None listed
Conditions
Brief summary
This Phase 1b study entails administration of GS-9688 in CHB subjects for the first time with the objective of evaluating its safety, tolerability, PK and PD, and thereby understand the clinical pharmacology profile of GS-9688 to determine if it is suitable for clinical development as a treatment for CHB. The results from this study will form the basis for further evaluation of GS 9688 and dose selection for a Phase 2 study in subjects with CHB. This study will proceed in two parts, governed within and between parts by reviews of safety data and application of stopping rules, as applicable. Based on safety and available PK and PD data, and at the discretion of the sponsor in consultation with the investigators, any cohort may be repeated at the same dose level, be held until further safety, PK or PD data are available, or not be initiated.
Interventions
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 d
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.
Sponsors
Gilead Sciences, Inc.
Study design
Allocation
Randomised controlled trial
Intervention model
Other
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
No
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
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
Outcome results
None listed