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Trial registered on ANZCTR


Registration number
ACTRN12615000915550
Ethics application status
Not yet submitted
Date submitted
13/07/2015
Date registered
2/09/2015
Date last updated
2/09/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of peginterferon-alfa intervention to achieve hepatitis B surface antigen loss in chronic hepatitis B participants under long-term viral suppression with nucleoside analogues
Scientific title
Peg-interferon-alfa to achieve HBsAg loss in chronic hepatitis B
under long-term viral suppression with nucleoside analogues
Secondary ID [1] 287074 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
TRUST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B 295574 0
Condition category
Condition code
Infection 295847 295847 0 0
Other infectious diseases
Oral and Gastrointestinal 295848 295848 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
The intervention is: Addition of peginterferon-alpha (pegIFNa) to existing nucleos(t)ide analogues (NA) therapy in patients who are on long-term NA therapy and have achieved viral suppression but not clearance.
The dose of pegIFNa is 180mcg subcutaneously weekly.

The patients recruited into the trial will already be on an antiviral , either entecavir or tenofovir. The usual doses of enetcavir and tenofovir in standard of care are 0.5-1 mg daily (oral tablet) for entercavir and 300 mg daily (oral tablet) for tenofovir. At the time of entry into the trial, patients are on either entecavir or tenofovir, not both oral agents at the same time.

Duration of pegIFNa: 24 weeks or 48 weeks depending on stopping rules
Stopping rules :
There will be stopping rules at week 24. These are:
* HBV DNA detectable at week 24
* HBsAg > 1000 IU/mL at week 24
* HBsAg decline <0.1 Log IU/mL at week 24

The doses of entecavir or tenofovir will be the doses provided as part of standard of care which are the existing dose that the participants are already on. Patients will be on only one oral agent- either tenofovir or entecavir.
There will be no changes to NA doses from what the participant is already taking at the time of entry into the trial.
The dose of entecavir is 0.5 mg- 1 mg . this is determined by the treating clinician depending on renal function (patients with renal impairment are on a smaller dose). the dose of entecavir will not be changed for the purposes of the trial.

If the pegIFNa intervention is futile (based on HBV viral load and HBsAg titres), treatment will be ceased. Patients who have responded will receive consolidation pegIFNa for up to 48 weeks
Mode of administration: subcutaneous injection of interferon, oral tablets for NA
strategies used to monitor adherence to the intervention: counting drug tablets , history taking from the patient
Intervention code [1] 292308 0
Treatment: Drugs
Comparator / control treatment
Patients not suitable or refusing pegIFNa will be our control group
Control group will consist on patients who are continuing existing NA therapy
Control group
Active

Outcomes
Primary outcome [1] 295532 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] 295532 0
48 weeks after commencement of treatment
Secondary outcome [1] 315787 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] 315787 0
at 24 weeks of treatment, 48 weeks of treatment and 24 weeks post treatment cessation
Secondary outcome [2] 315788 0
Rates of HBsAg loss at 24 weeks and end of treatment (48 weeks)
This will be determined using the Roche Elecsys assay
Timepoint [2] 315788 0
At 24 and 48 weeks of treatment
Secondary outcome [3] 315789 0
In patients who stop therapy, the rate of serological (serum HBsAg, HBeAg level) relapse will be evaluated
This will be determined using the Roche Elecsys assay
Timepoint [3] 315789 0
At 24 and 48 weeks after commencement of treatment
Secondary outcome [4] 315790 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 [4] 315790 0
48 weeks of treatment and 24 weeks post treatment
Secondary outcome [5] 316157 0
Rates of HBsAg seroconversion at 24 weeks of treatment, 48 weeks of treatment and 24 weeks . This will be assessed using the Roche Elecsys assay
Timepoint [5] 316157 0
at 24 weeks of treatment, 48 weeks of treatment and 24 weeks post treatment cessation
Secondary outcome [6] 316286 0
In patients who stop therapy, the rate of virological (serum HBV DNA level) relapse will be evaluated
This will be assessed using the Roche Elecsys assay
Timepoint [6] 316286 0
at 24 and 48 weeks after commencement of treatment.

Eligibility
Key inclusion criteria
*Informed consent
*Age > 18 years
*HBsAg-positive
*HBeAg negative
*On entecavir or tenofovir > 18 months
*HBV DNA level undetectable for > 18 months
*HBsAg < 1000 IU/mL
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Severe liver disease which excludes them from peg-interferon

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)
Patients will be recruited from outpatients clinic
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
NA
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
There will be clear stopping rules at week 24:
1. HBV DNA detectable
2. HBsAg > 1000 IU/mL
3. HBsAg decline <0.1 Log IU/mL
4. HBsAg seroconversion (stop after 8 weeks consolidation)


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 sample size was determined using power calculation.
The mean change in HBsAg level and the standard deviation of HBsAg in patients on long term NA therapy (using previous clinical trials), was used to estimate parameters for power calculation. With 50 patients, we calculate > 80% power to detect a 0.5 log10 IU/mL change in HBsAg level at 48 weeks, with a standard deviation of 1 log10 IU/mL. The level of significance was set to 0.05, with a 2-sided test.

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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/09/2015
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 4038 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 4039 0
The Alfred - Prahran
Recruitment hospital [3] 4040 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [4] 4041 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 4042 0
Western Hospital - Footscray
Recruitment hospital [6] 4043 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [7] 4044 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 9954 0
3084 - Heidelberg
Recruitment postcode(s) [2] 9955 0
3181 - Prahran
Recruitment postcode(s) [3] 9956 0
3065 - Fitzroy
Recruitment postcode(s) [4] 9957 0
3128 - Box Hill
Recruitment postcode(s) [5] 9958 0
3011 - Footscray
Recruitment postcode(s) [6] 9959 0
3168 - Clayton
Recruitment postcode(s) [7] 9960 0
3050 - Royal Melbourne Hospital

Funding & Sponsors
Funding source category [1] 291637 0
Commercial sector/Industry
Name [1] 291637 0
Gilead
Country [1] 291637 0
Australia
Funding source category [2] 291639 0
Commercial sector/Industry
Name [2] 291639 0
Bristol-Myers Squibb
Country [2] 291639 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] 290309 0
Individual
Name [1] 290309 0
Alex Thompson
Address [1] 290309 0
Department of Gastroenterology
Level 4 Daly Wing
St Vincent's Hospital
44 Victoria Parade
Fitzroy 3065
Country [1] 290309 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 293165 0
St Vincent's ethics committee
Ethics committee address [1] 293165 0
Research Governance Unit
Level 5, Mary Aikenhead Building
27 Victoria Parade
Fitzroy
VIC 3065
Ethics committee country [1] 293165 0
Australia
Date submitted for ethics approval [1] 293165 0
20/07/2015
Approval date [1] 293165 0
Ethics approval number [1] 293165 0

Summary
Brief summary
This is a study to see if add-on peginterferon-alfa (pegIFNa) can help lose hepatitis B surface antigen in patients who have
chronic hepatitis B and treated with longterm nucleotide analogue therapy.
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 or entecavir for at least 18 months
Those suitable will be treated with a minimum 24 weeks of pegIFNa. Depending on their response, pegIFNa therapy may be extended for up to 48 weeks or ceased.
Trial website
NA
Trial related presentations / publications
NA
Public notes
We have sought sponsorship of the study from Gilead and Bristol-Myer Squibb. The sponsorship will include providing medication only. This is an investigator driven study.

Contacts
Principal investigator
Name 58726 0
Prof Peter Angus
Address 58726 0
Liver Transplant Unit Austin Health 145 Studley Rd,
Heidelberg 3084
Victoria
Country 58726 0
Australia
Phone 58726 0
+61 3 94965353
Fax 58726 0
Email 58726 0
[email protected]
Contact person for public queries
Name 58727 0
Dr Zina Valaydon
Address 58727 0
Department of Gastroenterology
Level 4 Daly Wing
St Vincent's Hospital
44 Victoria parade, Fitzroy
VIC 3065
Country 58727 0
Australia
Phone 58727 0
61431608006
Fax 58727 0
Email 58727 0
[email protected]
Contact person for scientific queries
Name 58728 0
Prof Peter Angus
Address 58728 0
Austin Health 145 Studley Rd, Heidelberg 3084 Victoria
Country 58728 0
Australia
Phone 58728 0
+61 3 94965353
Fax 58728 0
Email 58728 0
[email protected]

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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