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    Clinical Trial Results:
    A Multicenter, Open-Label Study to Evaluate ARC-520 Administered Alone and in Combination with Other Therapeutics in Patients with Chronic Hepatitis B Virus (HBV) Infection (MONARCH)

    Summary
    EudraCT number
    		 2015-005499-46
    Trial protocol
    		 BG  
    Global end of trial date
    28 Dec 2016

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Heparc-2008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02577029
    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. , +1 626-696-4707, sboynton@arrowheadpharma.com
    Scientific contact
    Susan Boynton, Arrowhead Pharmaceuticals, Inc. , +1 626-696-4707, 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
    28 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    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
    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study at any time for any reason or, if necessary, the Principal Investigator, or medically trained designee, may have withdrawn a subject from the study, according to the following protocol specified criteria, to protect the subject's health: • the need to take medication which may have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 subject 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
    		 The patients were also required to take concomitant medications (0.5 mg once daily entecavir OR 300 mg once daily tenofovir [Cohorts 2-6]; 180 mcg pegylated interferon-alpha [PEG-IFN α; Cohorts 2-7]). Cohorts 1 and 8 were not required to take any concomitant medication and received ARC-520 Injection as monotherapy. The treatment period for entecavir/tenofovir started concurrently with ARC-520 Injection dosing and was scheduled for 60 weeks. This could be extended if so considered by the assessing investigator however all treatment was to stop once seroconversion was achieved. The PEG-IFN α start was delayed and started at Day 87 for Cohorts 2-6 or Day 15 for Cohort 7, of treatment. PEG–IFN α treatment was scheduled for 48 weeks. PEG-IFN α was administered weekly as per protocol and any dose reductions were made based on locally approved PEG-IFN α label instructions. All subjects were pre-treated with an oral antihistamine selected by the investigator from the list of approved antihistamines that is available in that country. Acceptable antihistamines were: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Moldova, Republic of: 15
    Country: Number of subjects enrolled
    Thailand: 25
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Worldwide total number of subjects
    79
    EEA total number of subjects
    15
    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)
    79
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study included up to 60 days of screening period.

    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
    		 Cohort 1
    Arm description
    		 Treatment-naïve, hepatitis B “e” antigen (HBeAg)-positive subjects with chronic hepatitis B (CHB) of any genotype administered ARC-520 (2 mg/kg intravenous [IV]) every 4 weeks for 48 weeks (13 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 2
    Arm description
    		 Treatment-naïve, HBeAg-positive, Genotype B subjects 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 peginterferon (PEG IFN) alpha 2a for 48 weeks starting Day 87.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 3
    Arm description
    		 Treatment-naïve, HBeAg-negative, Genotype B subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 4
    Arm description
    		 Treatment-naïve, HBeAg-positive, Genotype C subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 5
    Arm description
    		 Treatment-naïve, HBeAg-negative, Genotype C subjects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 6
    Arm description
    		 Treatment-naïve, HBeAg-negative, Genotype D subects 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 7
    Arm description
    		 Treatment-naïve, HBeAg-negative or HBeAg-positive subjects with hepatitis delta virus (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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		 Cohort 8
    Arm description
    		 Treatment-naïve, HBeAg-positive subjects with CHB of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks (13 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ARC-520 Injection
    Investigational medicinal product code
    ARC-520
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    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
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Started
    10
    2
    7
    12
    11
    13
    12
    12
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    10
    2
    7
    12
    11
    13
    12
    12
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    1
    -
    -
         Sponsor termination of the study
    9
    2
    5
    12
    10
    12
    12
    12
         Adverse event
    1
    -
    2
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Treatment-naïve, hepatitis B “e” antigen (HBeAg)-positive subjects with chronic hepatitis B (CHB) of any genotype administered ARC-520 (2 mg/kg intravenous [IV]) every 4 weeks for 48 weeks (13 doses).

    Reporting group title
    Cohort 2
    Reporting group description
    		 Treatment-naïve, HBeAg-positive, Genotype B subjects 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 peginterferon (PEG IFN) alpha 2a for 48 weeks starting Day 87.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype B subjects 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.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Treatment-naïve, HBeAg-positive, Genotype C subjects 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.

    Reporting group title
    Cohort 5
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype C subjects 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.

    Reporting group title
    Cohort 6
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype D subects 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.

    Reporting group title
    Cohort 7
    Reporting group description
    		 Treatment-naïve, HBeAg-negative or HBeAg-positive subjects with hepatitis delta virus (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.

    Reporting group title
    Cohort 8
    Reporting group description
    		 Treatment-naïve, HBeAg-positive subjects with CHB of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks (13 doses).

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8 Total
    Number of subjects
    		 10 2 7 12 11 13 12 12 79
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.5 ± 11.09 29.5 ± 0.71 40.4 ± 7.37 36.3 ± 9.32 39.6 ± 12.61 38.2 ± 7.97 39.6 ± 7.73 36.7 ± 7.32 -
    Gender categorical
    Units: Subjects
        Female
    		 7 1 4 6 3 2 6 5 34
        Male
    		 3 1 3 6 8 11 6 7 45

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Treatment-naïve, hepatitis B “e” antigen (HBeAg)-positive subjects with chronic hepatitis B (CHB) of any genotype administered ARC-520 (2 mg/kg intravenous [IV]) every 4 weeks for 48 weeks (13 doses).

    Reporting group title
    Cohort 2
    Reporting group description
    		 Treatment-naïve, HBeAg-positive, Genotype B subjects 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 peginterferon (PEG IFN) alpha 2a for 48 weeks starting Day 87.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype B subjects 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.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Treatment-naïve, HBeAg-positive, Genotype C subjects 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.

    Reporting group title
    Cohort 5
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype C subjects 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.

    Reporting group title
    Cohort 6
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype D subects 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.

    Reporting group title
    Cohort 7
    Reporting group description
    		 Treatment-naïve, HBeAg-negative or HBeAg-positive subjects with hepatitis delta virus (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.

    Reporting group title
    Cohort 8
    Reporting group description
    		 Treatment-naïve, HBeAg-positive subjects with CHB of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks (13 doses).

    Primary: Percentage of Subjects Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) Compared to Baseline

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    End point title
    		 Percentage of Subjects Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) Compared to Baseline [1]
    End point description
    The percentage of subjects 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.
    End point type
    Primary
    End point timeframe
    Baseline, Week 60
    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: The final statistical analysis plan was released after the study termination. Planned analysis per protocol for any efficacy variables including virology assessments, immunogenicity, pharmacokinetics and pharmacodynamics were not conducted and not planned for per the SAP.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [2] - Analysis was not planned or conducted per SAP due to study termination.
    [3] - Analysis was not planned or conducted per SAP due to study termination.
    [4] - Analysis was not planned or conducted per SAP due to study termination.
    [5] - Analysis was not planned or conducted per SAP due to study termination.
    [6] - Analysis was not planned or conducted per SAP due to study termination.
    [7] - Analysis was not planned or conducted per SAP due to study termination.
    [8] - Analysis was not planned or conducted per SAP due to study termination.
    [9] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Primary: Percentage of Subjects Achieving a 1-log Reduction in HBsAg and Achieving an HBsAg Level < 100 IU/L

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    End point title
    		 Percentage of Subjects Achieving a 1-log Reduction in HBsAg and Achieving an HBsAg Level < 100 IU/L [10]
    End point description
    End point type
    Primary
    End point timeframe
    Weeks 52, 60, 72 and 96
    Notes
    [10] - 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: The final statistical analysis plan was released after the study termination. Planned analysis per protocol for any efficacy variables including virology assessments, immunogenicity, pharmacokinetics and pharmacodynamics were not conducted and not planned for per the SAP.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [11] - Analysis was not planned or conducted per SAP due to study termination.
    [12] - Analysis was not planned or conducted per SAP due to study termination.
    [13] - Analysis was not planned or conducted per SAP due to study termination.
    [14] - Analysis was not planned or conducted per SAP due to study termination.
    [15] - Analysis was not planned or conducted per SAP due to study termination.
    [16] - Analysis was not planned or conducted per SAP due to study termination.
    [17] - Analysis was not planned or conducted per SAP due to study termination.
    [18] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to Week 96 +/- 3 days
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    10
    2
    7
    12
    11
    13
    12
    12
    Units: subjects
        Related TEAE
    1
    0
    3
    2
    3
    4
    3
    3
        Related Serious TEAE
    0
    0
    0
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HBsAg Loss (Based on Qualitative Assay)

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    End point title
    		 Percentage of Subjects With HBsAg Loss (Based on Qualitative Assay)
    End point description
    The qualitative HBsAg assay gives a binary result, positive or negative.
    End point type
    Secondary
    End point timeframe
    Weeks 52, 60, 72 and 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [19] - Analysis was not planned or conducted per SAP due to study termination.
    [20] - Analysis was not planned or conducted per SAP due to study termination.
    [21] - Analysis was not planned or conducted per SAP due to study termination.
    [22] - Analysis was not planned or conducted per SAP due to study termination.
    [23] - Analysis was not planned or conducted per SAP due to study termination.
    [24] - Analysis was not planned or conducted per SAP due to study termination.
    [25] - Analysis was not planned or conducted per SAP due to study termination.
    [26] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Time to HBsAg Loss

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    End point title
    		 Time to HBsAg Loss
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [27]
    0 [28]
    0 [29]
    0 [30]
    0 [31]
    0 [32]
    0 [33]
    0 [34]
    Units: hours
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [27] - Analysis was not planned or conducted per SAP due to study termination.
    [28] - Analysis was not planned or conducted per SAP due to study termination.
    [29] - Analysis was not planned or conducted per SAP due to study termination.
    [30] - Analysis was not planned or conducted per SAP due to study termination.
    [31] - Analysis was not planned or conducted per SAP due to study termination.
    [32] - Analysis was not planned or conducted per SAP due to study termination.
    [33] - Analysis was not planned or conducted per SAP due to study termination.
    [34] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion

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    End point title
    		 Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [35]
    0 [36]
    0 [37]
    0 [38]
    0 [39]
    0 [40]
    0 [41]
    0 [42]
    Units: hours
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [35] - Analysis was not planned or conducted per SAP due to study termination.
    [36] - Analysis was not planned or conducted per SAP due to study termination.
    [37] - Analysis was not planned or conducted per SAP due to study termination.
    [38] - Analysis was not planned or conducted per SAP due to study termination.
    [39] - Analysis was not planned or conducted per SAP due to study termination.
    [40] - Analysis was not planned or conducted per SAP due to study termination.
    [41] - Analysis was not planned or conducted per SAP due to study termination.
    [42] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Anti-HBs Seroconversion

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    End point title
    		 Percentage of Subjects With Anti-HBs Seroconversion
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 52, 60, 72 and 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [43]
    0 [44]
    0 [45]
    0 [46]
    0 [47]
    0 [48]
    0 [49]
    0 [50]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [43] - Analysis was not planned or conducted per SAP due to study termination.
    [44] - Analysis was not planned or conducted per SAP due to study termination.
    [45] - Analysis was not planned or conducted per SAP due to study termination.
    [46] - Analysis was not planned or conducted per SAP due to study termination.
    [47] - Analysis was not planned or conducted per SAP due to study termination.
    [48] - Analysis was not planned or conducted per SAP due to study termination.
    [49] - Analysis was not planned or conducted per SAP due to study termination.
    [50] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HBeAg Loss and Anti-Hepatitis B e Antigen (Anti-HBe) Seroconversion (if HBeAg-Positive at Study Entry)

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    End point title
    		 Percentage of Subjects With HBeAg Loss and Anti-Hepatitis B e Antigen (Anti-HBe) Seroconversion (if HBeAg-Positive at Study Entry)
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 52, 60, 72 and 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [51]
    0 [52]
    0 [53]
    0 [54]
    0 [55]
    0 [56]
    0 [57]
    0 [58]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [51] - Analysis was not planned or conducted per SAP due to study termination.
    [52] - Analysis was not planned or conducted per SAP due to study termination.
    [53] - Analysis was not planned or conducted per SAP due to study termination.
    [54] - Analysis was not planned or conducted per SAP due to study termination.
    [55] - Analysis was not planned or conducted per SAP due to study termination.
    [56] - Analysis was not planned or conducted per SAP due to study termination.
    [57] - Analysis was not planned or conducted per SAP due to study termination.
    [58] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Resistance to ARC-520 Injection by Week 52

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    End point title
    		 Percentage of Subjects With Resistance to ARC-520 Injection by Week 52
    End point description
    Resistance is defined as > 1.0 log IU/mL quantitative HBsAg (qHBsAg) increase from nadir, confirmed by repeat test.
    End point type
    Secondary
    End point timeframe
    through Week 52
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [59]
    0 [60]
    0 [61]
    0 [62]
    0 [63]
    0 [64]
    0 [65]
    0 [66]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [59] - Analysis was not planned or conducted per SAP due to study termination.
    [60] - Analysis was not planned or conducted per SAP due to study termination.
    [61] - Analysis was not planned or conducted per SAP due to study termination.
    [62] - Analysis was not planned or conducted per SAP due to study termination.
    [63] - Analysis was not planned or conducted per SAP due to study termination.
    [64] - Analysis was not planned or conducted per SAP due to study termination.
    [65] - Analysis was not planned or conducted per SAP due to study termination.
    [66] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Resistance to the Combination Therapy From Baseline to Week 60

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    End point title
    		 Percentage of Subjects With Resistance to the Combination Therapy From Baseline to Week 60
    End point description
    Resistance is defined as > 1.0 log IU/mL increase in HBV DNA from nadir, confirmed by repeat test.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 60
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [67]
    0 [68]
    0 [69]
    0 [70]
    0 [71]
    0 [72]
    0 [73]
    0 [74]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [67] - Analysis was not planned or conducted per SAP due to study termination.
    [68] - Analysis was not planned or conducted per SAP due to study termination.
    [69] - Analysis was not planned or conducted per SAP due to study termination.
    [70] - Analysis was not planned or conducted per SAP due to study termination.
    [71] - Analysis was not planned or conducted per SAP due to study termination.
    [72] - Analysis was not planned or conducted per SAP due to study termination.
    [73] - Analysis was not planned or conducted per SAP due to study termination.
    [74] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HDV With Undetectable HDV Ribonucleic Acid (RNA) After 48 Weeks of Concomitant ARC-520 Injection and PEG IFN Alpha 2a Therapy (Cohort 7 Only)

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    End point title
    		 Percentage of Subjects With HDV With Undetectable HDV Ribonucleic Acid (RNA) After 48 Weeks of Concomitant ARC-520 Injection and PEG IFN Alpha 2a Therapy (Cohort 7 Only)
    End point description
    End point type
    Secondary
    End point timeframe
    Weeks 52, 60, 72 and 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [75]
    0 [76]
    0 [77]
    0 [78]
    0 [79]
    0 [80]
    0 [81]
    0 [82]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [75] - Analysis was not planned or conducted per SAP due to study termination.
    [76] - Analysis was not planned or conducted per SAP due to study termination.
    [77] - Analysis was not planned or conducted per SAP due to study termination.
    [78] - Analysis was not planned or conducted per SAP due to study termination.
    [79] - Analysis was not planned or conducted per SAP due to study termination.
    [80] - Analysis was not planned or conducted per SAP due to study termination.
    [81] - Analysis was not planned or conducted per SAP due to study termination.
    [82] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Secondary: Log Change From Baseline in Quantitative HBV Deoxyribonucleic Acid (DNA) Serum Levels

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    End point title
    		 Log Change From Baseline in Quantitative HBV Deoxyribonucleic Acid (DNA) Serum Levels
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 60, 72 and 96
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Number of subjects analysed
    0 [83]
    0 [84]
    0 [85]
    0 [86]
    0 [87]
    0 [88]
    0 [89]
    0 [90]
    Units: log change
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [83] - Analysis was not planned or conducted per SAP due to study termination.
    [84] - Analysis was not planned or conducted per SAP due to study termination.
    [85] - Analysis was not planned or conducted per SAP due to study termination.
    [86] - Analysis was not planned or conducted per SAP due to study termination.
    [87] - Analysis was not planned or conducted per SAP due to study termination.
    [88] - Analysis was not planned or conducted per SAP due to study termination.
    [89] - Analysis was not planned or conducted per SAP due to study termination.
    [90] - Analysis was not planned or conducted per SAP due to study termination.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to Week 96 +/- 3 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Treatment-naïve, HBeAg-positive subjects with CHB of any genotype administered ARC-520 (2 mg/kg IV) every 4 weeks for 48 weeks (13 doses).

    Reporting group title
    Cohort 2
    Reporting group description
    		 Treatment-naïve, HBeAg-positive, Genotype B subjects 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.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype B subjects 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.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Treatment-naïve, HBeAg-positive, Genotype C subjects 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.

    Reporting group title
    Cohort 5
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype C subjects 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.

    Reporting group title
    Cohort 6
    Reporting group description
    		 Treatment-naïve, HBeAg-negative, Genotype D subjects 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.

    Reporting group title
    Cohort 7
    Reporting group description
    		 Treatment-naïve, HBeAg-negative or HBeAg-positive subjects 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.

    Reporting group title
    Cohort 8
    Reporting group description
    		 Treatment-naïve, HBeAg-positive subjects with CHB of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks (13 doses).

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Vestibular neuronitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    0 / 2 (0.00%)
    4 / 7 (57.14%)
    5 / 12 (41.67%)
    5 / 11 (45.45%)
    8 / 13 (61.54%)
    9 / 12 (75.00%)
    6 / 12 (50.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Peripheral coldness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vasoconstriction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Surgical and medical procedures
    Hernia repair
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Skin neoplasm excision
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Administration site bruise
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    3
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
    3 / 11 (27.27%)
    3 / 13 (23.08%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    0
    3
    4
    0
    1
    Feeling cold
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    5
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    Swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    2 / 11 (18.18%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Euphoric mood
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    2
    Head discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Sedation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    2
    0
    0
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    3
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    4 / 12 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    Lymphopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    5 / 12 (41.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    3 / 13 (23.08%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    3
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Flushing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Muscle tightness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    0
    2
    Viral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    2 / 11 (18.18%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    2
    2
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 2 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2015
    1. Modify Schedule of Assessments to collect Quantitative and qualitative anti-HBs, qualitative anti-Hbe, and HbsAg epitope mapping Baseline samples at the Day 1 visit for all enrolled patients. 2. Correction of administrative, grammatical, formatting errors, and inconsistencies.
    20 Nov 2015
    1. Addition of Cohort 7 (Treatment naïve HBeAg negative or HBeAg positive Hepatitis Delta Virus (HDV) patients administered ARC-520 (2 mg/kg IV) every 4 weeks for 48 weeks concomitantly with PEG IFN alpha 2a and Cohort 8 (Treatment naïve, HBeAg positive, Chronic Hepatitis B (CHB) patients of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks). HDV infection requires HBsAg present in chronic HBV infection. Therefore, targeting HBV and specifically HBsAg with ARC-520 may prove therapeutic for HDV. Cohort 8 utilizes a 4 mg/kg dose, which has been extensively studied as a single dose treatment in HBeAg negative and HBeAg positive patients in the Heparc-2001 study. The addition of this cohort is intended to compare monotherapy response between low dose (Cohort 1, 2 mg/kg) and high dose (Cohort 9, 4 mg/kg). 2. Expansion of the study to addition Asia/Pacific and European countries. 3. Correction of administrative, grammatical, formatting errors, and inconsistencies.
    22 Jan 2016
    1. Addition of Tenofovir (TDF) as an alternative to Entecavir (ETV) for treatments used in Cohorts 2-6. This addition is intended to provide an appropriate NUC alternative if entecavir is not available. 2. Removal of Cetirizine 10 mg p.o. as an acceptable antihistamine. Sponsor prefers use of antihistamines that are less H1 receptor selective. 3. Changes made to the Exclusion Criteria in protocol version 2.0 (20 November 2015): a. Exclusion criterion #3 modified to allow for enrollment of patients with recent minor infections. b. Exclusion criterion #22 was removed as the exclusion of subjects with these conditions is covered by other exclusion criteria. c. Exclusion criterion #25 modified for clarity. d. Exclusion criterion #29 removed as Sponsor has found no reason why fever alone within 2 weeks of screening should exclude a subject. 4. Cytokines will now be drawn and evaluated for all patients at the pre-dose blood draw regardless of evidence of ALT flares. Sponsor recently presented data at Hepdart in December 2015 showing that 7 of 9 chimps, all being treated with ARC-520 showed signs of cytokine induction. This was seen in the presence of declining HBV viral antigens and ALT flare was not routinely present. Thus, ALT flare may not be necessary to see signs of immune reconstitution in humans. 5. Correction of administrative, grammatical, formatting errors, and inconsistencies.
    20 Apr 2016
    1. Changes made to the Inclusion/Exclusion Criteria in protocol version 3.0 (22 January 2016): a. Inclusion criterion #11 was modified for HBeAg positive subjects only: i. ALT at screening ≥ 35 U/L (males) or ≥ 30 U/L (females) ii. Source document verifiable ALT ≥ 35 U/L (males) or ≥ 30 U/L (females) within the last 6 months iii. Tests 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. b. Exclusion criterion #5 was revised for Liver Elastography (i.e. FibroScan®) score > 10.59 or FibroTest/Fibrosure score > 0.7 at screening. c. Exclusion criterion #8 was removed as Sponsor did not feel the need to exclude patients with poorly controlled diabetes mellitus with a diagnosis of fatty liver disease. d. Exclusion criterion #14 was revised to allow patients with well-controlled blood pressure on hypertensive medication regardless of the time duration. e. Exclusion criterion #17 was removed as it duplicates inclusion criterion #4. f. Exclusion criterion #22 was removed as it duplicates exclusion criteria #27-28. 2. Addition of basal core promoter mutation test for the HBV Genotyping lab sample collected at Screening. 3. Addition of treatment stopping rule that ARC-520 may be discontinued in any subject with treatment emergent platelet count of < 35,000 per microliter. 4. Update to the ARC-520 risk assessment for patients. 5. Additional allowance of Acetaminophen use at the discretion of the PI during pre-treatment or post-treatment or at any other time during the study. 6. Change “Arrowhead Research Corporation” to “Arrowhead Pharmaceuticals, Inc.” due to Sponsor name change. 7. Minor corrections.
    12 May 2016
    1. Correct typo in the protocol secondary objective to determine the percentage of patients achieving a 1-log reduction in achieving a HBsAg level < 100 IU/mL. 2. Change made to the Inclusion/Exclusion Criteria in protocol version 4.0 (20 April 2016): a. Inclusion criterion #8 does not apply to Cohort 7 HDV patients 3. Correction of administrative, grammatical, formatting errors, and inconsistencies.

    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 ARC-520 Injection development program was terminated early for regulatory and business reasons secondary to findings occurring in a non-clinical toxicology study. Program termination was not due to safety findings in humans.
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