Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000554763
Ethics application status
Approved
Date submitted
9/05/2013
Date registered
16/05/2013
Date last updated
14/11/2022
Date data sharing statement initially provided
14/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
OVERT Study: Optimizing Valganciclovir Efficacy in Renal Transplantation
Scientific title
A randomised study comparing universal valganciclovir prophylaxis with quantitative polymerase chain reaction (PCR) based preemptive therapy for cytomegalovirus (CMV) disease in renal transplant recipients.
Secondary ID [1] 282485 0
Nil
Universal Trial Number (UTN)
U1111-1142-8990
Trial acronym
OVERT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cytomegalovirus infection after renal transplantation 289118 0
Condition category
Condition code
Infection 289454 289454 0 0
Studies of infection and infectious agents
Renal and Urogenital 289455 289455 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral valganciclovir (VALCYTE, Roche) 900mg/day for 3 months (cytomegalovirus serology combinations: donor+/recipient+ and donor-/recipient+) or 6 months (cytomegalovirus serology combination: donor+/recipient-) after transplantation started within 1 week post transplant.

To monitor adherence to drug intake patients will asked during each clinical visit to self report their adherence to valganciclovir use. However, no calculation of tablet return or ganciclovir plasma levels will be performed.
Intervention code [1] 287134 0
Treatment: Drugs
Intervention code [2] 287172 0
Prevention
Comparator / control treatment
Monitoring for cytomegalovirus (CMV) DNAemia detection using quantitative real-time PCR 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 with 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).
Control group
Active

Outcomes
Primary outcome [1] 289554 0
Acute rejection diagnosed by renal allograft biopsy (defined according to Banff criteria including both cellular and humoral rejection).
Timepoint [1] 289554 0
12 months
Primary outcome [2] 289555 0
Moderate-to-severe interstitial fibrosis/tubular atrophy (IF/TA) in protocol biopsy at 36 months (according to Banff criteria, moderate-to-severe IF/TA will be used for sample size calculation), intrarenal expression of messenger ribonucleic acid (mRNA) cytokines evaluated in each biopsy for severity of IF/TA assessment.
Timepoint [2] 289555 0
36 months
Secondary outcome [1] 302722 0
Cumulative incidence of cytomegalovirus (CMV) disease (defined by clinical symptoms + presence of CMV viremia by quantitative PCR CMV DNA test).
Timepoint [1] 302722 0
12 months
Secondary outcome [2] 302723 0
Cumulative incidence of cytomegalovirus (CMV) DNAemia defined by positive PCR for CMV DNA in whole blood.
Timepoint [2] 302723 0
12 and 24 months
Secondary outcome [3] 302724 0
Cytomegalovirus (CMV) ganciclovir resistant DNAemia based on UL97 or UL54 mutation.
Timepoint [3] 302724 0
12 months
Secondary outcome [4] 302725 0
Level of cytomegalovirus (CMV)-specific T cell immunity assessed by Elispot-Fluorospot assay.
Timepoint [4] 302725 0
12 and 36 months
Secondary outcome [5] 302726 0
Level of alloreactive T cell immunity assessed by Elispot-Flurospot assay
Timepoint [5] 302726 0
12 and 36 months
Secondary outcome [6] 302727 0
Cumulative incidence of donor specific antibodies assessed by solid antigen based (SAB) Luminex assay
Timepoint [6] 302727 0
12 and 36 months
Secondary outcome [7] 302728 0
Other infections assessed by clinical symptoms, microbiological cultures, blood tests
Timepoint [7] 302728 0
12 and 36 months
Secondary outcome [8] 302729 0
Cumulative patient and graft survival (defined as death or graft loss) based on prospective observation
Timepoint [8] 302729 0
12, 36, and 48 months
Secondary outcome [9] 302731 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 [9] 302731 0
12 and 36 months
Secondary outcome [10] 302732 0
Renal function assessed by serum creatinine and estimated glomerular filtration rate calculated by MDRD7 formula
Timepoint [10] 302732 0
12, 36, and 48 months
Secondary outcome [11] 302733 0
Daily urine protein excretion and urine protein/creatinine ratio
Timepoint [11] 302733 0
12 and 36 months
Secondary outcome [12] 302735 0
Delayed graft function (defined as a need of dialysis within first week post transplant)
Timepoint [12] 302735 0
1 week
Secondary outcome [13] 302736 0
Late onset cytomegalovirus (CMV) disease (defined by clinical symptoms + presence of CMV DNAemia by quantitative PCR CMV DNA test).
Timepoint [13] 302736 0
36 months

Eligibility
Key inclusion criteria
Adult renal transplant candidates, 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 compatible or incompatible) donors with known cytomegalovirus (CMV) serology before transplantation, CMV serology: donor(D)/recipient (R) serostatus of D+/R-, D+/R+, and D-/R+, 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, treatment of systemic viral infection within 2 weeks before transplantation except for active hepatitis B or hepatitis C infection, therapy with systemic antiviral agents within 2 weeks before transplantation except for treatment of hepatitis B (lamivudine, adefovir, entecavir), white blood cell (WBC) count <3.0 x 10exp9/L, platelet count <100 x 10exp9/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 (all renal transplant candidates) will be randomized to pre-emptive therapy with valganciclovir or to valganciclovir prophylaxis. 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.
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
Intention-to-treat analysis.

Sample size calculation:
For 12-month primary end point
The anticipated biopsy-proven acute rejection rate in the valganciclovir group is 10% based on our previous study (2VAL Study, manuscript in preparation) comparing valganciclovir and valacyclovir prophylaxis considering a complete replace of cyclosporine by tacrolimus in initial immunosuppression. Ninety patients are required to detect increase in the incidence of BPAR to 25% in pre-emptive therapy group (power = 0.80; alpha = 0.05).
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) IF/TA is 40%. This number correlates with the finding obtained with valacyclovir prophylaxis in our study (Reischig T, 2012). Based on the same study in which prophylaxis was associated with 2.5 fold increased risk of moderate-to-severe IF/TA compared to pre-emptive therapy we presume a 60% decreased relative risk of IF/TA in patients with pre-emptive therapy. In such a scenario a minimum of 62 patients with late protocol biopsy is required to ensure 80% power for detection of a treatment difference with type 1 error of 0.05.
To meet both short-term and long-term end points a total of 92 subjects should be enrolled given the anticipated number of patients to be lost to follow-up.

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: 1588-1597

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
27/05/2013
Actual
14/06/2013
Date of last participant enrolment
Anticipated
30/06/2016
Actual
2/05/2018
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
92
Accrual to date
Final
140
Recruitment outside Australia
Country [1] 5074 0
Czech Republic
State/province [1] 5074 0

Funding & Sponsors
Funding source category [1] 287261 0
Government body
Name [1] 287261 0
Project ED2.1.00/03.0076 from European Regional Development Fund.
Country [1] 287261 0
Czech Republic
Funding source category [2] 287262 0
University
Name [2] 287262 0
Charles University Research Fund (project number P36)
Country [2] 287262 0
Czech Republic
Funding source category [3] 298536 0
University
Name [3] 298536 0
Charles University Research Fund (Progres Q39)
Country [3] 298536 0
Czech Republic
Primary sponsor type
Individual
Name
ass. 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] 286017 0
None
Name [1] 286017 0
Address [1] 286017 0
Country [1] 286017 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294447 0
Charles University Hospital Ethics committee
Ethics committee address [1] 294447 0
Ethics committee country [1] 294447 0
Czech Republic
Date submitted for ethics approval [1] 294447 0
14/03/2013
Approval date [1] 294447 0
04/04/2013
Ethics approval number [1] 294447 0

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

Contacts
Principal investigator
Name 39954 0
A/Prof Tomas Reischig, M.D., Ph.D.
Address 39954 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 39954 0
Czech Republic
Phone 39954 0
+420 377103650
Fax 39954 0
Email 39954 0
[email protected]
Contact person for public queries
Name 39955 0
Tomas Reischig, M.D., Ph.D.
Address 39955 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 39955 0
Czech Republic
Phone 39955 0
+420 377103650
Fax 39955 0
Email 39955 0
[email protected]
Contact person for scientific queries
Name 39956 0
Tomas Reischig, M.D., Ph.D.
Address 39956 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 39956 0
Czech Republic
Phone 39956 0
+420 377103650
Fax 39956 0
Email 39956 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?
To researchers who provide a methodologically sound proposal, to clinicians on case-by-case basis.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Approvals by Principal Investigator after request using email ([email protected])


What supporting documents are/will be available?




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.