Extension Study of the Safety and Efficacy of Multi-dose Intravenous ARC-520 in Patients With Chronic Hepatitis B (HBV) Infection

Study Overview
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Brief Summary
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Chronic HBV patients will receive 9 doses of open-label ARC-520 once every 4 weeks and be evaluated for safety and efficacy.

Detailed Description
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Open-label, multi-center extension study of intravenous ARC-520 in combination with entecavir or tenofovir in patients with chronic HBV infection. Patients who successfully completed the Heparc-2002 (NCT02604199) and Heparc-2003 (NCT02604212) studies and responded to therapy are eligible to participate. Responders are defined as patients who showed a ½ log or greater reduction in their serum Hepatitis B Surface Antigen (HBsAg) levels from baseline to day 71 ± 3 days of the primary Heparc-2002 and Heparc-2003 studies. Patients who have signed a Human Research Ethics Committee approved informed consent and have met all of the protocol eligibility criteria will continue receiving daily oral entecavir or tenofovir and intravenous (IV) injections of ARC-520. Study visits will occur once every 4 weeks for a total of 9 visits for monitoring and ARC-520 administration. 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 (AEs), 12-lead electrocardiograms (ECGs), concomitant medications, blood sample collection for hematology, coagulation, chemistry, creatine kinase, troponin, hemoglobin A1c, exploratory pharmacodynamic (PD) measures, urinalysis, HBV serology, immunogenicity, and pregnancy testing for females of childbearing potential. Patients will be monitored for HBV virology, AEs, and exploratory PD measures for a total of 24 weeks after the last dose of ARC-520.

Official Title
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A Multicenter, Extension Study of the Safety and Efficacy of Multi-dose Intravenous ARC-520 in Combination With Entecavir or Tenofovir in Patients With Chronic Hepatitis B Virus (HBV) Infection

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: ARC-520 Injection
* Drug: entecavir
* Drug: tenofovir
* Drug: antihistamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient showed a ½ log or greater reduction in serum HBsAg levels from baseline to Day 71 ± 3 days or Day 99 ± 3 days in the primary Heparc-2002 or Heparc-2003 study. Able to have first dose within 2 months of day 113 end-of-study visit in the primary Heparc-2002 or Heparc-2003 study. Able to provide written informed consent prior to the performance of any study specific procedures. Have no abnormalities in 12-lead ECG assessment that, in the opinion of the investigator, may compromise patient safety Willing and able to comply with all study assessments and adhere to the protocol schedule. Have no new abnormal finding of clinical relevance at the screening evaluation. Using 2 effective methods of contraception (double barrier contraception or hormonal contraceptive along with a barrier contraceptive) (both male and female partners) during the study and for 3 months following the last dose of (ARC 520). Exclusion Criteria: Pregnant or lactating. Acute signs of hepatitis/other infection within 4 weeks of screening and/or at the screening examination. Use of prescription medication (including anticoagulants) within 14 days prior to administration of ARC-520. Has had major surgery within 3 months of screening. Has evidence of severe systemic acute inflammation, sepsis, or hemolysis. Diagnosed with a significant psychiatric disorder that would prevent participation in the study. Unable or unwilling to return for all scheduled study visits. Has any other condition that, in the opinion of the investigator, would render the patient unsuitable for enrollment, or could interfere with his/her participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARC-520 Injection<br>Multiple administrations of ARC-520 starting at a dose level of 2 mg/kg, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day) | Drug: ARC-520 Injection<br>* IV injection<br>Drug: entecavir<br>* All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.<br>Drug: tenofovir<br>* All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.<br>Drug: antihistamine<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Initial Responders to ARC-520 Therapy Achieving a 1-log Reduction in HBsAg at Week 36 Compared to Baseline | Initial responders are defined as participants who showed a ½ log or greater reduction in their serum HBsAg levels from baseline to Day 71 ± 3 days of the primary Heparc-2002 and Heparc-2003 studies, where baseline is defined as the average of pre-dose values. | Baseline, Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (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 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. | From first dose of study drug up to 28 weeks of treatment, plus up to 24 weeks of follow-up | 
| Percentage of Initial Responders to ARC-520 Therapy With HBsAg Loss (Qualitative) Compared to Baseline Over Time | The qualitative HBsAg assay gives a binary result, positive or negative. Baseline is defined as the average of the pre-dose values in the primary Heparc-2002 and Heparc-2003 studies. | Baseline, Weeks 36, 48, and 60 |