible Party: | Montefiore Medical Center |
| ClinicalTrials.gov Identifier: | NCT01473732 History of Changes |
| Other Study ID Numbers: | 11-05-196 |
| Study First Received: | November 14, 2011 |
| Last Updated: | November 16, 2011 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Montefiore Medical Center:
|
CNI toxicity CAI |
Additional relevant MeSH terms:
|
Everolimus Sirolimus Tacrolimus Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions |
Antibiotics, Antineoplastic Antineoplastic Agents Therapeutic Uses Antifungal Agents Anti-Infective Agents Anti-Bacterial Agents |
ClinicalTrials.gov processed this record on May 22, 2013