Clinical trial NCT01473732: 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
Overall status: TERMINATED
Phase: NA
Conditions: Chronic Allograft Injury
Calcineurin Inhibitor Toxicity
Keywords: CNI toxicity
CAI
Lead sponsor: Montefiore Medical Center
Sponsor class: OTHER
First posted: 2011-11-17
Enrollment: 2
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test
timeFrame: Baseline, One year
Secondary outcomes:
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
Study officials:
affiliation: Montefiore Medical Center/AECOM
name: Enver Akalin, MD
role: PRINCIPAL_INVESTIGATOR
References: