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Trial registered on ANZCTR


Registration number
ACTRN12611001236987
Ethics application status
Approved
Date submitted
1/03/2011
Date registered
2/12/2011
Date last updated
2/12/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
Asses the safety and efficacy of switching to tenofovir and lamivudine therapy in patients who have been receiving Hepatitis B Immunoglobulin and lamivudine prophylasix post liver transplant.
Scientific title
A study to assess the safety and efficacy of tenofovir disoproxil fumarate (TDF) substitution for HBIg in liver transplantation patients receiving long-term low dose IM HBIg / lamivudine (LAM) prophylaxis.
Secondary ID [1] 252624 0
IN-AU-174-0139
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
prevent Hepatitis B virus re-infection following liver transplantation with the use of tenofovir and lamivudine, withdrawing HBIG. 258117 0
Condition category
Condition code
Infection 258296 258296 0 0
Other infectious diseases
Oral and Gastrointestinal 268483 268483 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
Patients originally receiving Lamivudine and Hepatitis B immunoglobulin will now receive lamivudine 100mg orally daily and tenofovir 300mg orally daily- Hepatitis B Immunoglobulin (HBIG) will be ceased once starting tenofovir. Patients will be excluded if they have evidence of HBV viral recurrence. In the screening phase the patients will be HBsAg negative and HBV DNA negative by PCR. At visit 1 the patient will be switched from HBIG and lamivudine to lamivudine and Tenofovir and taken once daily, orally, in the morning. The dose will be adjusted of both drugs according to renal function. The drugs will continue for the duration of the study- which is 5 years.
Intervention code [1] 257136 0
Treatment: Drugs
Intervention code [2] 257137 0
Early detection / Screening
Intervention code [3] 266992 0
Prevention
Comparator / control treatment
there is no control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 259144 0
The aim of the proposed study is to assess the safety and efficacy of switching to tenofovir and lamivudine
therapy in patients who have been receiving long-term HBIg and lamivudine prophylaxis post-liver
transplant. primary endpoint will be the rate of hepatitis B recurrence as assessed by the appearance of HBsAg and HBVDNA in serum at 96 weeks post enrollment . This will be done on blood tests. Patients will be assessed every 3 months by medical staff and have monthly blood tests monitoring the Hepatitis B sAg and DNA and its recurrence.
Timepoint [1] 259144 0
An initial analysis of outcomes will be performed at 48 weeks and then at 96 weeks.
Secondary outcome [1] 265467 0
It is expected that TDF/LAM will prove to be both safe and effective when used in this patient population to
prevent HBV recurrence- blood tests will be taken to monitor Hepatitis B sAg levels and Hepatitis B DNA levels. Patients will also be monitored regularly (every 3 months) by medical staff in regards to side effects and adverse events.
Impaired renal function:
Dosing interval adjustment is required in all patients with creatinine clearance <50 ml/min. Clinical response to treatment and renal function should be closely monitored in these patients. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.
It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy and, as clinically appropriate, during VIREAD therapy. Patients at risk for, or with a history of, renal dysfunction should be routinely monitored for changes in serum creatinine and phosphorus.
Lactic Acidosis/Severe Hepatomegaly with Steatosis:
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including tenofovir disoproxil fumarate, in the treatment of HIV infection. A majority of these cases have been reported in women. The preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, a class effect of nucleoside analogues is low for tenofovir disoproxil fumarate. However, as tenofovir is structurally related to nucleoside analogues, this risk cannot be excluded. Caution should be exercised when administering VIREAD to any patient, and particularly to those with known risk factors for liver disease. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Drug interactions:
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.
Tenofovir is excreted renally. Coadministration of VIREAD with medicinal products that decrease or compete for renal clearance may increase serum concentrations of tenofovir.
Since tenofovir is primarily eliminated by the kidneys, co-administration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs.
HIV and HBV co-infection:
Due to the risk of development of HIV resistance, VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients.
Carcinogenicity and Mutagenicity:
In a long-term carcinogenicity study conducted in mice with tenofovir disoproxil fumarate there was a low incidence of duodenal tumours with the highest dose of 600 mg /kg/day. These were associated with a high incidence of duodenal mucosal hyperplasia, which was also observed with a dose of 300 mg/kg/day. These findings may be related to high local drug concentrations in the gastro-intestinal tract, likely to result in much higher exposure margins than that based on the AUC. At therapeutic doses the risk of these duodenal effects occurring in humans is likely to be low. The systemic drug exposure (AUC) with the 600 mg/kg/day dose was approximately 15 times the human exposure at the therapeutic dose of 300 mg/day. No tumourigenic response was observed in rats treated with doses of up to 300 mg/kg/day (5 times the human systemic exposure at the therapeutic dose based on AUC).
Tenofovir disoproxil fumarate was mutagenic in an in vitro mouse L5178Y lymphoma cell assay (tk locus) and in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes, but it was negative in in vitro bacterial assays for gene mutation and an in vivo mouse micronucleus test for chromosomal damage. Tenofovir base was not active in in vitro bacterial assays for gene mutation, and an equivocal response was seen in the in vitro mouse L5178Y lymphoma assay at a high concentration.
Impairment of fertility:
Male and female rat fertility and mating performance or early embryonic development were unaffected by an oral tenofovir disoproxil fumarate dose (600 mg/kg/day) that achieved systemic drug exposures that were in excess of the value in humans receiving the therapeutic dose (5-fold based on plasma AUC). There was, however, an alteration of the oestrous cycle in female rats.
Use in pregnancy:
Pregnancy Category B3. No clinical data are available for pregnant women being treated with VIREAD. Reproductive toxicity studies performed in rats and rabbits did not reveal any evidence of harm to the foetus due to tenofovir at respective exposures (AUC) of 4-13 and 66-fold the human exposure. Subcutaneous treatment of pregnant rhesus monkeys with a dose of 30 mg/kg/day of the tenofovir base during the last half of pregnancy resulted in reduced foetal serum phosphorus concentrations. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed.
Use in lactation:
In animal studies tenofovir was excreted in milk after oral administration of tenofovir disoproxil fumarate (rats) and after subcutaneous administration of tenofovir base (non-human primates). It is not known whether tenofovir is excreted in human milk. It is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant.
Bone Effects:
Bone toxicities including a reduction in bone mineral density have been observed in studies in three animal species (see Animal Toxicology, below). Clinically relevant bone abnormalities have not been seen in long term clinical studies (>3 years). However, bone abnormalities may be associated with proximal renal tubulopathy (see ADVERSE REACTIONS: Post-Marketing Surveillance). If bone abnormalities are suspected during therapy then appropriate consultation should be obtained.
Animal Toxicology:
Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) between 6 and 12 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity in unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and /or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
Effects on ability to drive and use machines:
No studies on the effects on ability to drive or use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.
Timepoint [1] 265467 0
week 48 and 96, patients will be monitored for a total of 5 years

Eligibility
Key inclusion criteria
Post liver transplant recipients
Patients transplanted for Hepatitis B
Current prophylaxis- lamivudine and Hepatitis B immunoglobumlin
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
those patients not transplanted for hepatitis B

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 2851 0
New Zealand
State/province [1] 2851 0

Funding & Sponsors
Funding source category [1] 257592 0
Self funded/Unfunded
Name [1] 257592 0
Country [1] 257592 0
Primary sponsor type
Individual
Name
Professor Peter Angus
Address
Liver Transplant Unit,
Level 8 Harold Stokes Building
Austin Hopsital
Studley Rd, Heidelberg, Vic 3084
Country
Australia
Secondary sponsor category [1] 256820 0
None
Name [1] 256820 0
Address [1] 256820 0
Country [1] 256820 0
Other collaborator category [1] 251476 0
Individual
Name [1] 251476 0
Simone Strasser
Address [1] 251476 0
AW Marrow Gastroenterology and Liver Centre
Royal Prince Alfred Hospital
Missendon Rd, Camperdown, NSW 2050
Country [1] 251476 0
Australia
Other collaborator category [2] 251477 0
Individual
Name [2] 251477 0
A/Professor Ed Gane
Address [2] 251477 0
Liver transplant Unit
Auckland CIty Hospital
2 Park Rd, Grafton, 1023 New Zealand
Country [2] 251477 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259609 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 259609 0
Ethics committee country [1] 259609 0
Australia
Date submitted for ethics approval [1] 259609 0
Approval date [1] 259609 0
11/03/2010
Ethics approval number [1] 259609 0
H2010/03786

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

Contacts
Principal investigator
Name 31599 0
Address 31599 0
Country 31599 0
Phone 31599 0
Fax 31599 0
Email 31599 0
Contact person for public queries
Name 14846 0
Professor Peter Angus
Address 14846 0
Liver Transplant Unit
Level 8 Harold Stokes Building
Austin Health
Studley rd, Heidelberg, Vic 3084
Country 14846 0
Australia
Phone 14846 0
+61 3 9496 5859
Fax 14846 0
+61 3 9496 3487
Email 14846 0
peter.angus@austin.org.au
Contact person for scientific queries
Name 5774 0
Professor Peter Angus
Address 5774 0
Liver Transplant Unit
Level 8 Harold Stokes Building
Austin Health
Studley rd, Heidelberg, Vic 3084
Country 5774 0
Australia
Phone 5774 0
+61 3 9496 5859
Fax 5774 0
+61 3 9496 3487
Email 5774 0
peter.angus@austin.org.au

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No Supporting Document Provided



Results publications and other study-related documents

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