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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Chow Kai Ming, Chinese University of Hong Kong
ClinicalTrials.gov Identifier:
NCT01046045
First received: January 6, 2010
Last updated: July 3, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Chronic Allograft Dysfunction in Renal Transplantation
Drug: everolimus
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Impact and Efficacy of Everolimus Rescue Immunosuppression in the Treatment of Chronic Allograft Dysfunction in Renal Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Chinese University of Hong Kong:

Primary Outcome Measures:
  • change in glomerular filtration rate decline rate and histological degree of fibrosis before and after treatment with everolimus [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • estimated glomerular filtration rate at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • morphometric studies [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • cytokines before and after everolimus conversion [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 17
Study Start Date: April 2008
Study Completion Date: June 2013
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Everolimus
before and after everolimus; in other words, comparison of specified outcome before and after treatment with everolimus
Drug: 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 Name: Certican
Active Comparator: Calcineurin-inhibitor immunosuppression
Cyclosporin-based immunosuppression without everolimus
Drug: 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 Name: Certican

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01046045

Locations
Hong Kong
Prince of Wales Hospital
Hong Kong, Hong Kong
Sponsors and Collaborators
Chinese University of Hong Kong
Investigators
Principal Investigator: Kai Ming Chow, MBChB Chinese University of Hong Kong, Prince of Wales Hospital
  More Information

No publications provided

Responsible Party: Chow Kai Ming, Associate Consultant, Chinese University of Hong Kong
ClinicalTrials.gov Identifier: NCT01046045     History of Changes
Other Study ID Numbers: CRE-2008.004-T
Study First Received: January 6, 2010
Last Updated: July 3, 2013
Health Authority: Hong Kong: Joint CUHK-NTEC Clinical Research Ethics Committee

Keywords provided by Chinese University of Hong Kong:
mammalian target-of-rapamycin inhibitors
chronic allograft dysfunction
everolimus
calcineurin inhibitors

Additional relevant MeSH terms:
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents

ClinicalTrials.gov processed this record on September 16, 2014