BK Virus Infection
Conditions
Keywords
BK infection, BK viremia, BK nephropathy, polyomavirus, fluoroquinolone, ciprofloxacin
Brief summary
BK infection is an important cause of graft dysfunction and graft loss after renal transplantation. It has been widely accepted that emergence of BK virus correlates with the more potent immunosuppressive agents used to lower acute rejection rates. In contrast to other opportunistic infections after transplantation, for which routine prophylactic agents are administered, there is no effective agent for the prevention of BK infection. Some data, however, suggests that quinolone antibiotics such as ciprofloxacin may have activity against BK virus. This has led us to investigate whether routine, short-term ciprofloxacin administration post-transplant can lower the incidence of BK infection.
Detailed description
BK virus is a member of the virus family polyomaviridae (polyoma). The virus, which can manifest as a viral nephritis, was first described in a renal transplant recipient in 1971, however it was not until the past decade that infection with BK virus became known as an important contributor to graft dysfunction and graft loss after renal transplantation. It has been widely accepted that emergence of BK virus correlates with the more potent immunosuppressive agents currently used to lower acute rejection rates. In contrast to other opportunistic infections after transplantation, for which routine prophylactic agents are administered, there is no effective agent for the prevention of BK infection, nor is there an effective agent for treating BK infection once it occurs. Ciprofloxacin is a well known anti-infective agent in the fluoroquinolone class of antibiotics. It is most active against gram-negative enteric pathogens, and is commonly used for a variety of infectious indications. Though classified as antibacterial agents, fluoroquinolones have been suggested to exhibit anti-BK viral effects by interfering with helicase activity of the BK virus large T antigen. Ciprofloxacin has been shown in previous studies to reduce urine BK viral load, and BK-associated hemorrhagic cystitis in the stem cell transplant population. Ciprofloxacin has also been associated with a lower incidence of BK viremia in one retrospective study in kidney transplant recipients. Based on these reports, the investigators hope to find a reduction BK viremia and BK nephropathy using a prospective, randomized study design.
Interventions
DRUGCiprofloxacin
Patients will be randomized 2:1 active comparator, Cipro, to placebo comparator.
DRUGplacebo
Patients will be randomized 2:1 placebo comparator to active comparator, Cipro.
Sponsors
The Methodist Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects over the age of 18 years * Recipients of a primary or repeat renal allograft either alone (from a deceased or living donor) or as a dual-kidney transplant * Signed informed consent form prior to any research assessment
Exclusion criteria
* Patients with known severe allergy to ciprofloxacin * History of tendon rupture or tendinitis * Use of antiarrythmic drugs known to prolong the QT interval such as class IA antiarrhythmic drugs (e.g. quinidine, procainamide, disopyramide), class III antiarrhythmic drugs (e.g. amiodarone, sotalol) * Patients with history of previous non-renal transplantation * Recipients administered rituximab within one year prior to transplantation, or recipients expected to receive rituximab as part of desensitization strategy or for the presence of historical donor specific antibodies * QTc interval interval of greater than 500 msec on admission or post-operative EKG * BK nephropathy with previous transplant * BK viremia on admission * Any condition present during the initial transplant hospitalization that in the investigator's judgment would increase the risk associated with participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Developing BK Infection at 6 Months Post-transplant | 6 months | Number of patients (followed by proportion) developing BK infection at 6 months post-transplant. BK infection is defined as the presence of a detectable BK viral load in plasma by polymerase chain reaction (PCR), or the presence of BK viral inclusions on kidney biopsy specimens. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Gram Negative Urinary Tract Infections at 6 Months | 6 months | Number of patients with gram negative urinary tract infections as defined by a midstream urine sample containing 10\^4 or more colony-forming units per mL |
| Number of Patients With Bacteremia at 6 Months | 6 months | Number of patients with bacteremic infection at 6 months. Bacteremia defined by a single positive blood culture that was not thought to be contaminated. |
| Number of Patients With Quinolone-resistant Infection at 6 Months | 6 months | Number of patients with quinolone-resistant gram negative bacterial infections, among those with a gram-negative infection |
| Clostridium Difficile at 6 Months | 6 months | Clostridium difficile infection at 6 months |
| Serious Adverse Events | 4 months | Serious adverse events collected for up to 4 months (3 months on study drug plus 1 additional month) |
| First Plasma Viral Loads | 12 months | First BK plasma viral loads |
| Acute Rejection at 1 Year | 12 months | Number of patients with biopsy-proven acute rejection of the allograft at 1 year, based on Banff classification |
| Time to BK Infection | 12 months | Median time to initial BK viremia episode, days |
| BK Viremia at 1 Year | 12 months | Proportion of patients developing BK viremia at 1 year |
Other
| Measure | Time frame | Description |
|---|---|---|
| Graft Loss at 1 Year | 12 months | kidney failure within first 1 year of transplant |
| Death at 1 Year | 12 months | Patient death at 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ciprofloxacin Ciprofloxacin will be administered as two-250 mg capsules, administered once daily for 3 months post-transplant
Ciprofloxacin: Patients will be randomized 2:1 active comparator to placebo comparator. | 133 |
| Placebo Matching placebo will be administered as two-capsules given once daily for 3 months post-transplant
placebo | 67 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Other | 1 | 1 |
| Overall Study | patient non-adherent | 2 | 0 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Ciprofloxacin |
|---|---|---|---|
| Age, Continuous | 44 years | 48 years | 49 years |
| Race/Ethnicity, Customized Asian | 7 Participants | 17 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 46 Participants | 32 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 17 Participants | 51 Participants | 34 Participants |
| Race/Ethnicity, Customized Other or Unknown | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 28 Participants | 85 Participants | 57 Participants |
| Repeat Transplant | 4 Participants | 14 Participants | 10 Participants |
| Sex: Female, Male Female | 20 Participants | 74 Participants | 54 Participants |
| Sex: Female, Male Male | 47 Participants | 126 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 133 | 1 / 67 |
| other Total, other adverse events | 108 / 133 | 55 / 67 |
| serious Total, serious adverse events | 35 / 133 | 18 / 67 |
Outcome results
Primary
Number of Patients Developing BK Infection at 6 Months Post-transplant
Number of patients (followed by proportion) developing BK infection at 6 months post-transplant. BK infection is defined as the presence of a detectable BK viral load in plasma by polymerase chain reaction (PCR), or the presence of BK viral inclusions on kidney biopsy specimens.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Number of Patients Developing BK Infection at 6 Months Post-transplant | 25 Participants |
| Placebo | Number of Patients Developing BK Infection at 6 Months Post-transplant | 5 Participants |
Secondary
Acute Rejection at 1 Year
Number of patients with biopsy-proven acute rejection of the allograft at 1 year, based on Banff classification
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Acute Rejection at 1 Year | 14 Participants |
| Placebo | Acute Rejection at 1 Year | 7 Participants |
Secondary
BK Viremia at 1 Year
Proportion of patients developing BK viremia at 1 year
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | BK Viremia at 1 Year | 31 Participants |
| Placebo | BK Viremia at 1 Year | 8 Participants |
Secondary
Clostridium Difficile at 6 Months
Clostridium difficile infection at 6 months
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Clostridium Difficile at 6 Months | 1 Participants |
| Placebo | Clostridium Difficile at 6 Months | 0 Participants |
Secondary
First Plasma Viral Loads
First BK plasma viral loads
Time frame: 12 months
Population: included 31 ciprofloxacin and 8 placebo patients who became BK viremic during the first year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ciprofloxacin | First Plasma Viral Loads | 2514 copies/mL |
| Placebo | First Plasma Viral Loads | 1423 copies/mL |
Secondary
Number of Patients With Bacteremia at 6 Months
Number of patients with bacteremic infection at 6 months. Bacteremia defined by a single positive blood culture that was not thought to be contaminated.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Number of Patients With Bacteremia at 6 Months | 3 Participants |
| Placebo | Number of Patients With Bacteremia at 6 Months | 2 Participants |
Secondary
Number of Patients With Gram Negative Urinary Tract Infections at 6 Months
Number of patients with gram negative urinary tract infections as defined by a midstream urine sample containing 10\^4 or more colony-forming units per mL
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Number of Patients With Gram Negative Urinary Tract Infections at 6 Months | 17 Participants |
| Placebo | Number of Patients With Gram Negative Urinary Tract Infections at 6 Months | 14 Participants |
Secondary
Number of Patients With Quinolone-resistant Infection at 6 Months
Number of patients with quinolone-resistant gram negative bacterial infections, among those with a gram-negative infection
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Number of Patients With Quinolone-resistant Infection at 6 Months | 15 Participants |
| Placebo | Number of Patients With Quinolone-resistant Infection at 6 Months | 7 Participants |
Secondary
Serious Adverse Events
Serious adverse events collected for up to 4 months (3 months on study drug plus 1 additional month)
Time frame: 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Serious Adverse Events | 35 Participants |
| Placebo | Serious Adverse Events | 18 Participants |
Secondary
Time to BK Infection
Median time to initial BK viremia episode, days
Time frame: 12 months
Population: Included 31 ciprofloxacin and 8 placebo patients who became BK viremic during the first 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ciprofloxacin | Time to BK Infection | 90 days |
| Placebo | Time to BK Infection | 76.5 days |
Other Pre-specified
Death at 1 Year
Patient death at 1 year
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Death at 1 Year | 1 Participants |
| Placebo | Death at 1 Year | 1 Participants |
Other Pre-specified
Graft Loss at 1 Year
kidney failure within first 1 year of transplant
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ciprofloxacin | Graft Loss at 1 Year | 14 Participants |
| Placebo | Graft Loss at 1 Year | 7 Participants |