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Trial registered on ANZCTR


Registration number
ACTRN12618000143224
Ethics application status
Approved
Date submitted
23/01/2018
Date registered
31/01/2018
Date last updated
21/01/2020
Date data sharing statement initially provided
21/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Evaluate the Safety, Tolerability and Antiviral Activity of GS-9688 in Virally-Suppressed Adult Subjects with Chronic Hepatitis B
Scientific title
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the Safety, Tolerability and Antiviral Activity of GS-9688 in Virally-Suppressed Adult Subjects with Chronic Hepatitis B
Secondary ID [1] 293821 0
GS-US-389-2024
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B 306257 0
Condition category
Condition code
Infection 305359 305359 0 0
Other infectious diseases
Oral and Gastrointestinal 305492 305492 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
Within each cohort, approximately 25 subjects will be randomized in
a 1:2:2 in ratio to one of the three treatment arms (A: B: C). All
subjects will remain on their current commercially available OAV
therapy for the duration of the study, 48 weeks, in addition to the
following treatments:
Treatment Arm A: Approximately 5 subjects will be administered
placebo-to-match (PTM) orally on the same day once a week (every
7 days) for 24 doses
Treatment Arm B: Approximately 10 subjects will be administered
GS-9688 1.5 mg orally on the same day once a week (every 7 days)
for 24 doses
Treatment Arm C: Approximately 10 subjects will be administered
GS-9688 3 mg orally on the same day once a week (every 7 days) for
24 doses
All GS-9688 study drug doses will be administered in fasted state. Study drug will be administered at approximately the same time each day following an overnight
fast (no food or drinks, except water, for at least 8 hours with no food or drinks, including water, for the 1 hour before dosing). After dosing, subjects will continue to fast (no food or drinks, including water) for 2 hours. After 2 hours postdose, water is allowed and after 4 hours postdose,patients are allowed to eat any food or drinks.
After the 24th dose (Week 23 visit), GS-9688/PTM will be
discontinued. Subjects will continue being treated with their original
approved OAV and will be followed until the end of study (Week
48/ED). The total study duration for each subject will be 48 weeks
inclusive of the treatment period. Subjects should take their OAV
treatment and other commercially available medications no earlier
than 2 hours after GS-9688/PTM dosing.
Drug accountability will be performed at every in-clinic visit through capsule count.
Intervention code [1] 300089 0
Treatment: Drugs
Comparator / control treatment
PTM GS-9688 tablets contain the following inactive ingredients: microcrystalline cellulose,
lactose monohydrate, croscarmellose sodium, and magnesium stearate. The white tablet filmcoating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol (PEG) 3350, and talc. PTM GS-9688 tablets are identical in size, shape, color and appearance to the active GS-9688 tablets.
Control group
Placebo

Outcomes
Primary outcome [1] 304506 0
-To evaluate the safety and tolerability of multiple oral doses of GS-9688 at Week 24 in virally suppressed chronic hepatitis B (CHB) adult subjects on oral antivirals (OAV)
Timepoint [1] 304506 0
-Safety will be evaluated by assessment of clinical laboratory tests, ECGs/Holter monitoring, periodic physical examinations including vital signs at various time points during the study, and by documentation of AEs and concomitant medications.
-Clinical laboratory tests include blood and urine samples;
-Hematology :Hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, white blood cell (WBC) count with differential (absolute and percentage), including lymphocytes,
monocytes, neutrophils, eosinophils, basophils, and mean corpuscular volume (MCV),
and coagulation panel (screening only, prothrombin time, partial thromboplastin time
[PTT] and INR),
-Chemistry: Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, totalcholesterol, high-density lipoprotein (HDL), LDL, triglycerides (TG), total protein,
albumin, lactic acid dehydrogenase (LDH), CK, bicarbonate, blood urea nitrogen (BUN),
calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium,
sodium, uric acid, and lipase
-Serum pregnancy test
-FSH testing
-HIV, HDV, and HCV testing
-HBV Viral Parameters: Qualitative HBV Serology, HBV DNA levels, HBV Resistance Surveillance,Quantitative HBsAg, Quantitative HBCrAg, Quantitative HBeAg, and HBV RNA
-Urine: Urine samples will be collected for urinalysis, alcohol and drug screen assessments and urine pregnancy as applicable.
-Holter recording will be obtained via continuous 12-lead digital recorder. Holter monitoring will be taken at Day 1: Pre-dose (less than or equal to 5 minutes of dose) through 4 hours, and 24 hours, Week 11: Pre-dose (less than or equal to 5 minutes of dose) through 4 hours and Week 23: Pre-dose (less than or equal to5 minutes of dose) through 4 hours, and 24 hours.
Secondary outcome [1] 342179 0
To evaluate the antiviral activity of GS-9688 at Weeks 4, 8, 12 and 48 as measured by the proportion of subjects with greater than or equal to 1 log10 IU/mL decline from baseline in serum qHBsAg
Timepoint [1] 342179 0
-Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg [reflex HBsAb if HBsAg is negative]) at Screening, Weeks 24, 36, and 48/ED
Secondary outcome [2] 342602 0
To evaluate the antiviral activity of GS-9688 at Weeks 4, 8, 12 and 48 as measured by the proportion of subjects with greater than or equal to 1 log10 IU/mL decline from baseline in serum qHBsAg
Timepoint [2] 342602 0
-Quantitative HBsAg at Screening, Day 1 and Weeks 2, 4, 8, 11, 12, 16, 20, 23, 24, 36, and 48/ED

Eligibility
Key inclusion criteria
Must have the ability to understand and sign a written informed
consent form, which must be obtained prior to initiation of study
procedures
2) Adult male and non-pregnant, non-lactating female subjects,
18-65 years of age inclusive based on the date of the Screening
visit
3) Documented evidence of chronic HBV infection
(e.g. HBsAg positive for more than 6 months) with detectable
HBsAg levels at Screening
4) Females of childbearing potential
must have a negative serum pregnancy test at Screening and a
negative urine pregnancy test at Baseline prior to enrollment.
5) Male and female subjects of childbearing potential who engage in
heterosexual intercourse must agree to use protocol specified
method(s) of contraception
6) Have been on commercially available HBV OAV treatment(s)
(tenofovir alafenamide, tenofovir disoproxil fumurate, entecavir,
adefovir, lamivudine, telbivudine, either as single agents or in
combination) for at least 6 months with no change in regimen for
3 months prior to screening.
7) HBV Deoxyribonucleic acid (DNA) less than or equal to 20 IU/mL (lower limit of
quantitation [LLOQ]; measured at least once by local laboratory
assessment) for 6 or more months prior to Screening
8) HBV DNA greater than 20 IU/mL at Screening
9) Screening Electrocardiogram (ECG) without 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.
10) 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
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 greater than 0.48 and APRI greater than 1, or
c) Historic FibroScan with a result greater than 9 kPa within less 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) Subjects meeting any of the following laboratory parameters at
screening:
a) Hemoglobin greater than 12 g/dL (for males) or greater than 11 g/dL (for females)
b) White Blood cell count greater than 2500 cells/mm3
c) Neutrophil count < 1500 cells/mm3 (or < 1000 cells/mm3 if
considered a physiological variant in a subject of African
descent)
d) Alanine aminotransferase (ALT) >3x Upper Limit of Normal
(ULN)
e) International normalized ratio (INR) > ULN unless the subject
is stable on an anticoagulant regimen affecting INR
f) Albumin < 3.5 g/dL
g) Direct bilirubin >1.5x ULN
h) Platelet Count < 100,000/uL
i) Estimated creatinine clearance (CrCl) < 60 mL/min (using the
Cockcroft-Gault method) based on serum creatinine and
actual body weight as measured at the screening evaluation,
i.e.,
Male: (140 – Age [years]) x (Weight [kg]) divided by 72 x (Serum Creatinine [mg/dL]) equal CrCl (mL/min)
Female: (140 – Age [years]) x (Weight [kg]) x 0.85 divided by 72 x (Serum Creatinine [mg/dL]) equal CrCl (mL/min)

3) Co-infection with human immunodeficiency virus (HIV),
hepatitis C virus (HCV) or hepatitis D virus (HDV)
-Subjects who are HCV Ab positive, but have a documented
negative HCV RNA, are eligible
4) Prior history of hepatocellular carcinoma (HCC) (e.g. as
evidenced by prior imaging) or screening alpha-fetoprotein
(AFP) greater than or equal to 50 ng/mL without imaging to rule out HCC
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 in
the opinion of the investigator
7) Diagnosis of autoimmune disease (e.g., systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease,
autoimmune hepatitis, sarcoidosis, psoriasis of greater than mild
severity, autoimmune uveitis), poorly controlled diabetes
mellitus, significant psychiatric illness, severe chronic obstructive
pulmonary disease (COPD), hemoglobinopathy, retinal disease,
or are immunosuppressed
8) Chronic liver disease of a non-HBV etiology (e.g. Wilson’s
disease, hemochromatosis, alpha-1-antitrypsin deficiency,
cholangitis, nonalcoholic steatohepatitis), except for nonalcoholic
fatty liver disease
9) Received solid organ or bone marrow transplant
10) Received prolonged therapy with immunomodulators
(e.g. corticosteroids) or biologics (e.g. monoclonal antibody,
interferon) within 3 months of screening
11) Use of another investigational agent within 90 days 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 or formulation excipients
14) Women who are breastfeeding, pregnant or who wish to become
pregnant during the course of the study
15) Female subjects unwilling to refrain from egg donation and in
vitro fertilization during and until at least 30 days after the last
study drug dose
16) Male subjects unwilling to refrain from sperm donation during
and until at least 90 days after the last study drug dose
17) Use of any prohibited concomitant medications
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)
central randomisation by phone/fax/computer 
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerized sequence generation. Randomized 1:1 to Cohort 1 & Cohort 2
Within each Cohort 1:2:2 to receive either placebo, 1.5mg GS-9688 or 3mg GS-9688.
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
Cohort 1: HBeAg-positive CHB subjects
Cohort 2: HBeAg-negative CHB subjects

Within each cohort, approximately 25 subjects will be randomized in
a 1:2:2 in ratio to one of the three treatment arms (A: B: C).

-Treatment Arm A: Approximately 5 subjects will be administered
placebo-to-match (PTM) orally on the same day once a week (every
7 days) for 24 doses
-Treatment Arm B: Approximately 10 subjects will be administered
GS-9688 1.5 mg orally on the same day once a week (every 7 days)
for 24 doses
-Treatment Arm C: Approximately 10 subjects will be administered
GS-9688 3 mg orally on the same day once a week (every 7 days) for
24 doses
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/04/2018
Actual
6/04/2018
Date of last participant enrolment
Anticipated
Actual
5/10/2018
Date of last data collection
Anticipated
Actual
6/09/2019
Sample size
Target
50
Accrual to date
Final
48
Recruitment outside Australia
Country [1] 9504 0
New Zealand
State/province [1] 9504 0
Country [2] 9505 0
United States of America
State/province [2] 9505 0

Funding & Sponsors
Funding source category [1] 298434 0
Commercial sector/Industry
Name [1] 298434 0
Gilead Sciences, Inc.
Country [1] 298434 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc.
Address
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country
United States of America
Secondary sponsor category [1] 297576 0
None
Name [1] 297576 0
Address [1] 297576 0
Country [1] 297576 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299430 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 299430 0
Ethics committee country [1] 299430 0
New Zealand
Date submitted for ethics approval [1] 299430 0
25/01/2018
Approval date [1] 299430 0
20/02/2018
Ethics approval number [1] 299430 0

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

Contacts
Principal investigator
Name 80378 0
Prof Edward Gane
Address 80378 0
Auckland Clinical Studies Limited
3 Ferncroft Street, Auckland 1042
Country 80378 0
New Zealand
Phone 80378 0
+64 9 373 3474
Fax 80378 0
Email 80378 0
edgane@adhb.govt.nz
Contact person for public queries
Name 80379 0
Priyanka Nadig
Address 80379 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country 80379 0
United States of America
Phone 80379 0
+1 (650) 425-5527
Fax 80379 0
Email 80379 0
priyanka.nadig@gilead.com
Contact person for scientific queries
Name 80380 0
Susanna Tan
Address 80380 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country 80380 0
United States of America
Phone 80380 0
+1 (650) 425-5065
Fax 80380 0
Email 80380 0
Susanna.Tan3@gilead.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.