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Trial registered on ANZCTR


Registration number
ACTRN12618000913279
Ethics application status
Approved
Date submitted
22/05/2018
Date registered
30/05/2018
Date last updated
16/07/2021
Date data sharing statement initially provided
14/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cytomegalovirus-specific immune monitoring to guide pre-emptive therapy surveillance protocol for prevention of cytomegalovirus infection after renal transplantation.
Scientific title
Randomized study comparing QuantiFERON-CMV based versus standard cytomegalovirus (CMV) surveillance protocol in pre-emptive therapy for cytomegalovirus prevention after renal transplantation.
Secondary ID [1] 294958 0
None
Universal Trial Number (UTN)
U1111-1214-4324
Trial acronym
CMV-SIPHER (CMV-Specific Immune monitoring for Pre-emptive tHERapy)
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Cytomegalovirus infection after renal transplantation 307954 0
Condition category
Condition code
Infection 306987 306987 0 0
Studies of infection and infectious agents
Renal and Urogenital 306988 306988 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
QuantiFERON-CMV assay at 3 weeks after transplatation, based on the result:

1) QuantiFERON-CMV positive recipients: monitoring for cytomegalovirus (CMV) DNAemia detection using quantitative real-time PCR from whole blood once a week for 4 weeks and subsequently, at months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, and 24. For safety reasons and for equal probability to detect all episodes of CMV DNAemia, PCR CMV be evaluated at weekly intervals up to Month 4 post-transplantation similarly as in the control group. PCR CMV once a week will be likewise performed during pre-emptive valganciclovir therapy or treatment of CMV disease. In cases of antirejection therapy with methylprednisolone pulses or lymphocyte depleting antibodies (antithymocyte globuline or rituximab) and/or treatment of antibody-medaited rejection (plasmapheresis, immunoadsorption, IVIG, bortezomib) a new Quantiferon-CMV evaluation will be performed 1 week after antirejection therapy initiation. If Quantiferon-CMV positive result persists at least one single PCR CMV test will be performed 1 month after antirejection therapy initiation. In the case of negative or indeterminate QuantiFERON-CMV result weekly PCR CMV monitoring will be started and continued up to Months 4 post-transplantation or for 1 month in later post-transplantation period. Similarly, QuantiFERON-CMV will be reassessed at the end of pre-emptive valganciclovir therapy or therapy of CMV disease. In the case of negative or indeterminate QuantiFERON-CMV result a switch to weekly PCR CMV monitoring will be started and continued up to Month 4 after transplantation. In all QuantiFERON-CMV positive patients with CMV viral load of more than 1000 IU/mL detected at sheduled time points, pre-emtive therapy with valganciclovir (Valcyte; Hoffman-La Roche, Grenzach-Wyhlen, Germany) will be instituted at a dose of 900 mg twice daily with food within 7 days at the latest and continued until reaching clearance of CMV DNAmia in 2 consecutive measurements (<50 IU/mL, at least for 14 days).

2) QuantiFERON-CMV negative/inderminated recipients: same weekly PCR CMV monitoring as in the control group including the same schedule of QuantiFERON-CMV assessments. Weekly PCR CMV monitoring up to Month 4 will be maintained irrespective to the change of QuantiFERON-CMV result in later post-transplant period.. Pre-emptive oral valganciclovir (VALCYTE; Roche) therapy at a dose of 900 mg twice daily if CMV viral load exceeds 1000 IU/mL. Pre-emptive valganciclovir will be started within 7 days and continued until reaching clearance of CMV DNAmia in 2 consecutive measurements (<50 IU/mL, at least for 14 days).
Intervention code [1] 301277 0
Early detection / Screening
Intervention code [2] 301278 0
Prevention
Intervention code [3] 301279 0
Treatment: Drugs
Comparator / control treatment
Monitoring for cytomegalovirus (CMV) DNAemia detection using quantitative real-time PCR (RealStar® CMV PCR kit 1.0, Altona Diagnostics; Germany) from whole blood once a week for 16 weeks and, subsequently, at months 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, and 24. PCR will be likewise performed at least once a week in cases with a positive previous test and during pre-emptive valganciclovir therapy. In cases of antirejection therapy with lymphocyte depleting antibodies (antithymocyte globuline or rituximab) and/or treatment of antibody-medaited rejection (plasmapheresis, immunoadsorption, IVIG, bortezomib) a new weekly PCR monitoring will be started and continued for 1 month. Pre-emptive oral valganciclovir (VALCYTE; Roche) therapy at a dose of 900 mg twice daily will be given if CMV viral load exceeds 1000 IU/mL. Pre-emptive valganciclovir will be started within 7 days and continued until reaching clearance of CMV DNAmia in 2 consecutive measurements (<50 IU/mL, at least for 14 days).
Control group
Active

Outcomes
Primary outcome [1] 305971 0
Cumulative incidence of CMV infection (DNAemia) with viral load of 2000 (or more) IU/mL defined by positive PCR for CMV DNA in whole blood.
Timepoint [1] 305971 0
12 months post-transplant
Primary outcome [2] 305972 0
Moderate-to-severe interstitial fibrosis/tubular atrophy (IF/TA) and/or IF/TA associated with inflammation (including i 1 (or more) score, ti 2 (or more) score or i-IFTA 2 (or more) score) in protocol biopsy at 36 months (according to Banff2017 criteria), intrarenal expression of messenger ribonucleic acid (mRNA) cytokines evaluated in each biopsy for severity of IF/TA assessment
Timepoint [2] 305972 0
36 months post-transplant
Secondary outcome [1] 347135 0
Cumulative incidence of CMV disease (defined by clinical symptoms + presence of CMV DNAemia by quantitative PCR CMV DNA test).
All episodes of CMV disease will be analysed in a detail including the severity (syndrome/end-organ disease), diagnostic tests used, the course of therapy, duration of hospitalisation, viral load data, concomitant infections.
(Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017;64(1):87-91.).
Timepoint [1] 347135 0
12 months post-transplant
Secondary outcome [2] 347136 0
Cumulative incidence of CMV infection (DNAemia) defined by positive PCR for CMV DNA in whole blood.
Timepoint [2] 347136 0
12 months, and 24 months post-transplant
Secondary outcome [3] 347137 0
Cumulative incidence of CMV infection (DNAemia) with high viral load defined by positive PCR for CMV DNA in whole blood of 10,000 (or more) IU/mL.
Timepoint [3] 347137 0
12 months post-transplant
Secondary outcome [4] 347138 0
Incidence of CMV ganciclovir resistant infection based on UL97 or UL54 mutation. CMV resistant strains will be detected by genotypic analysis of the UL97 kinase and the UL54 DNA polymerase genes based on known mutations for current anti-CMV drugs.
Timepoint [4] 347138 0
12 months post-transplant
Secondary outcome [5] 347139 0
Acute rejection diagnosed by renal allograft biopsy (defined according to Banff criteria including both cellular and humoral (antibody-mediated) rejection).
All acute rejection episodes will be analysed in a detail including the severity and type (cellular/humoral, steroid-resistant rejection, subclinical rejection at 3 month protocol biopsy, Banff grades), antirejection therapy (high-dose methylprednisolon, antilymphocyte antibody, plasmapheresis, IVIG, bortezomib, rituximab, eculizumab, tocilizumab).
Timepoint [5] 347139 0
12 months post-transplant
Secondary outcome [6] 347140 0
Level of CMV-specific T cell immunity assessed by Elispot-Fluorospot
Timepoint [6] 347140 0
3 weeks, 4 months, and 36 months post-transplant
Secondary outcome [7] 347141 0
Level of CMV-specific T cell immunity assessed by QuantiFERON-CMV
Timepoint [7] 347141 0
3 weeks, 4 months, and 36 months post-transplant
Secondary outcome [8] 347142 0
Cumulative incidence of donor specific antibodies (DSA) assessed by single antigen beads (SAB) Luminex. Qualitative DSA evaluation will be performed with the use of commercially available kits (LIFECODES LSATM Class I; LIFECODES LSATM Class II; Gen-Probe Transplant Diagnostics, USA). The intensity of signals of each microparticle is analyzed by software and evaluated as positive or negative for antitibody binded. The results are expressed as a mean fluorescence intensity (MFI) for each HLA specificity. For the study pusposes, a fixed cutoff of 1000 normalized MFI will be applied.
Timepoint [8] 347142 0
12 months, and 36 months post-transplant
Secondary outcome [9] 347143 0
Incidence of other infections assessed by the results of regular study visits which comprise clinical examination, blood tests including routine laboratory evaluation, microbiological cultures, and imaging methods (ultrasound, CT, MRI, etc.) if required. All study patients will be followed within the study site (Charles University Teaching Hospital) thus all potential infectious complications will be diagnosed and treated within study site.
Timepoint [9] 347143 0
12 months, and 36 months post-transplant
Secondary outcome [10] 347144 0
Cumulative graft survival (defined as death or graft loss) assessed by regular study visits. In the case of sudden death at home (as the reason of graft loss) telephone follow-up with family members will used to achieve information.
Timepoint [10] 347144 0
12 months, 36 months, and 48 months post-transplant.
Secondary outcome [11] 347147 0
Adverse events and study drug discontinuation or dose reduction due to adverse event based on prospective observation (examples of side effects - haematological - leukopenia, trombocytopenia, anemia, psychiatric - hallucinations+confusion, liver enzyme abnormalities, de novo post transplant diabetes, de novo malignancy, cardiovascular events, etc.)
Timepoint [11] 347147 0
12 months, and 36 months post-transplant.
Secondary outcome [12] 347148 0
Renal function assessed by serum creatinine and estimated glomerular filtration rate calculated by MDRD7 formula
(Levey AS, Bosh JP, Breyer-Lewis J et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130: 877-884).
Timepoint [12] 347148 0
12 months, 36 months, and 48 months post-transplant.
Secondary outcome [13] 347149 0
Daily urine protein excretion.
Timepoint [13] 347149 0
12 months, and 36 months post-transplant.
Secondary outcome [14] 347150 0
Incidence of delayed graft function (defined as a need of dialysis within first week post transplant). Dialysis indication and performace will be assessed from medical records as a part of prospective clinical follow-up.
Timepoint [14] 347150 0
1 week post-transplant.
Secondary outcome [15] 347151 0
Late onset CMV disease (defined by clinical symptoms + presence of CMV DNAemia by quantitative PCR CMV DNA test) according to Ljungman et al. CMV disease will be assessed from medical and laboratory records as a part of prospective clinical follow-up.

Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017;64(1):87-91.
Timepoint [15] 347151 0
36 months post-transplant.
Secondary outcome [16] 347152 0
Pharmacoeconomic analysis assessed as actual expenses incurred directly in connection with CMV management. All study patients will be followed within transplant centre (=study site) thus complete resourse use information related to CMV management will be assessed prospectively during clinical follow up including the exact doses of antival drugs, Calculations include prices of drugs administered for pre-emptive therapy, PCR monitoring, QuantiFERON-CMV, diagnostic procedures in CMV activation (routine laboratory tests, CMV pp65 antigenemia, CMV blood culture, CMV serology), and CMV disease. The cost of hospitalization due to CMV disease will be calculated. The resources used (as mentioned above) with corresponding prices based on national health-insurance system will be collected prospectively during clinical follow-up. All costs will correspond to 2022 prices (=end of short-term study) while considering the effect of inflation. Sensitivity analyses will be calculated assuming low/high drug costs and low/high PCR costs. Patients with graft loss within 2 weeks in conjuction with immunosuppression and CMV preventive regimen withdrawal will be excluded from economic evaluation.
Timepoint [16] 347152 0
12 months post-transplant.
Secondary outcome [17] 347365 0
Cumulative patient survival assessed by regular study visits and medical records. In the case of sudden death at home telephone follow-up with family members will used to achieve information.
Timepoint [17] 347365 0
12 months, 36 months and 48 months post-transplant.
Secondary outcome [18] 347366 0
Urine protein/creatinine ratio.
Timepoint [18] 347366 0
12 months and 36 months post-transplant

Eligibility
Key inclusion criteria
Adult (>18 years with no upper age limit) renal transplant candidates, male or female.
Complement-dependent cytotoxicity (CDC) cross-match negative at the time of transplantation.
Deceased (non-heart-beating donors or dual kidney transplantation are allowed) or living (both related and unrelated, AB0/HLA compatible or incompatible) donors with known CMV serology before transplantation. Donor CMV serology will be performed in transplant center which procures the donor.
Donor/Recipient CMV serostatus of D+/R-, D+/R+, and D-/R+. Recipient CMV serology will be regularly (every 3 months) evaluated in all wait-listed patients at the Department of Virology, Universtity Hospital in Pilsen and finally confirmed at the time of transplantation.
Ability to sign informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unknown pretransplantation CMV serology of the donor or recipient.
D-/R- CMV serostatus.
Active systemic viral infection within 2 weeks before transplantation except for active hepatitis B or hepatitis C infection neccesitating antiviral therapy.
Therapy with systemic antiviral agents within 2 weeks before transplantation except for treatment of hepatitis B or C (lamivudine, adefovir, entecavir, DAAs).
White blood cell (WBC) count <3.0 x 109/L.
Platelet count <100 x 109/L.
Allergy to ganciclovir.
Inclusion to another clinical trial.
Inability to provide 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)
Before transplantation and after informed consent signature, eligible patients will be randomized to QuantiFERON-CMV guided or to standard protocol guided pre-emptive therapy. Randomization will be stratified according to donor/recipient (D/R) CMV serostatus before transplantation, i.e. high-risk patients (D+/R- subgroup) will be randomized separatelly. Transplant nephrologist will be responsible for randomization. Sequentially numbered sealed envelopes will be used for allocation concealment.
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
Physicians assessing the PCR CMV, QuantiFERON-CMV, CMV-specific cellular immune respose by ELISpot, donor-specific antibody by single antigen beads (Luminex), and renal graft histopathology which will be blinded to the study group of patients.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
For 12-month primary end point
The anticipated rate of CMV DNAemia 2000 (or more) IU/mL in the control group is 35% based on our previous study comparing valganciclovir pre-emptive therapy with valacyclovir prophylaxis. The study is designed as a noninferiority trial. QuantiFERON-CMV guided pre-emptive therapy will be considered noninferior if the incidence of CMV DNAemia 2000 (or more) IU/mL will be 55% or less (accepted range of noninferiory +20%-points absolute). A total of 142 (71 per group) patients will be required to detect statistically significant noninferiory (power = 0.80; alpha = 0.05). Given the anticipated number of patients to be lost to follow-up, a target of 150 patients will be enrolled.

For 36-month primary end point
Due to high donor age and frequent use of expanded criteria donors the anticipated incidence of moderate-to-severe (Banff grade II or III) IFTA and/or IFTA with inflammation is 30%. This number correlates with the findings obtained with pre-emptive therapy group in several CMV prophylaxis studies in our centre. QuantiFERON-CMV guided pre-emptive therapy will be considered noninferior if the incidence of moderate-to-severe IFTA and/or IFTA with inflammation will be 50% or less (accepted range of noninferiory +20%-points absolute). A total of 130 (65 per group) patients will be required to detect statistically significant noninferiory (power = 0.80; alpha = 0.05). To meet both short-term and long-term end points a total of 150 subjects should be enrolled given the anticipated number of patients to be lost to follow-up.

Predefined interim analysis
For safety reasons after enrollment of 92 participants and completed 12-month follow-up an interim analysis is planned to exclude superiority of control (standard monitoring) group over experimental (QuantiFERON-CMV guided) group. The analysis will compare the incidence of primary end point (CMV DNAemia 2000 or more IU/mL) and CMV disease or high-grade CMV DNAemia (10,000 or more IU/mL). In the case of proven statistically significant superiority of the control group in any of above mentioned outcomes, the study will be stopped.

Quantitative parametric data will be compared between the groups using Student’s t-test and the Mann-Whitney U-test in non-parametric distribution. Qualitative data will be analyzed using Fisher’s exact test or Chi-square test. Patient and graft survival, incidence of CMV disease and DNAmia, and incidence of acute rejection will be calculated using Kaplan-Meier curves, with the log-rank test used for comparison. Cox proportional univariate hazard model will be used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for CMV DNAemia in the QuantiFERON-CMV guided pre-emptive therapy group as compared with control group. Data will be analyzed according to the intention-to-treat principle. Values of p<0.05 are considered statistically significant.

Reischig T, Kacer M, Hruba P, et al. The impact of viral load and time to onset of cytomegalovirus replication on long-term graft survival after kidney transplantation. Antivir Ther. 2017;22(6):503-513.

Reischig T, Jindra P, Hes O, Svecova M, Klaboch J, Treska V. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant. 2008;8(1):69-77.

Reischig T, Hribova P, Jindra P, et al. Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. J Am Soc Nephrol. 2012;23(9):1588-1597.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2018
Actual
1/06/2018
Date of last participant enrolment
Anticipated
31/05/2023
Actual
Date of last data collection
Anticipated
31/05/2027
Actual
Sample size
Target
150
Accrual to date
87
Final
Recruitment outside Australia
Country [1] 10493 0
Czech Republic
State/province [1] 10493 0

Funding & Sponsors
Funding source category [1] 299543 0
Government body
Name [1] 299543 0
National Sustainability Program I [LO1503] awarded by Ministry of Education, Youth, and Physical Training of the Czech Republic
Country [1] 299543 0
Czech Republic
Funding source category [2] 299544 0
Government body
Name [2] 299544 0
Project No. CZ.02.1.01/0.0/0.0/16_019/0000787 „Fighting INfectious Diseases“ awarded by Ministry of Education, Youth, and Physical Training of the Czech Republic, financed from The European Regional Development Fund.
Country [2] 299544 0
Czech Republic
Funding source category [3] 299545 0
University
Name [3] 299545 0
Charles University Research Fund [Progres Q39]
Country [3] 299545 0
Czech Republic
Primary sponsor type
Individual
Name
associate Prof. Tomas Reischig, M.D., Ph.D.
Address
Head of Division of Nephrology, Department of Internal Medicine I Charles University Medical School and Teaching Hospital, alej Svobody 80, 30460 Pilsen Czech Republic
Country
Czech Republic
Secondary sponsor category [1] 298847 0
Individual
Name [1] 298847 0
Martin Kacer, M.D., Ph.D.
Address [1] 298847 0
Department of Internal Medicine I Charles University Medical School and Teaching Hospital, alej Svobody 80, 30460 Pilsen Czech Republic
Country [1] 298847 0
Czech Republic

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300443 0
Charles University Hospital Ethics committee
Ethics committee address [1] 300443 0
Ethics committee country [1] 300443 0
Czech Republic
Date submitted for ethics approval [1] 300443 0
25/04/2018
Approval date [1] 300443 0
03/05/2018
Ethics approval number [1] 300443 0
186/2018

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

Contacts
Principal investigator
Name 83682 0
A/Prof Tomas Reischig, M.D., Ph.D.
Address 83682 0
Head of Nephrology Division, Internal Medicine I (Division of Nephrology and Transplant Center), Charles University Medical School and Teaching Hospital, Alej Svobody 80, 30460 Pilsen, CZECH REP.
Country 83682 0
Czech Republic
Phone 83682 0
+420 377103650
Fax 83682 0
+420 377103506
Email 83682 0
[email protected]
Contact person for public queries
Name 83683 0
Tomas Reischig, M.D., Ph.D.
Address 83683 0
Head of Nephrology Division, Internal Medicine I (Division of Nephrology and Transplant Center), Charles University Medical School and Teaching Hospital, Alej Svobody 80, 30460 Pilsen, CZECH REP.
Country 83683 0
Czech Republic
Phone 83683 0
+420 377103650
Fax 83683 0
+420 377103506
Email 83683 0
[email protected]
Contact person for scientific queries
Name 83684 0
Tomas Reischig, M.D., Ph.D.
Address 83684 0
Head of Nephrology Division, Internal Medicine I (Division of Nephrology and Transplant Center), Charles University Medical School and Teaching Hospital, Alej Svobody 80, 30460 Pilsen, CZECH REP.
Country 83684 0
Czech Republic
Phone 83684 0
+420 377103650
Fax 83684 0
+420 377103506
Email 83684 0
[email protected]

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?
Any purpose.
How or where can data be obtained?
Approvals by Principal Investigator after request via email ([email protected])


What supporting documents are/will be available?




Results publications and other study-related documents

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