Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity

Not Applicable

Terminated

• Conditions: Chronic Allograft Injury; Calcineurin Inhibitor Toxicity
• Interventions: Drug: Tacrolimus; Drug: Everolimus; Drug: Mycophenolic acid

• Registration Number: NCT01473732
• Lead Sponsor: Montefiore Medical Center

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.

Study Timeline

• Study First Submitted: 2011-11-14
• Study First Submitted QC: 2011-11-16
• Study First Posted: 2011-11-17
• Study Start: 2012-03
• Primary Completion: 2012-08
• Study Completion: 2012-08
• Results First Submitted: 2018-06-11
• Results First Submitted QC: 2018-08-20
• Status Verified: 2018-09
• Last Update Submitted: 2018-09-17
• Results First Posted: 2018-09-18
• Last Update Posted: 2018-10-16

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Everolimus (Zortress)	Mycophenolic acid	-
Reduced dose Tacrolimus (Prograf)	Tacrolimus	-
Everolimus (Zortress)	Everolimus	-
Reduced dose Tacrolimus (Prograf)	Mycophenolic acid	-

Primary Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States