Clinical Trials List
Protocol Number205670
NCT Number(ClinicalTrials.gov Identfier)NCT03020745
2017-02-01 - 2019-06-30
Others
Recruiting8
ICD-10B18.1
Chronic viral hepatitis B without delta-agent
ICD-10B18
Chronic viral hepatitis
ICD-9070.32
Viral hepatitis B without mention of hepatic coma, chronic, without mention of hepatitis delta
A Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 in Chronic Hepatitis B Subjects
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Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
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Sponsor
GlaxoSmithKline Research & Development Limited
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Wei-Fan Hsu Digestive System Department
- Hung-Wei Wang Digestive System Department
- 陳昇弘 Digestive System Department
- 蘇文邦 Digestive System Department
- Hung-Yao Chen Digestive System Department
- Hsueh-Chou Lai Digestive System Department
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Pin-Nan Cheng Digestive System Department
- 吳毅晉 Digestive System Department
- 邱彥程 Digestive System Department
- Chiu Hung Chiu Digestive System Department
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Co-Principal Investigator
- Jing-Houng Wang Digestive System Department
- 洪肇宏 Digestive System Department
- 紀廣明 Digestive System Department
- 嚴毅豪 Digestive System Department
- 張國欽 Digestive System Department
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- 楊宏志 Digestive System Department
- Chun-Jen Liu Digestive System Department
- 蘇東弘 Digestive System Department
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Jee-Fu Huang Digestive System Department
- Chia-Yen Dai Digestive System Department
- Ming-Lung Yu Digestive System Department
- 黃駿逸 Digestive System Department
- Chung-Feng Huang Digestive System Department
- Ming-Lun Yeh Digestive System Department
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
The plan includes adult male and female CHB subjects aged 18 to 70 (inclusive) who are not currently receiving CHB treatment. Part 1 (Groups A, B, C, and D) will include HBeAg-positive subjects, while Part 1 (Group C1) will include HBeAg-negative subjects. After completing part 1 of the administration (after reviewing the safety, tolerability, PK and PD differences between HBeAg status), the specific CHB group included in part 2 will be determined
Objectives
To assess the safety, tolerability, and PK profile of GSK3389404 in single (Part 1) and multiple (Part 2) administration in subjects with CHB.
To identify one or more efficacious dose(s) and dosing regimen(s) of GSK3389404 over a planned duration of 3 months (Part 2).
To assess the PD effect of GSK3389404 in subjects with CHB (Part 1 and Part 2).
To investigate the PK of the metabolite of GSK3389404, also known as ISIS 505358, following single and multiple dose administration of GSK3389404 (Part 1 and Part 2).
To assess PD differences in HBeAg-positive and HBeAg-negative subjects with CHB (Part 1 and Part 2, if applicable).
Test Drug
GSK3389404
Active Ingredient
GSK3389404
Dosage Form
Solution for Injection
Dosage
100 mg/mL
Endpoints
Safety and Tolerability
As measured by clinical assessments including, but not limited to
Vital signs
Physical examinations
12-lead electrocardiograms (ECGs)
Laboratory measurements (e.g., chemistry, hematology)
Adverse events
Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters including, but not limited
to area under the concentration-time curve (AUC), maximum observed
concentration (Cmax), time of maximum observed concentration (tmax), terminal
half-life (t½, and apparent subcutaneous plasma clearance (CL/F)
Efficacy
Response rate (RR) based on the proportion of subjects with at least a
1.5 times log 10 copies/mL reduction of hepatitis B surface antigen (HBsAg)
levels from baseline anytime during the study.
Correlation between GSK3389404 PK parameters and PD parameters,
including hepatitis B virus (HBV) deoxyribonucleic acid (DNA), HBsAg,
and HBeAg levels (as appropriate, HBeAg-positive subjects).
Derived ISIS 505358 plasma PK parameters including, but not limited
to AUC, Cmax, tmax, and t½.
Correlation between PD parameters, including HBV DNA and HBsAg.
As measured by clinical assessments including, but not limited to
Vital signs
Physical examinations
12-lead electrocardiograms (ECGs)
Laboratory measurements (e.g., chemistry, hematology)
Adverse events
Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters including, but not limited
to area under the concentration-time curve (AUC), maximum observed
concentration (Cmax), time of maximum observed concentration (tmax), terminal
half-life (t½, and apparent subcutaneous plasma clearance (CL/F)
Efficacy
Response rate (RR) based on the proportion of subjects with at least a
1.5 times log 10 copies/mL reduction of hepatitis B surface antigen (HBsAg)
levels from baseline anytime during the study.
Correlation between GSK3389404 PK parameters and PD parameters,
including hepatitis B virus (HBV) deoxyribonucleic acid (DNA), HBsAg,
and HBeAg levels (as appropriate, HBeAg-positive subjects).
Derived ISIS 505358 plasma PK parameters including, but not limited
to AUC, Cmax, tmax, and t½.
Correlation between PD parameters, including HBV DNA and HBsAg.
Inclution Criteria
Subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Subject is able to understand and is capable of giving written informed
consent, is willing to comply with protocol requirements, instructions and
protocol-stated restrictions, and is likely to complete the study as planned.
2. Between 18 and 70 years of age, inclusive, at the time of signing the informed
consent form. (The subject participating in this study in Taiwan must be at or over 20 years of age.)
3. A body mass index (BMI) between 18 to 30 kg/m2 , inclusive.
4. Male or female if they satisfy the following:
(1) Females of reproductive potential are not permitted. Eligible females
must meet the following criteria:
a. Non-pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test); AND
b. Non-lactating at screening and prior to dosing; AND
c. Non-reproductive potential as defined by at least one of the following conditions:
(a) Premenopausal females without reproductive potential
defined by one of the following:
i. Documented salpingectomy;
ii. Hysterectomy;
iii. Documented bilateral oophorectomy.
(b) Postmenopausal defined as 12 months of spontaneous amenorrhea.
(c) A blood sample for simultaneous follicle-stimulating
hormone (FSH) and estradiol levels may be collected at the
discretion of the investigator or site to confirm
non-reproductive potential. Please refer to laboratory
reference ranges for confirmatory levels for menopause.
(2) Male subjects with a female partner of child-bearing potential must
agree to meet one of the contraception requirements from the time of first
dose of study treatment until the final Follow-up visit.
a. Vasectomy
b. Male condom plus partner’s use of one of the contraceptive
options below that meets the standard operating procedure (SOP)
effectiveness criteria including a <1% rate of failure per year, as
stated in the product label:
(a) Contraceptive subdermal implant
(b) Intrauterine device or intrauterine system
(c) Combined estrogen and progestogen oral contraceptive
(d) Injectable progestogen
(e) Contraceptive vaginal ring
(f) Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used
consistently, correctly and in accordance with the product label. The investigator
is responsible for ensuring that subjects understand how to properly use these
methods of contraception.
5. Documented chronic HBV infection, defined as positive serum HBsAg ≥6 months prior to screening.
6. Treatment naive or have had prior treatment with interferon (pegylated or
non-pegylated) that must have ended at least 12 months prior to the Baseline
visit (Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that must have
ended at least 6 months prior to the Baseline visit.
7. Plasma HBV DNA concentration:
a. ≥20,000 IU/mL for HBeAg-positive subject
b. ≥2000 IU/mL for HBeAg-negative subjects
8. Serum HBsAg concentration >50 IU/mL.
9. Alanine aminotransferase (ALT) concentration >60 U/L for males, >38 U/L for females, and ≤10 X the upper limit of normal (ULN).
1. Subject is able to understand and is capable of giving written informed
consent, is willing to comply with protocol requirements, instructions and
protocol-stated restrictions, and is likely to complete the study as planned.
2. Between 18 and 70 years of age, inclusive, at the time of signing the informed
consent form. (The subject participating in this study in Taiwan must be at or over 20 years of age.)
3. A body mass index (BMI) between 18 to 30 kg/m2 , inclusive.
4. Male or female if they satisfy the following:
(1) Females of reproductive potential are not permitted. Eligible females
must meet the following criteria:
a. Non-pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test); AND
b. Non-lactating at screening and prior to dosing; AND
c. Non-reproductive potential as defined by at least one of the following conditions:
(a) Premenopausal females without reproductive potential
defined by one of the following:
i. Documented salpingectomy;
ii. Hysterectomy;
iii. Documented bilateral oophorectomy.
(b) Postmenopausal defined as 12 months of spontaneous amenorrhea.
(c) A blood sample for simultaneous follicle-stimulating
hormone (FSH) and estradiol levels may be collected at the
discretion of the investigator or site to confirm
non-reproductive potential. Please refer to laboratory
reference ranges for confirmatory levels for menopause.
(2) Male subjects with a female partner of child-bearing potential must
agree to meet one of the contraception requirements from the time of first
dose of study treatment until the final Follow-up visit.
a. Vasectomy
b. Male condom plus partner’s use of one of the contraceptive
options below that meets the standard operating procedure (SOP)
effectiveness criteria including a <1% rate of failure per year, as
stated in the product label:
(a) Contraceptive subdermal implant
(b) Intrauterine device or intrauterine system
(c) Combined estrogen and progestogen oral contraceptive
(d) Injectable progestogen
(e) Contraceptive vaginal ring
(f) Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used
consistently, correctly and in accordance with the product label. The investigator
is responsible for ensuring that subjects understand how to properly use these
methods of contraception.
5. Documented chronic HBV infection, defined as positive serum HBsAg ≥6 months prior to screening.
6. Treatment naive or have had prior treatment with interferon (pegylated or
non-pegylated) that must have ended at least 12 months prior to the Baseline
visit (Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that must have
ended at least 6 months prior to the Baseline visit.
7. Plasma HBV DNA concentration:
a. ≥20,000 IU/mL for HBeAg-positive subject
b. ≥2000 IU/mL for HBeAg-negative subjects
8. Serum HBsAg concentration >50 IU/mL.
9. Alanine aminotransferase (ALT) concentration >60 U/L for males, >38 U/L for females, and ≤10 X the upper limit of normal (ULN).
Exclusion Criteria
Subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. Medical history
a. History of or active diagnosis of liver disease other than CHB, such as
autoimmune hepatitis, non-alcoholic fatty liver disease/non-alcoholic
steatohepatitis, hemochromatosis, or liver failure.
b.History or other clinical evidence of hypertension, significant or unstable
cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina,
congestive heart failure, myocardial infarction, diastolic dysfunction,
significant arrhythmia, coronary heart disease and/or clinically significant ECG abnormalities).
c. History of, or active diagnosis of, primary or secondary renal disease (e.g.,
renal disease secondary to diabetes, hypertension, vascular disease, etc.).
d.History of extrahepatic disorders possibly related to HBV immune
complexes (e.g., glomerulonephritis and polyarteritis nodosa).
e. History of bleeding diathesis or coagulopathy.
f. History of or suspected presence of vasculitis.
g.History of Gilbert’s Syndrome.
h. History of malignancy within the past 5 years with the exception of specific
cancers that are cured by surgical resection (e.g., skin cancer), subjects
under evaluation for possible malignancy are not eligible.
2. History of/sensitivity to GSK3389404 or components thereof or a history of drug
or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
3. Confirmed or suspected HCC as evidenced by:
a. Alpha-fetoprotein concentration ≥ 200 ng/mL. If the screening
alpha-fetoproteinconcentration is ≥ 50 ng/mL and <200 ng/mL, the
absence of liver mass must be documented by imaging within 6 months before randomization
4. Liver cirrhosis or evidence of cirrhosis as determined by any of the following:
a. Positive liver biopsy (i.e., Metavir Score F4) within 12 months of screening
b. Fibroscan >12 kPa within 12 months of screening
c. Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure result >0.7 within 12 months of screening
For subjects without a test for cirrhosis in the above timeframes, APRI and
FibroSure should be performed during the screening period to rule out cirrhosis.
5. A positive hepatitis C virus (HCV) antibody test
6. A positive human immunodeficiency virus (HIV) antibody test
7. Positive hepatitis D virus (HDV) antibody test
8. Laboratory results as follows:
a. Total bilirubin concentration >1.25 X ULN
b.Serum albumin concentration <3.5 g/dL
c. International normalized ratio (INR) >1.25
d.Platelet count <140 X 109/L
e. Serum creatinine concentration greater than the ULN
f. Glomerular filtration rate (GFR) <90 mL/min as calculated by the Chronic
Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula.
Subjects with GFR <90 mL/min but 80 mL/min may be considered
after consultation with the GSK medical monitor.
g.Urine albumin to creatinine ratio (ACR) ≥ 0.03 mg/mg. In the event of an
ACR above this threshold, eligibility may be confirmed by a second measurement
9. Positive test for blood in urine. In the event of a positive test, the test may be
repeated once, and if repeat is negative or if urine microscopy reveals <5 red
blood cells (RBC) per high-power field (HPF), the subject is considered eligible.
10. Fridericia’s QT correction formula (QTcF) ≥ 450 msec (mean of triplicate measurements).
11. Currently taking, or took within 3 months of screening, any immunosuppressing
drugs (e.g., prednisone), other than a short course of therapy (≤ 2 weeks).
12. Current alcohol use as judged by investigator to potentially interfere with participant compliance.
13. A positive pre-study treatment screen or an unwillingness to refrain from use of
the illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
14. Where participation in the study would result in donation of blood or blood
products in excess of 500 mL within a 56-day period.
15. The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the
current study: 5 half-lives (if known) or twice the duration (if known) of the
biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown).
16. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
17. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within
12 months prior to the first dosing day.
apply:
1. Medical history
a. History of or active diagnosis of liver disease other than CHB, such as
autoimmune hepatitis, non-alcoholic fatty liver disease/non-alcoholic
steatohepatitis, hemochromatosis, or liver failure.
b.History or other clinical evidence of hypertension, significant or unstable
cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina,
congestive heart failure, myocardial infarction, diastolic dysfunction,
significant arrhythmia, coronary heart disease and/or clinically significant ECG abnormalities).
c. History of, or active diagnosis of, primary or secondary renal disease (e.g.,
renal disease secondary to diabetes, hypertension, vascular disease, etc.).
d.History of extrahepatic disorders possibly related to HBV immune
complexes (e.g., glomerulonephritis and polyarteritis nodosa).
e. History of bleeding diathesis or coagulopathy.
f. History of or suspected presence of vasculitis.
g.History of Gilbert’s Syndrome.
h. History of malignancy within the past 5 years with the exception of specific
cancers that are cured by surgical resection (e.g., skin cancer), subjects
under evaluation for possible malignancy are not eligible.
2. History of/sensitivity to GSK3389404 or components thereof or a history of drug
or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
3. Confirmed or suspected HCC as evidenced by:
a. Alpha-fetoprotein concentration ≥ 200 ng/mL. If the screening
alpha-fetoproteinconcentration is ≥ 50 ng/mL and <200 ng/mL, the
absence of liver mass must be documented by imaging within 6 months before randomization
4. Liver cirrhosis or evidence of cirrhosis as determined by any of the following:
a. Positive liver biopsy (i.e., Metavir Score F4) within 12 months of screening
b. Fibroscan >12 kPa within 12 months of screening
c. Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure result >0.7 within 12 months of screening
For subjects without a test for cirrhosis in the above timeframes, APRI and
FibroSure should be performed during the screening period to rule out cirrhosis.
5. A positive hepatitis C virus (HCV) antibody test
6. A positive human immunodeficiency virus (HIV) antibody test
7. Positive hepatitis D virus (HDV) antibody test
8. Laboratory results as follows:
a. Total bilirubin concentration >1.25 X ULN
b.Serum albumin concentration <3.5 g/dL
c. International normalized ratio (INR) >1.25
d.Platelet count <140 X 109/L
e. Serum creatinine concentration greater than the ULN
f. Glomerular filtration rate (GFR) <90 mL/min as calculated by the Chronic
Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula.
Subjects with GFR <90 mL/min but 80 mL/min may be considered
after consultation with the GSK medical monitor.
g.Urine albumin to creatinine ratio (ACR) ≥ 0.03 mg/mg. In the event of an
ACR above this threshold, eligibility may be confirmed by a second measurement
9. Positive test for blood in urine. In the event of a positive test, the test may be
repeated once, and if repeat is negative or if urine microscopy reveals <5 red
blood cells (RBC) per high-power field (HPF), the subject is considered eligible.
10. Fridericia’s QT correction formula (QTcF) ≥ 450 msec (mean of triplicate measurements).
11. Currently taking, or took within 3 months of screening, any immunosuppressing
drugs (e.g., prednisone), other than a short course of therapy (≤ 2 weeks).
12. Current alcohol use as judged by investigator to potentially interfere with participant compliance.
13. A positive pre-study treatment screen or an unwillingness to refrain from use of
the illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
14. Where participation in the study would result in donation of blood or blood
products in excess of 500 mL within a 56-day period.
15. The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the
current study: 5 half-lives (if known) or twice the duration (if known) of the
biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown).
16. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
17. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within
12 months prior to the first dosing day.
The Estimated Number of Participants
-
Taiwan
64 participants
-
Global
120 participants
