Everolimus Rescue Immunosuppression in the Treatment of Chronic Allograft Dysfunction in Renal Transplant Recipients

June 19, 2015 updated by: Chow Kai Ming, Chinese University of Hong Kong

Impact and Efficacy of Everolimus Rescue Immunosuppression in the Treatment of Chronic Allograft Dysfunction in Renal Transplant Recipients

Despite the remarkable improvement in short-term patient and graft survival among the recipients of kidney transplants, the progressive renal dysfunction (chronic allograft dysfunction) accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes and glomerulosclerosis remains the chief cause of graft loss. As a result of this damage from immunologic and non-immunologic injury, the long-term survival of kidney transplants has changed little during the past decade. And, among the non-immunologic factors, calcineurin inhibitor nephrotoxicity has been shown to be the most common factor leading to long-term graft damage and progression to graft failure. This is further supported by the previous finding that long-term use of calcineurin inhibitor-based therapy leads to deterioration in kidney function, even in recipients of non-renal organ transplants.

The growing interest in calcineurin inhibitor minimisation protocols to optimize renal transplant outcome offers a new therapeutic options in the management of patients with chronic allograft dysfunction. Recently, mammalian target-of-rapamycin inhibitors (mTOR inhibitors) including everolimus has been shown to achieve an improvement of long-term function through an early modulation of immunosuppressive regimen. In this aspect, percutaneous renal graft biopsy represents an important diagnostic tool to allow visualization of the lesions of chronic allograft dysfunction and therefore the ability to delineate the potential improvement after introduction of everolimus. Histologic and morphometric findings from a protocol-mandated biopsies obtained from renal transplant recipients who are suffering from chronic allograft dysfunction and treated with everolimus are needed to provide a clinical blueprint for the drug's efficacy, if confirmed.

Study Overview

Status

Completed

Intervention / Treatment

Detailed Description

The objective of the present study is to evaluate the a priori hypothesis that calcineurin inhibitor and rescue immunosuppression with everolimus-based therapy would attenuate the renal parenchymal injury associated with long-term use of calcineurin inhibitors in renal transplant recipients with declining kidney function. Another objective of this study is to elucidate the efficacy of our approach to arrest the progression of allograft dysfunction by means of protocol renal allograft biopsy.

Study Type

Interventional

Enrollment (Actual)

17

Phase

  • Phase 4

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

      • Hong Kong, Hong Kong
        • Prince of Wales Hospital

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

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Aged 18-65 years
  • Biopsy-confirmed chronic allograft dysfunction or chronic allograft nephropathy, in the absence of acute rejection episode within the preceding 2 months
  • Proteinuria < 0.8 g/day (or spot urine protein < 0.8 g/g-Cr) in 2 consecutive samples within 8 weeks
  • Serum creatinine < 220 μmol/L or estimated glomerular filtration rate > 40 ml/min/1.73m2 by the Nankivell formula, which had been validated in kidney transplant recipients; this equation was expressed for use with a standard serum creatinine assay: glomerular filtration rate = 6.7/(standardized serum creatinine in μmol/L / 1000) + weight (kg)/4 - urea (mmol/L)/2 - 100 / height2 (m) + 35 if the subject is male (or 25 if the subject is female)
  • Willingness to give written consent and comply with the study protocol

Exclusion Criteria:

  • Pregnancy, lactating or childbearing potential without effective method of birth control
  • Severe gastrointestinal disorders that interfere with their ability to receive or absorb oral medication
  • Serum cholesterol > 7.8 mmol/L and/or serum triglycerides > 4.5 mmol/L despite lipid-lowering agents before conversion
  • Systemic infection requiring therapy at study entry
  • Participation in any previous trial on everolimus or sirolimus
  • Patients receiving treatment of sirolimus or everolimus for other medical reasons within the past 12 months
  • On other investigational drugs within last 30 days
  • History of a psychological illness or condition such as to interfere with the patient's ability to understand the requirement of the study
  • History of non-compliance
  • Chronic lung disease
  • Known history of sensitivity or allergy to everolimus

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: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Everolimus
before and after everolimus; in other words, comparison of specified outcome before and after treatment with everolimus
everolimus at an initial daily loading dose between 1 and 4 mg dose of everolimus will be adjusted to maintain a trough everolimus level between 5 and 12 ng/mL
Other Names:
  • Certican
Active Comparator: Calcineurin-inhibitor immunosuppression
Cyclosporin-based immunosuppression without everolimus
everolimus at an initial daily loading dose between 1 and 4 mg dose of everolimus will be adjusted to maintain a trough everolimus level between 5 and 12 ng/mL
Other Names:
  • Certican

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
change in glomerular filtration rate decline rate and histological degree of fibrosis before and after treatment with everolimus
Time Frame: 12 months
12 months

Secondary Outcome Measures

Outcome Measure
Time Frame
estimated glomerular filtration rate at 12 months
Time Frame: 12 months
12 months
morphometric studies
Time Frame: 12 months
12 months
cytokines before and after everolimus conversion
Time Frame: 12 months
12 months

Collaborators and Investigators

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

Investigators

  • Principal Investigator: Kai Ming Chow, MBChB, Chinese University of Hong Kong, Prince of Wales Hospital

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

April 1, 2008

Primary Completion (Actual)

November 1, 2011

Study Completion (Actual)

June 1, 2013

Study Registration Dates

First Submitted

January 6, 2010

First Submitted That Met QC Criteria

January 8, 2010

First Posted (Estimate)

January 11, 2010

Study Record Updates

Last Update Posted (Estimate)

June 22, 2015

Last Update Submitted That Met QC Criteria

June 19, 2015

Last Verified

June 1, 2015

More Information

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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