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Trial registered on ANZCTR


Registration number
ACTRN12610000787088
Ethics application status
Approved
Date submitted
3/09/2010
Date registered
22/09/2010
Date last updated
15/02/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
Prevention of Cytomegalovirus (CMV) disease in liver transplant patients: studies of antiviral prophylaxis and pre-emptive therapy.
Scientific title
Prevention of Cytomegalovirus (CMV) disease in liver transplant patients: studies of antiviral prophylaxis and pre-emptive therapy.
Secondary ID [1] 252625 0
nil
Universal Trial Number (UTN)
Trial acronym
CMV
Linked study record

Health condition
Health condition(s) or problem(s) studied:
CMV and liver transplantation 258123 0
Condition category
Condition code
Infection 258297 258297 0 0
Other infectious diseases
Oral and Gastrointestinal 258334 258334 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
High risk group and prophylaxis group are assigned to receive 900mg (two 450mg tablets) of valganciclovir (Valcyte) once daily for 3 months commenced within 72 hrs after liver transplantation and monitored regularly for CMV infection/disease. Dose will be changed based on creatinine clearance.

Pre- Emptive group Monitored regularly for CMV infection only. If this occurs patients will be given 5 mg/kg intravenously over one hour, of ganciclovir (GCV) twice daily for 2 weeks CMV infection is determined on testing with Qualitative Polymerease chain reaction (PCR)

Valganciclovir doses as per creatinine clearance:
Creatinine clearance >/=60 ml/min 900mg daily
Creatinine clearance 40-59 ml/min 450mg daily
Creatinine clearance 25-39 ml/min 450mg second daily
Creatinine clearance 10-24 ml/min 450 mg twice weekly
Intervention code [1] 257138 0
Early detection / Screening
Intervention code [2] 257175 0
Treatment: Drugs
Intervention code [3] 257176 0
Prevention
Comparator / control treatment
High risk recipients- CMV positive donor to CMV negative recipient received valganciclovir and are monitored weekly for CMV in blood for 3 months, then monthly for the next 12 months.
All other combinations ( CMV positive donor and CMV positive recipient, CMV negative donor and CMV negative recipient, CMV negative donor and CMV positive recipient were randomised to either receive valganciclovir or monitoring. Which is the same as the high risk group- weekly CMV monitoring through blood (CMV PCR testing) weekly for the first 3 months then monthly for the next 12 months.
Control group
Active

Outcomes
Primary outcome [1] 259145 0
Primary incidence of CMV infection and disease in both arms:
Identification of active CMV replication in patients within either the prophylactic or pre-emptive group will be based on:
1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [1] 259145 0
Timepoints- 3, 6, 9, 12 and 15 months, throughout the 15 months of the study
Primary outcome [2] 259146 0
Incidence of CMV infection and disease in the high risk group treated with prophylactic valganciclovir:


1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [2] 259146 0
Timepoints- 3, 6, 9, 12 and 15 months, throughout the 15 months of the study
Primary outcome [3] 259150 0
CMV infection and disease in lower-risk liver transplant recipients in the observational/preemptive therapy arm:


1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [3] 259150 0
Timepoints- 3, 6, 9, 12 and 15 months, throughout the the 15 months of study
Secondary outcome [1] 265468 0
Assess viral characteristics of infection in the two largest liver transplant units in Australia:


1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [1] 265468 0
throughout the 15 months of the study
Secondary outcome [2] 265469 0
Determine quantitative polymerase chain reaction (QPCR) results in blood in both groups of patients and determine values indicative of later CMV disease:

1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [2] 265469 0
throughout the 15 months of the study
Secondary outcome [3] 265470 0
Determine incidence of antiviral resistance CMV in liver transplant recipients receiving valganciclovir:

1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [3] 265470 0
Timepoints- 3, 6, 9, 12 and 15 months, throughout the the 15 months of the study
Secondary outcome [4] 265471 0
Determine the CMV genotypes (initially gB, gN genotypes) involved in CMV infection in both groups:

1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [4] 265471 0
throughout the 15 month of the study
Secondary outcome [5] 265472 0
Assess the association between host factors and outcomes of CMV infection:

All unexpected untoward adverse events will be recorded.
They are defined as:
Any untoward, undesired unplanned clinical event such as physical signs, symptoms, disease or laboratory observation including:
Worsening of a pre-existing condition
Overdose whether accidental or intentional
An event that causes discontinuation of the trial product for any reason
Timepoint [5] 265472 0
throughout the 15 months of the study
Secondary outcome [6] 265473 0
Determine and compare the incidence of other opportunistic viral infections, Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) in the blood using a multiplex qualitative PCR
Timepoint [6] 265473 0
Timepoints- 3, 6, 9, 12 and 15 months, throughtout the the 15 months of the study
Secondary outcome [7] 265477 0
Determine efficacy of valganciclovir prophylaxis, in terms of timing and duration, for prevention of CMV disease in liver transplant recipients:

1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or;
2. Increasing viral load by greater than 0.5 log or;
3. Clinical or histopathological evidence of CMV disease, or
4. Seroconversion in seronegative recipients.
Timepoint [7] 265477 0
throughout the 15 months of the study

Eligibility
Key inclusion criteria
1. Male or female > 16 years of age
2. Patients undergoing liver transplantation
3. Single or multi-organ transplant
4. Patients meet transplant criteria
5. Chronic liver disease or fulminant hepatic failure
6. Able to give written informed consent
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients under the age of 16 years
2. History of hypersensitivity to ganciclovir or valganciclovir
3. Patients involved in any other clinical trials
4. Patients taking any other investigational drugs within 2 months prior to the study screening.
5. Use of any other antiviral therapy against herpes virus within 2 months prior to transplant will be noted and this population analysed as a subgroup
6. Patients unable to give consent
7. Inadequate renal function defined as creatinine clearance < 10 mL/sec

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)
sequentially numbered sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The study has two arms:

Valganciclovir will be given prophylactically to patients with Donor positive/Recipient negative serostatus - these are the high risk group.
Other serostatus group patients (Donor positive/Recipient postive, Donor negative/Recipient negative and Donor negative/Recipient positive) will be selected randomly to either receive valganciclovir and monitoring or monitoring alone. This will be done using Sequentially numbered sealed opaque envelopes that are opened within 72 hours of completion of liver transplantation and treatment is assigned.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
A study of valganciclovir prophylaxis in high risk Donor CMV positive/Recipient CMV negative population. It is already known that this group of patients requires prophylactic therapy with the use of valganciclovir, but the duration of the therapy is variable.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
24/11/2004
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 257593 0
Self funded/Unfunded
Name [1] 257593 0
Country [1] 257593 0
Primary sponsor type
Hospital
Name
Austin Health
Address
Profesor Robert Jones
Liver Transplant Unit
Level 8 Harold Stokes Building
Austin Health
Studley Rd, Heidelberg, Vic 3084
Country
Australia
Secondary sponsor category [1] 256821 0
Hospital
Name [1] 256821 0
Prince of Wales Hospital
Address [1] 256821 0
A/Prof. William Rawlinson, Head of Virology Division
Virology Research Division, Department of Microbiology, Prince of Wales Hospital and UNSW
Prince of Wales Hospital,
Barker Street, Randwick NSW 2031
Country [1] 256821 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259615 0
Austin Health, Human Research Ethics Committee
Ethics committee address [1] 259615 0
Ethics committee country [1] 259615 0
Date submitted for ethics approval [1] 259615 0
Approval date [1] 259615 0
24/11/2004
Ethics approval number [1] 259615 0
H2004/01943

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

Contacts
Principal investigator
Name 31600 0
Address 31600 0
Country 31600 0
Phone 31600 0
Fax 31600 0
Email 31600 0
Contact person for public queries
Name 14847 0
Professor Robert Jones
Address 14847 0
Liver Transplant Unit
Level 8 Harold Stokes Building
Austin Health
Studley Rd
Heidelberg, Vic 3084
Country 14847 0
Australia
Phone 14847 0
+ 61 3 9496 5721
Fax 14847 0
+ 61 3 9496 3487
Email 14847 0
robert.jones@austin.org.au
Contact person for scientific queries
Name 5775 0
Dr Gillian Scott
Address 5775 0
Virology Division,
Department of Microbiology,
South Eastern Area Laboratory Service, Prince of Wales Hospital,
Barker Street, Randwick NSW 2031
Country 5775 0
Australia
Phone 5775 0
+61 2 9382-9096
Fax 5775 0
+61 2 9382-8533
Email 5775 0
ScottGi@SESAHS.NSW.GOV.AU

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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