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

September 17, 2018 updated by: Enver Akalin, Montefiore Medical Center
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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

2

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Everolimus (Zortress)
Drug: Everolimus
Starting dose 1.5 mg bid, target trough level 6-10 ng/ml.
Other Names:
  • Zortress
Drug: Mycophenolic acid
Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year.
Other Names:
  • Myfortic
Active Comparator: Reduced dose Tacrolimus (Prograf)
Drug: Mycophenolic acid
Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year.
Other Names:
  • Myfortic
Drug: Tacrolimus
Target trough level of Tacrolimus 3-5 ng/ml.
Other Names:
  • Prograf

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test
Time Frame: 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.
Baseline, One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Montefiore Medical Center

Investigators

  • Principal Investigator: Enver Akalin, MD, Montefiore Medical Center/AECOM

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2012

Primary Completion (Actual)

August 1, 2012

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

November 14, 2011

First Submitted That Met QC Criteria

November 16, 2011

First Posted (Estimate)

November 17, 2011

Study Record Updates

Last Update Posted (Actual)

October 16, 2018

Last Update Submitted That Met QC Criteria

September 17, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11-05-196

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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