Phase 2
N=12
A Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3389404 in Chronic Hepatitis B (CHB) Subjects
Hepatitis B
Bottom Line
View on ClinicalTrials.gov: NCT03020745 ↗Enrolled (actual)
12
Serious AEs
5.1%
Results posted
Jan 2020
Primary outcome: Primary: Part 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time Points — -3.67; 3.00; 0.50; -5.33 Millimeters of mercury (mmHg)
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- GSK3389404 (Drug); Placebo (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- GlaxoSmithKline
- Primary completion
- Jan 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time Points |
-3.67; 3.00; 0.50; -5.33; -3.33; -4.33 | — |
| PRIMARY Part 2: Change From Baseline in SBP and DBP at Indicated Time Points (Up to Day 169-Interim Analysis) |
5.8; 2.3; -1.9; 1.0; -0.7; 2.1 | — |
| PRIMARY Part 2: Change From Baseline in SBP and DBP at Indicated Time Points (Up to Day 450-Optional Follow-up) |
-9.0; 7.0; -18.0; 3.0 | — |
| PRIMARY Part 1: Change From Baseline in Heart Rate at Indicated Time Points |
4.78; 1.44; -5.00; 13.94; 4.61; -2.17 | — |
| PRIMARY Part 2: Change From Baseline in Heart Rate at Indicated Time Points (Up to Day 169-Interim Analysis) |
9.9; 6.2; 2.8; 5.7; 5.2; 9.2 | — |
| PRIMARY Part 2: Change From Baseline in Heart Rate at Indicated Time Points (Up to Day 450-Optional Follow-up) |
-26.0; -11.0 | — |
| PRIMARY Part 1: Change From Baseline in Respiratory Rate at Indicated Time Points |
-0.67; -1.00; -0.33; -0.50; -1.00; 0.00 | — |
| PRIMARY Part 2: Change From Baseline in Respiratory Rate at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.00; -0.8; 0.5; -0.3; -0.3; -0.2 | — |
| PRIMARY Part 2: Change From Baseline in Respiratory Rate at Indicated Time Points (Up to Day 450-Optional Follow-up) |
0.0; 2.0 | — |
| PRIMARY Part 1: Change From Baseline in Body Temperature at Indicated Time Points |
0.10; 0.37; 0.25; 0.20; -0.03; 0.08 | — |
| PRIMARY Part 2: Change From Baseline in Body Temperature at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.24; -0.02; 0.18; -0.15; -0.11; 0.18 | — |
| PRIMARY Part 2: Change From Baseline in Body Temperature at Indicated Time Points (Up to Day 450-Optional Follow-up) |
-0.40; 0.40 | — |
| PRIMARY Part 1: Number of Participants With Abnormal Findings in Physical Examination |
— | — |
| PRIMARY Part 2: Number of Participants With Abnormal Findings in Physical Examination (Up to Day 169-Interim Analysis) |
— | — |
| PRIMARY Part 2: Number of Participants With Abnormal Findings in Physical Examination (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Number of Participants With Maximum Post-Baseline Grade by Category in Hematology and Coagulation Parameters |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Hematology and Coagulation Parameters (Up to Day 169-Interim Analysis) |
0; 1; 0; 0; 0; 0 | — |
| PRIMARY Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Hematology and Coagulation Parameters (Up to Day 450-Optional Follow-up) |
0; 1; 0; 0; 0; 0 | — |
| PRIMARY Part 1: Change From Baseline in Complement C3 and Complement C4 Level at Indicated Time Points |
-8.7; -13.0; -16.3; -2.0; -2.3; -4.2 | — |
| PRIMARY Part 2: Change From Baseline in Complement C3 and Complement C4 Level at Indicated Time Points (Up to Day 169-Interim Analysis) |
-11.0; -13.5; -11.3; -10.9; -17.7; -3.5 | — |
| PRIMARY Part 2: Change From Baseline in Complement C3 and Complement C4 Level at Indicated Time Points (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Change From Baseline in Complement Bb Level at Indicated Time Points |
0.193; 0.023; 0.150 | — |
| PRIMARY Part 2: Change From Baseline in Complement Bb Level at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.245; 0.198; 0.315; 0.115; -0.007 | — |
| PRIMARY Part 2: Change From Baseline in Complement Bb Level at Indicated Time Points (Up to Day 450-Optional Follow-up) |
0.304; 0.365; 0.436; 0.173; 0.107 | — |
| PRIMARY Part 1: Change From Baseline in Complement C5a Level at Indicated Time Points |
1.497; 0.373; -1.267 | — |
| PRIMARY Part 2: Change From Baseline in Complement C5a Level at Indicated Time Points (Up to Day 169-Interim Analysis) |
1.112; 0.860; 1.781; 0.353; -0.093 | — |
| PRIMARY Part 2: Change From Baseline in Complement C5a Level at Indicated Time Points (Up to Day 450-Optional Follow-up) |
1.324; 2.053; 2.040; 0.470; 0.567 | — |
| PRIMARY Part 1: Number of Participants With Maximum Post-Baseline Grade by Category in Clinical Chemistry Parameters |
0; 0; 0; 0; 0; 1 | — |
| PRIMARY Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Clinical Chemistry Parameters (Up to Day 169-Interim Analysis) |
1; 0; 2; 0; 4; 0 | — |
| PRIMARY Part 2: Number of Participants With Maximum Post-Baseline Grade by Category in Clinical Chemistry Parameters (Up to Day 450-Optional Follow-up) |
2; 0; 3; 0; 4; 0 | — |
| PRIMARY Part 1: Change From Baseline in Urine Albumin at Indicated Time Points |
-0.090; 0.000; -0.003; -0.090; 0.000; -0.003 | — |
| PRIMARY Part 2: Change From Baseline in Urine Albumin at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.484; 0.000; 0.004; -0.044; 0.054; -0.038 | — |
| PRIMARY Part 2: Change From Baseline in Urine Albumin at Indicated Time Points (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Change From Baseline in Urine Creatinine at Indicated Time Points |
-6.333; -7.500; -0.500; -4.133; -7.467; -0.533 | — |
| PRIMARY Part 2: Change From Baseline in Urine Creatinine at Indicated Time Points (Up to Day 169-Interim Analysis) |
1.250; 3.100; 1.620; 0.621; 1.129; -0.250 | — |
| PRIMARY Part 2: Change From Baseline in Urine Creatinine at Indicated Time Points (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Change From Baseline in Urine Potential of Hydrogen (pH) at Indicated Time Points |
0.333; 0.167; 0.083; 0.000; 1.000; 0.333 | — |
| PRIMARY Part 2: Change From Baseline in Urine pH at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.300; -0.333; -0.132; -0.071; -0.077; 0.200 | — |
| PRIMARY Part 2: Change From Baseline in Urine pH at Indicated Time Points (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Change From Baseline in Urine Specific Gravity at Indicated Time Points |
0.005; -0.011; -0.001; 0.003; -0.014; 0.000 | — |
| PRIMARY Part 2: Change From Baseline in Urine Specific Gravity at Indicated Time Points (Up to Day 169-Interim Analysis) |
-0.001; 0.004; -0.001; 0.000; 0.000; 0.002 | — |
| PRIMARY Part 2: Change From Baseline in Urine Specific Gravity at Indicated Time Points (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Change From Baseline in Urobilinogen at Indicated Time Points |
0.000; 0.000; 0.000; 0.000; 0.000; 0.000 | — |
| PRIMARY Part 2: Change From Baseline in Urobilinogen at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.000; 0.000; 0.000; 0.000; 0.000; 0.000 | — |
| PRIMARY Part 2: Change From Baseline in Urobilinogen at Indicated Time Points (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Number of Participants With Abnormal Electrocardiogram (ECG) Findings |
2; 1; 5; 0; 0; 0 | — |
| PRIMARY Part 2: Number of Participants With Abnormal ECG Findings (Up to Day 169-Interim Analysis) |
2; 2; 6; 6; 5; 0 | — |
| PRIMARY Part 2: Number of Participants With Abnormal ECG Findings (Up to Day 450-Optional Follow-up) |
— | — |
| PRIMARY Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |
1; 0; 1; 0; 0; 0 | — |
| PRIMARY Part 2: Number of Participants With AEs and SAEs (Up to Day 169-Interim Analysis) |
9; 4; 16; 11; 12; 1 | — |
| PRIMARY Part 2: Number of Participants With AEs and SAEs (Up to Day 450-Optional Follow-up) |
9; 4; 18; 11; 12; 1 | — |
| PRIMARY Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the Time of the Last Quantifiable Concentration (AUC[0-t]) for GSK3389404 |
1230; 17000 | — |
| PRIMARY Part 2: AUC (0-t) for GSK3389404 |
1930; 5920; 12000; 14400 | — |
| PRIMARY Part 1: Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) for GSK3389404 |
1460; 17100 | — |
| PRIMARY Part 2: AUC (0-infinity) for GSK3389404 |
2030; 5990; 12300; 14600 | — |
| PRIMARY Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3389404 |
227; 1880 | — |
| PRIMARY Part 2: Cmax of GSK3389404 |
214; 865; 1660; 1940 | — |
| PRIMARY Part 1: Time to Achieve Cmax (Tmax) of GSK3389404 |
1.40; 3.50 | — |
| PRIMARY Part 2: Tmax of GSK3389404 |
2.04; 3.46; 4.05; 4.02 | — |
| PRIMARY Part 1: Apparent Terminal Phase Half-life(t1/2) of GSK3389404 |
3.12; 4.31 | — |
| PRIMARY Part 2: t1/2 of GSK3389404 |
3.90; 3.24; 4.24; 2.89 | — |
| PRIMARY Part 1: Apparent Subcutaneous Plasma Clearance (CL/F) of GSK3389404 |
20.6; 7.03 | — |
| PRIMARY Part 2: CL/F of GSK3389404 |
14.8; 10.0; 9.75; 8.23 | — |
| PRIMARY Part 1: Number of Participants Achieving Response Rate (RR) Based on Reduction of Hepatitis B Surface Antigen (HBsAg) Level From Baseline |
0; 0; 0 | — |
| PRIMARY Part 2: Number of Participants Achieving RR Based on Reduction of HBsAg Level From Baseline |
0; 0; 1; 1; 1 | — |
| SECONDARY Part 1: Change From Baseline in log10 Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Viral Load in Plasma at Indicated Time Points |
-0.19; -0.03; 0.50; -0.06; 0.41; 0.20 | — |
| SECONDARY Part 2: Change From Baseline in log10 HBV DNA Viral Load in Plasma at Indicated Time Points (Up to Day 169-Interim Analysis) |
-0.128; -0.426; -0.643; -0.341; -0.256 | — |
| SECONDARY Part 2: Change From Baseline in log10 HBV DNA Viral Load in Plasma at Indicated Time Points (Up to Day 450-Optional Follow-up) |
-0.128; -0.426; -0.643; -0.426; -0.256 | — |
| SECONDARY Part 1: Change From Baseline in log10 Hepatitis B Virus Surface Antigen (HBsAg) Levels in Plasma at Indicated Time Points |
-0.03; 0.02; -0.02; 0.01; 0.00; -0.05 | — |
| SECONDARY Part 2: Change From Baseline in log10 HBsAg Levels in Plasma at Indicated Time Points (Up to Day 169-Interim Analysis) |
-0.0149; -0.0057; -0.0376; -0.0573; -0.0944; -0.0175 | — |
| SECONDARY Part 2: Change From Baseline in log10 HBsAg Level in Plasma at Indicated Time Points (Up to Day 450-Optional Follow-up) |
-0.0177; 0.0308; 0.0627; 0.0400; -0.0047; -0.0723 | — |
| SECONDARY Part 1: Change From Baseline in log10 Hepatitis B Virus E-antigen (HBeAg) Levels in Plasma at Indicated Time Points |
0.15; -0.03; 0.00; -0.01; -0.02; 0.00 | — |
| SECONDARY Part 2: Change From Baseline in log10 HBeAg Levels in Plasma at Indicated Time Points (Up to Day 169-Interim Analysis) |
0.039; 0.023; 0.010; -0.051; 0.012; 0.101 | — |
| SECONDARY Part 2: Change From Baseline in log10 HBeAg Level in Plasma at Indicated Time Points (Up to Day 450-Optional Follow-up) |
0.050; -0.028; -0.120; -0.041; 0.014; -0.153 | — |
| SECONDARY Part 1: AUC(0-t) for Metabolite of GSK3389404 (ISIS 505358) |
NA; 44.2 | — |
| SECONDARY Part 2: AUC(0-t) for Metabolite of GSK3389404 (ISIS 505358) |
NA; NA; 17.1 | — |
| SECONDARY Part 1: Cmax of GSK3389404 Metabolite (ISIS 505358) |
2.93 | — |
| SECONDARY Part 2: Cmax of GSK3389404 Metabolite (ISIS 505358) |
NA; NA; 2.91 | — |
| SECONDARY Part 1: Tmax of GSK3389404 Metabolite (ISIS 505358) |
7.88 | — |
| SECONDARY Part 2: Tmax of GSK3389404 Metabolite (ISIS 505358) |
7.93; 7.93; 8.00 | — |
| SECONDARY Part 1: t1/2 of GSK3389404 Metabolite (ISIS 505358) |
18.75 | — |
| SECONDARY Part 2: t1/2 of GSK3389404 Metabolite (ISIS 505358) |
10.66 | — |
Summary
GSK3389404 is being developed for the treatment of CHB virus infection. The development goal for GSK3389404 is the establishment of a finite duration treatment that results in sustained suppression of hepatitis B virus (HBV) replication and viral antigen production after cessation of all treatments for CHB due to the restoration of a functional immune response in the absence of high antigen levels. This study is a multicenter, randomized double-Blind (sponsor un-blinded in Part 1), Placebo-controlled Study which will evaluate the safety, tolerability, PK, and PD profile of GSK3389404 in subjects with CHB and aim to establish proof-of-mechanism. The study will be conducted in two parts. Part 1 plans to enroll subjects primarily from the Asia-pacific region, including Japan and will be conducted as a single ascending dose (SAD) study with 5 planned cohorts ranging from 30 milligram (mg) to a maximum of 240 mg GSK3389404. Within each cohort, subjects will be randomized to receive either GSK3389404 or placebo in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 is an optional cohort and may be dosed after Cohort C or in parallel with Cohort D. Part 2 will be conducted as a multiple-dose, dose-ranging study. Subjects will be randomized to different parallel dose levels and regimens or placebo. The dose levels of Part 2 will be selected after a review of Part 1 safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) data. The treatments selected are 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg GSK3389404 weekly or placebo. An optional Japanese part-2 sub-study is planned. The total study duration for part 1 including screening, treatment, and post-treatment follow-up, will not be expected to exceed 13 weeks for each subject and for part 2, including screening, treatment and post-treatment follow-up, will not be expected to exceed 65 weeks for each subject.
Eligibility Criteria
Inclusion Criteria
- 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.
- Between 18 and 70 years of age, inclusive, at the time of signing the informed consent form.
- A body mass index (BMI) between 18 to 30 kilogram (Kg)/meter (m^2), inclusive.
- Male or female if they satisfy the following: All females must meet the following criteria: Non-pregnant (as confirmed by a negative serum Human Chorionic Gonadotropin [hCG] test); AND Non-lactating at screening and prior to dosing; AND For Part 2, females of reproductive potential (FRP) must agree to follow (or confirm that they have and are currently following) one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP from at least 28 days prior to the first dose of study treatment until Follow-up visit Day 169 in conjunction with partner's use of male condom. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. For females of non-reproductive potential at least one of the following conditions must apply: Premenopausal females without reproductive potential defined by Documented salpingectomy, Hysterectomy or Documented bilateral oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea; 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; 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 Follow-up visit Day 169; Vasectomy; Male condom plus partner's use of one of the contraceptive options below that meets the Standard Operating Procedure (SOP) effectiveness criteria including a =6 months prior to screening.
- Subjects with HBV treatment history as follows: Part 1: Treatment naive or have had prior treatment with interferon (pegylated or non pegylated) that must have ended at least 6 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 or currently receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study. Part 2: Subjects with CHB receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study. Subjects with prior treatment with interferon (pegylated or non-pegylated) must have ended treatment at least 6 months prior to the Baseline visit (Day 1 pre-dose).
- Plasma or serum HBV DNA concentration: treatment naïve subjects or subjects not currently receiving treatment, there is no minimum HBV DNA requirement; Subjects who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA 50 IU/mL.
- Alanine aminotransferase (ALT) concentration: ALT =200 nanogram (ng)/mL. If the screening alpha-fetoprotein concentration is >=50 ng/mL and 12 kilopascals (kPa) within 12 months of screening. AST-Platelet Index (APRI) >2 and FibroSure result >0.7 within 12 months of screening and Investigator judgment. 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.
- Hepatitis C Virus (HCV) co-infection.
- Human Immunodeficiency Virus (HIV) co-infection.
- Hepatitis D Virus (HDV) co-infection.
- Laboratory results as follows: Total bilirubin concentration >1.25
Data sourced from ClinicalTrials.gov (NCT03020745). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.