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Trial registered on ANZCTR


Registration number
ACTRN12624001408572
Ethics application status
Approved
Date submitted
13/10/2024
Date registered
28/11/2024
Date last updated
28/11/2024
Date data sharing statement initially provided
28/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Reduction of Maintenance Immunosuppression in Kidney Transplant Recipients during Acute Complicated Urinary Tract Infection
Scientific title
Rates of Clinical Cure and Microbiological Eradication following Reduction of Maintenance Immunosuppression in Kidney Transplant Recipients during Acute Complicated Urinary Tract Infection
Secondary ID [1] 313175 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Kidney transplant recipients 335458 0
Complicated urinary tract infection 335459 0
Immunosuppressive therapy 335460 0
Condition category
Condition code
Renal and Urogenital 332018 332018 0 0
Kidney disease
Infection 332019 332019 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Reduction of maintenance immunosuppression

In eligible patients with cUTI requiring hospitalization, we completely withdraw the antimetabolite (mycophenolate mofetil or mycophenolate sodium) dose from maintenance immunosuppression. Antimetabolite will be discontinued within 24 hours (calculated to the first missed dose) after admission to the hospital. Treatment with full-dose antimetabolite will be reinitiated on the first day after clinical cure and microbiological eradication (overall treatment success). The vast majority of patients from our transplant center (Charles University Teaching Hospital in Pilsen) use a standard maintenance immunosuppressive protocol based on tacrolimus (rarely cyclosporine A) and mycophenolate mofetil (or mycophenolate sodium) with corticosteroid (prednisone). For clinical and study purpose, tacrolimus (or cyclosporine A) levels will be monitored at baseline and then at predefined checkpoints (days 3, 5, 7 and 14). In case of progression of the clinical condition to sepsis/septic shock after randomization requiring admission to the ICU, patients will be considered for modulation (complete discontinuation or lower target levels) of tacrolimus (or cyclosporine A) dose and steroid stress dose (e.g. hydrocortisone 50mg every 6 hours) in addition to antimetabolite withdrawal for safety reasons. Otherwise, if target levels are measured and the patient is stable, we will not adjust the dose of tacrolimus (or cyclosporine A) a priori. Calcineurin inhibitor dose adjustments will be made at the baseline and during the infection only if the level is measured outside the target range. Target trough levels of tacrolimus will be 5-12 ng/mL over the first 3 months after transplantation and subsequently 5-8 ng/mL. Similarly, we will not increase the maintenance dose of steroids (mostly prednisone 5 mg daily) in clinically stable patients. The transplant nephrologist, possibly in collaboration with the intensive care unit physician, will be responsible for any change in medication, including immunosuppressive and other therapy. In particular, an electronic database of medical and patient records will be used to monitor adherence to the intervention and related issues.
Intervention code [1] 329748 0
Prevention
Intervention code [2] 329749 0
Treatment: Drugs
Comparator / control treatment
Maintaining immunosuppression (control group)

Patients randomized to the group with no reduction of maintenance immunosuppression will continue to receive the antimetabolite at the full dose during infection corresponding to the mycophenolic acid (MPA) area under the curve (AUC) of 30-60 mg*h/L investigated in the past. The same rules will apply for steroid dosing, monitoring and potential tacrolimus (or cyclosporine A) dose adjustment as for the first group. Also, in case of progression of the clinical condition to sepsis/septic shock after randomization requiring ICU admission, antimetabolite dose will be completely discontinued, a stress dose of steroid (e.g. hydrocortisone 50 mg every 6 hours) and modulation of tacrolimus (or cyclosporine A) dose will be considered. The transplant nephrologist, possibly in collaboration with the intensive care unit physician, will be responsible for any change in medication, including immunosuppressive and other therapy. In particular, an electronic database of medical and patient records will be used to monitor adherence to the intervention and related issues.
Control group
Active

Outcomes
Primary outcome [1] 339621 0
Clinical cure and microbiological eradication (overall treatment success)
This will be assessed as a composite outcome of both clinical cure and microbiological eradication.
Timepoint [1] 339621 0
Day 7 after randomization
Secondary outcome [1] 440631 0
Clinical cure and microbiological eradication (overall treatment success)
This will be assessed as a composite outcome of both clinical cure and microbiological eradication.
Timepoint [1] 440631 0
Day 5 and 14 after randomization
Secondary outcome [2] 440632 0
Decrease in procalcitonin (PCT) < 0.25 µg/l or 80% or greater reduction in peak value and normalization of pyuria (< 10 white blood cells per cubic millimeter) or 90% or greater reduction in peak value
This will be assessed as a composite outcome of reduction in both procalcitonin and pyuria.
Timepoint [2] 440632 0
Day 3 and 5 after randomization
Secondary outcome [3] 440633 0
Comparison of procalcitonin absolute values during the first five days
Timepoint [3] 440633 0
Day 1, 3 and 5 after randomization
Secondary outcome [4] 440634 0
Progression to sepsis/septic shock requiring ICU admission after more than 48 hours of randomization (sepsis or septic shock must be related to cUTI)
Timepoint [4] 440634 0
From 48 hours after randomization continuously until clinical cure and microbiological eradication is achieved
Secondary outcome [5] 440635 0
Duration of intravenous antibiotic therapy
Timepoint [5] 440635 0
Day 14 after randomization
Secondary outcome [6] 440636 0
Microbiological eradication
Timepoint [6] 440636 0
Day 21 after randomization
Secondary outcome [7] 440637 0
Incidence of repeated (recurrent) urinary tract infections
Timepoint [7] 440637 0
6 months after randomization
Secondary outcome [8] 440638 0
Incidence of clostridial enterocolitis
Timepoint [8] 440638 0
6 months after randomization
Secondary outcome [9] 440639 0
Cumulative incidence of CMV infection (DNAemia) defined by positive PCR for CMV DNA in whole blood
Timepoint [9] 440639 0
6 months after randomization
Secondary outcome [10] 440640 0
Incidence of other infections (particular interest will be given to CMV disease, polyomavirus viremia/nephropathy, respiratory infections, soft tissue infections and fungal infection)
Timepoint [10] 440640 0
6 months after randomization
Secondary outcome [11] 440641 0
Tacrolimus (or cyclosporine A) levels
Timepoint [11] 440641 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [12] 440642 0
Incidence of de novo anti-HLA and DSA
Timepoint [12] 440642 0
6 months after randomization
Secondary outcome [13] 440643 0
Incidence of acute and active rejection diagnosed by renal allograft biopsy (defined according to Banff criteria including both cellular and antibody-mediated rejection)
Timepoint [13] 440643 0
6 months after randomization
Secondary outcome [14] 440644 0
Renal function assessed by serum creatinine, estimated glomerular filtration rate (eGFR) using CKD-EPI formula and urine albumin-to-creatinine ratio (ACR)
The parameters required to evaluate renal function will be evaluated as a composite outcome.
Timepoint [14] 440644 0
Day 7, 14 and 1, 3 and 6 months after randomization
Secondary outcome [15] 440647 0
Incidence of new-onset acute kidney injury between randomization and day 14 (new-onset AKI will be assessed compared to baseline or lowest prior serum creatinine level since enrollment according to definition of AKI)
Timepoint [15] 440647 0
Day 14 after randomization
Secondary outcome [16] 440648 0
Incidence of new (or worsening) graft dysfunction (defined as double or higher serum creatinine compared to pre-admission level or new need for renal replacement therapy)
Timepoint [16] 440648 0
Months 1, 3 and 6 after randomization
Secondary outcome [17] 440651 0
Comparison of white blood cell absolute values
Timepoint [17] 440651 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [18] 441382 0
Comparison of procalcitonin kinetics during the first five days.
Timepoint [18] 441382 0
Day 1, 3 and 5 after randomization
Secondary outcome [19] 441384 0
Severity of new-onset acute kidney injury between randomization and day 14 (new-onset AKI will be assessed compared to baseline or lowest prior serum creatinine level since enrollment according to definition of AKI)
Timepoint [19] 441384 0
Day 14 after randomization
Secondary outcome [20] 441385 0
Comparison of white blood cell kinetics
Timepoint [20] 441385 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [21] 441386 0
Comparison of hemoglobin concentration
Timepoint [21] 441386 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [22] 441387 0
Comparison of platelet counts
Timepoint [22] 441387 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [23] 441388 0
Comparison of aspartate aminotransferase (AST) activity
Timepoint [23] 441388 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [24] 441389 0
Comparison of alanine aminotransferase (ALT) activity
Timepoint [24] 441389 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [25] 441390 0
Comparison of bilirubin level
Timepoint [25] 441390 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [26] 441391 0
Comparison of C-reactive protein (CRP) absolute values
Timepoint [26] 441391 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [27] 441392 0
Comparison of C-reactive protein (CRP) kinetics
Timepoint [27] 441392 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [28] 441393 0
Comparison of serum creatinine level
Timepoint [28] 441393 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [29] 441394 0
Comparison of albuminuria
Timepoint [29] 441394 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [30] 441395 0
Comparison of sodium level
Timepoint [30] 441395 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [31] 441396 0
Comparison of potassium level
Timepoint [31] 441396 0
Day 3, 5, 7 and 14 after randomization
Secondary outcome [32] 441397 0
Comparison of chloride levels
Timepoint [32] 441397 0
Day 3, 5, 7 and 14 after randomization

Eligibility
Key inclusion criteria
1. Adult (18 years and over with no upper age limit) renal transplant patients, male or female.
2. Acute complicated urinary tract infection requiring hospitalization.
3. Ability to signed informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients presenting with clinical signs of sepsis or septic shock at baseline who require an intensive care unit (ICU).
Note: The timing of enrollment and randomization (the time period between hospital admission and randomization) will be decided by an experienced investigator based on the evolution of the patient’s clinical condition.
2. Patients who do not meet the signs or symptoms of complicated urinary tract infection.
3. Suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis or chronic bacterial prostatitis.
4. Suspected or confirmed cyst infection in polycystic kidney disease, renal corticomedullary or perinephric abscess.
5. Presence or treatment of any infection within the past 14 days and at the time of enrollment (will include patients requiring preemptive treatment with valganciclovir for significant CMV DNAemia or modulation of immunosuppression for significant BK polyomavirus viremia).
6. Treatment of biopsy-proven acute/active graft rejection 1 month or less before inclusion.
7. Patients not treated with antimetabolite at baseline.
8. Severe leukopenia or thrombocytopenia or gastrointestinal symptoms at baseline requiring antimetabolite withdrawal.
9. Inability to sign informed consent.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random-number table, at a 1:1 ratio with the use of random block sizes of 4
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The study will be designed as a superiority trial. The collected data from the randomized patients in the study will be primarily analyzed using microbiological intention-to-treat analysis (micro-ITT population). The microbiological ITT population will include all randomized patients with confirmed gram-negative or gram-positive bacteria of 10^5 CFU/ml or more in baseline urine culture (up to two isolated pathogens) or the same bacterial pathogen present in concurrent blood and urine culture. Figures from randomized trials in renal transplant patients with cUTI indicating the rate of clinical cure and microbiological eradication (overall success) are not available. The overall success rate of ATB therapy for cUTI in the general population ranges from 92 to 94% around day 8 of treatment. Therefore, based on these data and our clinical experience, we expect an 85 % clinical cure and microbiological eradication rate assessed on day 7 after randomization in renal transplant patients who will be completely withdrawn from antimetabolite therapy at the start of cUTI. In patients with cUTI and maintained immunosuppression, the overall treatment success rate on day 7 is anticipated to be 60 %. A total of 98 (49 per group) patients will be required to achieve an 85 % clinical cure and microbiological eradication rate (power = 0.80; alpha = 0.05). Given the anticipated number of patients with no baseline pathogens (<10^5 CFU/ml gram-negative or gram-positive bacteria in urine culture or absence of the same bacterial pathogen in concurrent blood and urine culture) and dropouts, a minimum target number of 112 patients will be enrolled.
Qualitative data will be analyzed using the Chi-square test or Fisher’s exact test. Quantitative data will be compared using Student’s t-test in parametric distribution and Mann-Whitney U-test or Wilcoxon signed-rank test in non-parametric distribution. Participants related covariates including comorbid conditions, posttransplant time, observed laboratory parameters involving renal allograft function, tacrolimus (or cyclosporine A) levels, CRP and PCT levels, the number of white blood cells per cubic millimeter in urine sample, and urinary pathogen characteristics will be assessed as potential risk factors to clinical and microbiological failure. Logistic regression analysis will be performed first. Covariates with a P value less than or equal to 0.2 will be included in multivariate stepwise logistic regression. Results will be expressed as odds ratio (OR) and 95% confidence interval (CI). Statistical calculations will be made using Statistica 8 software (StatSoft, Germany). Values of P <0.05 were considered statistically significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/01/2025
Actual
Date of last participant enrolment
Anticipated
15/01/2029
Actual
Date of last data collection
Anticipated
17/07/2029
Actual
Sample size
Target
112
Accrual to date
Final
Recruitment outside Australia
Country [1] 26632 0
Czech Republic
State/province [1] 26632 0
Pilsen

Funding & Sponsors
Funding source category [1] 317618 0
University
Name [1] 317618 0
Cooperatio Program, Charles University in Prague; research areas "Immunity and Infections" and "Internal Disciplines"
Country [1] 317618 0
Czech Republic
Primary sponsor type
Individual
Name
prof. Tomas Reischig, MD, PhD - Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital
Address
Country
Czech Republic
Secondary sponsor category [1] 319936 0
Individual
Name [1] 319936 0
Petr Drenko, MD, PhD - Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital
Address [1] 319936 0
Country [1] 319936 0
Czech Republic

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316323 0
Ethics Committee of The University Hospital and the Faculty of Medicine, Charles University in Pilsen
Ethics committee address [1] 316323 0
Ethics committee country [1] 316323 0
Czech Republic
Date submitted for ethics approval [1] 316323 0
08/07/2024
Approval date [1] 316323 0
01/08/2024
Ethics approval number [1] 316323 0
229/24

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 137522 0
Dr Petr Drenko
Address 137522 0
Department of Internal Medicine I, Biomedical Centre Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Alej Svobody 80 304 60 Pilsen, Czech Republic
Country 137522 0
Czech Republic
Phone 137522 0
+420 377103573
Fax 137522 0
Email 137522 0
drenkop@fnplzen.cz
Contact person for public queries
Name 137523 0
Petr Drenko
Address 137523 0
Department of Internal Medicine I, Biomedical Centre Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Alej Svobody 80 304 60 Pilsen, Czech Republic
Country 137523 0
Czech Republic
Phone 137523 0
+420 377103573
Fax 137523 0
Email 137523 0
drenkop@fnplzen.cz
Contact person for scientific queries
Name 137524 0
Petr Drenko
Address 137524 0
Department of Internal Medicine I, Biomedical Centre Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Alej Svobody 80 304 60 Pilsen, Czech Republic
Country 137524 0
Czech Republic
Phone 137524 0
+420 377103573
Fax 137524 0
Email 137524 0
drenkop@fnplzen.cz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial without identification of participants names.
When will data be available (start and end dates)?
Immediately following publication, no end date.
Available to whom?
Researchers who provide a methodologically sound proposal, clinicians case-by-case basis at the discretion of Primary Sponsor.
Available for what types of analyses?
For any purpose.
How or where can data be obtained?
Approval by Principal Investigator upon request by email (drenkop@fnplzen.cz).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
24266Study protocol  drenkop@fnplzen.cz 388616-(Uploaded-13-10-2024-04-21-16)-Protocol of the study.docx
24267Ethical approval  drenkop@fnplzen.cz 388616-(Uploaded-13-10-2024-04-24-09)-Ethical approval 1.pdf
24268Ethical approval  drenkop@fnplzen.cz 388616-(Uploaded-13-10-2024-04-24-38)-Ethical approval 2.pdf
24269Statistical analysis plan  drenkop@fnplzen.cz Statistical plan is included within the Study prot... [More Details] 388616-(Uploaded-13-10-2024-05-58-46)-Protocol of the study.docx
24270Informed consent form  drenkop@fnplzen.cz 388616-(Uploaded-13-10-2024-06-00-04)-Informed consent.docx


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.