Conditions: BK Virus Infection
Keywords: BK infection BK viremia BK nephropathy polyomavirus fluoroquinolone ciprofloxacin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 200
Healthy volunteers: no

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.

Arms:
arm 1: Ciprofloxacin will be administered as two-250 mg capsules, administered once daily for 3 months post-transplant arm 2: Matching placebo will be administered as two-capsules given once daily for 3 months post-transplant

Interventions: intervention 1: Ciprofloxacin intervention 2: placebo
Intervention descriptions: intervention 1: Patients will be randomized 2:1 active comparator, Cipro, to placebo comparator. intervention 2: Patients will be randomized 2:1 placebo comparator to active comparator, Cipro.

Protocol document:
Prot_SAP_000.pdf: 
Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 1 
C L I N I C A L  P R O T O C O L  
TITLE: 
Ciprofloxacin for Prevention of BK Infection in 
Renal Transplant Recipients 
 
ORGINIAL PROTOCOL DATE: 
15 March 2012 
 
 
PRINCIPAL INVESTIGATOR: 
A. Osama Gaber, MD 
6550 Fannin Ste 1661A 
Houston, TX 77030 
Phone (desk):713-441-6170 
Fax: 713-790-6839 
Email: aogaber@houstonmethodist.org 
 
VERSION: 
Amendment 9 approved 3/14/2016 
 
 
INVESTIGATOR SIGNATURE: 
Amendment 10, 30 MAR 2017 
 
PI name 
Date 
 
PROTOCOL AUTHOR: 
 
 
Samir J. Patel  
Charles W. Sydnor  
 
 
This clinical research protocol will be conducted in accordance with Good Clinical Practice and 
the guidelines of The Methodist Hospital Research Institute Institutional Review Board. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 2 
L I S T  O F  I N V E S T I G A T O R S  
Principal Investigator: 
 
A Osama Gaber, MD 
 
Co-investigators: 
 
Samir J. Patel, PharmD 
Richard Knight, MD 
Hemangshu Podder, MD 
Samantha Kuten, PharmD 
Jill Krisl, PharmD 
 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 3 
L I S T  O F  A B B R E V I A T I O N S  
Term 
Definition 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus  
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria of Adverse Event 
CV% 
Coefficient of Variance 
DCD 
Donors after Cardiac Death 
ECD 
Expanded Criteria Donor  
eCRF 
Electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
GFR 
Glomerular Filtration Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat   
msec 
Millisecond 
mTOR 
Mammalian Target of Rapamycin 
NPO 
Nothing by Mouth (Nil Per Os)  
PCP 
Pneumocystis Carinii Pneumonia  
PCR 
Polymerase Chain Reaction 
POD 
Post Operative Day 
QTc 
QT interval 
R 
Research  
SAE 
Serious Adverse Event 
SCD 
Standard Criteria Donor  
SOC 
Standard of Care  
TMHRI 
The Methodist Hospital Research Institute 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 4 
S T U D Y  S Y N O P S I S  
 
 
SPONSOR / PRINCIPAL 
INVESTIGATOR 
The Methodist Hospital Research Institute / A. Osama Gaber, MD 
TITLE: 
Ciprofloxacin for Prevention of BK Infection in Renal Transplant Recipients 
OBJECTIVES: 
The primary objective of this study is 
• 
To evaluate the efficacy of routine ciprofloxacin administration post-
transplantation for the reduction of the incidence of BK infection in 
renal transplant recipients 
 
Secondary objectives include:  
• 
To evaluate the safety and tolerability of routine ciprofloxacin 
administration in kidney transplantation 
TRIAL DESIGN: 
The proposed study is a single-center, randomized, prospective, double-
blind, placebo-controlled study 
TYPE AND NUMBER OF 
SUBJECTS: 
The study will be comprised of 180 kidney transplant subjects 
RANDOMIZATION 
2:1 study regimen to comparator group 
STUDY REGIMEN 
Ciprofloxacin 500 mg (dispensed as two-250 mg capsules) once daily for 
up to 90 days post-transplant 
COMPARATOR 
REGIMEN 
Placebo, dispensed as two-matching capsules, once daily for up to 90 
days post-transplant 
Main Inclusion 
criteria 
1. Male or female subjects over the age of 18 years 
2. Recipients of a primary or repeat renal allograft either alone (from 
a deceased or living donor) or as a dual-kidney transplant 
3. Signed informed consent form prior to any research assessment 
Main Exclusion 
criteria 
1. Patients with known severe allergy to ciprofloxacin 
2. History of tendon rupture or tendinitis 
3. 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) 
4. Patients with history of previous non-renal transplantation 
5. 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 
6. Any condition present during the initial transplant hospitalization 
that in the investigator’s judgment would increase the risk 
associated with participation in the study 
7. QTc interval of greater than 500 msec on admission or post-
operative EKG 
8. BK nephropathy with previous transplant 
9. BK viremia on admission 
 
TRIAL AND 
TREATMENT 
DURATION: 
• 
24 month enrollment + 12 month follow-up 
• 
3 month treatment duration 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 5 
T A B L E  O F  C O N T E N T S  
1 
INTRODUCTION ...................................................................................................................................... 7 
1.1 
BACKGROUND ..................................................................................................................................................................7 
2 
PURPOSE AND OBJECTIVES ................................................................................................................. 7 
2.1 
PURPOSE ............................................................................................................................................................................7 
2.2 
OBJECTIVES ......................................................................................................................................................................7 
2.2.1 
Primary objective ................................................................................................................................................ 7 
2.2.2 
Secondary objective ......................................................................................................................................... 7 
3 
DESIGN RATIONALE ............................................................................................................................... 8 
4 
EXPERIMENTAL PLAN ........................................................................................................................... 8 
4.1 
STUDY DESIGN .................................................................................................................................................................8 
4.1.1 
Study endpoints .................................................................................................................................................. 8 
4.1.1.1 
Primary endpoint..................................................................................................................................................................... 8 
4.1.1.2 
Secondary endpoint .............................................................................................................................................................. 8 
4.1.1.3 
Additional evaluations to be tracked .............................................................................................................................. 8 
4.1.2 
Number of subjects ........................................................................................................................................... 9 
4.1.3 
Study duration ...................................................................................................................................................... 9 
4.1.4 
Study population ................................................................................................................................................. 9 
4.1.4.1 
Inclusion criteria ...................................................................................................................................................................... 9 
4.1.4.2 
Exclusion criteria..................................................................................................................................................................... 9 
5 
TREATMENT PROCEDURES ................................................................................................................. 9 
5.1 
CIPROFLOXACIN ..............................................................................................................................................................9 
5.1.1 
Test Article and Administration .................................................................................................................. 9 
5.1.2 
Dosage and Administration.......................................................................................................................... 9 
5.1.3 
Dose Adjustments .......................................................................................................................................... 10 
5.1.3.1 
Renal Dose Adjustments ................................................................................................................................................. 10 
5.1.4 
Dose Interruptions .......................................................................................................................................... 10 
5.1.4.1 
Dose Interruptions ............................................................................................................................................................... 10 
5.1.4.2 
Concomitant Antibiotics .................................................................................................................................................... 10 
5.1.4.3 
Development of BK Viremia ........................................................................................................................................... 10 
5.2 
CONCOMITANT IMMUNE SUPPRESSION ............................................................................................................ 10 
5.2.1 
Calcineurin Inhibitors .................................................................................................................................... 10 
5.2.1.1 
Tacrolimus (Prograf) .......................................................................................................................................................... 10 
5.2.1.2 
Cyclosporine .......................................................................................................................................................................... 10 
5.2.2 
mTOR Inhibitors............................................................................................................................................... 11 
5.2.2.1 
Sirolimus (Rapamune) ...................................................................................................................................................... 11 
5.2.3 
Antimetabolites ................................................................................................................................................. 11 
5.2.3.1 
Mycophenolate Mofetil (Cellcept) ................................................................................................................................. 11 
       5.2.4      Induction agents………………………………………………………………………....11 
5.2.4.1 
 Alemutuzumab (Campath) induction……………………………………………………………………..11 
 
5.3 
STUDY DRUG HANDLING ............................................................................................................................................... 11 
 
6 
STUDY PROCEDURES ........................................................................................................................... 12 
6.1 
CONSENT PROCESS ................................................................................................................................................... 12 
6.2 
ASSESSMENT OF ELIGIBILITY ................................................................................................................................. 12 
6.3 
ENROLLMENT ................................................................................................................................................................. 12 
6.4 
PROCEDURES ................................................................................................................................................................ 12 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 6 
6.4.1 
Pre-treatment Data Collection................................................................................................................. 12 
6.4.2 
Post-treatment Data Collection .............................................................................................................. 12 
6.5 
STANDARD LABORATORY TESTS .......................................................................................................................... 12 
6.5.1 
Sequence of events ....................................................................................................................................... 13 
6.5.2 
Screening and eligibility .............................................................................................................................. 13 
6.5.3 
Study completion............................................................................................................................................. 14 
7 
BLINDING ................................................................................................................................................ 14 
7.1 
BLINDING METHOD......................................................................................................................................................... 14 
7.2 
RETENTION OF THE ASSIGNMENT SCHEDULE AND PROCEDURE FOR TREATMENT CODE BREAKING ...... 14 
8 
STATISTICAL ANALYSIS PLAN........................................................................................................... 14 
8.1.1 
Data analysis ..................................................................................................................................................... 14 
9 
REMOVAL OF SUBJECT FROM STUDY .............................................................................................. 15 
9.1 
DISCONTINUATION OF STUDY ................................................................................................................................ 15 
9.2 
WITHDRAWAL FROM STUDY ................................................................................................................................... 15 
9.2.1 
Discontinuation of Study Drug ................................................................................................................ 15 
9.2.2 
Early Withdrawal/Study Termination ................................................................................................... 15 
10 
ADVERSE EVENT REPORTING ....................................................................................................... 15 
10.1 
DEFINITION AND GRADING INTENSITY OF ADVERSE EVENTS (AE) ..................................................... 15 
10.2 
CRITERIA FOR DETERMINING RELATIONSHIP TO DRUG ........................................................................... 15 
10.3 
SERIOUS ADVERSE EVENT ...................................................................................................................................... 16 
10.4 
POTENTIAL RISKS AND DISCOMFORTS............................................................................................................... 16 
10.4.1 
Risks ....................................................................................................................................................................... 16 
10.4.1.1 
Ciprofloxacin .......................................................................................................................................................................... 16 
10.4.1.2 
Risks associated with blood draws.............................................................................................................................. 17 
10.4.2 
Potential benefits............................................................................................................................................. 17 
11 
ETHICS ................................................................................................................................................. 17 
11.1 
RESPONSIBILITIES OF THE INVESTIGATOR ...................................................................................................... 17 
11.2 
INSTITUTIONAL REVIEW BOARD APPROVAL ..................................................................................................... 17 
12 
DATA HANDLING AND RECORDKEEPING .................................................................................. 18 
12.1 
CONFIDENTIALITY ........................................................................................................................................................ 18 
12.2 
FLOW OF INFORMATION AND RECORDS TO BE KEPT .................................................................................. 18 
13 
FINANCING ......................................................................................................................................... 18 
14 
PUBLICATION POLICY ..................................................................................................................... 18 
15 
REFERENCES ...................................................................................................................................... 18 
16 
APPENDICES ...................................................................................................................................... 18 
16.1 
APPENDIX 1: CIPROFLOXACIN PACKAGE INSERT ........................................................................................ 19 
16.2 
APPENDIX 2: EQUATIONS FOR ESTIMATING GLOMERULAR FILTRATION RATE ................................ 19 
 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 7 
1 
Introduction 
1.1 
Background  
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 ([1] Brennan et al. Am J Transpl 2005; 
5(3):583-94).  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 ([2] Ali et al. 
Antivir Ther 2007; 12:1-6).  Ciprofloxacin has been shown in previous studies to reduce urine 
BK viral load ([3] Leung et al. Clin Infect Dis 2005; 40:528), and BK-associated hemorrhagic 
cystitis ([4] Miller et al. Biol Blood Marrow Transplant 2011) 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 ([5] Gabardi et al. Clin J Am Soc Nephrol 
2010; 5: 1298).  Based on these reports, we hope to find a reduction BK viremia and BK 
nephropathy using a prospective, randomized study design. 
2 
Purpose and objectives 
2.1 
Purpose 
The purpose of this study is to evaluate the safety and efficacy of ciprofloxacin for the 
prevention of BK infection in renal transplant recipients. 
2.2 
Objectives 
2.2.1 Primary objective 
To determine whether routine ciprofloxacin administration post-transplantation can lower the 
incidence of BK infection in renal transplant recipients 
2.2.2 Secondary objective 
To evaluate the safety and tolerability of routine ciprofloxacin administration in kidney 
transplantation with respect to: 
• 
Incidence of adverse events 
• 
Incidence of urinary tract infections as defined by a midstream urine sample containing 
10^4 or more colony-forming units per mL 
• 
Incidence of quinolone-resistant urinary tract and bloodstream infections 
• 
Incidence of clostridium difficile infections 
• 
Incidence and severity of BK nephropathy 
• 
Time to onset of and quantitation of BK viremia 
• 
Graft outcomes 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 8 
3 
Design Rationale 
The proposed study is a randomized, prospective, double-blind, placebo-controlled study.  The 
rationale for a placebo-controlled arm is that there are no established preventative strategies for 
BK infection.  Currently, there are no prospective studies evaluating preventative or treatment 
agents for BK infection. 
4 
Experimental Plan 
4.1 
Study Design 
This is a single-center, randomized, prospective, double-blind, placebo-controlled study. Eligible 
subjects who enroll in this study will be randomized prior to discharge from the initial transplant 
hospitalization in a 1:2 ratio standard of care (placebo), or 90 days of once-daily ciprofloxacin. 
Patients will be stratified based on the use of alemtuzumab (Campath) induction. 
4.1.1 Study Endpoints 
4.1.1.1 Primary Endpoint 
The primary endpoint will be the proportion of patients 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.  All detectable PCRs must be confirmed by repeat PCR to be considered positive. 
4.1.1.2 Secondary Endpoint 
Secondary endpoints will include:  
• 
Incidence of urinary tract infections. Incidence of urinary tract infections as defined by a 
midstream urine sample containing 10^4 or more colony-forming units per mL at 6 
months 
• 
Incidence of bloodstream infections at 6 months. Bloodstream infection is defined by a 
single positive blood culture that was not thought to be contaminated. 
• 
Incidence of quinolone-resistant urinary tract and bloodstream infections at 6 months 
• 
Incidence of clostridium difficile infection at 6 months 
• 
Serious adverse events related to therapy 
• 
Severe adverse events (CTC grade 3 or higher) 
• 
Time to BK infection  
• 
Proportion of patients developing BK infection at 1 year 
• 
First and peak plasma viral loads  
• 
Incidence of acute rejection at 1 year  
• 
Incidence and severity of BK nephropathy, as defined by positive staining of 
histopathological specimen, at 1 year 
 
4.1.1.3 Additional Evaluations to be Tracked 
The following safety parameters will be assessed and measured during the study period: 
• 
Dose discontinuation due to adverse event related to therapy 
• 
Serum creatinine concentrations at 1, 3, 6, 9, and 12 months post-transplant 
• 
Graft loss at 1 year 
• 
Death at 1 year  


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 9 
4.1.2 Number of Subjects 
A total of 180 kidney transplant recipients will be enrolled. 
4.1.3 Study Duration 
The study will begin at the time of transplant and subjects will be enrolled for 12 months post-
transplant.  
4.1.4 Study Population 
Patients with end stage renal disease who are receiving a kidney transplant and who satisfy the 
following criteria will be considered for participation in this study. 
4.1.4.1 Inclusion Criteria 
1. Male or female subjects over the age of 18 years 
2. Recipients of a primary or repeat renal allograft either alone (from a deceased or living 
donor) or as a dual-kidney transplant 
3. Signed informed consent form prior to any research assessment 
4.1.4.2 Exclusion Criteria 
1. Patients with known severe allergy to ciprofloxacin 
2. History of tendon rupture or tendinitis 
3. 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) 
4. Patients with history of previous non-renal transplantation 
5. 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 
6. Any condition present during the initial transplant hospitalization that in the investigator’s 
judgment would increase the risk associated with participation in the study 
7. QTc interval of greater than 500 msec on admission or post-operative EKG 
8. BK nephropathy with previous transplant 
9. BK viremia on admission 
 
5 
Treatment Procedures 
5.1 
Ciprofloxacin 
5.1.1 Test Article and Administration 
The test article is defined as ciprofloxacin, and is supplied as 250 mg capsules by the 
sponsor.  Matching placebo capsules will also be supplied by the sponsor. 
In order to maintain blinding among subjects and investigators, study medication will be 
dispensed in pre-fill containers of 200 capsules each and labeled as “ciprofloxacin/placebo”.  
5.1.2 Dosage and Administration  
The dosages of ciprofloxacin/placebo will be 500 mg daily, i.e. two of the 250 mg capsules once 
daily.  This can be administered in the morning or in the evening.  All study medication should 
be administered at least 1 hour prior to or 2 hours after administration of any antacid, 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 10 
multivitamin, or other medications that contain divalent or trivalent cations (i.e. magnesium or 
calcium-containing supplements). 
 
5.1.3 Dose Adjustments  
5.1.3.1 Renal Dose Adjustments 
In patients with a estimated glomerular filtration rate of less than 30 ml/min/1.73m2, dosing of 
ciprofloxacin/placebo should be reduced to 1 capsule once daily. 
5.1.4 Dose Interruptions 
5.1.4.1 Dose Interruptions  
In situations where holding of the study drug is required (i.e. patient is NPO or patient requires 
treatment with fluoroquinolone antibiotic as described in section 5.1.4.2), study drug can be held 
for up to 14 days.  After 14 days of being off study drug, the investigator may consider 
withdrawing the subject from the study. 
5.1.4.2 Concomitant Antibiotics  
All infectious complications or conditions requiring antibiotic administration will be managed per 
routine standards.  In cases where ciprofloxacin or alternative quinolone can be administered as 
a treatment option, study drug should be held during administration for the appropriate 
duration.  Upon completion of treatment the study drug can be resumed for remainder of study 
duration. If the study drug is held longer than 14 days the investigator may consider withdrawing 
the subject from study. In cases where an alternate class of medication is deemed necessary, 
the study drug should be continued throughout the duration of concomitant antibiotic use. 
5.1.4.3 Development of BK Viremia 
Subjects who develop BK viremia or BK nephropathy will be managed according to the center’s 
routine protocol.  Except in the case of an SAE, study drug should continue for the remainder of 
its specified course.  
5.2 
Concomitant Immune Suppression  
All patients are required to remain on concomitant maintenance immune suppression therapies, 
including at least 2 of the following agents: calcineurin inhibitors, antimetabolites, or mTOR 
inhibitors. 
5.2.1 Calcineurin Inhibitors 
5.2.1.1 Tacrolimus (Prograf)  
Tacrolimus (Prograf) dosages are administered every 12 hours and adjusted to target 12-hour 
trough concentrations of 5 – 15 ng/mL. 
5.2.1.2 Cyclosporine 
Cyclosporine modified dosages are administered every 12 hours and are adjusted to target 12-
hour trough concentrations of 150 – 250 ng/mL. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 11 
5.2.2 mTOR Inhibitors 
5.2.2.1 Sirolimus (Rapamune)  
Sirolimus (Rapamune) dosages are administered once daily and adjusted to target 24-hour 
trough concentrations of 5 – 10 ng/mL. 
When combined with tacrolimus, sirolimus and tacrolimus concentrations will be adjusted to 
maintain a total combined level of 8-12 ng/mL. 
 
5.2.3 Antimetabolites 
5.2.3.1 Mycophenolate Mofetil (Cellcept) 
Mycophenolate mofetil (Cellcept) will be administered to target a cumulative dosage of 1000 to 
2000 mg per day. Dosages may be reduced for common adverse effects such as 
gastrointestinal intolerance or leukopenia.   
 
5.2.4 Induction agents 
 
Induction therapy will be determined by the prescriber based on the centers standard of care 
protocol. 
 
5.2.4.1 Patients will be stratified upon enrollment based on alemutuzumab induction. 
 
5.2.5 Corticosteroids 
 
All patients will receive intraoperative intravenous methylprednisolone, which will be tapered to 
an oral prednisone dosage at discharge.  Long-term maintenance steroid use will be determined 
by the prescriber based on the centers standard of care protocol..   
5.3 
Study Drug Handling 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist. Study drug accountability throughout the study must be documented. 
The following guidelines are therefore pertinent: 
• 
The investigator agrees not to supply study drugs to any persons except the subjects in 
this study. 
• 
The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs. 
• 
A study drug inventory will be maintained by the investigator/pharmacist. The inventory 
will include details of when they were dispensed and to which subject. 
• 
At the conclusion or termination of this study, the investigator/pharmacist agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record.  
• 
Used or unused study drug may be destroyed at the study center according to standard 
institutional procedures after drug accountability has been conducted. A copy of the 
standard institutional procedure for destroying investigational drugs will be provided to 
the Sponsor or designee upon request. Unused study drug not destroyed at the site 
must be returned to the Sponsor or designee at the end of the study or upon expiration.  


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 12 
6 
Study Procedures 
6.1 
Consent Process 
After approval by The Methodist Hospital Research Institute’s Institutional Review Board, the 
Principal Investigator, or a designated member of his study team, will approach potential 
subjects prior to transplantation regarding participation in the study. The study will be described 
by explaining the purpose of the study, the methods and objectives, and the potential risks 
associated with the study. An informed consent form (ICF) will be provided. Patients will be 
given time to read the ICF, and will be allowed to ask questions about the study. They will be 
informed that their participation is voluntary and that choosing not to be involved will not 
influence their care at The Methodist Hospital. They will be informed that they may choose to 
withdraw from the study at anytime for any reason. Subjects will be given an ICF to keep. The 
informed consent process will be documented in the patient’s chart.  
Any new information about the study medications that may be provided by the manufacturer or 
the Food and Drug Administration will be provided to the Institutional Review Board. Subjects 
will also be provided this information through a revised ICF and will be given the opportunity to 
decide whether or not to continue in the study. 
6.2 
Assessment of Eligibility 
At the time of transplant or, if possible, up to 14 days prior to transplant, the subject may be 
approached regarding potential interest in study involvement. Their medical history will be 
reviewed to assess for eligibility. Prior to performing any research-related procedures, informed 
consent will be obtained. Subjects must meet all inclusion criteria and none of the exclusion 
criteria or enrollment into the study will not be possible. 
6.3 
Enrollment 
Subjects who qualify for enrollment in this study after signing informed consent will be enrolled, 
and proceed into the study at the time of transplantation. 
6.4 
Procedures 
6.4.1 Pre-treatment Data Collection 
BK PCR from plasma will be collected during the initial hospital visit prior to study drug 
administration (per standard of care).  Study drug will be initiated upon discharge from initial 
hospitalization, and no later than day 7 post-transplant. 
6.4.2 Post-treatment Data Collection 
Patients will remain on study medication for 90 days post-transplant.  All routine standard of 
care procedures/visits will apply.  Patients are to have routine BK PCR drawn at 1, 2, 3, 6, 9, 
and 12 months post-transplant. Study visits will occur at baseline, 2 weeks, and 1, 2, 3, 6, 9, 
and 12 months post-transplant.  
6.5 
Standard Laboratory Tests 
At transplantation, prior to the transplant surgery, the following tests are routinely performed: 
Hematology and a Comprehensive metabolic panel (chemistry) (described below in Section 
6.5.1). Daily hematology and chemistry are performed during hospitalization and upon 
discharge. A schedule of follow-up visits include basic hematology and chemistry assessments 
that will be recorded in the clinical record and in the study record. See Section 6.5.1 Sequence 
of events below for detail. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 13 
6.5.1 Sequence of Events 
Time of Visit 
Screening/Baseline 
-14 to 7 days 
post transplant 
2 Weeks 
Post TXP 
1 Month 
Post TXP 
2 Months 
Post TXP 
3 Months 
Post TXP 
6 Months 
Post TXP 
9 Months 
Post TXP 
12 
Months 
Post TXP 
Visit Window 
N/A 
+7 Days 
+ 7 Days 
+ 7 Days 
+ 14 
Days 
+14 Days 
 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Inclusion/Exclusion criteria 
X (R) 
 
 
 
 
 
 
 
Informed consent 
X (R) 
 
 
 
 
 
 
 
Med History1 
X (R) 
 
 
 
 
 
 
 
Concomitant Medications 2 
X (R) 
X (R) 
X (R) 
X (R) 
X (R) 
X (R) 
X (R) 
X (R) 
Transplant Data Collection 3 
X (R) 
 
 
 
 
 
 
 
Randomization4 
X (R) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Medication Dispensation or 
Return 
X (R) 
X (R) 
X (R) 
 
X (R) 
 
 
 
Study medication record 
X (R) 
X (R) 
X (R) 
 
X (R) 
 
 
 
BK PCR (serum) 
X (SOC) 
 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
AE/SAE Assessment 
X (R) 
X (R) 
X (R) 
X (R) 
X (R) 
 
 
 
Serum Creatinine 
X (SOC) 
 
X (SOC) 
 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
Urine Analysis and culture (if 
applicable) and blood cultures 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
 
 
Tacrolimus/Sirolimus levels 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
Urine Protein to Creatinine Ratio 
 
 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
X (SOC) 
 
 
 
 
6.5.2 Screening and Eligibility 
Between day -14 and day 7 post-transplant after obtaining informed consent, subjects who fulfill 
all of the inclusion criteria and none of the exclusion criteria will be enrolled into the study. 
Documentation of the fulfillment of criteria will be included in the study files.  
                                               
1 Medical history includes history of age, diagnosis for renal failure, history of diabetes,  duration and type of dialysis, 
cytomegalovirus (CMV) serology, and HLA typing. 
2 Immunosuppressant medications, including medications used to treat rejection, and concomitant anti-microbial use 
will be captured. At months 6,9 and 12 only immunosuppressant dosages are required. 
3. Transplant information includes donor demographics (age, sex, race) and CMV serology, donor history (terminal 
serum creatinine, cause of death), type of transplant (ECD, DCD, or SCD), ischemia times, peak PRA and most 
recent PRA prior to transplant. 
4 Subject must meet all Inclusion and Exclusion Criteria prior to randomization. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 14 
6.5.3 Study Completion 
Subjects who attend the 12-month study visit and have completed all study-related evaluations 
described in Section 6.5.1 will be considered as having completed the study. 
Subjects who elect to discontinue pre-maturely or are withdrawn from the study by the 
investigator, will be converted to standard of care treatment, will return any unused study drug, 
and will be asked to attend a final end-of-study safety evaluation visit. If it is not possible to 
complete the end-of-study visit, every attempt will be made to determine safety endpoints 
(adverse events, rejection, graft loss or death information) occurring since the previous visit. A 
phone visit may be utilized for this information if the subject is unable or unwilling to attend the 
end-of-study visit. 
Subjects will be followed as standard of care after the study regimen has been completed or 
discontinued. Standard of care may include the continued monitoring of BK PCRs.  
7 
Blinding 
7.1 
Blinding Method 
This is a double-blind, randomized, prospective study. Subjects will be assigned to a double-
blind treatment arm in the order in which they meet the criteria for randomization. The 
pharmacist will be unblinded to treatment. All other study site staff and all members will remain 
blinded to treatment arm except as described below.  
7.2 
Retention of the Assignment Schedule and Procedure for Treatment Code Breaking 
The randomization schedule will be stored in the Site Pharmacy holding area. Study drug 
treatment may be revealed only for reasons relating to the subject’s safety and when critical 
therapeutic decisions are contingent on knowing the assigned study drug. Withdrawal of a 
subject from the study is not a sufficient reason to break the study blind. If the blind is broken for 
a subject, the reason is to be documented as a written entry in the source document.  
 
8 
Statistical Analysis Plan  
8.1.1 Data Analysis 
A full analysis will be conducted based on the intent-to-treat (ITT) population. The ITT 
population will be defined as all randomized subjects who take at least one dose of the assigned 
therapy after randomization. A per-protocol analysis will be performed on all randomized 
patients completing 90 days of study drug.  The primary endpoint of the difference in proportion 
of patients developing BK infection within 6 months will be determined using the chi-square test. 
All secondary and safety outcomes will be analyzed using chi-square or fisher exact testing for 
categorical variables, and analysis of variance or t-tests for continuous variables. Time to BK 
infection and graft survival will be estimated using Kaplan-Meier methodology. Univariate and 
multivariate proportional hazards Cox models will be developed to determine the risk factors of 
study outcomes. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 15 
9 
Removal of Subject from Study 
9.1 
Discontinuation of Study 
The Principal Investigator reserves the right to discontinue this study at any time. Should this 
occur, the appropriate authorities (eg, Institutional Review Board, FDA, and the funding agency) 
will be informed, and the reason for discontinuation will be indicated in the Case Report Form 
(CRF). A study termination CRF must be completed. 
9.2 
Withdrawal from Study 
9.2.1 Discontinuation of Study Drug 
The Principal Investigator will discontinue dosing a subject if he believes it is in the subject’s 
best interest. When a subject discontinues receiving study drug, the subject should be followed 
for 30 days from the last dose. The date that the subject discontinues receiving study drug will 
be recorded. Subjects experiencing adverse reactions that are believed to be related to the 
study drug should be followed until the reaction has resolved, stabilized, or are otherwise 
explained. 
9.2.2 Early Withdrawal/Study Termination 
Reasons why a subject may discontinue or be withdrawn from the study include, but are not 
limited to; intolerability to study drug, an adverse event, subject request, or investigator request. 
10 Adverse event reporting 
10.1 Definition and Grading Intensity of Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Study drug includes the investigational drug under evaluation and the comparator 
drug or placebo that is given during the study. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting study drug. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms, are considered clinically significant, or require therapy. 
 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits, through physical examination, laboratory tests, or other 
assessments. Adverse events will by collected for up to 4 weeks after completion of study drug 
administration.  All adverse events must be recorded on the Adverse Events eCRF with the 
following information: 
1. the severity grade (mild, moderate, severe) 
2. its relationship to the study drug(s)  
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
10.2 Criteria for Determining Relationship to Drug 
The clinical investigator will make a determination of the relationship of the AE to the study drug 
using a four category system (not related, possibly related, probably related, definitely related). 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 16 
Not related: Any untoward AE that either was clearly pre-existent, or occurred at the time of test 
drug administration but sufficient information exists to indicate the etiology is unrelated to the 
clinical trial medication.  
Possibly related: An AE that does not follow a reasonable temporal sequence from 
administration of the medication, does not follow a known or suspected response pattern, or 
could be explained by another etiology. 
Probably related: An AE that follows a reasonable temporal sequence from administration of the 
medication, follows a known or suspected pattern of response to the medication, and cannot be 
reasonably explained by the known characteristics of the patient's clinical state. 
Definitely related: An AE that follows a reasonable temporal sequence from administration of the 
drug and is characterized by either: 
• A positive result in drug sensitivity tests, or 
• A toxic level of the drug in the blood.  
10.3 Serious Adverse Event 
A Serious Adverse Event (SAE) is any adverse event occurring for up to 4 weeks after 
completion of study drug administration that results in any of the following outcomes: 
• 
Death 
• 
Graft loss 
• 
A life threatening event which may place the patient at an immediate risk of death 
• 
Persistent or significant disability 
• 
Hospitalization for administration of intravenous antibiotics due to presence of multidrug 
resistant infection 
• 
Cardiac arrhythmia 
• 
Tendon rupture 
SAEs considered “definitely” related to the study drug must be submitted to IRB. 
10.4 Potential Risks and Discomforts 
10.4.1 Risks 
10.4.1.1 Ciprofloxacin  
The most common adverse effects associated with ciprofloxacin in clinical trials were nausea 
(2.5%), diarrhea (1.6%), liver function test abnormalities (1.3%) vomiting (1%) and rash (1%). 
Fluoroquinolone antibiotics, including ciprofloxacin, have been associated with an increased risk 
of tendinitis and tendon rupture. The risk may be increased in patients over the age of 60, and in 
kidney, heart, and lung transplant recipients.  Patients should be advised to report signs of 
tendonitis or tendon pain, swelling, or inflammation immediately. Overall, musculoskeletal 
adverse effects occur in less than 1% of adults treated with ciprofloxacin.  
Fluoroquinolone antibiotics, including ciprofloxacin, have the potential to cause QT prolongation 
and should be used cautiously in patients with known QT prolongation, and in those taking 
concomitant medications that are known to prolong the QT interval.   
Fluoroquinolone antibiotics, including ciprofloxacin, should be used cautiously in patients with 
central nervous system disorders. Seizures have occurred in <1% although the risk can be 
increased in cases of overdosage. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 17 
All antibacterial agents alter the normal flora of the gastrointestinal tract and promote the growth 
of clostridia. 
Other potential risks associated with fluoroquinolone antibiotics include sensitivity to the sun, 
sunburn like reactions, nerve pain, including tingling, burning, numbness, or weakness, tremors, 
hallucinations, depression and convulsions. 
 
10.4.1.2 Risks associated with Blood Draws 
The risk associated with multiple blood draws for PK assessments will be the increased 
potential for hematoma at the blood draw site.  
10.4.2 Potential Benefits 
This study will improve the knowledge of a potential prophylaxis strategy against BK virus in 
transplant recipients.  Current data demonstrated increased graft loss among patients 
developing BK virus and BK nephropathy.  Knowledge about possible preventative strategies 
may lead to reductions in BK-related adverse outcomes. 
11 Ethics 
11.1 Responsibilities of the Investigator 
The Principal Investigator will maintain complete study files (electronic and/or paper) to enable 
full documentation of the study procedures and data for purpose of verification and study 
analysis.  
The Principal Investigator, or his designee, will explain the nature of the study to the subject, 
inform the subject that participation is voluntary, and that withdrawal at any time is allowed. The 
Principal Investigator will maintain documentation of written informed consent. 
This study will be conducted using Good Clinical Practice as identified by 
• International Conference on Harmonization (ICH) Tripartite Guidelines for Good Clinical 
Practice 
• US Code of Federal Regulation (CFR) dealing with clinical studies (21 CFR parts 50, 54, 
56 and 312) 
• The principles stated in the Declaration of Helsinki concerning medical research in 
humans 
11.2 Institutional Review Board Approval 
This study will be reviewed and approved by The Methodist Hospital Research Institute 
Institutional Review Board (TMHRI IRB) prior to commencement of any subject-specific 
activities. A current letter of IRB approval will be maintained with the study files.  No changes to 
the protocol or informed consent form will be made prior, to or without documented approval 
from TMHRI IRB.  
All subjects will provide consent (indicated by their signature or their legally authorized 
representative’s signature on the approved Informed Consent Form) prior to initiation of any 
study-related activities. Signed and dated ICFs will be maintained with the study archives. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 18 
12 Data Handling and Recordkeeping 
12.1 Confidentiality 
In order to maintain confidentiality, the subject will be identified only by his/her study screening 
number and/or randomization number. 
12.2 Flow of Information and Records to be Kept 
Throughout the conduct of this study, all required data will be recorded in electronic CRFs that 
have been specifically designed to record all observations and other data pertinent to this 
clinical investigation.  Data reported on eCRFs should be consistent with source documents 
when applicable, or the discrepancies should be explained. Any change or correction to a CRF 
will produce an audit trail within the eCRF system and will identify the user, date and time of the 
change.  
The eCRFs should be completed in a timely fashion. The complete eCRFs will be maintained by 
the study site, as is required by institutional, local and government regulations.  
The clinical investigator is responsible for maintaining adequate and accurate records as 
specified in Essential Documents for the Conduct of a Clinical Trail (section 8 of the ICH 
Guideline for Good Clinical Practice) to enable the conduct of the study to be fully documented, 
and the study data to be subsequently verified. The clinical investigator must notify the Sponsor 
prior to destroying any clinical study records.  
Upon study termination, original documents will be maintained at TMHRI.  
13 Financing 
Funding for this study will be provided by the Methodist Hospital Department of Surgery and the 
Methodist Hospital Department of Pharmacy. 
14 Publication Policy 
The Principal Investigator holds final approving authority over whether or not any proposed 
publication (eg, abstract, manuscript) based on the data generated from this study can or should 
be submitted for publication to journals, scientific meetings, or any other medium. 
15 References 
1. Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine 
and impact of preemptive immunosuppression reduction 
2. Ali SH, Chandraker A, DeCaprio JA, et al. Inhibition of Simian virus 40 large T antigen 
helicase activity by fluoroquinolones. Antivir Ther. 2007;12(1):1-6. 
3. Leung AY, Chan MT, Yuen KY, et al. Ciprofloxacin decreased polyoma BK virus load in 
patients who underwent allogeneic hematopoietic stem cell transplantation. Clin Infect 
Dis. 2005 15;40(4):528-37.  
4. Miller AN, Glode A, Hogan KR, et al. 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;17(8):1176-81. 
5. Gabardi S, Waikar SS, Martin S, et al. Evaluation of fluoroquinolones for the prevention 
of BK viremia after renal transplantation. Clin J Am Soc Nephrol. 2010;5(7):1298-304. 


Patel, SJ 
 
Ciprofloxacin for Prevention of BK Infection  
 
page 19 
 
 
 
16 Appendices 
16.1 Appendix 1: Ciprofloxacin Package Insert 
 
The package insert for ciprofloxacin can be found at the following URL:   
http://www.univgraph.com/bayer/inserts/ciprotab.pdf 
 
16.2 Appendix 2: Equation for Estimating Glomerular Filtration Rate 
 
IDMS-traceable MDRD equation for estimating Glomerular Filtration Rate (eGFR). 
 
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American) (conventional units)