Using mTOR Inhibitors in the Prevention of BK Nephropathy

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Columbia University
Sponsor:
Collaborators:
Pfizer
Cornell University
Information provided by (Responsible Party):
Sumit Mohan, MD, Columbia University
ClinicalTrials.gov Identifier:
NCT01649609
First received: July 23, 2012
Last updated: February 5, 2014
Last verified: February 2014
  Purpose

BK virus infections after kidney transplant are increasing and can result in damage to the transplanted kidney. Currently, the universally accepted treatment is to decrease the strength of the antirejection medications but it is unclear what medications should be lowered and to what extent. The investigators propose to perform a study with patients who have BK virus detected in their blood during routine screening that appears to be increasing. The investigators will use two different strategies that involve different combinations of standard anti-rejection medications at lower dosages. Patients will be assigned to one of the two groups in a random manner across the two hospitals participating in the study. Patients will be followed for at least a year to determine if one strategy was more effective than the other in preventing an increase in the number of viruses in the blood stream and whether either one was more effective in reducing the negative impact of the infection on the functioning of the transplanted kidney.


Condition Intervention
BK Viremia
BK Nephropathy
Drug: Reduction of standard immunosuppression
Drug: mTOR Substitution

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Using mTOR Inhibitors in the Prevention of BK Nephropathy

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • BK Viral load <600 copies/mL, confirmed by blood test [ Time Frame: Up to 12 months from enrollment ] [ Designated as safety issue: Yes ]
    A Viral load of <600 copies/mL for at least 3 months indicates sustained clearance of BK viremia.


Secondary Outcome Measures:
  • Incidence of BK Nephropathy [ Time Frame: Up to 24 months from randomization ] [ Designated as safety issue: No ]
    Incidence of BK Nephropathy in each of the two Arms


Estimated Enrollment: 60
Study Start Date: March 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Reduction of standard immunosuppression
Low dose tacrolimus with low dose mycophenolic acid
Drug: Reduction of standard immunosuppression
Low dose tacrolimus with low dose mycophenolic acid
Active Comparator: mTOR Arm
Low dose sirolimus with low dose mycophenolic acid
Drug: mTOR Substitution
Replacing tacrolimus (a calcineurin inhibitor) with sirolimus (an mTOR inhibitor) along with reduction of mycophenolic acid

Detailed Description:

The incidence of BK viremia, an early complication after renal transplantation and the associated rates of graft loss resulting from BK nephropathy have been steadily rising since a series of cases that were reported in the mid-1990's. While this is at least partly related to the introduction of newer immunosuppressive agents, recent United Network for Organ Sharing (UNOS) data analyses suggest that there is a continuing rise in the incidence of BK viremia and associated nephropathy with a 3.5% incidence rate in 2009 representing a dramatic rise from just 0.9% only 4 years earlier. Single center data reports have suggested much lower rates of BK viremia and nephropathy in cohorts treated with mTOR (mammalian target of rapamycin) based immunosuppressive regimens when compared to the overall national incidence rates. Recent data has demonstrated that calcineurin inhibitors at concentrations routinely used in clinical practice interfere with the BK virus specific T cell responses; an interference that is not seen to occur with mTOR inhibitors. Further, recent evidence that inhibition of the mTOR pathway has a direct and consequential negative impact on BK infected cells provides additional insight into the observed benefit associated with mTOR inhibitors. The growing problem of BK viremia among renal transplant patients is further compounded by the absence of effective management strategies that have been tested in a rigorous or controlled setting - a fact that was highlighted in a recent systematic review. The cornerstone for management so far has been the reduction of immunosuppression, largely based on the outcome of a single center study of screening patients for viremia and following with preemptive lowering of immunosuppression. Conversion from calcineurin inhibitors to mTOR inhibitors has been reported in small case series to be an effective measure that appears to be superior to merely lowering immunosuppression; however, this approach has not been tested with a robust clinical study design.

Currently, the diagnosis of BK nephropathy requires a renal biopsy, an invasive procedure with its own risks. In addition, identification of patients with viremia who progress to nephropathy and subsequent graft failure i.e. prognostication does not appear possible with the renal biopsy results at present. Validation of potential non-invasive biomarkers provides a unique opportunity for both detection and risk stratification of patients with BK viremia subsequent failure, which could lead to more informed therapeutic interventions while supporting the development of newer therapies.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Renal transplant recipients age 18 years or over

Exclusion Criteria:

  1. Patients with multiorgan transplants
  2. Patients on immunosuppressive regimens that include steroids or Sirolimus at the time of detection of viremia
  3. ABO incompatible renal transplants
  4. Three or more previous renal transplants
  5. Patients with contraindications to tacrolimus, sirolimus, mycophenolate mofetil or mycophenolic acid.
  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: NCT01649609

Contacts
Contact: Sumit Mohan, MD 212-305-5020 sm2206@columbia.edu
Contact: Melanie Foley 212-305-5038 mf2162@columbia.edu

Locations
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Principal Investigator: Sumit Mohan, MD         
Sponsors and Collaborators
Columbia University
Pfizer
Cornell University
Investigators
Principal Investigator: Sumit Mohan, MD Columbia University
  More Information

No publications provided

Responsible Party: Sumit Mohan, MD, Assistant Professor of Clinical Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT01649609     History of Changes
Other Study ID Numbers: AAAI9004, WS2036051
Study First Received: July 23, 2012
Last Updated: February 5, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Columbia University:
BK Viremia
BK Nephropathy
mTOR inhibitor
renal transplant

Additional relevant MeSH terms:
Kidney Diseases
Viremia
Urologic Diseases
Virus Diseases
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Mycophenolic Acid
Sirolimus
Mycophenolate mofetil
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 23, 2014