| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Virus (HBV) Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis B Virus (HBV) Infection |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the percentage of chronic HBV patients 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 |
|
| E.2.2 | Secondary objectives of the trial |
• percentage (%) of pts. with HBsAg loss at W 52, 60, 72, and 96
• % of pts. achieving a 1-log reduction in HBsAg AND achieving a HBsAg level < 100 IU/mL at W 52, 60, 72, and 96
• Time to HBsAg loss
• Time to anti-HBs seroconversion
• % of pts. with anti-HBs seroconversion at W 52, 60, 72, and 96
• % of pts. with HBeAg loss and Anti-HBe seroconversion at W 52, 60, 72, and 96 (if HBeAg positive at study entry)
• % of pts. with resistance to ARC-520 by W 52
• % of pts. with resistance to the combination th. (where applicable) from baseline to W 60
• incidence and frequency of AEs possibly or probably related to treatment as a measure of safety and tolerability of ARC-520 alone or when coadm. with combination th.
• % of HDV pts. with undetectable HDV RNA at W 52, 60, 72, and 96 after completion of 48 weeks ARC-520 treatment concomitantly with 48 weeks of weekly peginterferon alpha 2a (Cohort 7 only)
• effect of ARC-520 (as monoth. or as combination th.) on HBV DNA serum levels |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for enrollment, the following criteria must be met:
1. Male or female, 18 to 75 years of age, inclusive, at the time of
informed consent.
2. Able to provide written informed consent prior to the performance of any study specific procedures
3. Body mass index (BMI) between 17.5 and 35.0 kg/m2, inclusive.
Patients with BMI above or below the cutoff may be enrolled at the
discretion of the investigator based on risks and co-morbidities.
BMI = weight (kg)/(height [m])2
4. Have no abnormalities at screening or pre-dose 12-lead ECG
assessment (measured after the patient is supine for at least 3 minutes) that, in the opinion of the principal investigator, may compromise the patient's safety in this study.
5. Willing and able to comply with all study assessments and adhere to
the protocol schedule.
6. Have suitable venous access for blood sampling.
7. Have a diagnosis of HBeAg negative or positive chronic HBV infection.
8. HBV DNA at screening > 2000 IU/mL (does not apply to cohort 7)
9. Positive HDV RNA at screening using RT-PCR (Cohort 7 only)
10. HBsAg ≥ 1000 IU/mL
11. In HBeAg positive subjects only, any one of the following criteria will qualify for enrollment:
a. ALT at screening ≥35 U/L (males) or ≥30 U/L (females)
b. Source document verifiable ALT≥35 U/L (males) or ≥30 U/L (females) within the last 6 months
c. Test positive at Screening for presence of basal core promoter
mutation
For clarity, once any of the above criteria are met in an HBeAg positive
subject, this inclusion criteria is to be considered met and the subject
can be enrolled. Additionally, there are no corresponding criteria for
HBeAg negative subjects. All HBeAg negative subjects can be enrolled
assuming they meet all other inclusion and exclusion criteria.
12. Must be HBsAg (+) during screening.
13. Identify as treatment naïve:
a. Never on PEG IFN and/or ETV or TDF and
b. No history of any NUCs within the last 2 years prior to Day 1 dosing
14. Patients must use 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 ARC-520 study treatment. Males must not donate sperm for at least 3 months post-dose of the last study
treatment. Male partners of female patients and female partners of male patients must also use contraception, if they are of childbearing
potential. Females of childbearing potential must have a negative urine pregnancy test at screening and pre-dose on Day 1. Females not of childbearing potential must be postmenopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone (FSH) indicative of post-menopausal state.
Contraception that is deemed acceptable in this study includes the
following:
a. Condom
b. Birth control pills (The Pill)
c. Depot or injectable birth control (administered at least 3 months prior to planned study dose)
d. Intrauterine device
e. Birth Control Patch (eg, Ortho Evra®)
f. NuvaRing®
g. Surgical sterilization (ie, bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy for women or vasectomy for men)
Rhythm methods WILL NOT be considered as highly effective methods of contraception, however abstinence may be allowed based on opinion of treating physician.
15. For Cohorts 2-6, have a lab confirmed HBV Genotype B, C or D, as
applicable. |
|
| E.4 | Principal exclusion criteria |
1. Female patients have a positive pregnancy test or are lactating.
2. Known hypersensitivity to any part of study treatment regimens
3. Acute signs of hepatitis/other severe infection (e.g., moderate fever, jaundice, nausea, vomiting, and abdominal pain) evident within 4 weeks of screening and/or at the screening examination (recent URIs or viral syndromes are acceptable).
4. Hepatic transaminases (ALT or AST) > 5X upper limits of normal at
screening.
5. Liver Elastography (i.e. FibroScan®) score > 10.5 at screening (if
FibroScan® is not available, the following tests/criteria are acceptable:
FibroTest/Fibrosure score > 0.7; Accoustic Radiation Force Impulse
(ARFI, e.g Siemens Acuson) >1.55 m/s; Shear Wave Elastography (e.g.
Aixplorer) >10.0 kPa at screening).
6. Use within the last 14 days or an anticipated requirement for
anticoagulants (aspirin is acceptable), systemic (oral, depot or
intravenous) corticosteroids, immunomodulators, or
immunosuppressants (other than used in the study).
7. Use of prescription medication within 14 days prior to administration of study treatment that in the opinion of the PI or the Sponsor would interfere with study conduct. Topical products without systemic absorption, statins (except rosuvastatin), hypertensive medications, OTC and prescription pain medication or hormonal contraceptives (females) are acceptable.
8. Patients with any of the following laboratory abnormalities:
a. Serum creatinine > 1.5 mg/dL (132.6 μmol/L)
b. International normalized ratio (INR) > 1.25 × ULN
c. Platelets < 70,000 cells per mL
9. Has any history of poorly controlled autoimmune disease or any
history of autoimmune hepatitis.
10. Has a history of heterozygous or homozygous familial
hypercholesterolemia.
11. Has human immunodeficiency virus (HIV) infection, as shown by the presence of anti-HIV antibody (sero-positive).
12. Is sero-positive for HCV, or a history of delta virus hepatitis (not
including Cohort 7 where delta virus infection is acceptable).
13. Has hypertension defined as blood pressure > 170/100 mmHg at
screening confirmed by repeat. Patients with well-controlled blood
pressure on anti-hypertensive medication will be allowed.
14. Patients with a history of torsades de pointes, ventricular rhythm
disturbances (eg, ventricular tachycardia or fibrillation), pathologic
symptomatic bradycardia (heart rate < 45 bpm), 2nd degree or 3rd
degree heart block, congenital long QT syndrome, prolonged QT interval due to medications, or new elevation or depression in the part of an ECG immediately following the QRS complex and merging into the T wave (ST segment) or new pathologic inverted T waves, or new pathologic Q waves on ECG
15. Has a family history of congenital long QT syndrome, Brugada
syndrome or unexplained sudden cardiac death.
16. Has experienced symptomatic heart failure, unstable angina,
myocardial infarction, severe cardiovascular disease (ejection fraction < 40%, transient ischemic attack, or cerebrovascular accident) within 6
months prior to study entry.
17. Patients with a history of malignancy, including hepatocellular
carcinoma within the last 5 years, except for adequately treated basal
cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer
18. Has had a major surgery within 1 month of screening.
19. Regularly uses alcohol within 6 months prior to the screening visit
(ie, more than 14 units of alcohol per week [1 unit = 150 mL of wine,360 mL of beer, or 45 mL of 40% alcohol]).
20. Use of recreational drugs such as cocaine, phencyclidine and
methamphetamines, within 1 year prior to the screening.
21. Has a history of allergy to bee venom or history of severe
hypersensitivity reaction, such as anaphylaxis
22. Has a clinically significant history of any alcoholic liver disease,
cirrhosis, Wilson's disease, hemochromatosis, or alpha-1 antitrypsin
deficiency
23. Patients with cholangitis, cholecystitis, cholestasis, or duct
obstruction
24. Has any clinically significant history or presence of poorly controlled or decompensated neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic, or other uncontrolled systemic disease, that may affect participation in the study.
25. Presence of any concomitant medical or psychiatric condition or
social situation that, in the opinion of the investigator, would make it
difficult to comply with protocol requirements or put the patient at
additional safety risk.
26. Has a history of coagulopathy or stroke within 6 months of baseline, and/or concurrent anticoagulant medication(s).
27. Unable or unwilling to return for all scheduled study visits.
28. Has any other condition that, in the opinion of the PI, would render the patient unsuitable for enrolment.
29. For Cohorts 2-6, have any contraindications as per package insert to ETV, TDF or PEG IFN alpha 2a (PEG IFN alpha 2a only for Cohort 7). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The percentage of patients with > 1-log of HBsAg reduction with varied treatment regimens of ARC-520 compared to baseline (mean of pre-dose values) after completion of 48 weeks of ARC-520 treatment.
The number and percent of patients with HBsAg reductions will be summarized by cohort. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy end points will be summarized by cohort:
1. Percent of patients with loss of HBsAg
2. Quantitative HBV DNA
3. Percent of patients with undetectable HDV RNA
4. Percentage of patients achieving a 1-log reduction in HBsAg AND achieving a HBsAg level < 100 IU/L
5. Percent of patients with HBeAg loss and Anti-HBe seroconversion
6. Percent of patients with resistance to ARC-520
7. Percent of patients with resistance to the combination therapy
8. Quantitative HBsAg (qHBsAg): Log change and duration of response
9. Frequency of responses (defined as loss of HBsAg) based on baseline HBsAg that fall in the following categories by cohort will be determined: 0 to < 0.5 log IU/mL; 0.5 to 1.0 log IU/mL; > 1.0 log IU/mL.
10. Incidence and frequency of adverse events possibly or probably related to treatment as a measure of safety and tolerability of ARC-520 alone or when coadministered with combination therapy
11. Time to occurrence of HBsAg loss (Kaplan Meier)
12. Percent of patients with anti-HBS seroconversion and time to occurrence (Kaplan Meier) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Weeks 52, 60, 72, and 96
2. Baseline, Week 52, 60, 72, and 96
3. Weeks 52, 60, 72 and 96
4. Weeks 52, 60, 72, and 96
5. Weeks 52, 60, 72, and 96
6. Week 52
7. Baseline, Week 60
8. Baseline, Weeks 52, 60, 72, and 96
9. evaluated for every collection
10. evaluated for every collection |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| ARC-520 alone or in combination with ETV or TDF and/or PEG IFN alpha 2a |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| ARC-520 administrated in combination with other therapeutics (ETV or TDF and/or PEG IFN alpha 2a) |
|
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bulgaria |
| Hong Kong |
| Korea, Republic of |
| Moldova, Republic of |
| New Zealand |
| Taiwan |
| Thailand |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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