A Randomized, Placebo-Controlled, Dose-Escalation Study to Assess the Safety and Effect of Cidofovir in Renal Transplant Recipients With BK Virus Nephropathy
| City: |
|
Dallas |
| State: |
|
Texas |
| Zip Code: |
|
75204 |
| Conditions: |
|
BK Virus (Nephropathy) |
| Purpose: |
|
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 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 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.
|
| 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.
|
| NCT ID: |
|
NCT00138424 |
| Primary Contact: |
|
Ajit P Limaye
Phone: (206) 598-6131
Email: limaye@u.washington.edu
|
| Backup Contact: |
|
N/A |
| Location Contact: |
|
Dallas, Texas 75204
United States
There is no listed contact information for this specific location.
Site Status: Active, not recruiting |
| Data Source: |
|
ClinicalTrials.gov |
| Date Processed: |
|
May 19, 2013 |
| Modifications to this listing: |
|
Only selected fields are shown, please use the link
below to view all information about this clinical trial. |
|
Click to view Full Listing
|