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    Clinical Trial Results:
    A Phase 1/2, Randomized, Single-Blind, Placebo-Controlled, Single-Ascending, and Multiple-Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-AAT in Healthy Adult Subjects and Patients with ZZ Type Alpha 1 Antitrypsin Deficiency Liver Disease

    Summary
    EudraCT number
    		 2015-001297-18
    Trial protocol
    		 GB  
    Global end of trial date
    03 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jan 2019
    First version publication date
    13 Jan 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALN-AAT-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02503683
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alnylam Pharmaceuticals, Inc.
    Sponsor organisation address
    300 Third Street, Cambridge, MA, United States, 02142
    Public contact
    Investor Relations and Corporate Communications, Alnylam Pharmaceuticals, Inc, 001 8663300326, Investors@alnylam.com
    Scientific contact
    Chief Medical Officer, Alnylam Pharmaceuticals, Inc, 001 8663300326, medinfo@alnylam.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
    03 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of single or multiple doses of ALN-AAT when administered to healthy adult subjects and patients with homozygous ZZ type AAT deficiency liver disease (PiZZ patients).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jul 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 26
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One clinical study site in the United Kingdom participated in this study.

    Pre-assignment
    Screening details
    		 Twenty six healthy subjects were enrolled in this study. In Part A, single ascending dose (SAD), twenty healthy subjects were dosed and in Part B, multiple ascending dose (MAD), six healthy subjects were dosed.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: SAD: Placebo
    Arm description
    		 A single dose of matching placebo was administered.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo (normal saline: 0.9% sodium chloride [NaCl]) was administered subcutaneously (SC) on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part A: SAD: ALN-AAT 0.1 mg/kg
    Arm description
    		 A single dose of 0.1 mg/kg ALN-AAT was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALN-AAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALN-AAT was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part A: SAD: ALN-AAT 0.3 mg/kg
    Arm description
    		 A single dose of 0.3 mg/kg ALN-AAT was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALN-AAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALN-AAT was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part A: SAD: ALN-AAT 1.0 mg/kg
    Arm description
    		 A single dose of 1.0 mg/kg ALN-AAT was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALN-AAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALN-AAT was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part A: SAD: ALN-AAT 3.0 mg/kg
    Arm description
    		 A single dose of 3.0 mg/kg ALN-AAT was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALN-AAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALN-AAT was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part A: SAD: ALN-AAT 6.0 mg/kg
    Arm description
    		 A single dose of 6.0 mg/kg ALN-AAT was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALN-AAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALN-AAT was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part B: MAD: Placebo
    Arm description
    		 Multiple doses (once every 4 weeks) of matching placebo were administered.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo (normal saline: 0.9% sodium chloride [NaCl]) was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Arm title
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Arm description
    		 Multiple doses (once every 4 weeks) of 1.0 mg/kg ALN-AAT were administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALN-AAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALN-AAT was administered SC on Day 0 for Part A: SAD and on Days 0, 28, 56, and 84 for Part B: MAD.

    Number of subjects in period 1
    		Part A: SAD: Placebo Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg Part B: MAD: Placebo Part B: MAD: ALN-AAT 1.0 mg/kg
    Started
    5
    3
    3
    3
    3
    3
    2
    4
    Completed
    5
    3
    3
    3
    2
    1
    2
    3
    Not completed
    0
    0
    0
    0
    1
    2
    0
    1
         Reason not specified
    -
    -
    -
    -
    -
    1
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    -
    1
         Withdrawal by subject
    -
    -
    -
    -
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: SAD: Placebo
    Reporting group description
    		 A single dose of matching placebo was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 0.1 mg/kg
    Reporting group description
    		 A single dose of 0.1 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 0.3 mg/kg
    Reporting group description
    		 A single dose of 0.3 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 1.0 mg/kg
    Reporting group description
    		 A single dose of 1.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 3.0 mg/kg
    Reporting group description
    		 A single dose of 3.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 6.0 mg/kg
    Reporting group description
    		 A single dose of 6.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part B: MAD: Placebo
    Reporting group description
    		 Multiple doses (once every 4 weeks) of matching placebo were administered.

    Reporting group title
    Part B: MAD: ALN-AAT 1.0 mg/kg
    Reporting group description
    		 Multiple doses (once every 4 weeks) of 1.0 mg/kg ALN-AAT were administered.

    Reporting group values
    		 Part A: SAD: Placebo Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg Part B: MAD: Placebo Part B: MAD: ALN-AAT 1.0 mg/kg Total
    Number of subjects
    		 5 3 3 3 3 3 2 4 26
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 30 ( 10.3 ) 29 ( 9.8 ) 31 ( 13.3 ) 45 ( 18.2 ) 44 ( 14.9 ) 30 ( 7.0 ) 28 ( 5.7 ) 32 ( 16.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 0 1 1 2 2 2 2 13
        Male
    		 2 3 2 2 1 1 0 2 13

    End points

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    End points reporting groups
    Reporting group title
    Part A: SAD: Placebo
    Reporting group description
    		 A single dose of matching placebo was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 0.1 mg/kg
    Reporting group description
    		 A single dose of 0.1 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 0.3 mg/kg
    Reporting group description
    		 A single dose of 0.3 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 1.0 mg/kg
    Reporting group description
    		 A single dose of 1.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 3.0 mg/kg
    Reporting group description
    		 A single dose of 3.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 6.0 mg/kg
    Reporting group description
    		 A single dose of 6.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part B: MAD: Placebo
    Reporting group description
    		 Multiple doses (once every 4 weeks) of matching placebo were administered.

    Reporting group title
    Part B: MAD: ALN-AAT 1.0 mg/kg
    Reporting group description
    		 Multiple doses (once every 4 weeks) of 1.0 mg/kg ALN-AAT were administered.

    Primary: Percentage of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Discontinuation

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Discontinuation [1]
    End point description
    An AE is any untoward medical occurrence in a clinical investigational subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose of study drug: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly or birth defect. Safety population included all subjects who received at least 1 dose of study drug (ALN-AAT or placebo).
    End point type
    Primary
    End point timeframe
    Part A: up to 160 days plus up to 24 months follow-up; Part B: up to 244 days plus up to 24 months follow-up
    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: Only descriptive data were planned to be reported for this Safety endpoint.
    End point values
    		 Part A: SAD: Placebo Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg Part B: MAD: Placebo Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    2
    4
    Units: percent
    number (not applicable)
        Adverse Events (AEs)
    100
    100
    100
    66.7
    100
    100
    100
    100
        Serious Adverse Events (SAEs)
    0
    0
    0
    0
    0
    0
    0
    0
        AEs Leading to Study Discontinuation
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A

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    End point title
    		 Maximum Concentration (Cmax) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A [2]
    End point description
    Pharmacokinetic (PK) population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    Notes
    [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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: nanogram (ng)/millilitre (mL)
        arithmetic mean (standard deviation)
    24.4 ( 7.52 )
    50.4 ( 11.9 )
    167 ( 56.2 )
    464 ( 48.6 )
    1270 ( 387 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Maximum Concentration (Cmax) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B [3]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    Notes
    [3] - 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: Pharmacokinetic (PK) endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 0
    179 ( 38.4 )
        Day 84
    133 ( 22.5 )
    No statistical analyses for this end point

    Secondary: Time to Cmax (tmax) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A

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    End point title
    		 Time to Cmax (tmax) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A [4]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    Notes
    [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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: hour (hr)
        median (full range (min-max))
    1.00 (0.50 to 4.00)
    4.00 (0.50 to 4.00)
    4.00 (4.00 to 4.00)
    6.03 (0.50 to 12.00)
    0.50 (0.50 to 4.00)
    No statistical analyses for this end point

    Secondary: Time to Cmax (tmax) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Time to Cmax (tmax) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B [5]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: hr
    median (full range (min-max))
        Day 0
    4.00 (4.00 to 4.00)
        Day 84
    4.00 (4.00 to 6.00)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-last) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A

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    End point title
    		 Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-last) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A [6]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    127 ( 26.3 )
    352 ( 41.4 )
    2130 ( 106 )
    9260 ( 2770 )
    17400 ( 4840 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-τ) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Area Under the Concentration-Time Curve from Time 0 to Time of Last Measurable Concentration (AUC0-τ) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B [7]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Day 0
    1470 ( 183 )
        Day 84
    1280 ( 262 )
    No statistical analyses for this end point

    Secondary: Terminal Half-life (t1/2) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A

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    End point title
    		 Terminal Half-life (t1/2) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A [8]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data. Here, 9999= not calculated.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: hr
        arithmetic mean (standard deviation)
    9999 ( 9999 )
    4.18 ( 1.32 )
    8.83 ( 2.75 )
    6.15 ( 1.01 )
    6.96 ( 0.436 )
    No statistical analyses for this end point

    Secondary: Terminal Half-life (t1/2) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Terminal Half-life (t1/2) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B [9]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data. Here, 9999= not calculated.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: hr
    arithmetic mean (standard deviation)
        Day 0
    3.59 ( 9999 )
        Day 84
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Apparent Systemic Clearance (CL/F) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A

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    End point title
    		 Apparent Systemic Clearance (CL/F) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A [10]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data. Here, 9999= not calculated.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: Litre (L)/ hr
        arithmetic mean (standard deviation)
    9999 ( 9999 )
    43.6 ( 0.000237 )
    31.6 ( 5.00 )
    22.5 ( 7.74 )
    21.9 ( 1.14 )
    No statistical analyses for this end point

    Secondary: Apparent Systemic Clearance (CL/F) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Apparent Systemic Clearance (CL/F) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B [11]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data. Here, 9999= not calculated.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: L/hr
    arithmetic mean (standard deviation)
        Day 0
    39.1 ( 9999 )
        Day 84
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (Vz/F) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A

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    End point title
    		 Apparent Volume of Distribution (Vz/F) of ALN-AAT in Plasma After Single Ascending Dose (SAD) Part A [12]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data. Here, 9999= not calculated.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: Litre (L)
        arithmetic mean (standard deviation)
    9999 ( 9999 )
    263 ( 83.1 )
    393 ( 61.8 )
    194 ( 36.1 )
    220 ( 18.0 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (Vz/F) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Apparent Volume of Distribution (Vz/F) of ALN-AAT in Plasma After Multiple Ascending Dose (MAD) Part B [13]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data. Here, 9999=not calculated.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0.5 hour (hr), 1, 2, 4, 6, 8, 12, 24, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: Litre (L)
    arithmetic mean (standard deviation)
        Day 0
    203 ( 9999 )
        Day 84
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Fraction Excreted in Urine (fe) of ALN-AAT After Single Ascending Dose (SAD) Part A

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    End point title
    		 Fraction Excreted in Urine (fe) of ALN-AAT After Single Ascending Dose (SAD) Part A [14]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Day 0: predose, 0-6 hr, 6-12 hr, 12-24 hr, 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    3
    3
    3
    3
    3
    Units: percent
        arithmetic mean (standard deviation)
    12.7 ( 4.50 )
    11.3 ( 1.36 )
    16.0 ( 0.964 )
    13.4 ( 2.07 )
    12.1 ( 7.38 )
    No statistical analyses for this end point

    Secondary: Fraction Excreted in Urine (fe) of ALN-AAT After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Fraction Excreted in Urine (fe) of ALN-AAT After Multiple Ascending Dose (MAD) Part B [15]
    End point description
    PK population included all subjects who received at least 1 dose of ALN AAT, had at least 1 post-dose PK parameter and who have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Days 0 and 84: predose, 0-6 hr, 6-12 hr, 12-24 hr and 48 hr
    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: PK endpoints are reported only for arms, which received ALN-AAT (not placebo). Part A and B arms are reported separately as PK data were collected at different days during the study.
    End point values
    		 Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    4
    Units: percent
    arithmetic mean (standard deviation)
        Day 0
    13.3 ( 3.57 )
        Day 84
    11.6 ( 5.88 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Serum Alpha-1 Antitrypsin (AAT) Levels After Single Ascending Dose (SAD) Part A

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    End point title
    		 Change from Baseline in Serum Alpha-1 Antitrypsin (AAT) Levels After Single Ascending Dose (SAD) Part A [16]
    End point description
    Serum AAT levels were analysed using a validated enzyme-linked immunosorbent assay (ELISA). AAT follow-up monitoring was repeated every 28 days. The reporting arms 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 6.0 mg/kg had 3, 8, 9, 20 and 28 follow-up monitoring visits respectively. Pharmacodynamic (PD) analysis set included all subjects who received at least 1 dose of study drug (ALN AAT or placebo) and had at least 1 post-dose serum AAT. Number of subjects analysed as indicated except: 0.1 mg/kg Follow-up Monitoring 1-3: n=2; 0.3 mg/kg Follow-up Monitoring 1-8: n=2; 1.0 mg/kg Follow-up Monitoring 4-8: n=2 and Follow-up Monitoring 9: n=1; 3.0 mg/kg Follow-up Monitoring 8-9: n=2 and Follow-up Monitoring 10-20: n=1; 6.0 mg/kg Follow-up Monitoring 4-7: n=2 and Follow-up Monitoring 8-28: n=1. 9999= no subject was analysed for follow-up monitoring and 99999= not calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 2, 7, 14, 21, 28, 35, 42, 56, 70, Follow up monitoring visit (every 28 days) up to 28 follow-up monitoring visits (approximately 784 days)
    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: Part A and B arms are reported separately as ATT data were collected at a different number of monitoring time points during follow-up.
    End point values
    		 Part A: SAD: Placebo Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg
    Number of subjects analysed
    5
    3
    3
    3
    3
    3
    Units: microgram (ug)/ mL
    arithmetic mean (standard deviation)
        Baseline
    1501.32 ( 292.554 )
    1072.59 ( 123.304 )
    1398.14 ( 89.754 )
    1324.76 ( 62.951 )
    1652.31 ( 224.862 )
    1687.27 ( 604.319 )
        Day 1
    -63.98 ( 233.611 )
    23.93 ( 97.432 )
    161.13 ( 247.049 )
    -156.16 ( 114.833 )
    -23.60 ( 277.341 )
    -118.88 ( 370.215 )
        Day 2
    -182.74 ( 282.496 )
    55.54 ( 105.483 )
    -75.98 ( 227.814 )
    42.79 ( 190.179 )
    68.90 ( 653.373 )
    -190.57 ( 331.197 )
        Day 7
    251.19 ( 433.017 )
    140.75 ( 97.611 )
    -65.79 ( 153.112 )
    -386.43 ( 53.904 )
    -279.27 ( 465.294 )
    181.10 ( 629.055 )
        Day 14
    -259.52 ( 151.892 )
    -77.26 ( 141.127 )
    -293.68 ( 167.243 )
    -547.89 ( 170.703 )
    -791.47 ( 191.362 )
    -951.52 ( 586.210 )
        Day 21
    24.99 ( 277.963 )
    -132.79 ( 194.798 )
    -408.23 ( 141.121 )
    -555.81 ( 236.204 )
    -954.19 ( 249.016 )
    -1228.73 ( 592.668 )
        Day 28
    44.80 ( 252.060 )
    -214.92 ( 192.059 )
    -324.93 ( 102.329 )
    -656.53 ( 161.615 )
    -1099.55 ( 263.405 )
    -1321.59 ( 594.704 )
        Day 35
    46.04 ( 217.424 )
    -271.23 ( 44.454 )
    -422.28 ( 303.545 )
    -695.15 ( 226.029 )
    -1115.95 ( 214.412 )
    -1356.90 ( 637.242 )
        Day 42
    95.11 ( 192.039 )
    -253.40 ( 172.277 )
    -585.86 ( 135.380 )
    -664.63 ( 242.678 )
    -1132.63 ( 130.877 )
    -1381.10 ( 576.775 )
        Day 56
    -76.71 ( 205.776 )
    -429.37 ( 197.559 )
    -618.68 ( 173.650 )
    -680.77 ( 133.329 )
    -1256.09 ( 139.961 )
    -1402.55 ( 568.159 )
        Day 70
    -16.72 ( 289.306 )
    -421.91 ( 105.216 )
    -553.01 ( 167.934 )
    -648.87 ( 154.921 )
    -1168.36 ( 215.997 )
    -1402.43 ( 571.959 )
        Follow-Up AAT Monitoring 1
    9999 ( 9999 )
    -226.15 ( 65.360 )
    -582.75 ( 52.849 )
    -548.90 ( 228.785 )
    -1105.29 ( 210.020 )
    -1327.43 ( 584.095 )
        Follow-Up AAT Monitoring 2
    9999 ( 9999 )
    -224.83 ( 190.612 )
    -299.97 ( 125.292 )
    -368.34 ( 179.988 )
    -1051.38 ( 342.808 )
    -1404.94 ( 603.714 )
        Follow-Up AAT Monitoring 3
    9999 ( 9999 )
    -117.53 ( 392.902 )
    -610.65 ( 61.462 )
    -457.28 ( 414.259 )
    -988.21 ( 127.026 )
    -1380.31 ( 579.965 )
        Follow-Up AAT Monitoring 4
    9999 ( 9999 )
    9999 ( 9999 )
    -431.58 ( 237.319 )
    -460.93 ( 7.590 )
    -939.66 ( 381.668 )
    -1028.50 ( 282.600 )
        Follow-Up AAT Monitoring 5
    9999 ( 9999 )
    9999 ( 9999 )
    -648.64 ( 206.001 )
    -458.80 ( 61.924 )
    -921.68 ( 333.010 )
    -1001.55 ( 289.515 )
        Follow-Up AAT Monitoring 6
    9999 ( 9999 )
    9999 ( 9999 )
    -277.67 ( 119.020 )
    -460.13 ( 64.738 )
    -735.26 ( 564.615 )
    -907.90 ( 171.026 )
        Follow-Up AAT Monitoring 7
    9999 ( 9999 )
    9999 ( 9999 )
    -357.66 ( 118.299 )
    -271.00 ( 10.192 )
    -825.95 ( 298.470 )
    -896.96 ( 215.729 )
        Follow-Up AAT Monitoring 8
    9999 ( 9999 )
    9999 ( 9999 )
    -39.29 ( 169.720 )
    -128.01 ( 112.305 )
    -514.41 ( 751.798 )
    -609.15 ( 99999 )
        Follow-Up AAT Monitoring 9
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -34.42 ( 99999 )
    -516.16 ( 537.665 )
    -524.23 ( 99999 )
        Follow-Up AAT Monitoring 10
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -892.07 ( 99999 )
    -554.68 ( 99999 )
        Follow-Up AAT Monitoring 11
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -873.49 ( 99999 )
    -663.54 ( 99999 )
        Follow-Up AAT Monitoring 12
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -776.81 ( 99999 )
    -560.19 ( 99999 )
        Follow-Up AAT Monitoring 13
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -403.93 ( 99999 )
    -307.12 ( 99999 )
        Follow-Up AAT Monitoring 14
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -683.10 ( 99999 )
    -551.76 ( 99999 )
        Follow-Up AAT Monitoring 15
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -787.45 ( 99999 )
    -465.69 ( 99999 )
        Follow-Up AAT Monitoring 16
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -619.24 ( 99999 )
    -468.27 ( 99999 )
        Follow-Up AAT Monitoring 17
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -100.74 ( 99999 )
    -437.77 ( 99999 )
        Follow-Up AAT Monitoring 18
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -448.64 ( 99999 )
    -312.95 ( 99999 )
        Follow-Up AAT Monitoring 19
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -257.20 ( 99999 )
    -252.67 ( 99999 )
        Follow-Up AAT Monitoring 20
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -514.99 ( 99999 )
    -345.95 ( 99999 )
        Follow-Up AAT Monitoring 21
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -103.09 ( 99999 )
        Follow-Up AAT Monitoring 22
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -32.48 ( 99999 )
        Follow-Up AAT Monitoring 23
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -191.16 ( 99999 )
        Follow-Up AAT Monitoring 24
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -95.06 ( 99999 )
        Follow-Up AAT Monitoring 25
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    11.06 ( 99999 )
        Follow-Up AAT Monitoring 26
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -58.99 ( 99999 )
        Follow-Up AAT Monitoring 27
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    -156.06 ( 99999 )
        Follow-Up AAT Monitoring 28
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    907.87 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Serum Alpha-1 Antitrypsin (AAT) Levels After Multiple Ascending Dose (MAD) Part B

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    End point title
    		 Change from Baseline in Serum Alpha-1 Antitrypsin (AAT) Levels After Multiple Ascending Dose (MAD) Part B [17]
    End point description
    Serum AAT levels were analysed using a validated ELISA. AAT follow-up monitoring was repeated every 28 days. The reporting arm 1.0 mg/kg had 19 follow-up monitoring visits. PD analysis set included all subjects who received at least 1 dose of study drug (ALN AAT or placebo) and had at least 1 post-dose serum AAT. Number of subjects analysed as indicated except: 1.0 mg/kg Follow-up Monitoring 6: n=3, Follow-up Monitoring 12-18: n=2 and Follow-up Monitoring 19: n=1. 9999= no subject was analysed for follow-up monitoring and 99999= not calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 7, 14, 21, 28, 42, 56, 70, 84, 98, 105, 112, 126, 140, 154 Follow up monitoring visit (every 28 days) up to 19 follow-up monitoring visits (approximately 532 days)
    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: Part A and B arms are reported separately as ATT data were collected at a different number of monitoring time points during follow-up.
    End point values
    		 Part B: MAD: Placebo Part B: MAD: ALN-AAT 1.0 mg/kg
    Number of subjects analysed
    2
    4
    Units: ug/mL
    arithmetic mean (standard deviation)
        Baseline
    1521.44 ( 320.595 )
    1630.96 ( 288.691 )
        Day 1
    -183.78 ( 29.147 )
    -85.44 ( 197.651 )
        Day 7
    -36.60 ( 246.625 )
    -349.78 ( 120.151 )
        Day 14
    -193.70 ( 228.254 )
    -555.10 ( 310.907 )
        Day 21
    -394.05 ( 118.377 )
    -832.45 ( 303.653 )
        Day 28
    -147.97 ( 29.020 )
    -841.91 ( 246.344 )
        Day 42
    -144.50 ( 123.730 )
    -1113.25 ( 227.318 )
        Day 56
    -59.15 ( 16.681 )
    -1215.76 ( 272.928 )
        Day 70
    -201.72 ( 31.855 )
    -1210.26 ( 278.535 )
        Day 84
    27.89 ( 74.154 )
    -1330.08 ( 212.621 )
        Day 98
    12.27 ( 543.687 )
    -1277.70 ( 211.994 )
        Day 105
    -18.10 ( 66.772 )
    -1352.05 ( 188.138 )
        Day 112
    -111.76 ( 241.604 )
    -1346.01 ( 208.292 )
        Day 126
    -384.62 ( 145.310 )
    -1306.78 ( 145.804 )
        Day 140
    -158.22 ( 57.573 )
    -1327.03 ( 192.588 )
        Day 154
    -235.20 ( 7.764 )
    -1268.20 ( 202.673 )
        Follow-Up AAT Monitoring 1
    9999 ( 9999 )
    -1225.79 ( 228.573 )
        Follow-Up AAT Monitoring 2
    9999 ( 9999 )
    -1209.57 ( 277.196 )
        Follow-Up AAT Monitoring 3
    9999 ( 9999 )
    -1132.19 ( 368.900 )
        Follow-Up AAT Monitoring 4
    9999 ( 9999 )
    -1100.38 ( 409.101 )
        Follow-Up AAT Monitoring 5
    9999 ( 9999 )
    -1065.72 ( 487.221 )
        Follow-Up AAT Monitoring 6
    9999 ( 9999 )
    -794.32 ( 400.770 )
        Follow-Up AAT Monitoring 7
    9999 ( 9999 )
    -961.89 ( 491.672 )
        Follow-Up AAT Monitoring 8
    9999 ( 9999 )
    -829.66 ( 587.410 )
        Follow-Up AAT Monitoring 9
    9999 ( 9999 )
    -782.48 ( 494.649 )
        Follow-Up AAT Monitoring 10
    9999 ( 9999 )
    -679.66 ( 448.771 )
        Follow-Up AAT Monitoring 11
    9999 ( 9999 )
    -607.71 ( 461.639 )
        Follow-Up AAT Monitoring 12
    9999 ( 9999 )
    -1055.14 ( 214.713 )
        Follow-Up AAT Monitoring 13
    9999 ( 9999 )
    -1147.27 ( 277.179 )
        Follow-Up AAT Monitoring 14
    9999 ( 9999 )
    -1118.70 ( 311.438 )
        Follow-Up AAT Monitoring 15
    9999 ( 9999 )
    -1041.33 ( 250.761 )
        Follow-Up AAT Monitoring 16
    9999 ( 9999 )
    -956.44 ( 372.872 )
        Follow-Up AAT Monitoring 17
    9999 ( 9999 )
    -903.09 ( 169.317 )
        Follow-Up AAT Monitoring 18
    9999 ( 9999 )
    -738.61 ( 406.417 )
        Follow-Up AAT Monitoring 19
    9999 ( 9999 )
    -630.47 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part A: up to 160 days plus up to 24 months follow-up; Part B: up to 244 days plus up to 24 months follow-up
    Adverse event reporting additional description
    Safety population included all subjects who received at least 1 dose of study drug (ALN-AAT or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Part A: SAD: Placebo
    Reporting group description
    		 A single dose of matching placebo was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 0.1 mg/kg
    Reporting group description
    		 A single dose of 0.1 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 0.3 mg/kg
    Reporting group description
    		 A single dose of 0.3 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 1.0 mg/kg
    Reporting group description
    		 A single dose of 1.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 3.0 mg/kg
    Reporting group description
    		 A single dose of 3.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part A: SAD: ALN-AAT 6.0 mg/kg
    Reporting group description
    		 A single dose of 6.0 mg/kg ALN-AAT was administered.

    Reporting group title
    Part B: MAD: Placebo
    Reporting group description
    		 Multiple dosed (once every 4 weeks) of matching placebo were administered.

    Reporting group title
    Part B: MAD: ALN-AAT 1.0 mg/kg
    Reporting group description
    		 Multiple doses (once every 4 weeks) of 1.0 mg/kg ALN-AAT were administered.

    Serious adverse events
    		 Part A: SAD: Placebo Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg Part B: MAD: Placebo Part B: MAD: ALN-AAT 1.0 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: SAD: Placebo Part A: SAD: ALN-AAT 0.1 mg/kg Part A: SAD: ALN-AAT 0.3 mg/kg Part A: SAD: ALN-AAT 1.0 mg/kg Part A: SAD: ALN-AAT 3.0 mg/kg Part A: SAD: ALN-AAT 6.0 mg/kg Part B: MAD: Placebo Part B: MAD: ALN-AAT 1.0 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    4 / 4 (100.00%)
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    1
    Injection site dysaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Injection site bruising
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Injection site pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Burns first degree
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Head injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Muscle rupture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    0
    2
    1
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Sensory disturbance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Pinguecula
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    1
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Umbilical hernia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Bladder irritation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 2 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    1
    1
    1
    2
    1
    2
    Fungal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Herpes simplex
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Labyrinthitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2017
    Amended primarily to revise the study follow-up period, with the objective of potentially reducing the total burden of study follow up for some study subjects while ensuring patient safety. Subjects must continue in follow up until the blood AAT level has reached 80 percent of pre-treatment values OR has reached the lower limit of the normal range.
    18 Dec 2017
    The purpose of Protocol Amendment 2 to ALN-AAT-001 is to permit a final evaluation of the one remaining subject participating in this study. Amended so that subjects are required to be followed until one of the following criteria are met: 1. AAT levels return to at least 80% of the subject’s mean pre treatment baseline, or 2. AAT levels return to the lower limit of the normal range, or 3. The subject has been followed for 24 months following administration of the last dose of study drug and blood AAT levels exceed 0.49 g/dL.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    03 Jan 2018
    Dosing of study subjects was suspended in February 2016, and subjects who had been dosed were followed per protocol until their AAT levels returned to normal, at which point the study was terminated. The study was terminated because of the observation of low incidence of asymptomatic, transiently elevated liver enzymes in a subset of study subjects.
    -

    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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