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Trial registered on ANZCTR


Registration number
ACTRN12617000235303
Ethics application status
Approved
Date submitted
10/02/2017
Date registered
15/02/2017
Date last updated
9/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9688 in Patients with Chronic Hepatitis B
Scientific title
A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9688 in Patients with Chronic Hepatitis B
Secondary ID [1] 291116 0
GS-US-389-2022
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B 301946 0
Condition category
Condition code
Infection 301597 301597 0 0
Other infectious diseases
Oral and Gastrointestinal 301694 301694 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
Part A (Pre-specified cohort 1 and Adaptive Cohorts 2 & 3):
Cohort 1 – 3: GS-9688 up to 30 mg will be administered orally once weekly for two doses
Cohort 1 - 3: Placebo To Match (PTM) to up to 30 mg strength GS 9688 will be administered orally once weekly for two doses

Part B (Adaptive cohort 4):
Cohort 4: GS-9688 up to 30 mg will be administered orally once weekly for two doses
Cohort 4: Placebo To Match (PTM) to up to 30 mg strength GS 9688 will be administered orally once weekly for two doses.

Dose selection in Cohort 1 will be based on safety, tolerability of the same dose evaluated in healthy subjects from Study GS-US-389-2021*. GS-9688 doses of up to 30 mg to be evaluated in Cohorts 2 and 3 will be selected after review of cumulative safety and available PK and PD data from the FIH evaluation (GS-US-389-2021) and previous cohort(s) within GS-US-389-2022. Based on safety and tolerability data up to Day 11 for Cohorts 1-3, the highest dose of GS-9688 tested and deemed safe from Cohorts 1-3 will be the dosage tested in Cohort 4.

Fasted - no food or drinks except water, for at least 10 hours

*Note: GS-US-389-2021 registration number: ACTRN12616001646437

The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study center will be administered by qualified study center staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be accurately recorded, which indicates the date and quantity of each dosage formulation dispensed to individual subjects.
Used and unused study drug supplies, including empty containers, are to be returned to the shipping facility from which it came for destruction following drug accountability and drug inventory reconciliation.
Intervention code [1] 297102 0
Treatment: Drugs
Comparator / control treatment
Placebo to match (PTM) GS 9688 tablets are identical in size, shape, color and appearance to the corresponding active strength GS 9688 tablets. The PTM GS-9688 tablet cores contain commonly used excipients including microcrystalline cellulose, lactose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc.
Control group
Placebo

Outcomes
Primary outcome [1] 300999 0
To evaluate the safety and tolerability of multiple oral doses of GS-9688 in chronic hepatitis B (CHB) subjects virally suppressed on oral antivirals (OAV) and CHB subjects not currently on treatment with OAV
Timepoint [1] 300999 0
Safety will be evaluated throughout the study.
Incidences of adverse events will be monitored continuously from screening to end of study.
Vital signs: Screening, Day1, 2, 4, 8, 9, 11, 15, 36 and Early Termination
ECG: Screening, Day1, 2, 4, 8, 9, 11, 15 and Early Termination
Lab assessments: Screening, Day1, 2, 4, 8, 9, 11, 22, 36 and Early Termination
Ophthalmologic exam: Screening, Days 2, 8, 9, and 15
Secondary outcome [1] 331391 0
To characterize the pharmacokinetics (PK) of GS-9688 in CHB subjects virally suppressed on OAV and CHB subjects not currently on treatment with OAV
Timepoint [1] 331391 0
Part A and B (Cohorts 1-4): Intensive PK sampling will occur relative to dosing of GS-9688 or placebo at the following time points for each cohort:
Day 1: 0 (predose, =< 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours postdose.
Days 8: 0 (predose, =< 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours postdose.
Secondary outcome [2] 331392 0
To evaluate the activity of GS 9688 on HBV in CHB subjects virally suppressed on OAV and CHB subjects not currently on treatment with OAV as measured by the change from Baseline (BL) in serum hepatitis B surface antigen (HBsAg log10 IU/mL) levels
Timepoint [2] 331392 0
HBV Serology HBeAg, HBsAg, reflex HBeAb, and HBsAb will be assessed as per the following:
HBsAG: Day 1, 8, 15, 36 and Early Termination
HBeAG: Day 1, 4, 8, 11, 15, 22, 36 and Early Termination

Eligibility
Key inclusion criteria
1. 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, (lactating females must agree to discontinue nursing before the study drug is administered and through the follow up period), 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 postmenopausal).
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. HBV DNA levels at Screening: < 20 IU/mL (for subjects in cohorts 1-3 only) and => 2000 IU/mL (for subjects in cohort 4 only).
7. Screening ECG without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia’s formula) =<450 msec for males and =<470 msec for females
8. Body mass index (BMI) 18-34 kg/m2, inclusive
9. Must be willing and able to comply with all study requirements
Additionally, subjects in Part A (Cohorts 1 – 3) should meet the following criteria to be eligible to participate in this study:
10. Have been on prescribed HBV OAV treatment(s) with no change in regimen for 3 months prior to screening.
11. HBV DNA below lower limit of quantitation (LLOQ) (measured at least once by local laboratory assessment) for 6 or more months prior to Screening
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 => 3 or Ishak fibrosis score => 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 =< 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 <12 g/dL (for males), <11 g/dL (for females)
b. White Blood cell count < 2500 IU/mL
c. Neutrophil count < 1500 cell/mm3 (or < 1000 cell/mm3 if considered a physiological variant in a subject of African descent)
d. ALT > 3x ULN
e. Direct bilirubin > 1.5x ULN
f. INR > ULN unless the subject is stable on an anticoagulant regimen affecting INR
g. Albumin < 3.9 g/dL
h. Platelet Count < 100,000 /mL
i. Estimate creatinine clearance (CLcr) < 80 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 HIV, hepatitis C virus (HCV) or hepatitis D virus (HDV). Subjects who are HCV positive, but have a documented negative HCV RNA, are eligible
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. Diagnosis of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, psoriasis of greater than mild severity), poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), malignancy (with exception of certain skin cancers) hemoglobinopathy, retinal disease, or are immunosuppressed
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 antibody, interferon) within 3 months of Screening
11. Use of another investigational agents within 30 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, metabolites or formulation excipients
14. Women who may wish to become pregnant during the course of the study
15. Male subjects unwilling to refrain from sperm donation for at least 90 days after the last dose of study drug
16. Use of any prohibited concomitant -medications
17. Believed by the Study Investigator to be inappropriate for study
Additionally, subjects in Part B (Cohort 4) who meet the following criterion are not to be enrolled in this study:
18. Received OAV treatment for HBV within 3 months of screening

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)
Part A: (Cohorts 1-3): 10 per cohort (8 GS-9688, 2 placebo-to-match)
Part B: (Cohorts 4): 10 per cohort (8 GS-9688, 2 placebo-to-match)

Part A: Pre-specified Cohort 1 and Adaptive Cohorts 2 and 3 in Virally Suppressed CHB subjects.
Part B: Adaptive Cohort 4 in CHB subjects not on Treatment

Allocation was concealed by central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation. Randomized 4:1 to receive either blinded GS-9688 (N=8) or matching placebo (N=2)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Part A (Cohorts 1-3): Randomized, blinded, placebo-controlled, multiple-doses with adaptive doses.
Part B (Cohort 4): Randomized, blinded, placebo-controlled, multiple-doses with adaptive dose selection.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
24/03/2017
Actual
2/05/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
36
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment outside Australia
Country [1] 8639 0
New Zealand
State/province [1] 8639 0
Country [2] 8640 0
Korea, Republic Of
State/province [2] 8640 0

Funding & Sponsors
Funding source category [1] 295555 0
Commercial sector/Industry
Name [1] 295555 0
Gilead Sciences, Inc.
Country [1] 295555 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] 294376 0
None
Name [1] 294376 0
Address [1] 294376 0
Country [1] 294376 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296876 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 296876 0
Ethics committee country [1] 296876 0
New Zealand
Date submitted for ethics approval [1] 296876 0
28/02/2017
Approval date [1] 296876 0
06/04/2017
Ethics approval number [1] 296876 0

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

Contacts
Principal investigator
Name 72302 0
Prof Edward Gane
Address 72302 0
Auckland Clinical Studies Limited
3 Ferncroft Street, Auckland 1042
Country 72302 0
New Zealand
Phone 72302 0
+64 9 373 3474
Fax 72302 0
Email 72302 0
edgane@adhb.govt.nz
Contact person for public queries
Name 72303 0
Priyanka Nadig
Address 72303 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country 72303 0
United States of America
Phone 72303 0
+1 650 425 5527
Fax 72303 0
Email 72303 0
Priyanka.Nadig@gilead.com
Contact person for scientific queries
Name 72304 0
Priyanka Nadig
Address 72304 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA 94404
Country 72304 0
United States of America
Phone 72304 0
+1 650 425 5527
Fax 72304 0
Email 72304 0
Priyanka.Nadig@gilead.com

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

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

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIDefective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand2018https://doi.org/10.1016/s2468-1253(18)30007-4
Dimensions AIInnovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond2018https://doi.org/10.1016/j.antiviral.2018.05.005
Dimensions AIModulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B2018https://doi.org/10.1016/j.coviro.2018.01.008
EmbaseSafety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B.2021https://dx.doi.org/10.1002/hep.31795
Dimensions AIRecent Drug Development in the Woodchuck Model of Chronic Hepatitis B2022https://doi.org/10.3390/v14081711
N.B. These documents automatically identified may not have been verified by the study sponsor.