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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2014-004201-33
    Trial protocol
    		 DE  
    Global end of trial date
    29 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2018
    First version publication date
    18 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Heparc-2007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02738008
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Arrowhead Pharmaceuticals, Inc
    Sponsor organisation address
    225 S. Lake Avenue, Suite 1050, Pasadena, CA, United States, 91101
    Public contact
    Susan Boynton, Arrowhead Pharmaceuticals, Inc, 001 626- 696-4707, sboynton@arrowheadpharma.com
    Scientific contact
    Susan Boynton, Arrowhead Pharmaceuticals, Inc, 001 626- 696-4707, sboynton@arrowheadpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the percentage of initial responders to ARC-520 therapy achieving a 1-log reduction in Hepatitis B Surface Antigen (HBsAg) at Week 36 of the extension study compared to baseline. Baseline is defined as the average of the pre-dose values in the primary Heparc-2002 and Heparc-2003 studies.
    Protection of trial subjects
    Subjects were advised that they were free to withdraw from the study at any time for any reason or, if necessary, the Principal Investigator, or medically trained designee, may have withdrawn a subject from the study, according to the following protocol specified criteria, to protect the subject's health: • the need to take medication which may have interfered with study measurements; • intolerable/unacceptable adverse experiences; • major violation or deviation of study protocol procedures; • non-compliance of participant with protocol; • subject unwilling to proceed and/or consent was withdrawn; or • withdrawal from the study if, in the Principal Investigator’s judgment, it was in the subject’s best interest.
    Background therapy
    		 All subjects took entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day) throughout the study. Subjects were pretreated with an oral antihistamine. The antihistamine was, in general, an H1>H2 receptor blocker and would include diphenhydramine 50 mg, cetirizine 10 mg, chlorpheniramine 8 mg or hydroxyzine 50 mg. The Investigator was free to choose any of these antihistamines available locally and consistent with their country’s Marketing Authorisation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Worldwide total number of subjects
    12
    EEA total number of subjects
    1
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    11
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in subjects who successfully completed the primary studies Heparc-2002 (2014-004145-27) and Heparc-2003 (2014-004751-31) through Day 113 and responded to therapy, except for those who achieved loss of Hepatitis B Surface Antigen (HBsAg) during the primary study.

    Pre-assignment
    Screening details
    		 No subjects were enrolled from the Heparc-2002 or Heparc-2003 placebo groups.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Heparc-2002: ARC-520 1.0 mg/kg
    Arm description
    		 ARC-520 2.0 mg/kg administered by intravenous (IV) infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 1.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ARC-520 was administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min for ARC-520 and 200 cc/hour for normal saline.

    Arm title
    		 Heparc-2002: ARC-520 2.0 mg/kg
    Arm description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ARC-520 was administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min for ARC-520 and 200 cc/hour for normal saline.

    Arm title
    		 Heparc-2003: ARC-520 2.0 mg/kg
    Arm description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2003 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ARC-520 was administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min for ARC-520 and 200 cc/hour for normal saline.

    Number of subjects in period 1
    		Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg
    Started
    1
    6
    5
    Completed
    0
    0
    0
    Not completed
    1
    6
    5
         Study terminated by sponsor
    1
    5
    3
         Adverse event
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Heparc-2002: ARC-520 1.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by intravenous (IV) infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 1.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group title
    Heparc-2002: ARC-520 2.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group title
    Heparc-2003: ARC-520 2.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2003 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group values
    		 Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg Total
    Number of subjects
    		 1 6 5 12
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 1 5 5 11
        >=65 years
    		 0 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 0 5 2 7
        Male
    		 1 1 3 5

    End points

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    End points reporting groups
    Reporting group title
    Heparc-2002: ARC-520 1.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by intravenous (IV) infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 1.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group title
    Heparc-2002: ARC-520 2.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group title
    Heparc-2003: ARC-520 2.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2003 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Primary: Percentage of Initial Responders to ARC-520 Therapy Achieving a 1-log Reduction in HBsAg at Week 36 Compared to Baseline

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    End point title
    		 Percentage of Initial Responders to ARC-520 Therapy Achieving a 1-log Reduction in HBsAg at Week 36 Compared to Baseline [1]
    End point description
    Initial responders are defined as subjects 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.
    End point type
    Primary
    End point timeframe
    Baseline, Week 36
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the early termination of the study, the planned clinical statistical plan could not be conducted; no efficacy endpoints were analyzed.
    End point values
    		 Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [2] - Due to the early termination of the study, no efficacy endpoints were analyzed.
    [3] - Due to the early termination of the study, no efficacy endpoints were analyzed.
    [4] - Due to the early termination of the study, no efficacy endpoints were analyzed.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point 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 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.
    End point type
    Secondary
    End point timeframe
    up to 60 weeks
    End point values
    		 Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg
    Number of subjects analysed
    1
    6
    5
    Units: subjects
    number (not applicable)
        AEs
    1
    4
    4
        SAEs
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Initial Responders to ARC-520 Therapy With HBsAg Loss (Qualitative) Compared to Baseline Over Time

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    End point title
    		 Percentage of Initial Responders to ARC-520 Therapy With HBsAg Loss (Qualitative) Compared to Baseline Over Time
    End point description
    Baseline is defined as the average of the pre-dose values in the primary Heparc-2002 and Heparc-2003 studies.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 36, 48, and 60
    End point values
    		 Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [5] - Due to the early termination of the study, no efficacy endpoints were analyzed.
    [6] - Due to the early termination of the study, no efficacy endpoints were analyzed.
    [7] - Due to the early termination of the study, no efficacy endpoints were analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 60 weeks
    Adverse event reporting additional description
    TEAEs are presented. TEAE=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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Heparc-2002: ARC-520 1.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 1.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group title
    Heparc-2002: ARC-520 2.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2002 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Reporting group title
    Heparc-2003: ARC-520 2.0 mg/kg
    Reporting group description
    		 ARC-520 2.0 mg/kg administered by IV infusion to subjects previously enrolled in the Heparc-2003 study and receiving ARC-520 2.0 mg/kg. Subjects continued their ongoing entecavir therapy (0.5 or 1.0 mg/day) or tenofovir therapy (300 mg/day).

    Serious adverse events
    		 Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Heparc-2002: ARC-520 1.0 mg/kg Heparc-2002: ARC-520 2.0 mg/kg Heparc-2003: ARC-520 2.0 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    4 / 6 (66.67%)
    4 / 5 (80.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    3
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    3
    Chills
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Hordeolum
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The decision to discontinue development of ARC-EXl-containing programs was not due to any safety findings in clinical studies.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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