Using mTOR Inhibitors in the Prevention of BK Nephropathy

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.

Study Overview

• Status: Completed
• Conditions: BK Viremia; BK Nephropathy
• Intervention / Treatment: Drug: Tacrolimus; Drug: Mycophenolate acid; Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Renal transplant recipients age 18 years or over

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Reduction of standard immunosuppression; Low dose Tacrolimus with low dose Mycophenolate acid	Drug: Tacrolimus; Reduction of standard immunosuppression - The standard of care immunosuppression treatment commonly used for renal transplant patients; Other Names: Prograf; Drug: Mycophenolate acid; Myfortic or CellCept - The standard of care immunosuppression treatment most commonly used for renal transplant patients; Other Names: mycophenolate antimetabolite
Active Comparator: mTOR Arm; Low dose Sirolimus with low dose Mycophenolate acid (mTOR Substitution)	Drug: Mycophenolate acid; Myfortic or CellCept - The standard of care immunosuppression treatment most commonly used for renal transplant patients; Other Names: mycophenolate antimetabolite; Drug: Sirolimus; mTOR Substitution - Replacing tacrolimus (a calcineurin inhibitor) with sirolimus (an mTOR inhibitor) along with reduction of mycophenolic acid; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With BK Viral Load <600 Copies/mL	A Viral load of <600 copies/mL for at least 3 months indicates sustained clearance of BK viremia, confirmed by blood test	Up to 12 months from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Incidence of BK Nephropathy	The number of people with incidence of BK Nephropathy in each of the two Arms	Up to 24 months from randomization

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Pfizer; Cornell University
• Investigators: Principal Investigator: Sumit Mohan, MD, Columbia University

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: July 23, 2012
• First Submitted That Met QC Criteria: July 24, 2012
• First Posted (Estimate): July 25, 2012

Study Record Updates

• Last Update Posted (Actual): February 28, 2018
• Last Update Submitted That Met QC Criteria: January 31, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: renal transplant; mTOR inhibitor; BK Viremia; BK Nephropathy
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Kidney Diseases; Viremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Sirolimus; Antimetabolites
• Other Study ID Numbers: AAAI9004; WS2036051 (Other Identifier: Pfizer)