A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Negative, Chronic Hepatitis B Virus (HBV) Infection

• Sponsor: Arrowhead Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02604199
• Collaborator: (none)
• Enrollment: 58
• Locations: 16
• Arms: 4
• Actual Duration (Months): 16
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Patients with chronic HBV infection will receive either ARC-520 or placebo in combination with entecavir or tenofovir, and be evaluated for safety and efficacy.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B	Drug: ARC-520 Injection; Other: placebo; Drug: entecavir; Drug: tenofovir; Drug: antihistamine	Phase 2

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 Hepatitis B 'e' Antigen (HBeAg) negative 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 60 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Multi-dose Study to Determine the Depth of Hepatitis B Surface Antigen (HBsAg) Reduction Following Intravenous ARC-520 in Combination With Entecavir or Tenofovir in Patients With HBeAg Negative, Chronic Hepatitis B Virus (HBV) Infection
• Actual Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: PBO Low Dose 0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Other: placebo; Placebo was administered concomitantly, IV with 0.9% normal saline using an infusion rate of 0.4 mL/min for study treatment and 3.6 mL/min for saline.; Drug: entecavir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: tenofovir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: antihistamine; All participants will be pretreated with an oral antihistamine, administered 2 hours (±30 minutes) pre-dose. 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.
Placebo Comparator: PBO High Dose 0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Other: placebo; Placebo was administered concomitantly, IV with 0.9% normal saline using an infusion rate of 0.4 mL/min for study treatment and 3.6 mL/min for saline.; Drug: entecavir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: tenofovir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: antihistamine; All participants will be pretreated with an oral antihistamine, administered 2 hours (±30 minutes) pre-dose. 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.
Experimental: ARC-520 Injection 1 mg/kg Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Drug: ARC-520 Injection; ARC-520 Injection was administered concomitantly, IV with 0.9% normal saline using an infusion rate of 0.4 mL/min for study treatment and 3.6 mL/min for saline.; Drug: entecavir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: tenofovir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: antihistamine; All participants will be pretreated with an oral antihistamine, administered 2 hours (±30 minutes) pre-dose. 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.
Experimental: ARC-520 Injection 2 mg/kg Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Drug: ARC-520 Injection; ARC-520 Injection was administered concomitantly, IV with 0.9% normal saline using an infusion rate of 0.4 mL/min for study treatment and 3.6 mL/min for saline.; Drug: entecavir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: tenofovir; All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.; Drug: antihistamine; All participants will be pretreated with an oral antihistamine, administered 2 hours (±30 minutes) pre-dose. 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time [Baseline, Day 15, 29, 43, 57, 71, 85, 99]

   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.

2. Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs [Through Day 169]

   An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any AE that: 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; or is a medically important event or reaction. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study medication administration and started at/after the time of initiation of administration of study medication, or an AE which was present prior to initiation of study medication administration, which increased in severity after study medication administration.

3. 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]

4. 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]

5. 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]

6. Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax) [Through 48 hours post-dosing on Day 1 and Day 85]

7. Pharmacokinetics of ARC-520: Clearance (CL) [Through 48 hours post-dosing on Day 1 and Day 85]

8. Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V) [Through 48 hours post-dosing on Day 1 and Day 85]

9. Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel) [Through 48 hours post-dosing on Day 1 and Day 85]

10. Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2) [Through 48 hours post-dosing on Day 1 and Day 85]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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 negative, immune active, chronic HBV infection

• 2 months 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Queen Mary Hospital	Hong Kong		China	999077
2	Prince of Wales Hospital	Hong Kong		China
3	Klinikum der Johann Wolfgang Goethe Universitaet	Frankfurt		Germany	60590
4	Asklepios Klinik St. Georg - Chirurgisch-Traumatologisches Zentrum	Hamburg		Germany	20099
5	Medizinische Hochschule Hannover	Hannover		Germany	30625
6	Eugastro Gmbh	Leipzig		Germany	04103
7	Universitaetsklinikum Leipzig	Leipzig		Germany	4103
8	Klinikum Der Ludwig-Maximilian-Universitaet Muenchen	Muenchen		Germany	81377
9	University Hospital of Tuebingen	Tuebingen		Germany	72076
10	Universitaetsklinikum Ulm, Klinik fur Innere Medizin I	Ulm		Germany	89081
11	Universitaetsklinikum Wuerzburg, Medizinische Klinik Und Poliklinik II	Wuerzburg		Germany	97080
12	Pusan National University Hospital	Busan		Korea, Republic of	602-739
13	Gachon University Gil Medical Center	Incheon		Korea, Republic of	405-760
14	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
15	Severance Hospital, Yonsei University College of Medicine	Seoul		Korea, Republic of	120-752
16	Pusan National University Yangsan Hospital	Yangsan-si Gyeongnam		Korea, Republic of	626-770

Sponsors and Collaborators

• Arrowhead Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arrowhead Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02604199
• Other Study ID Numbers: Heparc-2002; 2014-004145-27
• First Posted: Nov 13, 2015
• Last Update Posted: Apr 16, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Tenofovir; Entecavir; Histamine Antagonists; Histamine H1 Antagonists

Study Results

Participant Flow

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Period Title: Overall Study
STARTED	9	11	17	21
COMPLETED	9	8	17	18
NOT COMPLETED	0	3	0	3

Baseline Characteristics

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg	Total
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Total of all reporting groups
Overall Participants	9	11	17	21	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.2 (12.10)	48.7 (9.50)	45.0 (10.48)	45.7 (10.48)	46.2 (10.29)
Sex: Female, Male (Count of Participants)
Female	2 22.2%	1 9.1%	7 41.2%	9 42.9%	19 32.8%
Male	7 77.8%	10 90.9%	10 58.8%	12 57.1%	39 67.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	Placebo (low dose or high dose) 0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	15	14	15
Least Squares Mean (Standard Error) [log IU/mL]	-0.070 (0.033)	-0.157 (0.036)	-0.379 (0.033)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0810
	Comments	Mixed effect model repeat measurement (MMRM) includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
	Method	MMRM
	Comments	Within-subject covariance is unstructured.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.086
	Confidence Interval	(2-Sided) 95%; -0.183 to 0.011
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.309
	Confidence Interval	(2-Sided) 95%; -0.406 to -0.212
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.223
	Confidence Interval	(2-Sided) 95%; -0.322 to -0.124
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Description	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 15, 29, 43, 57, 71, 85, 99

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	Placebo (low dose or high dose) 0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	18	15	19
Day 15	3.297 (0.712)	3.084 (1.004)	2.506 (0.844)
Day 29	3.291 (0.694)	3.098 (0.986)	2.503 (0.846)
Day 43	3.188 (0.712)	3.016 (1.124)	2.509 (0.836)
Day 57	3.291 (0.705)	3.072 (1.061)	2.329 (0.971)
Day 71	3.206 (0.663)	3.051 (1.029)	2.301 (0.969)
Day 85	3.309 (0.736)	2.907 (0.963)	2.366 (0.862)
Day 99	3.302 (0.700)	2.938 (1.055)	2.360 (0.950)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0583
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.089
	Confidence Interval	(2-Sided) 95%; -0.181 to 0.003
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.046
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.176
	Confidence Interval	(2-Sided) 95%; -0.267 to -0.085
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.045
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 15
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0670
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.087
	Confidence Interval	(2-Sided) 95%; -0.181 to 0.006
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.047
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 29
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0875
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.070
	Confidence Interval	(2-Sided) 95%; -0.151 to 0.011
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.040
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 29
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.179
	Confidence Interval	(2-Sided) 95%; -0.259 to -0.100
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.040
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 29
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0099
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.109
	Confidence Interval	(2-Sided) 95%; -0.191 to -0.027
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.041
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 43
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.143
	Confidence Interval	(2-Sided) 95%; -0.229 to -0.057
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.043
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 43
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.265
	Confidence Interval	(2-Sided) 95%; -0.349 to -0.180
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.042
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 43
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0072
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.122
	Confidence Interval	(2-Sided) 95%; -0.209 to -0.035
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.043
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 57
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.118
	Confidence Interval	(2-Sided) 95%; -0.197 to -0.039
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.039
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 57
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.298
	Confidence Interval	(2-Sided) 95%; -0.376 to -0.221
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.039
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 57
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.181
	Confidence Interval	(2-Sided) 95%; -0.261 to -0.100
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.040
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 71
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0084
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.132
	Confidence Interval	(2-Sided) 95%; -0.228 to -0.035
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 71
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.338
	Confidence Interval	(2-Sided) 95%; -0.433 to -0.243
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.047
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 71
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.206
	Confidence Interval	(2-Sided) 95%; -0.304 to -0.108
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 85
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0589
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.096
	Confidence Interval	(2-Sided) 95%; -0.195 to 0.004
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.050
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 85
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.335
	Confidence Interval	(2-Sided) 95%; -0.433 to -0.236
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 85
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.239
	Confidence Interval	(2-Sided) 95%; -0.340 to -0.137
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.050
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 1 mg/kg
	Comments	Day 99
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0138
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.132
	Confidence Interval	(2-Sided) 95%; -0.236 to -0.028
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, ARC-520 Injection 2 mg/kg
	Comments	Day 99
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.355
	Confidence Interval	(2-Sided) 95%; -0.458 to -0.252
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.051
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	ARC-520 Injection 1 mg/kg, ARC-520 Injection 2 mg/kg
	Comments	Day 99
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	MMRM includes terms of parameter baseline as continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit. Within-subject covariance is unstructured.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.223
	Confidence Interval	(2-Sided) 95%; -0.329 to -0.117
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.053
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
Description	An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any AE that: 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; or is a medically important event or reaction. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study medication administration and started at/after the time of initiation of administration of study medication, or an AE which was present prior to initiation of study medication administration, which increased in severity after study medication administration.
Time Frame	Through Day 169

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who received at least 1 dose of study treatment or placebo, and had at least 1 post-dose safety assessment.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	9	11	17	21
≥ 1 AE	4 44.4%	5 45.5%	6 35.3%	12 57.1%
≥ 1 TEAE	4 44.4%	4 36.4%	6 35.3%	12 57.1%
≥ 1 Serious TEAE	0 0%	0 0%	2 11.8%	1 4.8%
Deaths	0 0%	0 0%	0 0%	0 0%
≥ 1 TEAE Leading to Study Discontinuation	0 0%	0 0%	0 0%	0 0%
≥ 1 TEAE Leading to Treatment Discontinuation	0 0%	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

5. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

6. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

7. Secondary Outcome

Title	Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax)
Time Frame	Through 48 hours post-dosing on Day 1 and Day 85

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

8. Secondary Outcome

Title	Pharmacokinetics of ARC-520: Clearance (CL)
Time Frame	Through 48 hours post-dosing on Day 1 and Day 85

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

9. Secondary Outcome

Title	Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V)
Time Frame	Through 48 hours post-dosing on Day 1 and Day 85

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

10. Secondary Outcome

Title	Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel)
Time Frame	Through 48 hours post-dosing on Day 1 and Day 85

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

11. Secondary Outcome

Title	Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2)
Time Frame	Through 48 hours post-dosing on Day 1 and Day 85

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PBO Low Dose	PBO High Dose	ARC-520 Injection 1 mg/kg	ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period	Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Measure Participants	0	0	0	0

Adverse Events

Time Frame	Through Day 169
Arm/Group Title	PBO Low Dose		PBO High Dose		ARC-520 Injection 1 mg/kg		ARC-520 Injection 2 mg/kg
Arm/Group Description	0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period		0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period		Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period		Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
All Cause Mortality
	PBO Low Dose		PBO High Dose		ARC-520 Injection 1 mg/kg		ARC-520 Injection 2 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PBO Low Dose		PBO High Dose		ARC-520 Injection 1 mg/kg		ARC-520 Injection 2 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/11 (0%)		2/17 (11.8%)		1/21 (4.8%)
General disorders
Pyrexia	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		1/21 (4.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocarcinoma	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	PBO Low Dose		PBO High Dose		ARC-520 Injection 1 mg/kg		ARC-520 Injection 2 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/9 (44.4%)		4/11 (36.4%)		4/17 (23.5%)		8/21 (38.1%)
Cardiac disorders
Sinus bradycardia	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Diarrhoea	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Toothache	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
General disorders
Chest discomfort	0/9 (0%)		1/11 (9.1%)		0/17 (0%)		1/21 (4.8%)
Chills	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
Fatigue	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		2/21 (9.5%)
Influenza like illness	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		1/21 (4.8%)
Malaise	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		1/21 (4.8%)
Pyrexia	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		2/21 (9.5%)
Infections and infestations
Nasopharyngitis	0/9 (0%)		1/11 (9.1%)		0/17 (0%)		1/21 (4.8%)
Tonsillitis	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
Upper respiratory tract infection	1/9 (11.1%)		1/11 (9.1%)		1/17 (5.9%)		3/21 (14.3%)
Investigations
Aspartate aminotransferase increased	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Blood cholesterol increased	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
Blood creatine phosphokinase increased	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Myalgia	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
Nervous system disorders
Headache	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		1/21 (4.8%)
Lethargy	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/9 (0%)		1/11 (9.1%)		0/17 (0%)		0/21 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/9 (0%)		1/11 (9.1%)		0/17 (0%)		0/21 (0%)
Rash	0/9 (0%)		0/11 (0%)		1/17 (5.9%)		0/21 (0%)
Vascular disorders
Hypotension	1/9 (11.1%)		0/11 (0%)		0/17 (0%)		0/21 (0%)

Limitations/Caveats

The ARC-520 Injection development program was terminated early for regulatory and business reasons secondary to findings occurring in a non-clinical toxicology study. Program termination was not due to safety findings in humans.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.