Hepatitis B, Hepatitis D
Conditions
Brief summary
Patients with chronic HBV infection will receive either ARC-520 alone or ARC-520 in combination with other treatments such as entecavir (ENT) or tenofovir (TDF) and/or pegylated interferon (PEG IFN) alpha 2a therapy, and be evaluated for safety and efficacy.
Detailed description
This is a multicenter, open-label study of ARC-520 based treatment regimens administered to patients with HBeAg positive or HBeAg negative immune active chronic Hepatitis B Virus (HBV) infection of various genotypes, or patients with Hepatitis D Virus (HDV). Eligible patients naive to previous treatment, and who have signed an Ethics Committee - approved informed consent, will be enrolled and will receive ARC-520 alone or ARC-520 plus additional treatments such as entecavir (ETV) or tenofovir (TDF) and/or pegylated interferon alpha 2a (PEG IFN) therapy. The study may initially involve up to a total of 96 eligible chronic HBV and HDV infected patients. Patients in all cohorts will receive a total of 13 doses of ARC-520 at 2mg/kg or 4 mg/kg. 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 ECGs, liver fibrosis testing, concomitant medication assessment, blood sample collection for hematology, coagulation, chemistry, exploratory Pharmacodynamic (PD) measures, urinalysis, HBV serology, cytokines, 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 96 weeks, from enrolment to last visit. Prior to enrolment there is a 60 day screening period. Addition of new cohorts and additional treatment regimens are anticipated for this study.
Interventions
DRUGARC-520
ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.
DRUGentecavir
0.5 mg once daily; oral
BIOLOGICALpegylated interferon alpha 2a
180 mcg; subcutaneous injection once weekly
DRUGtenofovir disoproxil
300 mg once daily; oral
DRUGantihistamine
All participants will be pre-treated with an oral antihistamine selected by the investigator from the list of approved antihistamines that is available in that country. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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 * Diagnosis of HBeAg negative or positive chronic HBV infection. * Must be HBsAg (+) during screening. * Must be treatment naïve: never on PEG IFN alpha 2a and/or ETV or TDF; and * Have not used nucleoside/nucleotide analogs (NUCs) within the last 2 years prior to dosing on Day 1 * 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 severe infections within 4 weeks of screening * Use within the last 14 days or anticipated requirement for anticoagulants, systemic 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, over-the-counter (OTC) and prescription pain medication or hormonal contraceptives * History of poorly controlled autoimmune disease or any history of autoimmune hepatitis * History of heterozygous or homozygous familial hypercholesterolemia. * Human immunodeficiency virus (HIV) infection * Is sero-positive for Hepatitis C Virus (HCV), or has a history of delta virus hepatitis (except for cohort in which delta virus infection is acceptable) * Has hypertension: blood pressure \> 170/100 mmHg; well-controlled blood pressure on hypertensive medication allowed * History of cardiac rhythm disturbances * Family history of 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 major surgery within 1 month of screening * Regular use of alcohol within 6 months prior to screening (ie, more than 14 units of alcohol per week) * Use of recreational drugs such as cocaine, phencyclidine (PCP), and methamphetamines, within 1 year prior to the screening * History of allergy to bee sting * Clinically significant history of any alcoholic liver disease, cirrhosis, Wilson's disease, hemochromatosis, or alpha-1 antitrypsin deficiency * Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction * Clinically significant history or presence of poorly controlled/uncontrolled systemic disease * Presence of any medical or psychiatric condition or social situation that impacts compliance or results in additional safety risk * History of coagulopathy/stroke within past 6 months, and/or concurrent anticoagulant medication(s)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) at Week 60 Compared to Baseline | Baseline, Week 60 | The percentage of participants with chronic HBV achieving a 1-log reduction in HBsAg compared to baseline (mean of pre-dose values) at Week 60 after completion of 48 weeks of ARC-520 Injection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | From first dose of study drug up to 36 weeks of treatment, plus up to 48 weeks of follow-up | The Principal Investigator (or medically qualified designee) will use clinical judgment to determine the relationship. An adverse event (AE) was considered possibly related when there is a reasonable possibility that the incident, experience, or outcome may have been caused by the product under investigation. An AE was considered probably related when there are facts, evidence, or arguments to suggest that the event is related to the product under investigation. Only AEs that occurred post-dose were considered treatment-emergent. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs. |
| Percentage of Participants With HBsAg Loss (Based on Qualitative Assay) Over Time | Weeks 52, 60, 72 and 96 | The qualitative HBsAg assay gives a binary result, positive or negative. |
| Percentage of Participants Achieving a 1-log Reduction in HBsAg and Achieving an HBsAg Level < 100 IU/L Over Time | Weeks 52, 60, 72 and 96 | — |
| Time to HBsAg Loss | Baseline through Week 96 | — |
| Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion | Baseline through Week 96 | — |
| Percentage of Participants With Anti-HBs Seroconversion Over Time | Weeks 52, 60, 72 and 96 | — |
| Percentage of Participants With Resistance to ARC-520 Injection by Week 52 | Week 52 | Resistance is defined as \> 1.0 log IU/mL quantitative HBsAg (qHBsAg) increase from nadir, confirmed by repeat test. |
| Percentage of Participants With Resistance to the Combination Therapy From Baseline to Week 60 | Baseline, Week 60 | Resistance is defined as \> 1.0 log IU/mL increase in HBV DNA from nadir, confirmed by repeat test. |
| Percentage of Participants With HDV With Undetectable HDV Ribonucleic Acid (RNA) After 48 Weeks of Concomitant ARC-520 Injection and PEG IFN Alpha 2a Therapy Over Time (Cohort 7 Only) | Weeks 52, 60, 72 and 96 | — |
| Log Change From Baseline in Quantitative HBV Deoxyribonucleic Acid (DNA) Serum Levels Over Time | Baseline, Weeks 52, 60, 72 and 96 | — |
| Percentage of Participants With HBeAg Loss and Anti-Hepatitis B e Antigen (Anti-HBe) Seroconversion (if HBeAg-Positive at Study Entry) Over Time | Weeks 52, 60, 72 and 96 | — |
Countries
Australia, Bulgaria, China, Moldova, New Zealand, South Korea, Taiwan, Thailand
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Treatment-naïve, HBeAg-positive participants with CHB of any genotype administered ARC-520 (2 mg/kg IV) every 4 weeks for 48 weeks (13 doses). | 10 |
| Cohort 2 Treatment-naïve, HBeAg-positive, Genotype B participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | 2 |
| Cohort 3 Treatment-naïve, HBeAg-negative, Genotype B participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | 7 |
| Cohort 4 Treatment-naïve, HBeAg-positive, Genotype C participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | 12 |
| Cohort 5 Treatment-naïve, HBeAg-negative, Genotype C participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | 11 |
| Cohort 6 Treatment-naïve, HBeAg-negative, Genotype D participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | 13 |
| Cohort 7 Treatment-naïve, HBeAg-negative or HBeAg-positive participants with HDV administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 15. | 12 |
| Cohort 8 Treatment-naïve, HBeAg-positive participants with CHB of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks (13 doses). | 12 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Sponsor Termination of the Study | 9 | 2 | 5 | 12 | 10 | 12 | 12 | 12 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 5 | Cohort 6 | Cohort 7 | Cohort 8 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 32.5 years STANDARD_DEVIATION 11.09 | 29.5 years STANDARD_DEVIATION 0.71 | 40.4 years STANDARD_DEVIATION 7.37 | 36.3 years STANDARD_DEVIATION 9.32 | 39.6 years STANDARD_DEVIATION 12.61 | 38.2 years STANDARD_DEVIATION 7.97 | 39.6 years STANDARD_DEVIATION 7.73 | 36.7 years STANDARD_DEVIATION 7.32 | 37.4 years STANDARD_DEVIATION 9.17 |
| Sex: Female, Male Female | 7 Participants | 1 Participants | 4 Participants | 6 Participants | 3 Participants | 2 Participants | 6 Participants | 5 Participants | 34 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 3 Participants | 6 Participants | 8 Participants | 11 Participants | 6 Participants | 7 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 10 | 0 / 2 | 4 / 7 | 5 / 12 | 5 / 11 | 8 / 13 | 9 / 12 | 6 / 12 |
| serious Total, serious adverse events | 0 / 10 | 0 / 2 | 0 / 7 | 0 / 12 | 0 / 11 | 1 / 13 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Percentage of Participants Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) at Week 60 Compared to Baseline
The percentage of participants with chronic HBV achieving a 1-log reduction in HBsAg compared to baseline (mean of pre-dose values) at Week 60 after completion of 48 weeks of ARC-520 Injection.
Time frame: Baseline, Week 60
Population: The study was terminated prior to any participant reaching Week 60 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Log Change From Baseline in Quantitative HBV Deoxyribonucleic Acid (DNA) Serum Levels Over Time
Time frame: Baseline, Weeks 52, 60, 72 and 96
Population: The study was terminated prior to any participant reaching Week 60 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment
The Principal Investigator (or medically qualified designee) will use clinical judgment to determine the relationship. An adverse event (AE) was considered possibly related when there is a reasonable possibility that the incident, experience, or outcome may have been caused by the product under investigation. An AE was considered probably related when there are facts, evidence, or arguments to suggest that the event is related to the product under investigation. Only AEs that occurred post-dose were considered treatment-emergent. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs.
Time frame: From first dose of study drug up to 36 weeks of treatment, plus up to 48 weeks of follow-up
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 1 Participants |
| Cohort 1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
| Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 0 Participants |
| Cohort 2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
| Cohort 3 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 3 Participants |
| Cohort 3 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
| Cohort 4 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 2 Participants |
| Cohort 4 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
| Cohort 5 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 3 Participants |
| Cohort 5 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
| Cohort 6 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 4 Participants |
| Cohort 6 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 1 Participants |
| Cohort 7 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
| Cohort 7 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 3 Participants |
| Cohort 8 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related TEAE | 3 Participants |
| Cohort 8 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | Related Serious TEAE | 0 Participants |
Secondary
Percentage of Participants Achieving a 1-log Reduction in HBsAg and Achieving an HBsAg Level < 100 IU/L Over Time
Time frame: Weeks 52, 60, 72 and 96
Population: The study was terminated prior to any participant reaching Week 52 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Percentage of Participants With Anti-HBs Seroconversion Over Time
Time frame: Weeks 52, 60, 72 and 96
Population: The study was terminated prior to any participant reaching Week 52 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Percentage of Participants With HBeAg Loss and Anti-Hepatitis B e Antigen (Anti-HBe) Seroconversion (if HBeAg-Positive at Study Entry) Over Time
Time frame: Weeks 52, 60, 72 and 96
Population: The study was terminated prior to any participant reaching Week 52 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Percentage of Participants With HBsAg Loss (Based on Qualitative Assay) Over Time
The qualitative HBsAg assay gives a binary result, positive or negative.
Time frame: Weeks 52, 60, 72 and 96
Population: The study was terminated prior to any participant reaching Week 52 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Percentage of Participants With HDV With Undetectable HDV Ribonucleic Acid (RNA) After 48 Weeks of Concomitant ARC-520 Injection and PEG IFN Alpha 2a Therapy Over Time (Cohort 7 Only)
Time frame: Weeks 52, 60, 72 and 96
Population: The study was terminated prior to any participant reaching Week 52 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Percentage of Participants With Resistance to ARC-520 Injection by Week 52
Resistance is defined as \> 1.0 log IU/mL quantitative HBsAg (qHBsAg) increase from nadir, confirmed by repeat test.
Time frame: Week 52
Population: The study was terminated prior to any participant reaching Week 52 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Percentage of Participants With Resistance to the Combination Therapy From Baseline to Week 60
Resistance is defined as \> 1.0 log IU/mL increase in HBV DNA from nadir, confirmed by repeat test.
Time frame: Baseline, Week 60
Population: The study was terminated prior to any participant reaching Week 60 of treatment; therefore, this outcome measure could not be analyzed.
Secondary
Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion
Time frame: Baseline through Week 96
Population: This analysis was not done since no events of HBsAg loss were observed to to Week 36. (No participant reached Week 96 of treatment due to study termination).
Secondary
Time to HBsAg Loss
Time frame: Baseline through Week 96
Population: This analysis was not done since no events of HBsAg loss were observed to to Week 36. (No participant reached Week 96 of treatment due to study termination).