Clinical Trials List
Protocol NumberGS-US-439-4660
2019-10-04 - 2020-12-28
Phase I
Recruiting4
A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GS-4224 in Healthy Volunteers and Subjects with the Chronic Hepatitis B (CHB) Virus
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Trial Applicant
GILEAD SCIENCES HONG KONG LIMITED
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Sponsor
Gilead Sciences Hong Kong Limited Taiwan Branch
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Ming-Lung Yu 無
- Ming-Lun Yeh 無
- Jee-Fu Huang 無
- Chia-Yen Dai 無
- 梁博程 無
- Chung-Feng Huang 無
- 黃駿逸 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Chronic Hepatitis B
Objectives
The primary objectives of this study are as follows:
To evaluate the safety and tolerability of multiple oral doses of GS-4224 in CHB subjects virally suppressed on oral antivirals (OAV) or viremic subjects not on OAV treatment
The secondary objectives of this study are as follows:
To characterize the PK of GS-4224 in CHB subjects virally suppressed on OAV or viremic subjects not on OAV treatment
Test Drug
GS-4224 Film-coated Tablets, 10mg and 100mg
Active Ingredient
GS-4224
Dosage Form
Film-coated Tablets
Film-coated Tablets
Film-coated Tablets
Dosage
10
100
100
Endpoints
Safety:
Parts A and B: Safety will be evaluated by assessment of clinical laboratory tests, ECGs, periodic physical examinations including vital signs at various time points during the study, and by documentation of AEs and concomitant medications.
Efficacy: Part A and B: Not Applicable
Pharmacokinetics:
Part A: The following plasma PK parameters will be calculated for each analyte, as applicable: AUCinf (single dose), AUClast, %AUCexp (single dose), CL/F (single dose), CLss/F (multiple dose), t1/2, Vz/F, Cmax, Tmax, Clast, Tlast, AUCtau (multiple dose) and, Ctau (multiple dose). The following urine PK parameters will be calculated: Ae, CLr, and %Doseexcreted
Part B: The following plasma PK parameters will be calculated for each analyte, as applicable: AUCinf (Day 1 only), AUClast, %AUCexp (Day 1 only), CL/F (Day 1 only), CLss/F (Day 28 only), t1/2, Vz/F, Cmax, Tmax, Clast, Tlast, AUCtau (Day 28 only) and, Ctau (Day 28 only)
Pharmacodynamics:
Part A: The PD parameters that will be estimated may include % target occupancy at 24 hours, maximum % target occupancy achieved, durability of target occupancy after drug clearance, and fold and absolute changes in immune activation markers. Dose and/or exposure-response relationships for GS-4224 may be explored.
Part B: Dose and/or exposure-response relationships for GS-4224 may be explored.
Parts A and B: Safety will be evaluated by assessment of clinical laboratory tests, ECGs, periodic physical examinations including vital signs at various time points during the study, and by documentation of AEs and concomitant medications.
Efficacy: Part A and B: Not Applicable
Pharmacokinetics:
Part A: The following plasma PK parameters will be calculated for each analyte, as applicable: AUCinf (single dose), AUClast, %AUCexp (single dose), CL/F (single dose), CLss/F (multiple dose), t1/2, Vz/F, Cmax, Tmax, Clast, Tlast, AUCtau (multiple dose) and, Ctau (multiple dose). The following urine PK parameters will be calculated: Ae, CLr, and %Doseexcreted
Part B: The following plasma PK parameters will be calculated for each analyte, as applicable: AUCinf (Day 1 only), AUClast, %AUCexp (Day 1 only), CL/F (Day 1 only), CLss/F (Day 28 only), t1/2, Vz/F, Cmax, Tmax, Clast, Tlast, AUCtau (Day 28 only) and, Ctau (Day 28 only)
Pharmacodynamics:
Part A: The PD parameters that will be estimated may include % target occupancy at 24 hours, maximum % target occupancy achieved, durability of target occupancy after drug clearance, and fold and absolute changes in immune activation markers. Dose and/or exposure-response relationships for GS-4224 may be explored.
Part B: Dose and/or exposure-response relationships for GS-4224 may be explored.
Inclution 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, 18-65 years of age inclusive based on the date of the Screening visit (In Taiwan, only subjects who are ≥ 20 years of age will be enrolled.)
3) A negative serum pregnancy test is required for female subjects (unless permanently 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 as described in section “BIRTH CONTROL REQUIREMENTS”.
5) Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months) with detectable HBsAg levels at Screening (no retest permitted if initial Screening HBsAg is negative)
6) HBV DNA levels by central lab at Screening:
a) < 20 IU/mL (for subjects in Cohorts 11–13 and if virally suppressed subjects are enrolled into Cohorts 15 and/or 16)
b) ≥ 2000 IU/mL (for subjects in Cohort 14 and if viremic subjects not on OAV therapy are enrolled into Cohorts 15 and/or 16)
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) BMI 18-34 kg/m2 (inclusive)
9) Must be willing and able to comply with all study requirements
Additionally, subjects in Cohorts 11–13 and IF virally suppressed subjects are selected for Cohorts 15 and/or 16 should meet the following criteria to be eligible to participate in this study:
10) Have been on prescribed OAV treatment(s) (TAF, TDF and approved generics of TDF,
ETV, adefovir, lamivudine, TBV, either as single agents or in combination) with no change in regimen for 3 months prior to Screening. ― TAF and TDF (or generics of TDF)are not permitted unless new data becomes available that would allow concomitant use of TAF or TDF (or generics of TDF) during the trial (Cohort 8)
11) HBV DNA <69 IU/mL measured at least once at local lab for 6 or more months prior to Screening
2) Adult male and non-pregnant, non-lactating female subjects, 18-65 years of age inclusive based on the date of the Screening visit (In Taiwan, only subjects who are ≥ 20 years of age will be enrolled.)
3) A negative serum pregnancy test is required for female subjects (unless permanently 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 as described in section “BIRTH CONTROL REQUIREMENTS”.
5) Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 6 months) with detectable HBsAg levels at Screening (no retest permitted if initial Screening HBsAg is negative)
6) HBV DNA levels by central lab at Screening:
a) < 20 IU/mL (for subjects in Cohorts 11–13 and if virally suppressed subjects are enrolled into Cohorts 15 and/or 16)
b) ≥ 2000 IU/mL (for subjects in Cohort 14 and if viremic subjects not on OAV therapy are enrolled into Cohorts 15 and/or 16)
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) BMI 18-34 kg/m2 (inclusive)
9) Must be willing and able to comply with all study requirements
Additionally, subjects in Cohorts 11–13 and IF virally suppressed subjects are selected for Cohorts 15 and/or 16 should meet the following criteria to be eligible to participate in this study:
10) Have been on prescribed OAV treatment(s) (TAF, TDF and approved generics of TDF,
ETV, adefovir, lamivudine, TBV, either as single agents or in combination) with no change in regimen for 3 months prior to Screening. ― TAF and TDF (or generics of TDF)are not permitted unless new data becomes available that would allow concomitant use of TAF or TDF (or generics of TDF) during the trial (Cohort 8)
11) HBV DNA <69 IU/mL measured at least once at local lab 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 Asparate aminotransferase platelet ratio (APRI) >
0.8, or
c) Historic FibroScan with a result > 8 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 central laboratory parameters at Screening:
a) Hemoglobin < 12 g/dL (for males) or < 11 g/dL (for females)
b) White Blood cell count < 2500 cells/uL
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) INR > ULN
f) Albumin < 3.5 g/dL
g) Direct bilirubin > 1.5x ULN
h) Platelet Count < 100,000 /ml
i) ANA > 1:80
j) SMA > 1:80
k) AMA > 1:40
l) anti-TPO > 1:40 or > ULN by central lab
3) Estimated 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, ie,
4) Co-infection with HIV, HCV or hepatitis D virus (HDV)
a) Subjects who are HCV or HDV positive by serology, but have a documented Screening
negative HCV or HDV RNA, respectively, are eligible
5) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
6) Significant cardiac disease (including history of myocardial infarction based on ECG
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or
dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of
long QT syndrome or unexplained death in an otherwise healthy individual between the
ages of 1 and 30 years
7) 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
8) Significant cardiovascular, pulmonary, or neurological disease
9) Documented myocardial infarction or unstable/uncontrolled cardiac disease (e.g., unstable
angina, congestive heart failure [New York Heart Association > Class II]) within 6 months
of randomization should be excluded
10) 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, autoimmune thyroid disease), poorly
controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive
pulmonary disease (COPD), malignancy (with exception of certain skin cancers),
hemoglobinopathy, or are immunosuppressed
11) Chronic liver disease of a non-HBV etiology (e.g. Wilson's disease, hemochromatosis,
alpha-1-antitrypsin deficiency, cholangitis), except for non-alcoholic fatty liver disease
12) History of hepatic decompensation (e.g. ascites, encephalopathy, or variceal
hemorrhage) within 5 years prior to Screening
13) Received solid organ or bone marrow transplant
14) Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics
(e.g. monoclonal antibody, interferon) within 3 months of Screening
15) Have received inactivated vaccinations (e.g. injectable influenza or pneumococcal) within 4 weeks prior to randomization or received live vaccinations within 4 weeks prior to Screening
16) Have donated blood within 28 days of screening or plasma within 7 days of screening
and must refrain from blood donation from screening, throughout the study period, and
continuing for at least 30 days following the last dose of study drug
17) Use of anticoagulant therapy
18) Use of another investigational agent within 30 days of Screening, unless allowed by the Sponsor
19) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
20) Known hypersensitivity to study drug, metabolites or formulation excipients
21) Women who are breastfeeding or may wish to become pregnant during the course of the
study
22) 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
23) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after the last dose of study drug
24) Use of any prohibited concomitant medications
25) Believed by the Study Investigator to be inappropriate for study participation for any reason not otherwise listed
Additionally, subjects in Cohort 14 and IF viremic subjects not on OAV therapy are selected for Cohorts 15 and/or 16 who meet the following criterion are not to be enrolled in this study:
26) Received OAV treatment for HBV within 3 months of Screening
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 Asparate aminotransferase platelet ratio (APRI) >
0.8, or
c) Historic FibroScan with a result > 8 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 central laboratory parameters at Screening:
a) Hemoglobin < 12 g/dL (for males) or < 11 g/dL (for females)
b) White Blood cell count < 2500 cells/uL
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) INR > ULN
f) Albumin < 3.5 g/dL
g) Direct bilirubin > 1.5x ULN
h) Platelet Count < 100,000 /ml
i) ANA > 1:80
j) SMA > 1:80
k) AMA > 1:40
l) anti-TPO > 1:40 or > ULN by central lab
3) Estimated 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, ie,
4) Co-infection with HIV, HCV or hepatitis D virus (HDV)
a) Subjects who are HCV or HDV positive by serology, but have a documented Screening
negative HCV or HDV RNA, respectively, are eligible
5) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
6) Significant cardiac disease (including history of myocardial infarction based on ECG
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or
dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of
long QT syndrome or unexplained death in an otherwise healthy individual between the
ages of 1 and 30 years
7) 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
8) Significant cardiovascular, pulmonary, or neurological disease
9) Documented myocardial infarction or unstable/uncontrolled cardiac disease (e.g., unstable
angina, congestive heart failure [New York Heart Association > Class II]) within 6 months
of randomization should be excluded
10) 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, autoimmune thyroid disease), poorly
controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive
pulmonary disease (COPD), malignancy (with exception of certain skin cancers),
hemoglobinopathy, or are immunosuppressed
11) Chronic liver disease of a non-HBV etiology (e.g. Wilson's disease, hemochromatosis,
alpha-1-antitrypsin deficiency, cholangitis), except for non-alcoholic fatty liver disease
12) History of hepatic decompensation (e.g. ascites, encephalopathy, or variceal
hemorrhage) within 5 years prior to Screening
13) Received solid organ or bone marrow transplant
14) Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics
(e.g. monoclonal antibody, interferon) within 3 months of Screening
15) Have received inactivated vaccinations (e.g. injectable influenza or pneumococcal) within 4 weeks prior to randomization or received live vaccinations within 4 weeks prior to Screening
16) Have donated blood within 28 days of screening or plasma within 7 days of screening
and must refrain from blood donation from screening, throughout the study period, and
continuing for at least 30 days following the last dose of study drug
17) Use of anticoagulant therapy
18) Use of another investigational agent within 30 days of Screening, unless allowed by the Sponsor
19) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
20) Known hypersensitivity to study drug, metabolites or formulation excipients
21) Women who are breastfeeding or may wish to become pregnant during the course of the
study
22) 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
23) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after the last dose of study drug
24) Use of any prohibited concomitant medications
25) Believed by the Study Investigator to be inappropriate for study participation for any reason not otherwise listed
Additionally, subjects in Cohort 14 and IF viremic subjects not on OAV therapy are selected for Cohorts 15 and/or 16 who meet the following criterion are not to be enrolled in this study:
26) Received OAV treatment for HBV within 3 months of Screening
The Estimated Number of Participants
-
Taiwan
27 participants
-
Global
246 participants
