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Trial registered on ANZCTR


Registration number
ACTRN12613000946718
Ethics application status
Approved
Date submitted
20/08/2013
Date registered
27/08/2013
Date last updated
5/03/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of peginterferon-alfa intervention to achieve hepatitis B surface antigen loss in multi-drug resistant chronic hepatitis B participants under long-term viral suppression with tenofovir DF +/- lamivudine salvage therapy (TDF-109 cohort)
Scientific title
Peg-interferon-alfa to achieve HBsAg loss in multi-drug resistance HBV under long-term viral suppression with tenofovir DF +/- lamivudine salvage therapy
Secondary ID [1] 282066 0
Nil know
Universal Trial Number (UTN)
Trial acronym
TRUST - 109
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic hepatitis B 288553 0
Condition category
Condition code
Infection 288882 288882 0 0
Other infectious diseases
Oral and Gastrointestinal 290281 290281 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
Hepatitis B virus is a major health issue worldwide and despite the advances in therapy, it is still the tenth leading cause of mortality. Currently there are two treatments available – peginterferon-alpha (pegIFNa) and nucleos(t)ide analogues (NA). PegIFNa is a drug which affects the immune system and is a finite treatment of 48 weeks, however majority end up on NA indefinitely, although not concurrently. NA are oral agents which are highly effective in controlling the virus, patients often flare once this medication is ceased. The ultimate goal of antiviral therapy is converting chronic hepatitis B (CHB) patients from surface antigen (HBsAg) positive to negative with development of surface antibodies (HBsAb) (HBsAg seroconversion).
The TDF-109 study (Project No H2006/02552) evaluated the efficacy of tenofovir DF (TDF) +/- lamivudine (LMV) rescue therapy for LMV/ adefovir (ADV)-experienced Asian patients (Protocol No IN-AU-174-0109). The initial two year data was published by Patterson SJ, George J, Strasser SI, Lee AU, Sievert W, Nicoll AJ, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247-54. Most patients have now completed 5 years of treatment and TDF has resulted in significant viral suppression in the majority of patients. Significant declines of HBsAg titre were observed however no seroconversion. At this stage, majority of the patients will be on NA life-long.
We believe that immunomodulation is required to achieve HBsAg loss, and that this explains the very low rates of HBsAg loss, and eventual plateau phase that have been observed during NA therapy. We hypothesize that in patients under long-term viral suppression with potent NA, add-on pegIFNa will reduce serum HBsAg levels and lead to HBsAg loss.
We propose an investigator-initiated proof-of-concept study to evaluate the efficacy of add-on pegIFNa therapy (180mcg subcutaneously weekly) in patients who have been treated with TDF +/- LMV therapy for at least 5 years as part of the TDF-109 study.
We will aim to recruit all the TF-109 patients into this study.
Those suitable will be treated with 48 weeks of pegIFNa. Strategies used to monitor adherence includes taking a history from the patients as well as counting drug tablet return on their reviews.
Intervention code [1] 286665 0
Treatment: Drugs
Comparator / control treatment
Those who are not suitable or refusing peg-interferon will be our control group.
Control group
Active

Outcomes
Primary outcome [1] 289014 0
Change in HBsAg titre during antiviral therapy (pegIFNa plus NA therapy) measured using the Roche Elecsys assay. This measures the quantitative hepatitis B surface antigen (qHBsAg) titers expressed in international units/mL (IU/mL).
Timepoint [1] 289014 0
At 48 weeks
Secondary outcome [1] 301565 0
Mean change in HBsAg titre over time, as estimated from the area between the baseline value and the curve of HBsAg titre divided by the duration of treatment
Timepoint [1] 301565 0
48 weeks of treatment
Secondary outcome [2] 301576 0
Rates of HBsAg loss and HBsAg seroconversion at end-of-treatment and 24 weeks post-treatment
Timepoint [2] 301576 0
At 48 weeks of treatment and 24 weeks post treatment
Secondary outcome [3] 301577 0
In HBeAg-positive patients:
- the change in HBeAg titre over the course of the study.
The Roche Elecsys assay will be used to measure the quantitative hepatitis e antigen (qHBeAg) titers expressed in international units per millilitre (IU/mL)

Timepoint [3] 301577 0
At 48 weeks of treatment and 24 weeks post treatment
Secondary outcome [4] 301578 0
In patients who stop therapy, the rate of serological (serum HBsAg, HBeAg level) and/or virological (serum HBV DNA level) relapse will be evaluated
- Protocol requires TDF to be restarted in the event of virological relapse:
- cirrhotics = detectable HBV DNA
- non-cirrhotics = HBV DNA > 2,000 IU/mL
The HBsAg and HBeAg will be analysed at the 3 monthly intervals.
Timepoint [4] 301578 0
Within the 48 weeks
Secondary outcome [5] 301579 0
Exploratory analysis of clinical / laboratory predictors for serological responses will be performed (baseline and on-treatment factors will be considered). This will included performing bioplex assays which detects the phenotypic variation of the surface antigen.
Timepoint [5] 301579 0
48 weeks of treatment and 24 weeks post treatment
Secondary outcome [6] 304302 0
In HBeAg positive patients
- the rate of HBeAg loss and HBeAg-seroconversion.
The HBeAg/Ab serology will be performed 3 monthly during the 48 weeks.
Timepoint [6] 304302 0
During the 48 weeks on peg-interferon therapy.

Eligibility
Key inclusion criteria
The initial TF109 has not been registered on ANZCTR. The initial 2 year data has been published by Patterson SJ, George J, Strasser SI, Lee AU, Sievert W, Nicoll AJ, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247-54. The key inclusion criteria is that they have to have been involved in the initial TF109 study - on long term tenofovir DF.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Severe liver disease which excludes them from peg-interferon therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All patients previously enrolled in the TDF-109 study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
All patients from the original TF109 cohort maintained on long-term (5 years) TDF +/- LMV therapy will treated with add-on pegIFNa-2a, 180ug, SC, weekly, for 48 weeks total.
This add-on study is not randomised - patients from TF109 will have liver biopsy to determine safety to treat with peg-interferon 180ug, SC, weekly, for 48 weeks total.
Those not suitable or unwilling to be treated will be recruited as the observational/control arm.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary efficacy variable, change in log10 HBsAg, will be analysed with ANCOVA using the baseline log10 HBsAg as the covariate. Similarly for change in log10 HBsAg during follow-up. The mean change in log10 HBsAg with be analysed with ANOVA. HBsAg loss and HBsAg seroconversion will be analysed with logistic regression.
Due to the limited numbers of participants in the TF109 cohort (n=59), the aim would be to recruit all the participants in the add-on study. However given not all the patients will be eligible or willing to partake in weekly injections - our aim is to have at least half (n=25-30) be treated with add-on peg-inteferon while the other half are the controls on tenofovir DF +/- lamivudine.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 713 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 714 0
The Alfred - Prahran
Recruitment hospital [3] 715 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [4] 716 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 717 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [6] 718 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [7] 719 0
Westmead Hospital - Westmead
Recruitment hospital [8] 720 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 6463 0
2050 - Camperdown
Recruitment postcode(s) [2] 6465 0
2139 - Concord Repatriation Hospital
Recruitment postcode(s) [3] 6464 0
2145 - Westmead
Recruitment postcode(s) [4] 6462 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [5] 6459 0
3065 - Fitzroy
Recruitment postcode(s) [6] 6457 0
3084 - Heidelberg
Recruitment postcode(s) [7] 6460 0
3168 - Clayton
Recruitment postcode(s) [8] 6458 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 286845 0
Commercial sector/Industry
Name [1] 286845 0
Gilead
Address [1] 286845 0
Gilead Sciences - Australia
Level 1, 128 Jolimont Road
East Melbourne 3002
Victoria Australia
Country [1] 286845 0
Australia
Funding source category [2] 286846 0
Commercial sector/Industry
Name [2] 286846 0
Roche
Address [2] 286846 0
4-10 Inman Road
Dee Why NSW 2099
Australia
Country [2] 286846 0
Australia
Primary sponsor type
Individual
Name
Peter Angus
Address
Department of Liver Transplant and Gastroenterology
Austin Health
145 Studley Rd Heidelberg 3084 Victoria
Country
Australia
Secondary sponsor category [1] 285637 0
None
Name [1] 285637 0
Address [1] 285637 0
Country [1] 285637 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288910 0
Austin Health Human Research Ethics Committee (EC00204)
Ethics committee address [1] 288910 0
Austin Hopsital
145 Studley Road, Heidelberg 3084 Victoria
Ethics committee country [1] 288910 0
Australia
Date submitted for ethics approval [1] 288910 0
26/02/2013
Approval date [1] 288910 0
08/07/2013
Ethics approval number [1] 288910 0
HREC/13/Austin/16

Summary
Brief summary
This is a study to see if add-on peginterferon-­alfa (pegIFNa) can help lose hepatitis B surface antigen in participants who have multi­drug resistant chronic hepatitis B and treated with long­term tenofovir DF +/- lamivudine salvage therapy (TDF­109 cohort)
We hypothesize that in participants under long ­term viral suppression with potent oral therapy nucleoside analogues, add­on pegIFNa will reduce serum HBsAg levels and lead to HBsAg loss.
We propose an investigator ­initiated proof­ of ­concept study to evaluate the efficacy of add­-on pegIFNa therapy in patients who have been treated with tenofovir and/or lamivudine therapy for at least 5 years as part of the TDF­109 study. We will aim to recruit all the TF­109 patients into this study. Those suitable will be treated with 48 weeks of pegIFNa.
Trial website
N/A
Trial related presentations / publications
The initial 2 year data was published by 1. Patterson SJ, George J, Strasser SI, Lee AU, Sievert W, Nicoll AJ, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247-54.
Public notes
Gilead and Roche have kindly agreed to sponsor this study by providing medications only. This is an investigator driven study.

Contacts
Principal investigator
Name 37606 0
Prof Peter Angus
Address 37606 0
Liver Transplant Unit
Austin Health
145 Studley Rd, Heidelberg 3084 Victoria
Country 37606 0
Australia
Phone 37606 0
61 03 94965353
Fax 37606 0
Email 37606 0
peter.angus@austin.org.au
Contact person for public queries
Name 37607 0
Dr Lucy Lim
Address 37607 0
Liver Transplant Unit
Austin Health
145 Studley Rd, Heidelberg 3084 Victoria
Country 37607 0
Australia
Phone 37607 0
61403300838
Fax 37607 0
Email 37607 0
lucy_lim8@yahoo.com.au
Contact person for scientific queries
Name 37608 0
Dr Peter Angus
Address 37608 0
Liver Transplant Unit
Austin Health
145 Studley Rd, Heidelberg 3084 Victoria
Country 37608 0
Australia
Phone 37608 0
61403300838
Fax 37608 0
Email 37608 0
peter.angus@austin.org.au

No information has been provided regarding IPD availability
Summary results
No Results