Cidofovir in Renal Transplant Recipients With BKVN
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|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|
- Safety and Tolerability of Cidofovir Assessed by Enumeration of Adverse Events Per Subject [ Time Frame: Baseline through day 49 ] [ Designated as safety issue: Yes ]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. ] [ Designated as safety issue: Yes ]
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. ] [ Designated as safety issue: Yes ]
The investigator's assessment of an AE's relationship to study drug is part of the documentation process. All adverse events had their relationship to study product assessed using the following terms: associated (related)or not associated (not related). To help assess, the following guidelines were used.
- Associated - There was a known temporal relationship and/or, if re-challenge was done, the event abates with de-challenge and reappears with re-challenge and/or the event was known to occur in association study product or with a product in a similar class of study products
- Not Associated -the AE was completely independent of study product administration; and/or evidence existed that the event was definitely related to another etiology.
- Changes Observed in the Physical Examination : Respiratory Rate (Per Minute) [ Time Frame: Baseline through day 49. ] [ Designated as safety issue: Yes ]Respiratory rate is the number of breaths per minute.
- Changes Observed in the Physical Examination: Blood Pressure (mm/hg) [ Time Frame: Baseline through day 49. ] [ Designated as safety issue: Yes ]Blood pressure (BP) is the pressure exerted by circulating blood upon the walls of blood vessels. "Blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, blood pressure varies between a maximum (systolic) and a minimum (diastolic) pressure. The measure is the difference between the baseline systolic and baseline diastolic value with the day 49 systolic and day 49 diastolic value.
- Changes Observed in the Physical Examination: Body Temperature (Fahrenheit) [ Time Frame: Baseline through day 49. ] [ Designated as safety issue: Yes ]The temperature is a measure of body temperature in fahrenheit (F). The measure is a change between baseline temperature and day 49 temperature.
- Changes Observed in the Physical Examination: Heart Rate (Per Minute) [ Time Frame: Baseline through day 49. ] [ Designated as safety issue: Yes ]The heart rate is the number of heart beats per minute. The outcome measure is the change from baseline heart rate to day 49 heart rate.
- Number of Subjects Experiencing at Least One Laboratory Abnormality [ Time Frame: Baseline through day 49 ] [ Designated as safety issue: Yes ]The following lab values assessed during the 49 days of subject involvement were the following: hemoglobin, hematocrit, platelets, sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), serum creatinine, calcium, phosphorous, serum albumin, glucose, uric acid, magnesium, total protein, total bilirubin, alanine aminotransferase (ALT), asparate aminotransferase (AST) and alkaline phosphate. The outcome measure is the number of subjects experiencing at least 1 grade 1 (mild) or higher event.
- 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. ] [ Designated as safety issue: No ]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. ] [ Designated as safety issue: No ]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. ] [ Designated as safety issue: No ]
- Number of Days to at Least 50% Reduction of Viral Load in Plasma and Urine [ Time Frame: Baseline through day 49. ] [ Designated as safety issue: No ]
- Allograft Function at the Completion of the Study [ Time Frame: Day 49. ] [ Designated as safety issue: No ]
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. ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]PK parameter change from baseline to day 35 for AUC4 and AUC12
|Study Start Date:||May 2006|
|Study Completion Date:||April 2011|
|Primary Completion Date:||June 2010 (Final data collection date for primary outcome measure)|
32 subjects will be randomized to 1 of 3 possible cohorts. Cohort I will receive dose 0.25 mg/kg; Cohort II will receive 0.5 mg/kg, Cohort III will receive 1.0 mg/kg. Maximum tolerated dose is to be determined.
Cidofovir is a marketed product for treatment of Cytomegalovirus disease (retinitis) in human immunodeficiency virus (HIV) infected patients. It is packaged as a sterile, hypertonic aqueous solution for intravenous infusion only. Dosages: 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg.
Placebo Comparator: Placebo
16 subjects to receive placebo.
The control for this study is sterile, 0.9% normal saline for intravenous use.
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 cohort) will be considered non-evaluable if they discontinue from the study or die for any reason except toxicities definitely related to study treatment, including DLTs. These subjects may be replaced. There will be a 5-week drug administration period (4 doses) followed by a 2 week end-of-study observation and evaluation period for each cohort. At about 3 months after last dose of study infusion, a member of the research staff will assess the study participant and counsel on pregnancy status via a phone call. The study will be overseen by a DSMB who will review the data after each dose cohort is completed. The primary endpoint of the study will assess the safety and tolerability of cidofovir in kidney transplant recipients this will be assessed by enumeration of adverse events (AEs) reported by the subjects and/or investigator, and changes observed in the physical examination (including vital signs) and laboratory evaluations during the drug administration and end-of-treatment observation and evaluation periods. The severity and relationship of AEs to receipt of study drug will be determined because the primary endpoint is focusing on the safety. The secondary endpoints are the effect of cidofovir on BK virus as determined by: percentage of subjects who achieve an undetectable BK virus urine and plasma PCR between baseline and end of treatment; rate of reduction in urine and plasma BK virus load by quantitative PCR between baseline and end of treatment; and time to reduction in BK virus urine and plasma PCR; the detailed PK of cidofovir will be evaluated in subjects at the MTD; the PD of cidofovir will be assessed by quantitating the change in BK virus deoxyribonucleic aci
|United States, Alabama|
|University of Alabama Hospital - Nephrology|
|Birmingham, Alabama, United States, 35249-0001|
|United States, California|
|California Pacific Medical Center - Sutter Pacific Medical Foundation - Transplant Nephrology|
|San Francisco, California, United States, 94115-1932|
|University of California San Francisco Medical Center at Parnassus - Organ Transplant|
|San Francisco, California, United States, 94143-2204|
|United States, Colorado|
|University of Colorado Denver|
|Aurora, Colorado, United States, 80045-2541|
|United States, Illinois|
|Northwestern University - Comprehensive Transplant Center|
|Chicago, Illinois, United States, 60611-2927|
|The University of Chicago Medical Center - Kindney Trasnplant - Nephrology|
|Chicago, Illinois, United States, 60637-1447|
|United States, Minnesota|
|University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine|
|Minneapolis, Minnesota, United States, 55455-0356|
|Mayo Clinic, Rochester - Infectious Diseases|
|Rochester, Minnesota, United States, 55905-0001|
|United States, New Hampshire|
|Dartmouth-Hitchcock Medical Center - Infectious Disease|
|Lebanon, New Hampshire, United States, 03756-1000|
|United States, Texas|
|Dallas Nephrology Associates - Dallas Transplant Institute|
|Dallas, Texas, United States, 75204-6168|
|United States, Washington|
|University of Washington - Medicine|
|Seattle, Washington, United States, 98195-7110|
|United States, Wisconsin|
|University of Wisconsin Hospital and Clinics - Clinical Science Center - Nephrology|
|Madison, Wisconsin, United States, 53792-0001|