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    Clinical Trial Results:
    A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients with Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)

    Summary
    EudraCT number
    2019-000068-86
    Trial protocol
    GB   DE   AT  
    Global end of trial date
    14 Dec 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Dec 2024
    First version publication date
    29 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AROAAT2002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03946449
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Arrowhead Pharmaceuticals, Inc.
    Sponsor organisation address
    177 East Colorado Boulevard, Suite 700, Pasadena, CA, United States, 91105
    Public contact
    Mei Ling Chang-Lok, Arrowhead Pharmaceuticals, Inc., 001 6263043400, mchanglok@arrowheadpharma.com
    Scientific contact
    Chief Operating Officer, Arrowhead Pharmaceuticals, Inc., 001 6263043400, info@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
    14 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate change from baseline over time in total, soluble, and insoluble Z-AAT concentrations in the liver of patients with AAT-associated liver disease.
    Protection of trial subjects
    All eligible participants had the study explained by the PI or designee. They received a full explanation, in lay terms, of the aims of the study, the discomforts, risks and benefits in taking part as well as of insurance and other procedures for compensation in case of injury. It was explained that the study is for research purposes only and was not expected to provide any therapeutic benefit to the individual. It was pointed out that they could withdraw from the study at any time without prejudice.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Oct 2019
    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
    United Kingdom: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    16
    EEA total number of subjects
    14
    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)
    14
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All eligible subjects required a pre-dose biopsy completed as part of the study within the screening window. Participants consisted of male and female adult homozygous Z allele individuals (PiZZ; based on genotype completed at Screening or from a source verifiable document) alpha-1 antitrypsin patients.

    Period 1
    Period 1 title
    Primary Study Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ARO-AAT 100 mg Cohort 1b
    Arm description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Arm title
    ARO-AAT 200 mg Cohort 1
    Arm description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Arm title
    ARO-AAT 200 mg Cohort 2
    Arm description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Number of subjects in period 1
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2
    Started
    4
    4
    8
    Completed
    4
    4
    8
    Period 2
    Period 2 title
    Treatment Extension I
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ARO-AAT 100 mg Cohort 1b
    Arm description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Arm title
    ARO-AAT 200 mg Cohort 1
    Arm description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Arm title
    ARO-AAT 200 mg Cohort 2
    Arm description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Number of subjects in period 2 [1]
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2
    Started
    4
    4
    7
    Completed
    4
    4
    7
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One subject who completed the Primary Study Period did not continue to the Treatment Extension I.
    Period 3
    Period 3 title
    Treatment Extension II
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ARO-AAT 100 mg Cohort 1b
    Arm description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. As of global protocol version 7.0 (21-Jul-2022) / German protocol version 2.6 (29-Jul-2022) and after applicable regulatory, Ethics Committee and local approval, participants in cohort 1b switched from 100 mg to 200 mg while maintaining their dosing schedule. The maximum number of doses for participants completing the treatment extension periods was 15 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Arm title
    ARO-AAT 200 mg Cohort 1
    Arm description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Arm title
    ARO-AAT 200 mg Cohort 2
    Arm description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    ARO-AAT Injection
    Investigational medicinal product code
    Other name
    fazirsiran, TAK-999
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of fazirsiran will be administered by subcutaneous injection.

    Number of subjects in period 3
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2
    Started
    4
    4
    7
    Completed
    4
    4
    4
    Not completed
    0
    0
    3
         Rolled over to another study
    -
    -
    2
         Consent withdrawn by subject
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ARO-AAT 100 mg Cohort 1b
    Reporting group description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 1
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 2
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.

    Reporting group values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2 Total
    Number of subjects
    4 4 8 16
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.8 ( 10.01 ) 44.5 ( 17.00 ) 54.6 ( 13.68 ) -
    Gender categorical
    Units: Subjects
        Female
    1 0 1 2
        Male
    3 4 7 14
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0 0 0
        Non-Hispanic or Latino
    4 4 8 16
    Race
    Units: Subjects
        White
    4 4 8 16
    Insoluble ZAAT
    Units: nmol/g
        arithmetic mean (standard deviation)
    35.9750 ( 16.51694 ) 33.2750 ( 53.31019 ) 37.4500 ( 27.73075 ) -
    Partial ZAAT
    Units: nmol/g
        arithmetic mean (standard deviation)
    26.3500 ( 5.18813 ) 24.3000 ( 10.58899 ) 23.3125 ( 7.59914 ) -
    Total ZAAT
    Units: nmol/g
        arithmetic mean (standard deviation)
    62.3250 ( 15.81210 ) 57.5750 ( 59.65391 ) 60.7625 ( 34.04199 ) -

    End points

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    End points reporting groups
    Reporting group title
    ARO-AAT 100 mg Cohort 1b
    Reporting group description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 1
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 2
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.
    Reporting group title
    ARO-AAT 100 mg Cohort 1b
    Reporting group description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 1
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 2
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.
    Reporting group title
    ARO-AAT 100 mg Cohort 1b
    Reporting group description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. As of global protocol version 7.0 (21-Jul-2022) / German protocol version 2.6 (29-Jul-2022) and after applicable regulatory, Ethics Committee and local approval, participants in cohort 1b switched from 100 mg to 200 mg while maintaining their dosing schedule. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 1
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 2
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.

    Primary: Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Partial (Soluble) Liver Z-AAT: Cohorts 1/1b

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    End point title
    Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Partial (Soluble) Liver Z-AAT: Cohorts 1/1b [1] [2]
    End point description
    Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    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: Statistics planned per protocol for this endpoint are presented in the data table.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: percent change
    arithmetic mean (standard deviation)
        Total Liver Z-AAT
    -83.07 ( 5.830 )
    -79.84 ( 10.519 )
        Insoluble Liver-ZAAT
    -81.58 ( 6.947 )
    -12.91 ( 131.702 )
        Partial (Soluble) Liver Z-AAT
    -85.36 ( 4.835 )
    -88.18 ( 5.718 )
    No statistical analyses for this end point

    Primary: Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Partial (Soluble) Liver Z-AAT: Cohort 2

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    End point title
    Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Partial (Soluble) Liver Z-AAT: Cohort 2 [3] [4]
    End point description
    Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    Notes
    [3] - 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: Statistics planned per protocol for this endpoint are presented in the data table.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    7
    Units: percent change
    arithmetic mean (standard deviation)
        Total Liver Z-AAT
    -90.26 ( 9.029 )
        Insoluble Liver-ZAAT
    -84.83 ( 19.920 )
        Partial (Soluble) Liver Z-AAT
    -92.64 ( 7.482 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Serum Z-AAT: Cohorts 1/1b

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    End point title
    Percent Change From Baseline in Serum Z-AAT: Cohorts 1/1b [5]
    End point description
    Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 16, 24
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: percent change
    arithmetic mean (standard deviation)
        Week 2
    -69.12 ( 12.381 )
    -77.28 ( 7.394 )
        Week 4
    -80.24 ( 8.880 )
    -88.07 ( 4.931 )
        Week 6
    -87.27 ( 6.140 )
    -91.79 ( 3.795 )
        Week 16
    -78.61 ( 9.186 )
    -83.08 ( 6.269 )
        Week 24
    -83.85 ( 5.426 )
    -89.47 ( 3.738 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Serum Z-AAT: Cohort 2

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    End point title
    Percent Change From Baseline in Serum Z-AAT: Cohort 2 [6]
    End point description
    Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 16, 22, 28, 34, 40, 48
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: percent change
    arithmetic mean (standard deviation)
        Week 2
    -72.08 ( 8.645 )
        Week 4
    -82.22 ( 7.476 )
        Week 6
    -89.92 ( 4.024 )
        Week 16
    -85.76 ( 6.106 )
        Week 22
    -90.87 ( 4.246 )
        Week 28
    -85.06 ( 7.847 )
        Week 34
    -89.54 ( 5.434 )
        Week 40
    -84.12 ( 12.433 )
        Week 48
    -89.58 ( 5.419 )
    No statistical analyses for this end point

    Secondary: Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b

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    End point title
    Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b [7]
    End point description
    Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: U/L
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=4, 4
    58.5 ( 41.36 )
    87.8 ( 30.42 )
        Day 2 (24-48 hr post-dose); n=4, 4
    58.5 ( 42.68 )
    88.3 ( 32.72 )
        Week 2; n=4, 4
    76.5 ( 55.24 )
    99.8 ( 53.89 )
        Week 4; n=4, 4
    62.3 ( 35.77 )
    106.5 ( 42.57 )
        Week 4 (24-48 hr post-dose); n=4, 4
    60.3 ( 33.97 )
    99.0 ( 38.58 )
        Week 6; n=4, 4
    49.8 ( 25.16 )
    77.0 ( 20.85 )
        Week 16; n=3, 4
    35.7 ( 8.50 )
    49.8 ( 5.25 )
        Week 16 (24-48 hr post-dose); n=4, 3
    31.5 ( 8.85 )
    42.7 ( 3.06 )
        Week 24; n=4, 4
    27.8 ( 9.29 )
    39.5 ( 3.11 )
    No statistical analyses for this end point

    Secondary: ALT Values Over Time: Cohort 2

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    End point title
    ALT Values Over Time: Cohort 2 [8]
    End point description
    Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: U/L
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=8
    62.1 ( 14.98 )
        Day 2 (24-48 hr post-dose); n=8
    58.6 ( 15.59 )
        Week 2; n=7
    61.9 ( 20.17 )
        Week 4; n=8
    55.3 ( 14.09 )
        Week 4 (24-48 hr post-dose); n=8
    53.0 ( 14.83 )
        Week 6; n=7
    54.9 ( 9.79 )
        Week 16; n=8
    39.6 ( 13.13 )
        Week 16 (24-48 hr post-dose); n=8
    37.5 ( 11.61 )
        Week 22; n=8
    41.0 ( 14.58 )
        Week 28; n=7
    36.7 ( 15.76 )
        Week 34; n=8
    39.4 ( 11.13 )
        Week 40; n=8
    33.4 ( 10.08 )
        Week 48; n=6
    34.5 ( 10.54 )
    No statistical analyses for this end point

    Secondary: Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b

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    End point title
    Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b [9]
    End point description
    Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: U/L
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=4, 4
    70.8 ( 35.30 )
    244.8 ( 355.68 )
        Day 2 (24-48 hr post-dose); n=4, 4
    70.5 ( 39.07 )
    247.3 ( 358.01 )
        Week 2; n=4, 4
    66.0 ( 37.15 )
    210.8 ( 304.4 )
        Week 4; n=4, 4
    73.0 ( 43.37 )
    222.0 ( 334.85 )
        Week 4 (24-48 hr post-dose); n=4, 4
    70.0 ( 45.19 )
    210.3 ( 312.0 )
        Week 6; n=4, 4
    64.0 ( 35.62 )
    199.3 ( 292.28 )
        Week 16; n=4, 4
    48.0 ( 23.25 )
    135.3 ( 190.31 )
        Week 16 (24-48 hr post-dose); n=4, 3
    48.0 ( 22.38 )
    161.7 ( 212.17 )
        Week 24; n=4, 4
    52.3 ( 28.31 )
    112.0 ( 156.92 )
    No statistical analyses for this end point

    Secondary: GGT Values Over Time: Cohort 2

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    End point title
    GGT Values Over Time: Cohort 2 [10]
    End point description
    Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: U/L
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=8
    62.5 ( 31.09 )
        Day 2 (24-48 hr post-dose); n=8
    62.1 ( 33.21 )
        Week 2; n=7
    60.6 ( 33.14 )
        Week 4; n=8
    59.1 ( 49.82 )
        Week 4 (24-48 hr post-dose); n=8
    57.6 ( 46.91 )
        Week 6; n=7
    58.0 ( 36.21 )
        Week 16; n=8
    49.1 ( 36.84 )
        Week 16 (24-48 hr post-dose); n=8
    48.3 ( 38.68 )
        Week 22; n=8
    48.5 ( 34.85 )
        Week 28; n=8
    44.5 ( 34.62 )
        Week 34; n=8
    45.3 ( 31.37 )
        Week 40; n=8
    45.3 ( 38.20 )
        Week 48; n=8
    48.5 ( 45.05 )
    No statistical analyses for this end point

    Secondary: Fibrosis-4 index (FIB4) Score Values Over Time: Cohorts 1/1b

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    End point title
    Fibrosis-4 index (FIB4) Score Values Over Time: Cohorts 1/1b [11]
    End point description
    The FIB 4 score evaluates the degree of fibrosis in patients suspected of or already diagnosed with hepatic fibrosis. FIB-4 is calculated as (Age (years) * aspartate aminotransferease) / (platelets * √(ALT)). The result provided from the above equation is interpreted according to two cut off values: ■ FIB 4 <1.45 indicates absence of cirrhosis (with a negative predictive value of 90% for advanced fibrosis); ■ FIB 4 between 1.45 - 3.25 are deemed inconclusive; ■ FIB 4 >3.25 indicates cirrhosis (with a positive predictive value of 65% for advanced fibrosis). Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: numerical score
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=4, 4
    1.425 ( 0.3613 )
    1.583 ( 0.9085 )
        Day 2 (24-48 hr post-dose); n=4, 4
    1.353 ( 0.2699 )
    1.618 ( 0.9668 )
        Week 2; n=4, 4
    1.580 ( 0.5806 )
    1.900 ( 1.3056 )
        Week 4; n=4, 4
    1.260 ( 0.3840 )
    1.750 ( 1.3273 )
        Week 4 (24-48 hr post-dose); n=4, 4
    1.333 ( 0.4194 )
    1.760 ( 1.3867 )
        Week 6; n=4, 4
    1.355 ( 0.4612 )
    2.013 ( 1.1073 )
        Week 16; n=3, 4
    1.257 ( 0.3326 )
    1.605 ( 1.221 )
        Week 16 (24-48 hr post-dose); n=3, 3
    1.227 ( 0.2230 )
    1.940 ( 1.6210 )
        Week 24; n=4, 4
    1.265 ( 0.3196 )
    1.688 ( 1.2563 )
    No statistical analyses for this end point

    Secondary: FIB4 Values Over Time: Cohort 2

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    End point title
    FIB4 Values Over Time: Cohort 2 [12]
    End point description
    The FIB 4 score evaluates the degree of fibrosis in patients suspected of or already diagnosed with hepatic fibrosis. FIB-4 is calculated as (Age (years) * aspartate aminotransferease) / (platelets * √(ALT)). The result provided from the above equation is interpreted according to two cut off values: ■ FIB 4 <1.45 indicates absence of cirrhosis (with a negative predictive value of 90% for advanced fibrosis); ■ FIB 4 between 1.45 - 3.25 are deemed inconclusive; ■ FIB 4 >3.25 indicates cirrhosis (with a positive predictive value of 65% for advanced fibrosis). Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 28 + 1 day, Week 34, Week 40, Week 48
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: numerical score
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=8
    1.395 ( 0.6634 )
        Day 2 (24-48 hr post-dose); n=8
    1.543 ( 0.8209 )
        Week 2; n=7
    1.383 ( 0.6358 )
        Week 4; n=8
    1.420 ( 0.7054 )
        Week 4 (24-48 hr post-dose); n=8
    1.356 ( 0.6344 )
        Week 6; n=7
    1.367 ( 0.6419 )
        Week 16; n=8
    1.299 ( 0.5636 )
        Week 16 (24-48 hr post-dose); n=8
    1.271 ( 0.6521 )
        Week 22; n=8
    1.336 ( 0.6269 )
        Week 28; n=7
    1.377 ( 0.7152 )
        Week 34; n=7
    1.239 ( 0.7527 )
        Week 40; n=8
    1.319 ( 0.5782 )
        Week 48; n=5
    1.502 ( 0.7680 )
    No statistical analyses for this end point

    Secondary: Aspartate aminotransferase-to-platelet ratio index (APRI) Values Over Time: Cohorts 1/1b

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    End point title
    Aspartate aminotransferase-to-platelet ratio index (APRI) Values Over Time: Cohorts 1/1b [13]
    End point description
    APRI is calculated as 100*(aspartate aminotransferase/40) / platelets The aspartate aminotransferase to platelet ratio index suggests the level of hepatic fibrosis and possible liver disease. Scores indicate the following: < 0.5: fibrosis is ruled out 0.5 – 0.7: Associated with some kind of liver damage 0.7 - 1: Significant fibrosis > 1: Associated with cirrhosis Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: numerical score
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=4, 4
    0.485 ( 0.2249 )
    0.745 ( 0.3877 )
        Day 2 (24-48 hr post-dose); n=4, 4
    0.463 ( 0.2133 )
    0.753 ( 0.3923 )
        Week 2; n=4, 4
    0.633 ( 0.3349 )
    0.910 ( 0.5231 )
        Week 4; n=4, 4
    0.463 ( 0.2185 )
    0.810 ( 0.4031 )
        Week 4 (24-48 hr post-dose); n=4, 4
    0.468 ( 0.1921 )
    0.785 ( 0.4171 )
        Week 6; n=4, 4
    0.433 ( 0.1688 )
    0.918 ( 0.1834 )
        Week 16; n=3, 4
    0.343 ( 0.0404 )
    0.555 ( 0.3008 )
        Week 16 (24-48 hr post-dose); n=3, 3
    0.330 ( 0.0700 )
    0.603 ( 0.4203 )
        Week 24; n=4, 4
    0.310 ( 0.0970 )
    0.513 ( 0.2892 )
    No statistical analyses for this end point

    Secondary: APRI Values Over Time: Cohort 2

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    End point title
    APRI Values Over Time: Cohort 2 [14]
    End point description
    APRI is calculated as 100*(aspartate aminotransferase/40) / platelets The aspartate aminotransferase to platelet ratio index suggests the level of hepatic fibrosis and possible liver disease. Scores indicate the following: < 0.5: fibrosis is ruled out 0.5 – 0.7: Associated with some kind of liver damage 0.7 - 1: Significant fibrosis > 1: Associated with cirrhosis Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 34, Week 40, Week 48
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: numerical score
    arithmetic mean (standard deviation)
        Baseline (Day 1); n=8
    0.500 ( 0.2102 )
        Day 2 (24-48 hr post-dose); n=8
    0.515 ( 0.2023 )
        Week 2; n=7
    0.486 ( 0.1551 )
        Week 4; n=8
    0.479 ( 0.2226 )
        Week 4 (24-48 hr post-dose); n=8
    0.454 ( 0.2127 )
        Week 6; n=7
    0.463 ( 0.1678 )
        Week 16; n=8
    0.372 ( 0.1812 )
        Week 16 (24-48 hr post-dose); n=8
    0.358 ( 0.2160 )
        Week 22; n=8
    0.386 ( 0.2011 )
        Week 28; n=7
    0.387 ( 0.2642 )
        Week 34; n=7
    0.379 ( 0.2449 )
        Week 40; n=8
    0.349 ( 0.1768 )
        Week 48; n=5
    0.440 ( 0.2310 )
    No statistical analyses for this end point

    Secondary: N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b

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    End point title
    N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b [15]
    End point description
    PRO-C3 may be a biomarker for the formation of fibrotic tissue in the liver. For serum, the normal range is 6.1 – 13.8 ng/mL (based on a study of human serum samples from healthy men and women). Due to ethnic, dietary and age variations, the reference limits given may not apply to all populations. A reduction in Pro-C3 over time may indicate a reduction in hepatic fibrogenesis. Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 16, 24
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: µg/L
    arithmetic mean (standard deviation)
        Baseline
    16.78 ( 2.960 )
    25.15 ( 9.310 )
        Week 4
    16.90 ( 3.539 )
    22.10 ( 7.202 )
        Week 16
    15.60 ( 1.818 )
    19.30 ( 0.245 )
        Week 24
    18.08 ( 2.159 )
    16.63 ( 1.621 )
    No statistical analyses for this end point

    Secondary: PRO-C3 Values Over Time: Cohort 2

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    End point title
    PRO-C3 Values Over Time: Cohort 2 [16]
    End point description
    PRO-C3 may be a biomarker for the formation of fibrotic tissue in the liver. For serum, the normal range is 6.1 – 13.8 ng/mL (based on a study of human serum samples from healthy men and women). Due to ethnic, dietary and age variations, the reference limits given may not apply to all populations. A reduction in Pro-C3 over time may indicate a reduction in hepatic fibrogenesis. Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 16, 28, 40, 48
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: µg/L
    arithmetic mean (standard deviation)
        Baseline
    18.21 ( 3.002 )
        Week 4
    15.81 ( 2.948 )
        Week 16
    17.03 ( 2.463 )
        Week 28
    14.31 ( 2.362 )
        Week 40
    15.10 ( 2.989 )
        Week 48
    17.09 ( 7.967 )
    No statistical analyses for this end point

    Secondary: FibroScan® Values Over Time: Cohorts 1/1b

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    End point title
    FibroScan® Values Over Time: Cohorts 1/1b [17]
    End point description
    FibroScan is a type of liver elastography. Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result is 75 kPa. Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: kPa
    arithmetic mean (standard deviation)
        Baseline
    7.28 ( 2.632 )
    12.70 ( 6.988 )
        Week 24
    7.30 ( 3.730 )
    10.55 ( 5.802 )
    No statistical analyses for this end point

    Secondary: FibroScan® Values Over Time: Cohort 2

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    End point title
    FibroScan® Values Over Time: Cohort 2 [18]
    End point description
    FibroScan is a type of liver elastography. Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result is 75 kPa. Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: kPa
    arithmetic mean (standard deviation)
        Baseline; n=8
    9.89 ( 3.205 )
        Week 48; n=7
    8.67 ( 3.263 )
    No statistical analyses for this end point

    Secondary: Portal Inflammation Over Time: Cohorts 1/1b

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    End point title
    Portal Inflammation Over Time: Cohorts 1/1b [19]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of portal inflammation, which was scored on a scale from 0 (none) to 3 (severe). Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    25.0
    50.0
        no change
    50.0
    50.0
        ≥ 1-point worsening
    25.0
    0.0
    No statistical analyses for this end point

    Secondary: Portal Inflammation Over Time: Cohort 2

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    End point title
    Portal Inflammation Over Time: Cohort 2 [20]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of portal inflammation, which was scored on a scale from 0 (none) to 3 (severe). Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    12.5
        no change
    37.5
        ≥ 1-point worsening
    0.0
    No statistical analyses for this end point

    Secondary: Interface Hepatitis Over Time: Cohorts 1/1b

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    End point title
    Interface Hepatitis Over Time: Cohorts 1/1b [21]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of interface hepatitis, which was scored on a scale from 0 (none) to 3 (severe). Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    50.0
    0.0
        no change
    0.0
    100.0
        ≥ 1-point worsening
    25.0
    0.0
    No statistical analyses for this end point

    Secondary: Interface Hepatitis Over Time: Cohort 2

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    End point title
    Interface Hepatitis Over Time: Cohort 2 [22]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of interface hepatitis, which was scored on a scale from 0 (none) to 3 (severe). Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    25.0
        no change
    25.0
        ≥ 1-point worsening
    0.0
    No statistical analyses for this end point

    Secondary: Lobular Inflammation Over Time: Cohorts 1/1b

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    End point title
    Lobular Inflammation Over Time: Cohorts 1/1b [23]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of lobular inflammation, which was scored on a scale from 0 (none) to 3 (severe). Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    0.0
    0.0
        no change
    25.0
    50.0
        ≥ 1-point worsening
    50.0
    50.0
    No statistical analyses for this end point

    Secondary: Lobular Inflammation Over Time: Cohort 2

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    End point title
    Lobular Inflammation Over Time: Cohort 2 [24]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of lobular inflammation, which was scored on a scale from 0 (none) to 3 (severe). Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    0.0
        no change
    62.5
        ≥ 1-point worsening
    12.5
    No statistical analyses for this end point

    Secondary: Hepatocyte Cell Death Over Time: Cohorts 1/1b

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    End point title
    Hepatocyte Cell Death Over Time: Cohorts 1/1b [25]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of hepatocyte cell death. Hepatocyte Cell Death Score: 0 = No acidophil bodies; 1 = Few acidophil bodies; 2 = Many acidophil. Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    4
    4
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    0.0
    0.0
        no change
    25.0
    0.0
        ≥ 1-point worsening
    25.0
    25.0
    No statistical analyses for this end point

    Secondary: Hepatocyte cell death Over Time: Cohort 2

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    End point title
    Hepatocyte cell death Over Time: Cohort 2 [26]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of hepatocyte cell death. Hepatocyte Cell Death Score: 0 = No acidophil bodies; 1 = Few acidophil bodies; 2 = Many acidophil. Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    0.0
        no change
    62.5
        ≥ 1-point worsening
    0.0
    No statistical analyses for this end point

    Secondary: METAVIR Fibrosis Stage Score Over Time: Cohorts 1/1b

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    End point title
    METAVIR Fibrosis Stage Score Over Time: Cohorts 1/1b [27]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the METAVIR fibrosis stage score. The METAVIR​ scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C. The stage represents the amount of fibrosis or scarring. F0: no fibrosis F1: portal fibrosis without septa F2: portal fibrosis with few septa F3: numerous septa without cirrhosis F4: cirrhosis Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1
    Number of subjects analysed
    3
    4
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    0.0
    50.0
        no change
    100.0
    50.0
        ≥ 1-point worsening
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: METAVIR Fibrosis Stage Score Over Time: Cohort 2

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    End point title
    METAVIR Fibrosis Stage Score Over Time: Cohort 2 [28]
    End point description
    Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the METAVIR fibrosis stage score. The METAVIR​ scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C. The stage represents the amount of fibrosis or scarring. F0: no fibrosis F1: portal fibrosis without septa F2: portal fibrosis with few septa F3: numerous septa without cirrhosis F4: cirrhosis Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are presented by individual cohort per protocol.
    End point values
    ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    8
    Units: percentage of participants
    number (not applicable)
        ≥ 1-point improvement
    50.0
        no change
    12.5
        ≥ 1-point worsening
    25.0
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An Adverse Event (AE) is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. Serious Adverse Event (SAE) is an 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, Is a medically important event or reaction. TEAEs are AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. Not related events include those reported as 'Not Related' to study drug. Related events include those reported as 'Possibly Related' or 'Probably Related' to study drug. Safety Analysis Set: all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    For a maximum duration of study follow-up of 202 weeks.
    End point values
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2
    Number of subjects analysed
    4
    4
    8
    Units: participants
        ≥ 1 TEAE
    4
    4
    8
        ≥ 1 Serious TEAE
    0
    3
    5
        TEAE Severity = Mild
    3
    1
    2
        TEAE Severity = Moderate
    1
    3
    4
        TEAE Severity = Severe
    0
    0
    2
        TEAE = Not Related to Study Drug (SD)
    1
    2
    3
        TEAE = Related to SD
    3
    2
    5
        TEAE Injection Site Reaction (ISR) Severity = Mild
    2
    1
    3
        TEAE ISR Severity = Moderate
    0
    0
    1
        TEAE ISR Severity = Severe
    0
    0
    0
        TEAE Leading to SD Discontinuation
    0
    0
    0
        TEAE Requiring Dose Interruption of SD
    0
    1
    3
        TEAE Leading to PRemature Withdrawal From Study
    0
    0
    0
        TEAE Causing Death
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For a maximum duration of study follow-up of 202 weeks.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    ARO-AAT 100 mg Cohort 1b
    Reporting group description
    Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 1
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses.

    Reporting group title
    ARO-AAT 200 mg Cohort 2
    Reporting group description
    Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses.

    Serious adverse events
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 4 (100.00%)
    5 / 8 (62.50%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    ARO-AAT 100 mg Cohort 1b ARO-AAT 200 mg Cohort 1 ARO-AAT 200 mg Cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    8 / 8 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    3
    Hypertensive crisis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Surgical and medical procedures
    Dental implantation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    0
    3
    Injection site reaction
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    7
    Fatigue
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    2
    Injection site bruising
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Injection site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Injection site inflammation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Social circumstances
    Denture wearer
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    2
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Loss of libido
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    2
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Blood potassium increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Coagulation test abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Heart rate irregular
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Spirometry abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Vaccination complication
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Wound
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Arthropod sting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Extrasystoles
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    3
    0
    1
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    2
    Lethargy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    2
    Sciatica
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Piriformis syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    0
    3
    Abdominal discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Oesophageal discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Skin irritation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    Renal and urinary disorders
    Incontinence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    0
    3
    Arthralgia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    2 / 8 (25.00%)
         occurrences all number
    3
    1
    4
    Bursitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Arthritis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 4 (100.00%)
    6 / 8 (75.00%)
         occurrences all number
    9
    16
    13
    COVID-19
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    4 / 8 (50.00%)
         occurrences all number
    3
    4
    5
    Anal candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Candida infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Hepatitis E
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    3
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Coronavirus infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Osteomyelitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Tooth infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Apr 2019
    OVERVIEW/RATIONALE: 1. The protocol was amended in response to recommendations based on review by the Medicines and Healthcare Products Regualtory Agency (MHRA). 2. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity.
    10 Mar 2020
    OVERVIEW/RATIONALE: 1. The protocol was amended to include cohort 1b at 100mg (N=4) as well as to add the inclusion of patients with Metavir F1 fibrosis or equivalent. • A 100mg cohort was added to compare with the 200mg cohort to see if study endpoints may have a dose response relationship. • An F1 fibrosis score (or equivalent) will be allowed as the study endpoints are now considered to be independent of the need to have Metavir fibrosis F2 and F3, or equivalent. 2. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity.
    14 Oct 2020
    OVERVIEW/RATIONALE: 1. The primary endpoint has been revised to evaluation of change (from baseline over time) in total, soluble and insoluble Z-AAT concentrations in the liver of study patients. The primary rationale for protocol version 4.0 is to better align primary and secondary endpoints with the stated purpose of the study. This is an open label pilot study, intended to evaluate various pharmacodynamic markers as well as to explore treatment effect variability with different treatment durations (e.g. biopsy at approximately 6, 12, 18- and 24-months post-dose). This will help to inform on the length of treatment required in later stage studies. A histologic AATD liver disease activity scale was originally proposed as a primary endpoint. This was a placeholder endpoint as sponsor was investigating the development of a histologic grading scale of liver disease severity in AATD patients. While histologic endpoints are still included, in protocol version 4.0 the primary endpoint has been changed to liver Z-AAT protein. Liver Z-AAT has been thoroughly described as the causative factor of AATD liver disease and liver Z-AAT protein correlates with severity of liver fibrosis and with clinical outcomes. Intra-hepatic Z-AAT protein is also readily quantifiable using a validated assay and does not suffer from intra-reader or inter-reader variability as is the case for pathologist histologic evaluation. Thus, it is more likely to reliably identify differences in pharmacodynamic effect with different treatment durations. Additionally, histologic characteristics found in AATD liver disease (e.g. peri-portal inflammation, steatosis) overlap with those found in other common liver diseases such as NAFLD and NASH which may not respond to ARO-AAT and may confound evaluation of treatment effect. In contrast, intra-hepatic Z-AAT protein is only present in the livers of patients with AATD. For these reasons, liver Z-AAT is now the primary endpoint of the study.
    14 Oct 2020
    (continued) 2. Rationale for additional endpoint changes: • Serum Z-AAT levels have been shifted to the 1st secondary endpoint as serum levels correlate well with intra-hepatic total Z-AAT, consistent with the liver as the main source of serum AAT. • Changes in ALT and GGT were prioritized as secondary endpoints as these are clinically relevant biomarkers of liver disease and have been shown to associate with severity of liver disease in an AATD population (Clark et al., 2018). • Other non-invasive measures of liver fibrosis including FibroScan and Pro-C3 have also been shifted to secondary endpoints. Histologic parameters are still included as secondary endpoints and will be evaluated. • MRE has become more broadly available and is included as an additional exploratory assessment of liver fibrosis. • Consequently, the study title was also revised. 3. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity.
    10 Feb 2021
    GENERAL OVERVIEW: 1. The Global Protocol has been amended to extend the Extension phase of the study by one year. For design clarity, the initial dosing period of the study is referred to as the Primary Study Period and the treatment extension period is referred to as Treatment Extension I and Treatment Extension II (12 month duration for each). 2. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity. Major changes: 1. Protocol Synopsis: The study has been extended for an additional year to include a new Treatment Extension II after Week 44. Rationale: The extension period allows subjects to remain on continuous ARO-AAT treatment for long-term safety evaluation. During this period, subjects will have the option to continue to receive the same dose level of ARO-AAT Q12W for up to an additional 12 months or until they roll over into another long-term Extension study, whichever comes first. 2. Protocol Synopsis: Secondary Endpoint : Secondary Endpoint was revised to replace Ishak with Metavir. Rationale: Although both methods are recognized methods for evaluating fibrosis, Metavir has a smaller scale and is more widely used in clinical practice.
    16 Nov 2021
    (continued) GENERAL OVERVIEW: 1. The Global Protocol has been amended to extend the Extension II part of the study by one year. 2. Assessment of immunogenicity (Incidence of anti-drug antibodies (ADAs) to ARO-AAT) was added as a safety endpoint. 3. Collection of ADAs was added. 4. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity. Major Changes: 1. Protocol Synopsis: Study Design/Methods: Extension II part of the study has been extended for an additional year. Rationale: The extension period allows subjects to remain on continuous ARO-AAT treatment for long-term safety evaluation. During this period, subjects will have the option to continue to receive the same dose level of ARO-AAT Q12W for up to an additional 12 months or until they roll over into another long-term Extension study, whichever comes first. 2. Protocol Synopsis: Secondary Endpoints: Assessment of immunogenicity (Incidence of anti-drug antibodies to ARO-AAT) was added as a safety endpoint. Rationale: Although results from a Phase I study (AROAAT1001) showed no evidence of drug-induced de novo formation of anti-ARO-AAT antibody formation after single or repeat doses of ARO-AAT in the healthy adult volunteers enrolled in study, anti-drug antibody (ADA) assessment has been added as a safety endpoint in study AROAAT2002. ADA was included to further evaluate the potential for immunogenicity following ARO-AAT treatment in patients with AATD.
    21 Jul 2022
    GENERAL OVERVIEW: 1. This global protocol has been amended to inform of fazirsiran dose selection by the Sponsor based on review of cumulative safety, efficacy, and pharmacodynamics data from the fazirsiran clinical program . The amendment specifies that all subjects continuing in Extension Treatment Period II will receive the selected fazirsiran dose (200 mg) following the respective country regulatory and ethics committees’ approvals (including local approvals as necessary) of AROAAT2002 protocol amendment v7.0. As such, all ongoing subjects in Extension Treatment Period II will be consented and subjects in Cohort 1b (100 mg) will begin receiving the selected dose at the next scheduled dosing timepoint. 2. Pulmonary function test (PFT) text was updated to clarify instructions for performing spirometry and diffusing capacity for carbon monoxide (DLCO), to acknowledge acceptability of following bronchodilator administration as per site practice, and to describe specific PFT data to include on the electronic case report form (eCRF). 3. The repeat liver biopsy in the treatment extension period will be optional. 4. Vital signs measurement and electrocardiogram (ECG) assessment text was updated to clarify patient positioning during the assessments. 5. Methods sections were updated to change the current pre-dose window for assessments from 60 minutes to 3 hours. 6. Investigational product (IP) nomenclature was updated to include fazirsiran and TAK-999 (also referred to as ARO-AAT). Drug product nomenclature was updated to include Fazirsiran Injection. 7. Fazirsiran supply, preparation, storage, and labelling information was updated, and includes guidance on allowing the fazirsiran vial to come to room temperature before administration. 8. A new section was added to provide more detail on pregnancy reporting. 9. Text was revised to make administrative updates, correct grammatical and formatting errors and inconsistencies, update abbreviations, update references.

    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.
    None reported
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