Ciprofloxacin for Prevention of BK Infection

• ClinicalTrials.gov Identifier: NCT01789203
• Recruitment Status: Completed
• First Posted: February 12, 2013
• Results First Posted: November 13, 2019
• Last Update Posted: November 13, 2019
• Sponsor: The Methodist Hospital System
• Information provided by (Responsible Party): Ahmed Osama Gaber, MD, The Methodist Hospital System

Study Description

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.

Condition or disease	Intervention/treatment	Phase
BK Virus Infection	Drug: Ciprofloxacin; Drug: placebo	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Ciprofloxacin for Prevention of BK Infection in Renal Transplant Recipients
• Actual Study Start Date: January 2013
• Actual Primary Completion Date: April 2017
• Actual Study Completion Date: October 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Ciprofloxacin; Ciprofloxacin will be administered as two-250 mg capsules, administered once daily for 3 months post-transplant	Drug: Ciprofloxacin; Patients will be randomized 2:1 active comparator, Cipro, to placebo comparator.; Other Name: Cipro
Placebo Comparator: Placebo; Matching placebo will be administered as two-capsules given once daily for 3 months post-transplant	Drug: placebo; Patients will be randomized 2:1 placebo comparator to active comparator, Cipro.; Other Names: inactive drug; innocuous medication

Outcome Measures

Primary Outcome Measures :

1. Number of Patients Developing BK Infection at 6 Months Post-transplant [ Time Frame: 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 Outcome Measures :

1. Number of Patients With Gram Negative Urinary Tract Infections at 6 Months [ Time Frame: 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
2. Number of Patients With Bacteremia at 6 Months [ Time Frame: 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.
3. Number of Patients With Quinolone-resistant Infection at 6 Months [ Time Frame: 6 months ]
   Number of patients with quinolone-resistant gram negative bacterial infections, among those with a gram-negative infection
4. Clostridium Difficile at 6 Months [ Time Frame: 6 months ]
   Clostridium difficile infection at 6 months
5. Serious Adverse Events [ Time Frame: 4 months ]
   Serious adverse events collected for up to 4 months (3 months on study drug plus 1 additional month)
6. Time to BK Infection [ Time Frame: 12 months ]
   Median time to initial BK viremia episode, days
7. BK Viremia at 1 Year [ Time Frame: 12 months ]
   Proportion of patients developing BK viremia at 1 year
8. First Plasma Viral Loads [ Time Frame: 12 months ]
   First BK plasma viral loads
9. Acute Rejection at 1 Year [ Time Frame: 12 months ]
   Number of patients with biopsy-proven acute rejection of the allograft at 1 year, based on Banff classification

Other Outcome Measures:

1. Graft Loss at 1 Year [ Time Frame: 12 months ]
   kidney failure within first 1 year of transplant
2. Death at 1 Year [ Time Frame: 12 months ]
   Patient death at 1 year

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Texas

Houston Methodist Hospital

Houston, Texas, United States, 77030

Sponsors and Collaborators

The Methodist Hospital System

Investigators

• Study Chair: Samir J Patel, Pharm.D.; Clinical Pharmacist
• Principal Investigator: Ahmed O Gaber, MD; Director, Houston Methodist Transplant Center

  Study Documents (Full-Text)

Documents provided by Ahmed Osama Gaber, MD, The Methodist Hospital System:

Study Protocol and Statistical Analysis Plan  [PDF] March 30, 2017

More Information

Publications:

Brennan DC, Agha I, Bohl DL, Schnitzler MA, Hardinger KL, Lockwood M, Torrence S, Schuessler R, Roby T, Gaudreault-Keener M, Storch GA. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant. 2005 Mar;5(3):582-94. Erratum in: Am J Transplant. 2005 Apr;5(4 Pt 1):839.

Ali SH, Chandraker A, DeCaprio JA. Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones. Antivir Ther. 2007;12(1):1-6.

Leung AY, Chan MT, Yuen KY, Cheng VC, Chan KH, Wong CL, Liang R, Lie AK, Kwong YL. Ciprofloxacin decreased polyoma BK virus load in patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2005 Feb 15;40(4):528-37. Epub 2005 Jan 21.

Miller AN, Glode A, Hogan KR, Schaub C, Kramer C, Stuart RK, Costa LJ. Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant. 2011 Aug;17(8):1176-81. doi: 10.1016/j.bbmt.2010.12.700. Epub 2010 Dec 23.

Gabardi S, Waikar SS, Martin S, Roberts K, Chen J, Borgi L, Sheashaa H, Dyer C, Malek SK, Tullius SG, Vadivel N, Grafals M, Abdi R, Najafian N, Milford E, Chandraker A. Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation. Clin J Am Soc Nephrol. 2010 Jul;5(7):1298-304. doi: 10.2215/CJN.08261109. Epub 2010 May 27.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Patel SJ, Knight RJ, Kuten SA, Graviss EA, Nguyen DT, Moore LW, Musick WL, Gaber AO. Ciprofloxacin for BK viremia prophylaxis in kidney transplant recipients: Results of a prospective, double-blind, randomized, placebo-controlled trial. Am J Transplant. 2019 Jun;19(6):1831-1837. doi: 10.1111/ajt.15328. Epub 2019 Apr 4.

• Responsible Party: Ahmed Osama Gaber, MD, Director, Houston Methodist Transplant Center, The Methodist Hospital System
• ClinicalTrials.gov Identifier: NCT01789203
• Other Study ID Numbers: Pro00007510; IRB0612-0114 ( Other Identifier: HMRI IRB )
• First Posted: February 12, 2013
• Results First Posted: November 13, 2019
• Last Update Posted: November 13, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Ahmed Osama Gaber, MD, The Methodist Hospital System:

BK infection; BK viremia; BK nephropathy; polyomavirus; fluoroquinolone; ciprofloxacin

Additional relevant MeSH terms:

Infection; Communicable Diseases; Ciprofloxacin; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors