Hepatitis B
Conditions
Brief summary
Patients with HBeAG positive, chronic HBV infection will receive either ARC-520 or placebo in combination with entecavir or tenofovir, and be evaluated for safety and efficacy.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, multi-dose study of ARC-520 in combination with entecavir or tenofovir administered to patients with HBeAg positive and immune active chronic HBV infection Eligible patients who have signed an Ethics Committee - approved informed consent, will be enrolled and will receive ARC-520 or placebo in combination with entecavir or tenofovir. The study will enroll up to a total of 90 eligible chronic HBV infected patients. Patients will undergo the following evaluations at regular intervals during the study: medical history, physical examinations, vital sign measurements (blood pressure, heart rate, respiratory rate and temperature), weight, adverse events assessment (AEs), 12 lead electrocardiograms (ECGs), liver fibrosis testing, concomitant medication assessment, blood sample collection for hematology, coagulation, chemistry, lactate, Pharmacokinetic (PK) measures (in a subset of patients), exploratory Pharmacodynamic (PD) measures, urinalysis, HBV serology, Follicle Stimulating Hormone (FSH) testing (post-menopausal females) and pregnancy testing for females of childbearing potential. Clinically significant changes including AEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the patient is lost to follow-up. For each patient the duration of the study is approximately 33 weeks from screening to the Day 169 follow-up visit. For patients enrolling into a planned extension study, the total duration of this study is approximately 25 weeks from screening to Day 113 end of study visit.
Interventions
DRUGARC-520
OTHERPlacebo
DRUGentecavir
All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.
DRUGantihistamine
All participants will be pretreated with an oral antihistamine. The antihistamine used should in general be an H1\>H2 receptor blocker and would include diphenhydramine 50 mg, cetirizine 10 mg, chlorpheniramine 8 mg or hydroxyzine 50 mg. The Investigator is free to choose any of these antihistamines available locally and consistent with their country's Marketing Authorisation.
DRUGtenofovir
All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 to 75 years of age. * Written informed consent. * No clinically significant abnormalities at screening/pre-dose 12-lead ECG assessment. * No new abnormal finding of clinical relevance at the screening evaluation. * Diagnosis of HBeAg positive, immune active, chronic HBV infection. * \> 2months of continuous treatment with daily, oral entecavir or tenofovir. * Willingness to continue taking entecavir or tenofovir throughout the study. * Must use 2 effective methods of contraception (double barrier contraception or hormonal contraceptive along with a barrier contraceptive) (both male and female partners).
Exclusion criteria
* Pregnant or lactating * Acute signs of hepatitis/other infection within 4 weeks of screening. * Antiviral therapy other than entecavir or tenofovir within 3 months of screening. * Prior treatment with interferon in the last 3 years. * Use within the last 6 months or anticipated requirement for anticoagulants, corticosteroids, immunomodulators, or immunosuppressants. * Use of prescription medication within 14 days prior to treatment administration except: topical products without systemic absorption, statins (except rosuvastatin), hypertension medications, or hormonal contraceptives. * Depot injection or implant of any drug within 3 months prior to treatment administration, except injectable/implantable birth control. * Diagnosis of diabetes mellitus. * History of autoimmune disease especially autoimmune hepatitis. * Human immunodeficiency virus (HIV) infection. * Sero-positive for Hepatitis C Virus (HCV), and/or a history of delta virus hepatitis. * Hypertension defined as blood pressure \> 150/100 mmHg. * History of cardiac rhythm disturbances. * Family history or congenital long QT syndrome, Brugada syndrome or unexplained sudden cardiac death. * Symptomatic heart failure, unstable angina, myocardial infarction, severe cardiovascular disease within 6 months prior to study entry. * History of malignancy except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. * Has had a major surgery within 3 months of screening. * History of alcohol and/or drug abuse \< 12 months from screening. * Regular uses of alcohol within 6 months prior to screening (ie, more than 14 units of alcohol per week). * Evidence of severe systemic acute inflammation, sepsis, or hemolysis. * Diagnosed with a significant psychiatric disorder. * Use of recreational drugs, such as marijuana, within 3 months prior to screening. * Use of drugs such as cocaine, phencyclidine (PCP), and methamphetamines, within 1 year prior to screening. * History of allergy to bee sting. * Use of investigational agents or devices within 30 days prior to planned study dosing or current participation in an investigational study. * Clinically significant history or presence of any gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease. * Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction. * Clinically significant history or presence of poorly controlled/uncontrolled systemic disease. * History of fever within 2 weeks of screening. * Immunized with a live attenuated vaccine within 7 days prior to dosing or planned vaccination (excluding flu vaccine by injection). * Presence of any medical or psychiatric condition or social situation that impacts compliance or results in additional safety risk. * Participated in excessive exercise/physical activity within 7 days of screening or planned during the trial. * History of coagulopathy/stroke within past 6 months, and/or concurrent anticoagulant medication(s).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113 | Baseline, Day 113 | Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Day 15 in Log qHBsAg, by Category | Baseline, Day 15 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 29 in Log qHBsAg, by Category | Baseline, Day 29 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 43 in Log qHBsAg, by Category | Baseline, Day 43 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 57 in Log qHBsAg, by Category | Baseline, Day 57 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 71 in Log qHBsAg, by Category | Baseline, Day 71 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 85 in Log qHBsAg, by Category | Baseline, Day 85 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 99 in Log qHBsAg, by Category | Baseline, Day 99 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline at Day 113 in Log qHBsAg, by Category | Baseline, Day 113 | Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit. |
| Change From Baseline in Log qHBsAg Over Time | Baseline, Days 15, 29, 43, 57, 71, 85, 99 | Change From Baseline in log qHBsAg up to Day 99 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. |
| Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Clearance (CL) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2) | Through 48 hours post-dosing on Day 1 and Day 85 | — |
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | Through Day 169 (± 3 days) | An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study drug administration and started at/after the time of initiation of administration of study drug, or an AE which was present prior to initiation of study drug administration, which increased in severity after study drug administration. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. |
Countries
China, Germany, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Low Dose Comparator Placebo (low dose comparator) once every 4 weeks for 4 doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day) | 6 |
| Placebo High Dose Comparator Placebo (high dose comparator) once every 4 weeks for 4 doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day) | 5 |
| ARC-520 1.0 mg/kg Low dose (1.0 mg/kg) ARC-520 once every 4 weeks for 4 doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day) | 10 |
| ARC-520 2.0 mg/kg High dose (2.0 mg/kg) ARC-520 once every 4 weeks for 4 doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day) | 11 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Study Terminated by Sponsor | 2 | 1 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Low Dose Comparator | Placebo High Dose Comparator | ARC-520 1.0 mg/kg | ARC-520 2.0 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.8 years STANDARD_DEVIATION 9.54 | 45.0 years STANDARD_DEVIATION 10.68 | 42.1 years STANDARD_DEVIATION 12.57 | 41.6 years STANDARD_DEVIATION 12.05 | 42.0 years STANDARD_DEVIATION 10.98 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 0 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 10 Participants | 5 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 0 / 5 | 5 / 10 | 3 / 11 |
| serious Total, serious adverse events | 0 / 6 | 0 / 5 | 0 / 10 | 0 / 11 |
Outcome results
Primary
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Time frame: Baseline, Day 113
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113 | -0.104 log IU/mL | Standard Error 0.073 |
| ARC-520 1.0 mg/kg | Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113 | -0.146 log IU/mL | Standard Error 0.065 |
| ARC-520 2.0 mg/kg | Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113 | -0.542 log IU/mL | Standard Error 0.061 |
p-value: 0.681595% CI: [-0.243, 0.159]MMRM
p-value: <0.000195% CI: [-0.638, -0.237]MMRM
p-value: <0.000195% CI: [-0.569, -0.223]MMRM
Secondary
Change From Baseline at Day 113 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 113
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 113 in Log qHBsAg, by Category | No Decrease | 0.042 log IU/mL | — |
| Placebo | Change From Baseline at Day 113 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.115 log IU/mL | Standard Deviation 0.171 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 113 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.142 log IU/mL | Standard Deviation 0.045 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 113 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.359 log IU/mL | Standard Deviation 0.049 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 113 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.726 log IU/mL | Standard Deviation 0.228 |
p-value: 1Fisher Exact
p-value: 0.0849Fisher Exact
p-value: 0.0849Fisher Exact
Secondary
Change From Baseline at Day 15 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 15
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 15 in Log qHBsAg, by Category | Decrease > 0 to < 0.5 log IU/mL | -0.035 log IU/mL | Standard Deviation 0.014 |
| Placebo | Change From Baseline at Day 15 in Log qHBsAg, by Category | No Decrease | 0.026 log IU/mL | Standard Deviation 0.015 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 15 in Log qHBsAg, by Category | Decrease > 0 to < 0.5 log IU/mL | -0.153 log IU/mL | Standard Deviation 0.144 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 15 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.707 log IU/mL | — |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 15 in Log qHBsAg, by Category | Decrease > 0 to < 0.5 log IU/mL | -0.266 log IU/mL | Standard Deviation 0.192 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 15 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.666 log IU/mL | — |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 15 in Log qHBsAg, by Category | No Decrease | 0.032 log IU/mL | Standard Deviation 0.035 |
p-value: 0.0867Fisher Exact
p-value: 0.6285Fisher Exact
p-value: 0.7214Fisher Exact
Secondary
Change From Baseline at Day 29 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 29
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 29 in Log qHBsAg, by Category | No Decrease | 0.048 log IU/mL | Standard Deviation 0.043 |
| Placebo | Change From Baseline at Day 29 in Log qHBsAg, by Category | Decrease > 0 to < 0.5 log IU/mL | -0.084 log IU/mL | Standard Deviation 0.078 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 29 in Log qHBsAg, by Category | Decrease > 0 to < 0.5 log IU/mL | -0.129 log IU/mL | Standard Deviation 0.083 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 29 in Log qHBsAg, by Category | No Decrease | 0.064 log IU/mL | — |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 29 in Log qHBsAg, by Category | Decrease > 0 to < 0.5 log IU/mL | -0.251 log IU/mL | Standard Deviation 0.19 |
p-value: 0.0325Fisher Exact
p-value: 0.1409Fisher Exact
p-value: 1Fisher Exact
Secondary
Change From Baseline at Day 43 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 43
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 43 in Log qHBsAg, by Category | No Decrease | 0.022 log IU/mL | Standard Deviation 0.012 |
| Placebo | Change From Baseline at Day 43 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.050 log IU/mL | Standard Deviation 0.051 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 43 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.226 log IU/mL | Standard Deviation 0.077 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 43 in Log qHBsAg, by Category | No Decrease | 0.017 log IU/mL | — |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 43 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.275 log IU/mL | Standard Deviation 0.137 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 43 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.633 log IU/mL | Standard Deviation 0.141 |
p-value: 0.0824Fisher Exact
p-value: 0.2217Fisher Exact
p-value: 0.1409Fisher Exact
Secondary
Change From Baseline at Day 57 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 57
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 57 in Log qHBsAg, by Category | No Decrease | 0.027 log IU/mL | Standard Deviation 0.012 |
| Placebo | Change From Baseline at Day 57 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.067 log IU/mL | Standard Deviation 0.072 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 57 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.176 log IU/mL | Standard Deviation 0.049 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 57 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.276 log IU/mL | Standard Deviation 0.156 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 57 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.571 log IU/mL | Standard Deviation 0.06 |
p-value: 0.0625Fisher Exact
p-value: 0.0684Fisher Exact
p-value: 0.2105Fisher Exact
Secondary
Change From Baseline at Day 71 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 71
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 71 in Log qHBsAg, by Category | No Decrease | 0.011 log IU/mL | Standard Deviation 0.012 |
| Placebo | Change From Baseline at Day 71 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.094 log IU/mL | Standard Deviation 0.079 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 71 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.235 log IU/mL | Standard Deviation 0.086 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 71 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.296 log IU/mL | Standard Deviation 0.119 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 71 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.662 log IU/mL | Standard Deviation 0.14 |
p-value: 0.175Fisher Exact
p-value: 0.0229Fisher Exact
p-value: 0.0294Fisher Exact
Secondary
Change From Baseline at Day 85 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 85
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 85 in Log qHBsAg, by Category | No Decrease | 0.009 log IU/mL | Standard Deviation 0.01 |
| Placebo | Change From Baseline at Day 85 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.112 log IU/mL | Standard Deviation 0.147 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 85 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.171 log IU/mL | Standard Deviation 0.037 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 85 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.293 log IU/mL | Standard Deviation 0.112 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 85 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.684 log IU/mL | Standard Deviation 0.179 |
p-value: 0.4615Fisher Exact
p-value: 0.0508Fisher Exact
p-value: 0.0769Fisher Exact
Secondary
Change From Baseline at Day 99 in Log qHBsAg, by Category
Change in log qHBsAg from baseline, categorized into the following groups: no decrease, decrease \> 0 to \< 0.5 log IU/mL; decrease 0.5 to 1.0 log IU/mL; decrease \> 1.0 log IU/mL, tabulated by dose and treatment for each visit.
Time frame: Baseline, Day 99
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline at Day 99 in Log qHBsAg, by Category | No Decrease | 0.027 log IU/mL | Standard Deviation 0.018 |
| Placebo | Change From Baseline at Day 99 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.160 log IU/mL | Standard Deviation 0.202 |
| ARC-520 1.0 mg/kg | Change From Baseline at Day 99 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.210 log IU/mL | Standard Deviation 0.07 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 99 in Log qHBsAg, by Category | 1 participant analyDecrease > 0 to < 0.5 log IU/mL | -0.343 log IU/mL | Standard Deviation 0.11 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 99 in Log qHBsAg, by Category | Decrease 0.5 to 1.0 log IU/mL | -0.652 log IU/mL | Standard Deviation 0.068 |
| ARC-520 2.0 mg/kg | Change From Baseline at Day 99 in Log qHBsAg, by Category | Decrease > 1.0 log IU/mL | -1.011 log IU/mL | — |
p-value: 0.0699Fisher Exact
p-value: 0.0179Fisher Exact
p-value: 0.043Fisher Exact
Secondary
Change From Baseline in Log qHBsAg Over Time
Change From Baseline in log qHBsAg up to Day 99 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Time frame: Baseline, Days 15, 29, 43, 57, 71, 85, 99
Population: Intent to treat population: all participants who received at least 1 dose of study drug and had valid qHBsAg values at baseline and at least one time point on or after the Day 15 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 57 | 3.793 log IU/mL | Standard Deviation 0.507 |
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 43 | 3.812 log IU/mL | Standard Deviation 0.463 |
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 29 | 3.692 log IU/mL | Standard Deviation 0.588 |
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 15 | 3.734 log IU/mL | Standard Deviation 0.519 |
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 99 | 3.767 log IU/mL | Standard Deviation 0.541 |
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 85 | 3.743 log IU/mL | Standard Deviation 0.543 |
| Placebo | Change From Baseline in Log qHBsAg Over Time | Day 71 | 3.756 log IU/mL | Standard Deviation 0.489 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 29 | 3.148 log IU/mL | Standard Deviation 0.658 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 15 | 3.069 log IU/mL | Standard Deviation 0.654 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 71 | 3.088 log IU/mL | Standard Deviation 0.626 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 85 | 3.198 log IU/mL | Standard Deviation 0.61 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 43 | 3.097 log IU/mL | Standard Deviation 0.664 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 57 | 3.148 log IU/mL | Standard Deviation 0.651 |
| ARC-520 1.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 99 | 3.048 log IU/mL | Standard Deviation 0.593 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 43 | 2.893 log IU/mL | Standard Deviation 0.436 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 85 | 2.698 log IU/mL | Standard Deviation 0.466 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 99 | 2.606 log IU/mL | Standard Deviation 0.477 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 57 | 2.882 log IU/mL | Standard Deviation 0.437 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 29 | 3.027 log IU/mL | Standard Deviation 0.395 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 15 | 3.000 log IU/mL | Standard Deviation 0.411 |
| ARC-520 2.0 mg/kg | Change From Baseline in Log qHBsAg Over Time | Day 71 | 2.714 log IU/mL | Standard Deviation 0.477 |
Comparison: Day 85p-value: <0.000195% CI: [-0.59, -0.219]MMRM
Comparison: Day 85p-value: 0.000295% CI: [-0.481, -0.156]MMRM
Comparison: Day 15p-value: 0.013195% CI: [-0.372, -0.044]MMRM
Comparison: Day 15p-value: 0.003695% CI: [-0.412, -0.082]MMRM
Comparison: Day 15p-value: 0.613695% CI: [-0.192, 0.113]MMRM
Comparison: Day 29p-value: 0.310495% CI: [-0.249, 0.08]MMRM
Comparison: Day 29p-value: 0.040195% CI: [-0.34, -0.008]MMRM
Comparison: Day 29p-value: 0.249495% CI: [-0.242, 0.063]MMRM
Comparison: Day 43p-value: 0.014995% CI: [-0.38, -0.042]MMRM
Comparison: Day 43p-value: 0.000395% CI: [-0.489, -0.149]MMRM
Comparison: Day 29p-value: 0.165595% CI: [-0.262, 0.045]MMRM
Comparison: Day 57p-value: 0.088995% CI: [-0.324, 0.023]MMRM
Comparison: Day 57p-value: 0.000495% CI: [-0.497, -0.147]MMRM
Comparison: Day 57p-value: 0.029895% CI: [-0.326, -0.017]MMRM
Comparison: Day 71p-value: 0.041595% CI: [-0.361, -0.007]MMRM
Comparison: Day 71p-value: <0.000195% CI: [-0.62, -0.261]MMRM
Comparison: Day 71p-value: 0.001595% CI: [-0.413, -0.1]MMRM
Comparison: Day 85p-value: 0.35195% CI: [-0.268, 0.096]MMRM
Comparison: Day 99p-value: 0.119895% CI: [-0.341, 0.04]MMRM
Comparison: Day 99p-value: <0.000195% CI: [-0.708, -0.325]MMRM
Comparison: Day 99p-value: <0.000195% CI: [-0.535, -0.197]MMRM
Secondary
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs
An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study drug administration and started at/after the time of initiation of administration of study drug, or an AE which was present prior to initiation of study drug administration, which increased in severity after study drug administration. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction.
Time frame: Through Day 169 (± 3 days)
Population: Safety Population: all participants who received at least one dose of study drug or placebo, and had at least one post-dose safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 AE | 4 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | Deaths | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE | 4 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Study Discontinuation | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 Serious TEAE | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Treatment Discontinuation | 0 participants |
| ARC-520 1.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Treatment Discontinuation | 0 participants |
| ARC-520 1.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | Deaths | 0 participants |
| ARC-520 1.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Study Discontinuation | 0 participants |
| ARC-520 1.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 Serious TEAE | 0 participants |
| ARC-520 1.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 AE | 0 participants |
| ARC-520 1.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Treatment Discontinuation | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 AE | 6 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Study Discontinuation | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE | 5 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 Serious TEAE | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | Deaths | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Study Discontinuation | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 AE | 3 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | Deaths | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE Leading to Treatment Discontinuation | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 Serious TEAE | 0 participants |
| ARC-520 2.0 mg/kg | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs | ≥ 1 TEAE | 3 participants |
Secondary
Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Clearance (CL)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.
Secondary
Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel)
Time frame: Through 48 hours post-dosing on Day 1 and Day 85
Population: Due to the early suspension and termination of the study, all pharmacokinetic analyses were removed from the initial statistical analysis plan for this study. No collected samples were analyzed and all were destroyed.