CompletedPhase 2ACTRN12618000143224

A Study to Evaluate the Safety, Tolerability and Antiviral Activity of GS-9688 in Virally-Suppressed Adult Subjects with Chronic Hepatitis B

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

Sponsor

Gilead Sciences, Inc.

Enrollment

50 participants

Start Date

Apr 6, 2018

Study Type

Interventional

Conditions

Chronic Hepatitis B

Summary

This Phase 2 study entails administration of GS-9688 to subjects with chronic hepatitis B (CHB) Evaluate the Safety, Tolerability and Antiviral Activity of GS-9688 in Virally-Suppressed Adult Subjects. Approximately 50 virally suppressed subjects currently being treated with a commercially available OAV for CHB will be enrolled into two cohorts within this study (1:1) that will run in parallel. Cohort 1 which will consists of HBeAg-positive CHB subjects and Cohort 2 will be 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). 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 and 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. The results from this study will form the basis for further evaluation of GS-9688 or upcoming studies in subjects with CHB.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 65 Yearss

Inclusion Criteria29

Must have the ability to understand and sign a written informed
consent form, which must be obtained prior to initiation of study
procedures
Adult male and non-pregnant, non-lactating female subjects,
-65 years of age inclusive based on the date of the Screening
visit
Documented evidence of chronic HBV infection
(e.g. HBsAg positive for more than 6 months) with detectable
HBsAg levels at Screening
Females of childbearing potential
must have a negative serum pregnancy test at Screening and a
negative urine pregnancy test at Baseline prior to enrollment.
Male and female subjects of childbearing potential who engage in
heterosexual intercourse must agree to use protocol specified
method(s) of contraception
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
months prior to screening.
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
HBV DNA greater than 20 IU/mL at Screening
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.
Must be willing and able to comply with all study requirements

Exclusion Criteria74

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
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)
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
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
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
Significant cardiovascular, pulmonary, or neurological disease in
the opinion of the investigator
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
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
Received solid organ or bone marrow transplant
Received prolonged therapy with immunomodulators
(e.g. corticosteroids) or biologics (e.g. monoclonal antibody,
interferon) within 3 months of screening
Use of another investigational agent within 90 days of screening,
unless allowed by the Sponsor
Current alcohol or substance abuse judged by the investigator to
potentially interfere with subject compliance
Known hypersensitivity to study drug or formulation excipients
Women who are breastfeeding, pregnant or who wish to become
pregnant during the course of the study
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
Male subjects unwilling to refrain from sperm donation during
and until at least 90 days after the last study drug dose
Use of any prohibited concomitant medications
Believed by the Study Investigator to be inappropriate for study
participation for any reason not otherwise listed

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Interventions

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 OA

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.