Disease Due to BK Polyomavirus, Kidney Transplant Infection
Conditions
Keywords
Kidney Transplant, BK Polyomavirus Infection
Brief summary
Primary Research Questions: Efficacy, safety and feasibility of a 3-month course of levofloxacin in a pilot study will be assessed. 1. Under efficacy, this pilot will determine whether levofloxacin can decrease the incidence of BK viruria and peak urine BK viral load. 2. Under safety, this pilot will determine the incidence of adverse events with levofloxacin. 3. Under feasibility, this pilot will determine the number of kidney transplant patients randomized over an eight month enrolment period, adherence to the levofloxacin and frequency of patient drop-out and loss to follow-up
Detailed description
BK virus infection has emerged as a major complication in renal transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. The investigators hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. A non-randomized study in kidney transplant recipients found that patients given levofloxacin or ciprofloxacin had a significantly lower incidence of BK viremia compared to those not receiving a quinolone (4% versus 24.5%, P=0.02). Objective: The primary objective of the full trial will be to determine if the quinolone levofloxacin decreases the occurrence of doubling creatinine, transplant failure or death in kidney transplant recipients. The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. Results from this pilot study will provide vital information to design and conduct a large, multi-centre trial to determine if quinolone therapy decreases meaningful clinical outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation it will provide important justification of biologic effect to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in renal transplantation will be strongly endorsed given the lack of proven therapies for this condition.
Interventions
DRUGLevofloxacin
500mg, PO, once daily for 3 months
Sponsors
Canadian Institutes of Health Research (CIHR)
St. Paul's Hospital, Canada
Vancouver General Hospital
University of Alberta
University of Manitoba
University Health Network, Toronto
Unity Health Toronto
St. Joseph's Healthcare Hamilton
London Health Sciences Centre
McGill University Health Centre/Research Institute of the McGill University Health Centre
Dalhousie University
Ottawa Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* a primary or repeat kidney transplant recipient (deceased or living donor) * age greater or equal to 18 years
Exclusion criteria
* Unable to provide informed consent * Greater than 5 days post-transplantation * BK virus nephropathy with a previous transplant * History of allergic reaction to any quinolone antibiotic * History of quinolone associated tendonitis or tendon rupture * Corrected QT interval prolongation on EKG as defined by Al-Khatib * Concomitant use of medication 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), azole antifungals (e.g. fluconazole) or macrolide antibiotics (e.g. erythromycin) * Pregnant or breastfeeding as safety of levofloxacin not established * Requires quinolone antibiotic for more than 14 days (e.g. for UTI prophylaxis) * Recipient of a multi-organ transplant (e.g. kidney-pancreas) * Currently enrolled in another interventional trial * Previously enrolled in this study * History of rhabdomyolysis * Significant allergic reaction to ≥ 3 classes of antibiotics as these patients may have no other option other than quinolones for routine infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of BK Viruria | 12 months post-transplantation | BK viruria was defined as 500 copies/mL or more of BK virus DNA in the urine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Rejection | 12 months | Incidence of Acute rejection |
| Clostridium Difficile Associated Diarrhea | 12 months | Incidence of microbiologically confirmed clostridium difficile associated diarrhea |
| Infections | 12 months | Incidence of other infections (viral, bacterial and fungal) based on established guidelines |
| Quinolone Resistance | 12 months | Incidence of quinolone resistance where a quinolone would have been a therapeutic option |
| Allograft Loss | 12 months | Absence of kidney function in allograft |
| Adverse Events | 12 months | Incidence and type of all adverse events |
| Adherence | 12 months | Proportion of randomized participants who are adherent to the protocol. |
| Use of Quinolones | 12 months | Use of quinolones outside of the protocol |
| Proportion of Patient Drop-out and Loss to Follow-up | 12 months | — |
| Quantitative BK Urine Viral Load | 12 months | — |
| BK Viremia | 12 months | BK viremia defined as ≥250 copies/mL of BK virus DNA in the plasma |
| Mortality | 12 months | — |
Countries
Canada
Participant flow
Recruitment details
The first patient was randomized on December 1, 2011, and recruitment continued until June 25, 2013. The last patient follow-up visit was February 25, 2014.
Pre-assignment details
Eligible patients with written informed consent were randomly assigned to receive either levofloxacin or placebo in a 1:1 fashion. Allocation was achieved through web-based central randomization in variable blocks stratified by center. An independent statistician prepared the randomization schemes. Physicians, nurses, investigators, and research staff were blinded to the randomization scheme, and active study medication and matching placebo were identical in appearance
Participants by arm
| Arm | Count |
|---|---|
| Levofloxacin Levofloxacin: 500mg, PO, once daily for 3 months | 76 |
| Sugar Pill Levofloxacin: 500mg, PO, once daily for 3 months | 78 |
| Total | 154 |
Baseline characteristics
| Characteristic | Levofloxacin | Sugar Pill | Total |
|---|---|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 14.2 | 48.2 years STANDARD_DEVIATION 12.7 | 48 years STANDARD_DEVIATION 13.5 |
| Race/Ethnicity, Customized Aboriginal | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 7 Participants | 10 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 7 Participants | 10 Participants |
| Race/Ethnicity, Customized Other | 14 Participants | 11 Participants | 25 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 49 Participants | 50 Participants | 99 Participants |
| Region of Enrollment Canada | 76 participants | 78 participants | 154 participants |
| Sex: Female, Male Female | 27 Participants | 16 Participants | 43 Participants |
| Sex: Female, Male Male | 49 Participants | 62 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 78 |
| other Total, other adverse events | 76 / 76 | 78 / 78 |
| serious Total, serious adverse events | 6 / 76 | 1 / 78 |
Outcome results
Primary
Occurrence of BK Viruria
BK viruria was defined as 500 copies/mL or more of BK virus DNA in the urine.
Time frame: 12 months post-transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Occurrence of BK Viruria | 22 Participants |
| Sugar Pill | Occurrence of BK Viruria | 26 Participants |
Secondary
Acute Rejection
Incidence of Acute rejection
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Acute Rejection | 6 Participants |
| Sugar Pill | Acute Rejection | 5 Participants |
Secondary
Adherence
Proportion of randomized participants who are adherent to the protocol.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levofloxacin | Adherence | 68.5 Percentage of participants |
| Sugar Pill | Adherence | 70.4 Percentage of participants |
Secondary
Adverse Events
Incidence and type of all adverse events
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Adverse Events | 27 Participants |
| Sugar Pill | Adverse Events | 29 Participants |
Secondary
Allograft Loss
Absence of kidney function in allograft
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Allograft Loss | 0 Participants |
| Sugar Pill | Allograft Loss | 1 Participants |
Secondary
BK Viremia
BK viremia defined as ≥250 copies/mL of BK virus DNA in the plasma
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | BK Viremia | 6 Participants |
| Sugar Pill | BK Viremia | 9 Participants |
Secondary
Clostridium Difficile Associated Diarrhea
Incidence of microbiologically confirmed clostridium difficile associated diarrhea
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Clostridium Difficile Associated Diarrhea | 36 Participants |
| Sugar Pill | Clostridium Difficile Associated Diarrhea | 30 Participants |
Secondary
Infections
Incidence of other infections (viral, bacterial and fungal) based on established guidelines
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levofloxacin | Infections | 1.4 Number of infections per patient | Standard Deviation 1.6 |
| Sugar Pill | Infections | 1.3 Number of infections per patient | Standard Deviation 2.2 |
Secondary
Mortality
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Mortality | 0 Participants |
| Sugar Pill | Mortality | 0 Participants |
Secondary
Proportion of Patient Drop-out and Loss to Follow-up
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Proportion of Patient Drop-out and Loss to Follow-up | 0 Participants |
| Sugar Pill | Proportion of Patient Drop-out and Loss to Follow-up | 0 Participants |
Secondary
Quantitative BK Urine Viral Load
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levofloxacin | Quantitative BK Urine Viral Load | 7550 copies/mL | Standard Deviation 16542 |
| Sugar Pill | Quantitative BK Urine Viral Load | 4503 copies/mL | Standard Deviation 5419 |
Secondary
Quinolone Resistance
Incidence of quinolone resistance where a quinolone would have been a therapeutic option
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Quinolone Resistance | 14 Participants |
| Sugar Pill | Quinolone Resistance | 15 Participants |
Secondary
Use of Quinolones
Use of quinolones outside of the protocol
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Levofloxacin | Use of Quinolones | 19 Participants |
| Sugar Pill | Use of Quinolones | 14 Participants |