Ciprofloxacin for Prevention of BK Infection

Study Overview
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Brief Summary
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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
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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.

Official Title
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Ciprofloxacin for Prevention of BK Infection in Renal Transplant Recipients

Conditions
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BK Virus Infection

Intervention / Treatment
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* Drug: Ciprofloxacin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ciprofloxacin<br>Ciprofloxacin will be administered as two-250 mg capsules, administered once daily for 3 months post-transplant | Drug: Ciprofloxacin<br>* Patients will be randomized 2:1 active comparator, Cipro, to placebo comparator.<br>* Other names: Cipro;|
| Placebo Comparator: Placebo<br>Matching placebo will be administered as two-capsules given once daily for 3 months post-transplant | Drug: placebo<br>* Patients will be randomized 2:1 placebo comparator to active comparator, Cipro.<br>* Other names: innocuous medication;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 6 months | 
| 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. | 6 months | 
| 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 | 6 months | 
| Clostridium Difficile at 6 Months | Clostridium difficile infection at 6 months | 6 months | 
| Serious Adverse Events | Serious adverse events collected for up to 4 months (3 months on study drug plus 1 additional month) | 4 months | 
| Time to BK Infection | Median time to initial BK viremia episode, days | 12 months | 
| BK Viremia at 1 Year | Proportion of patients developing BK viremia at 1 year | 12 months | 
| First Plasma Viral Loads | First BK plasma viral loads | 12 months | 
| Acute Rejection at 1 Year | Number of patients with biopsy-proven acute rejection of the allograft at 1 year, based on Banff classification | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BK infection, BK viremia, BK nephropathy, polyomavirus, fluoroquinolone, ciprofloxacin