• Purpose

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  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 participate for about 156 days which includes the screening period and 4 month follow-up phone call. Blood samples, urine samples, eye exams and physical exams are included in study procedures.
  

  
  

  status:	recruiting
  conditions:	BK Virus (Nephropathy)
  interventions:	Cidofovir ; Placebo
  phase:	Phase 1/Phase 2
  study type:	Interventional
  study design:	Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Dose Comparison, Parallel Assignment, Safety/Efficacy Study
  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

• Further study details (as provided by National Institute of Allergy and Infectious Diseases (NIAID))

  primary outcome measures:

  • Safety and tolerability of cidofovir assessed by enumeration of adverse events reported by the subjects and/or investigator, and changes observed in the physical examination (including vital signs) and laboratory evaluations. [ Time Frame: Through day 49. ]

  secondary outcome measures:

  • Allograft function. [ Time Frame: Day 49. ]
  • The detailed pharmacokinetics of cidofovir will be evaluated in subjects at the maximum tolerated dose. [ Time Frame: Day 35. ]
  • The pharmacodynamics of cidofovir will be assessed by quantitating the change in BK virus DNA in urine and plasma and correlating these changes to plasma and urine levels. [ Time Frame: End of treatment. ]
  • Allograft rejection. [ Time Frame: Day 49. ]
  • Viral load changes. [ Time Frame: Day 7, 21,35 and 49. ]

  enrollment: 48

  study start date: May 2006

  study completion date: July 2009

  
  

  Arms	Assigned Interventions
  Cidofovir: Experimental 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.	Drug: Cidofovir Cidofovir is a marketed product for treatment of Cytomegalovirus disease (retinitis) in Human Immunodeficiency Virus infected patients. It is packaged as a sterile, hypertonic aqueous solution for intravenous infusion only. Dosage: 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg.
  Placebo: Placebo Comparator 16 subjects to receive placebo.	Drug: Placebo The control for this study is sterile, 0.9% normal saline for intravenous use.

  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 Acid (DNA) in urine and plasma and correlating these changes to plasma and urine levels of cidofovir between baseline and end of treatment; allograft function at the completion of the study; and allograft rejection at the completion of the study.
  

• Eligibility

  ages eligible for study:	18 Years and older
  genders eligible for study:	Both

  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 os daily)
  • Foscarnet
  • Pentamidine (intravenous)
  • Probenecid
  • Leflunomide
  • Hypotony or uveitis.
    

• Contacts and locations

  Please refer to this study by its ClinicalTrials.gov identifier: NCT00138424

  Contacts

  Ajit Limaye   (206) 598-6131

  Locations

  United States , Alabama  - University of Alabama at Birmingham

  status:	recruiting
  facility:	Birmingham, Alabama, United States, 35294

  
  

  United States , California  - California Pacific Medical Center

  status:	recruiting
  facility:	San Francisco, California, United States, 94115

  
  

  United States , California  - University of California San Francisco

  status:	recruiting
  facility:	SAN FRANCISCO, California, United States, 94143

  
  

  United States , Colorado  - University of Colorado

  status:	recruiting
  facility:	Denver, Colorado, United States, 80262

  
  

  United States , Illinois  - Northwestern University Feinberg School of Medicine

  status:	recruiting
  facility:	Chicago, Illinois, United States, 60611

  
  

  United States , Illinois  - University of Chicago

  status:	recruiting
  facility:	Chicago, Illinois, United States, 60637

  
  

  United States , Minnesota  - University of Minnesota

  status:	recruiting
  facility:	Minneapolis, Minnesota, United States, 55455

  
  

  United States , Minnesota  - Mayo Clinic

  status:	recruiting
  facility:	Rochester, Minnesota, United States, 55905

  
  

  United States , New Hampshire  - Dartmouth Hitchcock Medical Center

  status:	recruiting
  facility:	Lebanon, New Hampshire, United States, 03756

  
  

  United States , Texas  - Dallas Baylor Health

  status:	recruiting
  facility:	Dallas, Texas, United States, 75204

  
  

  United States , Washington  - University of Washington

  status:	recruiting
  facility:	Seattle, Washington, United States, 98195-7110

  
  

  United States , Wisconsin  - University of Wisconsin Medical School

  status:	recruiting
  facility:	Madison, Wisconsin, United States, 53792

  
  

• Sponsors and collaborators

  National Institute of Allergy and Infectious Diseases (NIAID)
  

• More information

  first received:	August 26, 2005
  last updated:	September 24, 2009
  ClinicalTrials.gov Identifier:	NCT00138424
  health authority:	United States: Food and Drug Administration United States: Institutional Review Board United States: Federal Government

Information obtained from ClinicalTrials.gov on September 25, 2009   Link to the current ClinicalTrials.gov record.

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