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    Summary
    EudraCT Number:2015-005136-18
    Sponsor's Protocol Code Number:ARB-001467-002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-01-15
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-005136-18
    A.3Full title of the trial
    A Phase 2a, Single-Blind, Randomized, Placebo-Controlled Study Evaluating the Safety, Anti-Viral Activity, and Pharmacokinetics of ARB-001467 in Non-Cirrhotic, HBeAg-Negative and Positive Subjects with Chronic HBV Infection Receiving Nucleos(t)ide Analogue Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine how safe and effective the treatment is for patients diagnosed with hepatitis B. The study will also look at how the body breaks-down the drug. The patients need to be already receiving Nucleoside Analogue Therapy, and have no evidence of liver damage.
    A.4.1Sponsor's protocol code numberARB-001467-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorArbutus Biopharma Corporation
    B.1.3.4CountryCanada
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportArbutus Biopharma Corporation
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationArbutus Biopharma Corporation
    B.5.2Functional name of contact pointArbutus Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address100-8900 Glenlyon Parkway
    B.5.3.2Town/ cityBurnaby, British Columbia
    B.5.3.3Post codeV5J-5J8
    B.5.3.4CountryCanada
    B.5.4Telephone number1604419-3223
    B.5.5Fax number1604430-8347
    B.5.6E-mailregulatory@arbutusbio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameARB-001467
    D.3.2Product code ARB-001467
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot assigned
    D.3.9.2Current sponsor codeUsiHBV-1 (composed of three RNA duplexes: G9-8, P6-11, D6-11)
    D.3.9.3Other descriptive nameT05M
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatitis B virus e-antigen (HBeAg)-negative and HBeAg-positive subjects with chronic Hepatitis B virus (HBV)
    E.1.1.1Medical condition in easily understood language
    Hepatitis B
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054283
    E.1.2Term HBV DNA detectable
    E.1.2System Organ Class 100000004848
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of multiple doses of ARB-001467 in Hepatitis B virus e-antigen (HBeAg)-negative and HBeAg-positive subjects with chronic Hepatitis B virus (HBV) infection who are receiving nucleos(t)ide analogue (NA) therapy.
    E.2.2Secondary objectives of the trial
    Secondary
    - To evaluate the pharmacokinetics (PK) of multiple doses of ARB-001467 in subjects with CHB.
    - To evaluate antiviral activity of ARB-001467 for up to 72 weeks after the first dose of study treatment.
    Exploratory
    - To describe drug-resistant HBV variants associated with virologic breakthrough.
    - To explore the relationship between anti-viral activity and exposure to ARB-001467.
    - To explore the relationship between immunological markers and exposure to ARB-001467.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Documented chronic HBV infection for ≥12 months prior to Screening Visit.
    2. Quantitative HBV surface antigen (HBsAg) ≥1000 IU/mL by Elecsys HBsAg II (Roche) or Architect HBsAg QT (Abbott) at the Screening Visit. Subjects with HBsAg levels <1000 IU/mL and ≥250 IU/mL may be eligible after consultation with, and approval by, the Sponsor’s Medical Monitor.
    3. Subjects currently receiving NA therapy:
    a. Have been receiving entecavir and/or tenofovir for ≥12 months.
    b. HBV DNA negative (below the lower limit of quantification [LLOQ]).
    4. Historical HBeAg status from >3 months prior to the Screening Visit available for review.
    5. All subjects must have a Fibroscan® result of ≤9 kPa at the Screening assessment.
    6. Adult subjects, 18 (or other appropriate age of consent) to 70 years of age, inclusive.
    7. Body mass index (BMI) ≥18 kg/m2 and ≤35 kg/m2.
    8. Ability to review and agree to the nature of the study, and sign the informed consent document and comply with all protocol-specified visit schedules and requirements.
    9. Female subjects of child-bearing potential must not be pregnant or lactating, must have a negative pregnancy test at Screening and must be
    practicing an adequate method of birth control. Male subjects with female partners of child-bearing potential must also practice an adequate method of birth control. Refer to the protocol for additional details.
    E.4Principal exclusion criteria
    1. Known co-infection with any of the following:
    a. Human immunodeficiency virus (HIV),
    b. Hepatitis C virus (HCV)
    c. Hepatitis D virus (HDV); OR
    d. Hepatitis E virus (HEV).
    2. Treatment with any investigational drug or enrollment in any other clinical study ≤3 months prior to the first dose of study treatment, or at any time during participation in the study; or collection of additional blood, urine, or tissue samples beyond those specified in this study or required as part of the subject’s medical care.
    3. Receiving or planning to receive systemic immunosuppressive medications during the study or ≤2 months prior to the first dose of study treatment, including but not limited to: prednisone (>10 mg/day), methotrexate, or cyclosporine.
    4. Receiving or planning to receive interferon during the study or ≤12 months prior to the first dose of study treatment.
    5. Significant immunosuppression from, but not limited to immunodeficiency conditions such as common variable hypogammaglobulinemia.
    6. Clinical diagnosis of substance abuse with alcohol, narcotics, or cocaine ≤12 months prior to the Screening Visit, except for those subjects monitored in an opioid substitution maintenance program.
    7. Any known pre-existing medical or psychiatric condition that could interfere with the subject’s ability to provide informed consent or participate in study conduct, or that may confound study findings including, but not limited to:
    a. Immunologically-mediated disease e.g., inflammatory bowel disease (Crohn’s disease, ulcerative colitis), rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, scleroderma, or sarcoidosis.
    b. Current or history of any clinically significant cardiac abnormalities/dysfunction e.g., congestive heart failure, myocardial infarction ≤6 months prior to the Screening Visit, pulmonary hypertension, complex congenital heart disease, significant arrhythmia, active cardiac ischemia.
    c. Current uncontrolled hypertension or past medical history of hypertensive crisis.
    d. Evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding esophageal varices, hepatorenal syndrome, or hepatic encephalopathy.
    e. Clinically unstable medical condition ≤1 week prior to the first dose of study treatment.
    f. Psychiatric condition(s), including but not limited to suicidal or homicidal ideation and/or attempt.
    8. Poor venous access that precludes routine peripheral blood sampling or intravenous (IV) infusion required for this study.
    9. Evidence of active or suspected malignancy, or a history of malignancy, ≤3 years prior to the Screening Visit (except adequately treated carcinoma in situ and basal cell carcinoma of the skin). Subjects under evaluation for malignancy are not eligible.
    10. Known or suspected hypersensitivity or previous severe reactions to any of the constituents of ARB-001467, other lipid-based products, or
    products containing polyethylene glycol or the drugs used in the pre-treatment regimen (dexamethasone, ibuprofen, H1 and H2 blockers).
    11. Pregnant or nursing, or who intend to become pregnant during the study.
    12. Male subjects with partners who are, or intend to become, pregnant during the study.
    13. Employed as site personnel directly involved with this study.
    14. History of life-threatening SAE during the Screening period.
    Laboratory Exclusion Criteria
    If any of the following laboratory exclusion criteria are met, then the site may have the subject retested. If a single value is within ±10% of the listed laboratory exclusion criterion value upon retest, and the value is considered to be not clinically significant by the physician investigator, the subject may be considered for enrollment.
    15. Alanine transaminase (ALT) or aspartate transaminase (AST) >2 × upper limit of normal (ULN).
    16. Direct bilirubin >1.5 × ULN and total bilirubin >1.6 mg/dL.
    17. Serum albumin < 3.2 g/dL
    18. International normalized ratio (INR) >1.2.
    19. Hematologic, biochemical, and serologic criteria (growth factors may not be used to achieve study entry requirements):
    a. Hemoglobin Cohorts 1 to 3: <10 g/dL for females and <11 g/dL for males, Cohort 4: <11 g/dL for females and <12 g/dL for males
    b. Neutrophils <1500 /mm3 (Blacks: <1200 /mm3); AND
    c. Platelets Cohorts 1 to 3: <125,000 /mm3., Cohort 4: <150,000/mm3.
    20. Serum creatinine >1.5 × ULN.
    21. Poorly controlled diabetes mellitus with whole blood hemoglobin A1c (HbA1c) ≥8.5%.
    22. Alpha fetoprotein (AFP) >100 ng/mL. For subjects with AFP results of 50 to 100 ng/mL, a liver ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan is to be performed ≤3 months prior to the first dose of study treatment.
    23. Liver ultrasound or other imaging with findings suggestive of hepatocellular carcinoma (HCC).
    E.5 End points
    E.5.1Primary end point(s)
    The frequency and severity of treatment-emergent serious adverse events (SAEs), discontinuations due to adverse events (AEs), and laboratory abnormalities, by cohort.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the trial and until 28 days after the last infusion of study treatment
    E.5.2Secondary end point(s)
    Secondary
    - ARB-001467 PK at multiple time points from baseline through Day 85 (i.e., 28 days after the last infusion of study treatment) in cohorts 1 to 3 and cohort 4 (without extended treatment) and from baseline through 36 weeks of treatment (cohort 4 extended treatment).
    - The proportion of subjects in each dose level cohort with ≥0.5 log10 HBsAg decrease from baseline at EOS, and for these subjects, the changes from baseline (expressed as percentage and log10 change) in the following virologic markers will be assessed throughout the study:
    - Quantitative HBV surface antigen (HBsAg)
    - Quantitative HBV surface antibody (HBsAb)
    - Quantitative HBV-DNA and HBV-RNA (viral load)
    For the HBeAg-positive cohort only:
    - Quantitative HBV e-antigen (HBeAg)

    Exploratory
    - Identification of drug resistance mutations from RNA sequencing of drug-resistant HBV variants.
    - Assessment of the relationships between PK and virologic markers.
    - Assessment of the relationships between PK and immunologic markers.
    E.5.2.1Timepoint(s) of evaluation of this end point
    ARB-001467 PK at multiple time points from baseline through Day 85 (i.e., 28 days after the last infusion of study treatment) in cohorts 1 to 3 and cohort 4 without extended treatment) and from baseline through 36 weeks of treatment (cohort 4 extended treatment).

    The proportion of subjects in each dose level cohort with changes from baseline will be assessed throughout the study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Anti-viral Activity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    New Zealand
    Romania
    United Kingdom
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 46
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None - Patient's care post-trial managed by their own physician
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-03-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-03-21
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