Clinical trial NCT00138424: Cidofovir in Renal Transplant Recipients With BKVN
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: BK Virus (Nephropathy)
Keywords: Vistide®, Cidofovir, renal transplant, BK Virus Nephropathy
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2005-08-30
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 description: 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

Eligibility criteria: Inclusion Criteria:

* Aged greater than or equal to 18 years.
* Kidney or kidney/pancreas transplant recipient.
* New onset BK Virus Nephropathy (BKVN) diagnosed by a positive plasma polymerase chain reaction (PCR) assay for BK virus deoxyribonucleic acid (DNA) or by a renal biopsy demonstrating BK virus (by immunohistochemistry, electron microscopy and/or in situ hybridization) obtained as part of standard medical care within 60 days prior to receipt of first dose of study drug.
* BK virus load in plasma greater than 10,000 copies/mL within prior 21 days.
* Glomerular filtration rate greater than 30 mL/min using Levey calculations.
* Absolute neutrophil count greater than 1000/microliter \[with granulocyte colony stimulating factor (GCSF) support as necessary\].
* Women must be post-menopausal, surgically sterile or willing to use adequate contraception (barrier method with spermicide, intrauterine device, oral contraceptives, implant or other licensed hormone method) from time of study enrollment through 1 month after the last dose of study treatment. Men must be surgically sterile or willing to use contraception (barrier method with spermicide) from time of study enrollment through 3 months after the last dose of study treatment.

Exclusion Criteria:

* Unable to provide valid informed consent.
* History of intolerance to cidofovir or related compounds (i.e. other nucleotide derivatives \[adefovir or tenofovir\]).
* Pregnant or breast feeding women.
* Prior treatment with cidofovir within the last 2 weeks.
* Receipt of another investigational drug with proven nephrotoxic drug interaction with cidofovir or known antipolyoma virus activity one month prior to study entry.
* Contraindication to renal biopsy (e.g., anticoagulant medication, unwilling to undergo biopsy).
* Currently receiving or anticipated to receive any of the following within 2 weeks of randomization:
* Amphotericin preparation (intravenous)
* Aminoglycosides (intravenous)
* Platinum - based chemotherapeutic agents
* NSAIDs - non steroidal anti-inflammatory drugs (aspirin given for cardioprotective treatment is acceptable up to 650 mg per oral daily)
* Foscarnet
* Pentamidine (intravenous)
* Probenecid
* Leflunomide
* Hypotony or uveitis.

Primary outcomes:
measure: Safety and Tolerability of Cidofovir Assessed by Enumeration of Adverse Events Per Subject
timeFrame: Baseline through day 49
measure: Number of Adverse Events by Grade of Event
timeFrame: Baseline through day 49.
measure: Number of Related Adverse Events
timeFrame: Baseline through day 49.
measure: Changes Observed in the Physical Examination : Respiratory Rate (Per Minute)
timeFrame: Baseline through day 49.
measure: Changes Observed in the Physical Examination: Blood Pressure (mm/hg)
timeFrame: Baseline through day 49.
measure: Changes Observed in the Physical Examination: Body Temperature (Fahrenheit)
timeFrame: Baseline through day 49.
measure: Changes Observed in the Physical Examination: Heart Rate (Per Minute)
timeFrame: Baseline through day 49.
measure: Number of Subjects Experiencing at Least One Laboratory Abnormality
timeFrame: Baseline through day 49
Secondary outcomes:
measure: The Effect of Cidofovir on BK Virus Determined by Percentage of Subjects Achieving an Undetectable BK Virus in Urine and Plasma PCR
timeFrame: Day 35.
measure: Percentage Change of Viral Load in Urine and Plasma BK Virus by Quantitative PCR Between Baseline and Each Visit
timeFrame: Baseline, and each visit: day 7, 21, 35 and 49.
measure: Subjects Achieving 50% Reduction Viral Load in Plasma and Urine
timeFrame: Baseline through day 49.
measure: Number of Days to at Least 50% Reduction of Viral Load in Plasma and Urine
timeFrame: Baseline through day 49.
measure: Allograft Function at the Completion of the Study
timeFrame: Day 49.
measure: Allograft Rejection.
timeFrame: Day 49.
measure: 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
timeFrame: Baseline through day 35
measure: 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
timeFrame: Baseline through day 35
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Hospital - Nephrology
state: Alabama
city: San Francisco
country: United States
facility: California Pacific Medical Center - Sutter Pacific Medical Foundation - Transplant Nephrology
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center at Parnassus - Organ Transplant
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Chicago
country: United States
facility: Northwestern University - Comprehensive Transplant Center
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medical Center - Kindney Trasnplant - Nephrology
state: Illinois
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic, Rochester - Infectious Diseases
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center - Infectious Disease
state: New Hampshire
city: Dallas
country: United States
facility: Dallas Nephrology Associates - Dallas Transplant Institute
state: Texas
city: Seattle
country: United States
facility: University of Washington - Medicine
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics - Clinical Science Center - Nephrology
state: Wisconsin
Study officials:
References:
citation: Razonable RR. Management of viral infections in solid organ transplant recipients. Expert Rev Anti Infect Ther. 2011 Jun;9(6):685-700. doi: 10.1586/eri.11.43.