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Trial registered on ANZCTR


Registration number
ACTRN12614000628640
Ethics application status
Approved
Date submitted
4/06/2014
Date registered
13/06/2014
Date last updated
13/06/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety and Efficacy of GS-9620 for the Treatment of Virally-Suppressed Subjects with Chronic Hepatitis B
Scientific title
For virally-suppressed patients with Chronic Hepatitis B, will GS-9620 as compared to placebo be safer, better tolerated and more efficacious?
Secondary ID [1] 284704 0
GS-US-283-1059
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B 292057 0
Condition category
Condition code
Infection 292396 292396 0 0
Other infectious diseases
Oral and Gastrointestinal 292471 292471 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
Arm 1: OAV + 1mg GS-9620
Arm 2: OAV + 2mg GS-9620
Arm 3: OAV + 4mg GS-9620
Arm 4: OAV + Placebo

OAV = Oral Antiviral (must be commercially available)

OAV type, dose and duration will continue as previously prescribed by the patient’s clinician.

For all Arms (1, 2, 3 and 4) GS-9620/placebo will be taken once a week (every 7th day) as an oral tablet.

Participants will be randomised into 3 sequential cohorts:
- Cohort A participants will be treated with GS-9620 (1mg, 2mg or 4mg)/placebo once a week for 4 doses
- Cohort B participants will be treated with GS-9620 (1mg, 2mg or 4mg)/placebo once a week for 8 doses
- Cohort C participants will be treated with GS-9620 (1mg, 2mg or 4mg)/placebo once a week for 12 doses

All unused study drug and used study drug kits which are dispensed to participants must be returned to the investigative site for accountability.
Intervention code [1] 289492 0
Treatment: Drugs
Comparator / control treatment
OAV + Placebo to match GS-9620 tablets
Control group
Placebo

Outcomes
Primary outcome [1] 292257 0
To evaluate the safety and tolerability of GS-9620 in subjects with chronic hepatitis B infection (CHB) currently being treated with oral antivirals (OAV).

This outcome will be assessed through monitoring of Adverse Events/Serious Adverse Events, physical examinations, monitoring of vital signs and blood tests.
Timepoint [1] 292257 0
Safety/tolerability data will be collected through to week 48. Depending upon which cohort a participant is randomised to, the participant will have 4, 8, or 12 weeks of treatment and 44, 40, or 36 weeks of follow-up.
Primary outcome [2] 292258 0
To evaluate the efficacy of GS-9620 at Week 24 measured by the change from Baseline in serum hepatitis B surface antigen (HBsAg) ( log10 IU/ml) levels
Timepoint [2] 292258 0
The primary analysis will occur at Week 24 with the primary efficacy endpoint being the change in serum HBsAg (log10 IU/ml) levels from Baseline to Week 24
Secondary outcome [1] 308565 0
To evaluate the rates of HBsAg loss and seroconversion at Weeks 24 and 48.

This outcome will be measured using serum blood tests.
Timepoint [1] 308565 0
Weeks 24 and 48
Secondary outcome [2] 308566 0
To evaluate the rates of hepatitis B early antigen (HBeAg) loss and seroconversion at Weeks 24 and 48.

This outcome will be measured using serum blood tests.
Timepoint [2] 308566 0
Weeks 24 and 48
Secondary outcome [3] 308567 0
To evaluate the change in log10 IU/ml serum HBsAg from Baseline to Week 4, 8, 12 and 48
Timepoint [3] 308567 0
Weeks 4, 8, 12 and 48
Secondary outcome [4] 308568 0
To evaluate the proportion of subjects with serum HBsAg decline greater than or equal to 1 log10 IU/ml decline at Weeks 4, 8, 12, 24 and 48
Timepoint [4] 308568 0
Weeks 4, 8, 12, 24 and 48
Secondary outcome [5] 308569 0
To evaluate the proportion of subjects experiencing HBV virological breakthrough.

This outcome will be measured using serum blood tests.
Timepoint [5] 308569 0
The treatment and follow-up period will be up to 48 weeks.
Depending upon which cohort a participant is randomised to, the participant will have 4, 8, or 12 weeks of treatment and 44, 40, or 36 weeks of follow-up.
Secondary outcome [6] 308570 0
To evaluate the incidence of drug resistance mutations.

This outcome will be measured using plasma sample testing.
Timepoint [6] 308570 0
Week 48

Eligibility
Key inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible to participate in the study.

1. Must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
2. Adult male and non-pregnant, non-lactating female subjects, (lactating females must agree to discontinue nursing before the study drug is administered), 18–65 years of age inclusive based on the date of the screening visit
3. A negative serum pregnancy test is required for female subjects (unless surgically sterile or greater than two years post-menopausal).
4. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
5. Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months) with detectable HBsAg levels at screening
6. Have been on approved HBV OAV treatment for greater than or equal to 1 year prior to screening, with HBV DNA below LLOQ (measured at least once) 6 or more months prior to screening, and HBV DNA < 20 IU/ml at screening
7. Subjects currently taking an approved HBV OAV (tenofovir, entecavir, adefovir, lamivudine or telbivudine, either as single agents or in combination) with no change in regimen for 3 months prior to screening
8. Willing to provide blood sample for TLR-7 and IL28B SNP assessment
9. Must be willing and able to comply with all study requirements
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who meet any of the following exclusion criteria are not to be enrolled in the study:

1. Extensive bridging fibrosis or cirrhosis as defined clinically, by imaging or by the following:
a) Metavir greater than or equal to 3 or Ishak fibrosis score greater than or equal to 4 by a liver biopsy within 5 years of screening. or, in the absence of an appropriate liver biopsy, either
b) Screening FibroTest score of > 0.48 and APRI > 1, or
c) Historic FibroScan with a result > 9 kPa within less than than or equal to 6 months of screening (if available)
If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available).
If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or (c, if available). In the event of discordance between (b) and (c), the FibroScan results will take precedence.
2. Patients meeting any of the following laboratory parameters at screening:
- White Blood cell count < 2500 IU/Ml
- Neutrophil count < 1500 cell/ mm3 (or < 1000 cell/ mm3 if considered a physiological variant in a subject of African descent)
- ALT > 3x the upper limit of normal (ULN)
- INR > ULN unless the subject is stable on an anticoagulant regimen affecting INR
- Albumin < 3.9 g/dL
- Total bilirubin > 2 mg/dl
- Platelet Count < 125,000 /ml
- Estimate creatinine clearance (CLcr) < 50 ml/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the screening evaluation
3. Co-infection with HCV, HIV or HDV
4. Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5. Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (e.g. basal cell skin cancer). Subjects under evaluation for possible malignancy are not eligible
6. Significant cardiovascular, pulmonary, or neurological disease
7. Any of the following conditions that may worsen in response to IFN:
- Autoimmune disease (e.g. lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, moderate or severe psoriasis)
- Poorly controlled diabetes mellitus
- Significant psychiatric disorders
- Thyroid disorder (unless controlled under treatment)
- Significant pulmonary diseases (e.g. chronic obstructive pulmonary disease)
- Retinal disease
- Immunodeficiency disorders
8. Chronic liver disease of a non-HBV etiology (e.g. hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis)
9. Received solid organ or bone marrow transplant
10. Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics (e.g. monoclonal Ab, interferon) within 3 months of screening
11. Use of another investigational agents within 3 months of screening, unless allowed by the Sponsor
12. Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
13. Known hypersensitivity to study drug, metabolites or formulation excipients
14. Screening electrocardiogram (ECG) with clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) greater than or equal to 450 msec for males and greater than or equal to 470 msec for females
15. Women who may wish to become pregnant during the course of the study
16. Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose of study drug
17. Use of any prohibited con-medications as described in the protocol
18. Believed by the Study Investigator to be inappropriate for study participation for any reason not otherwise listed

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The randomisation will be performed via an Interactive Voice Response System (IVRS) or Interactive Web Response System (IWRS), whereby study treatment will be assigned to subjects according to the randomisation schedule. A unique subject number will be provided during randomisation. Eligible subjects (n = 150) will be randomised in a 1:3:3:3 ratio to receive placebo or GS-9620 1 mg, 2 mg or 4 mg.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by HBsAg levels (> 5000 IU/ml vs. less than or equal to 5000 IU/ml) and HBeAg status (positive vs. negative).

The randomisation will be performed via an Interactive Web Response System (IWRS), whereby study treatment will be assigned to participants according to the computer-generated randomisation schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Participants will be randomised in 3 sequential cohorts. Each cohort will dose for a different treatment period (4, 8 or 12 weeks). Cohorts will be explored in a sequential manner: 8 weeks of treatment will only be explored after completion and safety review of the 4 week treatment cohort; 12 weeks of treatment duration will only be explored upon complete evaluation of the 8 week treatment cohort. Within each cohort 50 subjects will be randomized in a 1:3:3:3 ratio to placebo or one of the following doses of GS-9620: 1, 2 or 4 mg. Participants will be followed up to Week 48.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
EFFICACY
The primary analysis set for efficacy analysis is the full analysis set (FAS) defined as all subjects who were randomised and received at least one dose of study drug.
Subjects will be analysed according to the randomised treatment assignment.

Primary analysis: will be conducted when the last subject in each treatment duration group reaches Week 24. The change from Baseline to Week 24 in HBsAg (log10 IU/ml) will be analysed using a mixed model for repeated measures (MMRM). The model will include the Baseline HBsAg level, Baseline HBeAg status, treatment, visit, and treatment-by-visit interaction as independent variables. An unstructured within subject covariance matrix will be employed. If convergence is an issue, another covariance matrix will be used.

Secondary analysis: The change from Baseline to Weeks 4, 8, 12 and 48 in HBsAg (log10 IU/ml) will be analysed using the same method as in the primary analysis. Categorical secondary endpoints will be summarised by number and percentage of subjects that meet the endpoint. Cochran-Mantel-Haenszel test will be used to compare the treatment groups, in an exploratory manner.

SAFETY
The primary analysis set for safety analyses is the safety analysis set (SAS) defined as all subjects who received at least one dose of study drug. Subjects will be analysed according to the treatment actually received.

Analysis: All safety data collected on or after the date that study drug was first dispensed up to the date of last dose of study drug will be summarised by treatment group (according to the study drug received). Data for the pretreatment will be included in data listings.

PHARMACOKINETICS
The PK analysis set will include all subjects who are enrolled and have received at least one dose of study drug and for whom concentration data of analytes are available.

Analysis: Pharmacokinetic parameters will be calculated from all subjects in the optional intensive PK sub-study and will be listed and summarised for using descriptive statistics (i.e. sample size, arithmetic mean, geometric mean, % coefficient of variation, standard deviation, median, minimum, and maximum). Plasma concentrations of GS-9620 over time will be plotted in semi logarithmic and linear formats as mean +/- standard deviation. Drug exposure in all study subjects with measurable GS-9620 concentrations from single PK samples will be evaluated in relation to GS-9620 PK from the optional intensive PK sub-study, as well as previous intensive PK data from earlier studies as appropriate to characterise the exposure profile of GS-9620 in this population.

BIOMARKERS
The primary analysis set for biomarkers is the biomarker analysis set, defined as all subjects who were randomised, received at least one dose of study drug and have the biomarkers available.


No power calculation was performed to determine sample size because this is an exploratory study to characterise the safety and efficacy of GS-9620 in chronic Hepatitis B.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/06/2014
Actual
Date of last participant enrolment
Anticipated
30/06/2015
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment outside Australia
Country [1] 6081 0
New Zealand
State/province [1] 6081 0
Auckland
Country [2] 6082 0
United States of America
State/province [2] 6082 0
Michigan
Country [3] 6112 0
United States of America
State/province [3] 6112 0
California
Country [4] 6113 0
United States of America
State/province [4] 6113 0
Hawaii
Country [5] 6114 0
United States of America
State/province [5] 6114 0
Massachusetts
Country [6] 6115 0
United States of America
State/province [6] 6115 0
New York
Country [7] 6116 0
Korea, Republic Of
State/province [7] 6116 0
Seoul
Country [8] 6117 0
Netherlands
State/province [8] 6117 0
Rotterdam
Country [9] 6118 0
Canada
State/province [9] 6118 0
Alberta
Country [10] 6119 0
Canada
State/province [10] 6119 0
British Columbia
Country [11] 6120 0
Canada
State/province [11] 6120 0
Manitoba
Country [12] 6121 0
Canada
State/province [12] 6121 0
Ontario
Country [13] 6122 0
Italy
State/province [13] 6122 0
Milano
Country [14] 6123 0
Italy
State/province [14] 6123 0
Pisa
Country [15] 6124 0
Italy
State/province [15] 6124 0
Parma
Country [16] 6125 0
Italy
State/province [16] 6125 0
Foggia

Funding & Sponsors
Funding source category [1] 289325 0
Commercial sector/Industry
Name [1] 289325 0
Gilead Sciences, Inc.
Country [1] 289325 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc.
Address
333 Lakeside Drive, Foster City, CA 94404
Country
United States of America
Secondary sponsor category [1] 288011 0
None
Name [1] 288011 0
Address [1] 288011 0
Country [1] 288011 0
Other collaborator category [1] 277983 0
Commercial sector/Industry
Name [1] 277983 0
Pharmaceutical Research Associates Pty Limited
Address [1] 277983 0
Level 17, Suite 1701, Central Square, 323 Castlereagh Street, Sydney, NSW, 2000
Country [1] 277983 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291091 0
Health and Disability Ethics Committees
Ethics committee address [1] 291091 0
Ethics committee country [1] 291091 0
New Zealand
Date submitted for ethics approval [1] 291091 0
08/05/2014
Approval date [1] 291091 0
27/05/2014
Ethics approval number [1] 291091 0
14/STH/57

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

Contacts
Principal investigator
Name 48854 0
Prof Edward Gane
Address 48854 0
Auckland Clinical Studies Ltd
3 Ferncroft Street
Grafton Auckland 1010
Country 48854 0
New Zealand
Phone 48854 0
+64 9 373 3474
Fax 48854 0
Email 48854 0
[email protected]
Contact person for public queries
Name 48855 0
Kerry Walker
Address 48855 0
Auckland Clinical Studies Ltd
3 Ferncroft Street
Grafton Auckland 1010
Country 48855 0
New Zealand
Phone 48855 0
+64 9 373 3474
Fax 48855 0
Email 48855 0
[email protected]
Contact person for scientific queries
Name 48856 0
Edward Gane
Address 48856 0
Auckland Clinical Studies Ltd
3 Ferncroft Street
Grafton Auckland 1010
Country 48856 0
New Zealand
Phone 48856 0
+64 9 373 3474
Fax 48856 0
Email 48856 0
[email protected]

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