Clinical Trial: Cidofovir in Renal Transplant Recipients With BKVN

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Randomized, Placebo-Controlled, Dose-Escalation Study to Assess the Safety and Effect of Cidofovir in Renal Transplant Recipients With BK Virus Nephropathy

Brief Summary: This study will look at the safety, tolerability and effectiveness of cidofovir in kidney transplant patients who have been diagnosed with BK virus nephropathy (BKVN), a viral condition that can cause patients to reject transplanted kidneys. Up to 48 adult (age 18 years and older) kidney or pancreas transplant recipients with newly diagnosed BKVN will receive 1 of 3 cidofovir dose levels or placebo (non medicated substance) to identify the maximum tolerated dose. Dosing will be administered intravenously (by a tube running into a blood vessel). In addition to the screening visit, volunteers will actively participate for approximately 8-10 weeks with a single follow up phone call at 4 months. Blood samples, urine samples, eye exams and physical exams are included in study procedures.

Detailed Summary: The primary objectives of this randomized, double-blind, placebo-controlled, dose-escalation study are to evaluate the safety and tolerability of 3 dose levels of cidofovir when administered to renal transplant recipients with BK virus nephropathy and to identify the maximum tolerated doses (MTD) among the 3 dose levels of cidofovir in renal transplant recipients with BK virus nephropathy. The secondary study objectives are to evaluate the antiviral effect of cidofovir at each of 3 dose levels; to evaluate the pharmacokinetics (PK) of cidofovir in renal transplant recipients with underlying renal impairment; to evaluate the pharmacodynamics (PD) of cidofovir in this setting; to evaluate allograft function at the completion of the study; and to assess allograft rejection at the completion of the study. Patients with BKVN (virus nephropathy) diagnosed by positive plasma polymerase chain reaction (PCR) or renal allograft biopsy will be randomized to receive study drug within 60 days of the date of the renal biopsy or plasma PCR assay that established the diagnosis of BKVN. The study consists of three dose cohorts (0.25 mg/kg, 0.5 mg/kg and 1.0 mg/kg); each cohort will consist of approximately 12 subjects randomized 2:1 to receive either cidofovir or placebo (0.9% normal saline) to define the MTD among the three specified doses of cidofovir. Once the MTD is established, approximately 12 additional patients will be enrolled at that dose. The MTD is defined as the dose in which no more than 2 of the 8 cidofovir treated subjects experience a dose limiting toxicity (DLT). The target enrollment is 48 subjects if all dose cohorts are fully enrolled. A 25% over-enrollment may be tolerated to allow for continued enrollment of subjects in the lower dose cohort if data are under concomitant review by the Data and Safety Monitoring Board (DSMB) or to replace non-evaluable study participants. Study participants who have been randomized and have received cidofovir/placebo (in any co
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Current Primary Outcome:

  • Safety and Tolerability of Cidofovir Assessed by Enumeration of Adverse Events Per Subject [ Time Frame: Baseline through day 49 ]
    The measure is the number of adverse events (ie: events that are change from baseline)experienced by subjects. The median or average number of events and the range of events across all subjects is reported.
  • Number of Adverse Events by Grade of Event [ Time Frame: Baseline through day 49. ]

    Adverse events are reported as grades:

    Toxicity Grade I: a mild event (an event that requires minimal or no treatment and does not interfere with the subject's daily activities.

    Toxicity Grade II: a moderate event (an event that results in a low level of inconvenience or concern with the therapeutic measures and may cause some interference with functioning.

    Toxicity Grade III: a severe event (an event that interrupts a subject's usual daily activity and may require systemic drug therapy or other treatment and may be incapacitating.

    Toxicity Grade IV: Life threatening (any adverse drug experience that places the patient or subject at immediate risk of death from the reaction as it occurred)

  • Number of Related Adverse Events [ Time Frame: Baseline through day 49. ]

    The investigator's assessment of an AE's relationship to study drug is part of the documentation process. All adverse events had their relation

    Original Primary Outcome:

    Current Secondary Outcome:

    • The Effect of Cidofovir on BK Virus Determined by Percentage of Subjects Achieving an Undetectable BK Virus in Urine and Plasma PCR [ Time Frame: Day 35. ]
      The outcome measure is the percent of subjects that achieved non-detectable BK virus in the urine and plasma polymerase chain reaction (PCR) at day 35 after staring study drug. Undetectable is a PCR viral load of less than 200.
    • Percentage Change of Viral Load in Urine and Plasma BK Virus by Quantitative PCR Between Baseline and Each Visit [ Time Frame: Baseline, and each visit: day 7, 21, 35 and 49. ]
      The percent change in viral load from baseline to day 7, day 21 and day 49 as measured in the urine and measured in the blood. A drop is identified by use of '-', an increase in viral load has no sign in front of the number.
    • Subjects Achieving 50% Reduction Viral Load in Plasma and Urine [ Time Frame: Baseline through day 49. ]
    • Number of Days to at Least 50% Reduction of Viral Load in Plasma and Urine [ Time Frame: Baseline through day 49. ]
    • Allograft Function at the Completion of the Study [ Time Frame: Day 49. ]

      Glomerular filtration rate (GFR) is a test used to check how well the kidneys are working. Specifically, it estimates how much blood passes through the tiny filters in the kidneys, called glomeruli, each minute. The normal health GFR is about 90 - 120 mL/min/1.73 m2. Older people will have lower normal GFR levels, because GFR decreases with age.

      Abnormal Results are expected to be below 60 mL/min/1.73 m2 for 3 or more months are a sign of chronic kidney disease. A GFR result below 15 mL/min/1.73 m2 may be a sign of kidney failure.

    • Allograft Rejection. [ Time Frame: Day 49. ]
      Allograft rejection is the number of subjects that rejected their kidney by the end of the study.
    • The Pharmacodynamics of Cidofovir Will be Assessed by Correlating the Percent Change in BK Virus DNA in Urine and Plasma With Pharmacokinetic Changes Between Baseline Through Day 35 [ Time Frame: Baseline through day 35 ]
      PK parameter change from baseline to day 35 for Cmax.
    • The Pharmacodynamics of Cidofovir Will be Assessed by Correlating the Percent Change in BK Virus DNA in Urine and Plasma With Pharmacokinetic Changes Between Baseline and Day 35 [ Time Frame: Baseline through day 35 ]
      PK parameter change from baseline to day 35 for AUC4 and AUC12


    Original Secondary Outcome:

    Information By: National Institute of Allergy and Infectious Diseases (NIAID)

    Dates:
    Date Received: August 26, 2005
    Date Started: May 2006
    Date Completion:
    Last Updated: February 28, 2013
    Last Verified: April 2011