None listed
Conditions
Brief summary
This Phase 1 study entails administration of GS-5801 to subjects with chronic hepatitis B (CHB) for the first time with the objective of evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GS 5801, and thereby determining the clinical pharmacology profile and antiviral activity of GS 5801 to evaluate if it is suitable for further clinical development as a treatment for CHB. The results from this study will form the basis for further evaluation of GS 5801 and dose selection for upcoming studies in subjects with CHB. The study will proceed in two parts, with the first part (Part A) evaluating the safety, tolerability, PK and PD of GS-5801 administered once daily for 7 days in the fasted state via a pre specified dose escalation through 2 cohorts. The second part (Part B) is designed to evaluate the safety, tolerability, PK, and PD of GS-5801 with adaptive dose selection (up to 100 mg administered once daily for 7 days). The doses evaluated in the adaptive cohorts (Part B) will be selected based on safety and available PK and PD data (up to day 14) from Part A (Cohorts 1-2) and available safety, PK and PD data from previously conducted cohorts from Study GS US 405 2064
Interventions
Part A (Dose-escalation, pre-specified cohorts 1 and 2):
Cohort 1: 2 mg GS-5801 (1 x 2 mg tablet) or placebo once daily (Days 1 to 7) - fasted
Cohort 2: 6 mg GS-5801 (3 x 2 mg tablet) or placebo once daily (Days 1 to 7) - fasted
Part B (Adaptive cohorts 3 - 6):
Cohort 3 - 6: 2 mg to 100 mg GS-5801 or placebo once daily (Days 1 to 7) - fasted
Dose selection will be based on safety, tolerability, PK and PD data from previously completed cohorts.
Fasted - no food or drinks except water, for at le
Part A (Dose-escalation, pre-specified cohorts 1 and 2): Cohort 1: 2 mg GS-5801 (1 x 2 mg tablet) or placebo once daily (Days 1 to 7) - fasted Cohort 2: 6 mg GS-5801 (3 x 2 mg tablet) or placebo once daily (Days 1 to 7) - fasted Part B (Adaptive cohorts 3 - 6): Cohort 3 - 6: 2 mg to 100 mg GS-5801 or placebo once daily (Days 1 to 7) - fasted Dose selection will be based on safety, tolerability, PK and PD data from previously completed cohorts. Fasted - no food or drinks except water, for at least 10 hours 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. Have been on approved HBV OAV treatment for =>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 Tenofovir DF, Tenofovir alafenamide, entecavir, adefovir, lamivudine, or telbivudine, either as single agent or in combination with no change in regimen for 3 months prior to screening. 8. 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 9. Body mass index (BMI) 18-34 kg/m2, inclusive 10. Must be willing and able to comply with all study requirements
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. ALT > 3x ULN d. Direct bilirubin > 1.5x ULN e. INR > ULN unless the subject is stable on an anticoagulant regimen affecting INR f. Albumin < 3.9 g/dL g. Platelet Count < 125,000 /mL h. 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) 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
Outcome results
None listed