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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Phase 2 Study Assessing the Safety, Tolerability and Efficacy of IONIS-AGT-LRX, an Antisense Inhibitor of Angiotensinogen Production, Administered Subcutaneously Over 12 Weeks in Patients With Chronic Heart Failure With Reduced Ejection Fraction

    Summary
    EudraCT number
    		 2020-005878-10
    Trial protocol
    		 HU   PL  
    Global end of trial date
    11 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Dec 2023
    First version publication date
    20 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 757456-CS5
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04836182
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc.
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, United States, 92010
    Public contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 (760) 931-9200, globalregulatoryaffairs@ionisph.com
    Scientific contact
    Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 (760) 931-9200, globalregulatoryaffairs@ionisph.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
    23 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aim of this study is to evaluate the effect of AGT-LRX weekly subcutaneous (SC) injection on plasma angiotensinogen (AGT) concentration from baseline to study day 85 (Week 13) in subjects with chronic heart failure (HF) with reduced ejection fraction (rEF).
    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
    21 May 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Poland: 48
    Worldwide total number of subjects
    72
    EEA total number of subjects
    53
    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)
    21
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 19 investigational sites in the United States, Hungary, and Poland from 21 May 2021 to 11 January 2023.

    Pre-assignment
    Screening details
    		 Subjects with Crohn's disease were randomised to receive placebo, ISIS 757456 40 mg, ISIS 757456 80 mg, or ISIS 757456 120 mg.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received AGT-LRX-matching placebo, subcutaneous (SC) injection once every week up to Day 78.
    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
    ISIS 757456-matching placebo, administered subcutaneously.

    Arm title
    		 AGT-LRX 40 mg
    Arm description
    		 Subjects received AGT-LRX 40 mg, SC injection once every week up to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AGT-LRX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AGT-LRX 40 mg, administered subcutaneously.

    Arm title
    		 AGT-LRX 80 mg
    Arm description
    		 Subjects received AGT-LRX 80 mg, SC injection once every week up to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AGT-LRX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AGT-LRX 80 mg, administered subcutaneously.

    Arm title
    		 AGT-LRX 120 mg
    Arm description
    		 Subjects received AGT-LRX 120 mg, SC injection once every week up to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AGT-LRX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    AGT-LRX 120 mg, administered subcutaneously.

    Number of subjects in period 1
    		Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Started
    21
    12
    26
    13
    Pharmacokinetic Set
    0
    12
    26
    13
    Safety Set
    20
    12
    26
    13
    Full Analysis Set
    20
    12
    26
    13
    Per Protocol Set
    17
    9
    19
    13
    Completed
    19
    10
    21
    13
    Not completed
    2
    2
    5
    0
         Voluntary Withdrawal
    1
    1
    -
    -
         Investigator Judgement
    -
    -
    1
    -
         Significant Protocol Deviation
    -
    -
    1
    -
         Adverse event or Serious Adverse Event (SAE)
    1
    1
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received AGT-LRX-matching placebo, subcutaneous (SC) injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 40 mg
    Reporting group description
    		 Subjects received AGT-LRX 40 mg, SC injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 80 mg
    Reporting group description
    		 Subjects received AGT-LRX 80 mg, SC injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 120 mg
    Reporting group description
    		 Subjects received AGT-LRX 120 mg, SC injection once every week up to Day 78.

    Reporting group values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg Total
    Number of subjects
    		 21 12 26 13
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 ± 67 ± 6 67 ± 7 70 ± 7 -
    Gender categorical
    Units: Subjects
        Male
    		 17 9 25 9 60
        Female
    		 4 3 1 4 12
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received AGT-LRX-matching placebo, subcutaneous (SC) injection once every week up to Day 78.

    Subject analysis sets values
    		 Placebo
    Number of subjects
    20
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69 ± 8
    Gender categorical
    Units: Subjects
        Male
        Female

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received AGT-LRX-matching placebo, subcutaneous (SC) injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 40 mg
    Reporting group description
    		 Subjects received AGT-LRX 40 mg, SC injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 80 mg
    Reporting group description
    		 Subjects received AGT-LRX 80 mg, SC injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 120 mg
    Reporting group description
    		 Subjects received AGT-LRX 120 mg, SC injection once every week up to Day 78.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received AGT-LRX-matching placebo, subcutaneous (SC) injection once every week up to Day 78.

    Primary: Percent Change in Plasma AGT Concentration From Baseline to Day 85

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    End point title
    		 Percent Change in Plasma AGT Concentration From Baseline to Day 85
    End point description
    PPS consisted of all FAS subjects who received at least 10 of the 12 doses of study drug, did not have major changes of screening life-saving HF medications during the treatment period and prior to study day 85, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments. Analysis of covariance (ANCOVA) was used for the analyses.
    End point type
    Primary
    End point timeframe
    Baseline to Day 85
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    17
    9
    19
    13
    Units: percent change
        least squares mean (confidence interval 95%)
    0.5 (-11.0 to 11.9)
    -44.1 (-59.5 to -28.7)
    -49.6 (-60.1 to -39.0)
    -64.5 (-77.4 to -51.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares (LS) Mean of Difference
    Point estimate
    -44.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.5
         upper limit
    		 -25.6
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.4
         upper limit
    		 -47.6
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.6
         upper limit
    		 -34.5

    Secondary: Absolute Level of Plasma AGT

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    End point title
    		 Absolute Level of Plasma AGT
    End point description
    FAS consisted of all randomised subjects who received at least 1 injection of study drug and had at least 1 post-baseline efficacy or exploratory measurement. ‘n’ indicates the number of subjects available for analysis at the given timepoints. '99999' indicates standard deviation was not evaluable for 1 subject.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 169
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    20
    12
    26
    13
    Units: nanomoles per litre (nmol/L)
    arithmetic mean (standard deviation)
        Baseline (n= 20, 12, 25, 13)
    858.1 ± 356.0
    805.5 ± 265.9
    727.9 ± 205.6
    704.2 ± 347.3
        Day 15 (n= 19, 12, 25, 13)
    847.9 ± 295.7
    623.5 ± 273.8
    565.7 ± 184.3
    448.8 ± 212.7
        Day 29 (n= 18, 11, 22, 13)
    769.4 ± 263.1
    592.5 ± 316.3
    456.2 ± 186.7
    291.5 ± 123.3
        Day 43 (n= 19, 10, 23, 13)
    815.3 ± 302.7
    484.4 ± 177.5
    444.9 ± 184.5
    264.5 ± 100.1
        Day 57 (n= 16, 10, 21, 13)
    773.9 ± 219.1
    415.4 ± 163.9
    404.4 ± 140.0
    245.8 ± 87.5
        Day 71 (n= 19, 10, 21, 13)
    798.5 ± 292.1
    380.9 ± 148.6
    384.3 ± 156.4
    292.3 ± 148.8
        Day 85 (n= 19, 10, 20, 13)
    802.7 ± 260.1
    400.0 ± 163.8
    370.8 ± 154.5
    260.6 ± 91.2
        Day 92 (n= 19, 11, 22, 12)
    743.3 ± 260.1
    471.3 ± 185.9
    399.2 ± 181.2
    298.4 ± 109.7
        Day 99 (n= 18, 10, 22, 13)
    784.1 ± 232.3
    488.0 ± 151.7
    429.9 ± 174.2
    390.3 ± 131.2
        Day 120 (n= 19, 11, 23, 13)
    749.5 ± 225.7
    689.1 ± 262.4
    533.9 ± 176.9
    509.2 ± 204.6
        Day 148 (n= 19, 11, 23, 13)
    797.9 ± 302.4
    718.0 ± 244.3
    667.4 ± 294.5
    539.0 ± 171.9
        Day 169 (n= 0, 1, 0, 0)
    0 ± 0
    844.8 ± 99999
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit

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    End point title
    		 Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit
    End point description
    FAS consisted of all randomised subjects who received at least 1 injection of study drug and had at least 1 post-baseline efficacy or exploratory measurement. ‘n’ indicates the number of subjects available for analysis at the given timepoints. '-99999' indicates upper limit and '99999' indicates lower limit for 95% CI were not evaluable for 1 subject.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 169
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    20
    12
    26
    13
    Units: nmol/L
    least squares mean (confidence interval 95%)
        Day 15 (n= 19, 12, 24, 13)
    14.647 (-73.963 to 103.258)
    -174.057 (-283.242 to -64.872)
    -199.879 (-276.467 to -123.291)
    -292.249 (-396.937 to -187.562)
        Day 29 (n= 18, 11, 21, 13)
    -43.475 (-141.481 to 54.531)
    -198.044 (-322.549 to -73.538)
    -322.420 (-411.196 to -233.645)
    -464.425 (-577.798 to -351.051)
        Day 43 (n= 19, 10, 22, 13)
    -0.306 (-88.721 to 88.110)
    -298.227 (-417.308 to -179.146)
    -313.819 (-393.296 to -234.341)
    -485.127 (-588.976 to -381.277)
        Day 57 (n= 16, 10, 20, 13)
    -49.605 (-122.719 to 23.509)
    -365.535 (-454.553 to -276.517)
    -362.547 (-425.168 to -299.925)
    -514.430 (-592.170 to -436.691)
        Day 71 (n= 19, 10, 20, 13)
    -25.450 (-107.300 to 56.400)
    -409.873 (-520.456 to -299.290)
    -392.864 (-470.220 to -315.507)
    -462.624 (-559.180 to -366.069)
        Day 85 (n= 19, 10, 20, 13)
    -8.006 (-86.504 to 70.491)
    -384.270 (-490.323 to -278.217)
    -404.984 (-479.172 to -330.796)
    -500.238 (-592.838 to -407.638)
        Day 92 (n= 19, 11, 21, 12)
    -80.433 (-163.080 to 2.214)
    -335.227 (-442.479 to -227.975)
    -368.335 (-444.870 to -291.800)
    -470.447 (-571.923 to -368.970)
        Day 99 (n= 18, 10, 21, 13)
    -46.275 (-121.120 to 28.570)
    -305.358 (-403.534 to -207.182)
    -334.772 (-401.978 to -267.567)
    -368.138 (-453.838 to -282.438)
        Day 120 (n= 19, 11, 22, 13)
    -62.844 (-136.107 to 10.419)
    -101.913 (-198.134 to -5.692)
    -217.345 (-284.478 to -150.211)
    -230.610 (-318.021 to -143.199)
        Day 148 (n= 19, 11, 22, 13)
    -34.360 (-141.639 to 72.919)
    -80.289 (-219.068 to 58.490)
    -78.438 (-175.381 to 18.504)
    -203.100 (-329.313 to -76.888)
        Day 169 (n= 0, 1, 0, 0)
    0 (0 to 0)
    -210.600 (-99999 to 99999)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Percent Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit

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    End point title
    		 Percent Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit
    End point description
    FAS consisted of all randomised subjects who received at least 1 injection of study drug and had at least 1 post-baseline efficacy or exploratory measurement. ‘n’ indicates the number of subjects available for analysis at the given timepoints. '-99999' indicates upper limit and '99999' indicates lower limit for 95% CI were not evaluable for 1 subject.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 169
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    20
    12
    26
    13
    Units: Percent Change
    least squares mean (confidence interval 95%)
        Day 15 (n= 19, 12, 24, 13)
    5.5 (-6.2 to 17.2)
    -22.0 (-36.5 to -7.6)
    -23.9 (-34.0 to -13.8)
    -35.9 (-49.7 to -22.0)
        Day 29 (n= 18, 11, 21, 13)
    -1.5 (-13.2 to 10.2)
    -24.8 (-39.7 to -10.0)
    -39.6 (-50.1 to -29.0)
    -58.7 (-72.2 to -45.2)
        Day 43 (n= 19, 10, 22, 13)
    2.4 (-8.6 to 13.3)
    -33.3 (-48.1 to -18.5)
    -39.4 (-49.2 to -29.5)
    -62.6 (-75.5 to -49.7)
        Day 57 (n= 16, 10, 20, 13)
    -5.5 (-14.8 to 3.8)
    -41.7 (-53.0 to -30.4)
    -44.9 (-52.9 to -37.0)
    -65.6 (-75.5 to -55.8)
        Day 71 (n= 19, 10, 20, 13)
    0.5 (-9.5 to 10.5)
    -49.4 (-62.9 to -35.9)
    -48.1 (-57.5 to -38.6)
    -60.8 (-72.6 to -49.0)
        Day 85 (n= 19, 10, 20, 13)
    5.8 (-5.6 to 17.2)
    -45.8 (-61.2 to -30.4)
    -50.1 (-60.9 to -39.3)
    -64.6 (-78.1 to -51.1)
        Day 92 (n= 18, 10, 21, 13)
    -4.4 (-14.5 to 5.6)
    -40.0 (-53.1 to -27.0)
    -45.2 (-54.5 to -35.9)
    -58.7 (-71.0 to -46.4)
        Day 99 (n= 18, 10, 21, 13)
    -0.4 (-9.6 to 8.8)
    -35.5 (-47.5 to -23.4)
    -41.1 (-49.3 to -32.8)
    -44.5 (-55.0 to -33.9)
        Day 120 (n= 19, 11, 22, 13)
    -0.8 (-11.8 to 10.2)
    -14.5 (-28.9 to 0.0)
    -25.5 (-35.6 to -15.4)
    -28.4 (-41.6 to -15.3)
        Day 148 (n= 19, 11, 22, 13)
    3.0 (-11.8 to 17.7)
    -10.1 (-29.2 to 9.0)
    -7.1 (-20.4 to 6.3)
    -19.9 (-37.2 to -2.5)
        Day 169 (n= 0, 1, 0, 0)
    0 (0 to 0)
    -20.0 (-99999 to 99999)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Absolute Level of NT-proBNP

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    End point title
    		 Absolute Level of NT-proBNP
    End point description
    FAS consisted of all randomised subjects who received at least 1 injection of study drug and had at least 1 post-baseline efficacy or exploratory measurement. ‘n’ indicates the number of subjects available for analysis at the given timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 169
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    20
    12
    26
    13
    Units: picogram per millilitre (pg/mL)
    arithmetic mean (standard deviation)
        Baseline (n = 20, 12, 26, 13)
    1432 ± 969
    2632 ± 3581
    2158 ± 3308
    1748 ± 1455
        Day 43 (n= 19, 10, 23, 13)
    1480 ± 954
    1442 ± 1245
    1758 ± 1729
    1539 ± 1346
        Day 85 (n= 18, 10, 21, 13)
    1386 ± 771
    1664 ± 1566
    1757 ± 1716
    1670 ± 1329
        Day 99 (n= 18, 10, 22, 13)
    1525 ± 1044
    1550 ± 1800
    2018 ± 2552
    1702 ± 1220
        Day 169 (n = 20, 10, 23, 13)
    1266 ± 809
    2190 ± 2569
    1852 ± 3184
    1651 ± 1169
    No statistical analyses for this end point

    Secondary: Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit

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    End point title
    		 Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit
    End point description
    FAS consisted of all randomised subjects who received at least 1 injection of study drug and had at least 1 post-baseline efficacy or exploratory measurement. ‘n’ indicates the number of subjects available for analysis at the given timepoints. ANCOVA was used for the analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 169
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    20
    12
    26
    13
    Units: pg/mL
    arithmetic mean (standard deviation)
        Day 43 (n= 19, 10, 23, 13)
    117 ± 484
    -228 ± 522
    -530 ± 2550
    -210 ± 468
        Day 85 (n= 18, 10, 21, 13)
    -11 ± 693
    -6 ± 887
    -537 ± 2095
    -78 ± 559
        Day 99 (n= 18, 10, 22, 13)
    128 ± 640
    -120 ± 1077
    -262 ± 1289
    -47 ± 713
        Day 169 (n= 20, 10, 23, 13)
    -166 ± 560
    520 ± 1226
    -381 ± 920
    -97 ± 868
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 43
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.284
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -176
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -897
         upper limit
    		 546
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 43
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -136
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -716
         upper limit
    		 443
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 43
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -779
         upper limit
    		 552
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 85
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.621
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    140
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -404
         upper limit
    		 683
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 85
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.665
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -532
         upper limit
    		 363
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 85
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -396
         upper limit
    		 607
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 99
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.525
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -171
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -758
         upper limit
    		 417
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 99
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.556
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -141
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -620
         upper limit
    		 338
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 99
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.709
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -618
         upper limit
    		 467
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 169
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    711
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 56
         upper limit
    		 1365
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 169
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.793
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -132
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -653
         upper limit
    		 390
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 169
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.503
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    102
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -501
         upper limit
    		 704

    Secondary: Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit

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    End point title
    		 Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit
    End point description
    FAS consisted of all randomised subjects who received at least 1 injection of study drug and had at least 1 post-baseline efficacy or exploratory measurement. ‘n’ indicates the number of subjects available for analysis at the given timepoints. ANCOVA was used for the analyses.
    End point type
    Secondary
    End point timeframe
    Baseline through Day 169
    End point values
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Number of subjects analysed
    20
    12
    26
    13
    Units: Percent Change
    arithmetic mean (standard deviation)
        Day 43 (n= 19, 10, 23, 13)
    16.8 ± 46.1
    3.2 ± 40.0
    -3.5 ± 42.8
    -4.5 ± 32.6
        Day 85 (n= 18, 10, 21, 13)
    20.7 ± 76.9
    22.2 ± 87.2
    9.4 ± 84.7
    9.5 ± 45.1
        Day 99 (n= 18, 10, 22, 13)
    26.9 ± 73.8
    0.6 ± 39.0
    14.9 ± 86.4
    13.1 ± 47.0
        Day 169 (n = 20, 10, 23, 13)
    1.9 ± 56.1
    42.6 ± 89.1
    -11.2 ± 34.2
    15.8 ± 69.0
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 43
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.456
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 19.4
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 85
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.8
         upper limit
    		 44.6
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 169
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    41.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 87
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 43
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.136
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -15.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.9
         upper limit
    		 9.6
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 43
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.168
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -19.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.4
         upper limit
    		 9.6
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 85
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.621
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.7
         upper limit
    		 62.4
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 85
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.642
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -8.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.2
         upper limit
    		 45.9
    Statistical analysis title
    		 Placebo and ISIS 757456 40 mg at Day 99
    Comparison groups
    Placebo v AGT-LRX 40 mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.525
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -24.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -78.7
         upper limit
    		 29.9
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 99
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.526
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -5.9
    Confidence interval
         level
    		 94%
         sides
    2-sided
         lower limit
    		 -50.2
         upper limit
    		 38.3
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 99
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.758
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.5
         upper limit
    		 38.8
    Statistical analysis title
    		 Placebo and ISIS 757456 80 mg at Day 169
    Comparison groups
    Placebo v AGT-LRX 80 mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.9
         upper limit
    		 26.4
    Statistical analysis title
    		 Placebo and ISIS 757456 120 mg at Day 169
    Comparison groups
    Placebo v AGT-LRX 120 mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.273
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    26.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.5
         upper limit
    		 56.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent form up to end of study (up to Day 169)
    Adverse event reporting additional description
    Safety set consisted of all subjects who were randomised and received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received AGT-LRX-matching placebo, subcutaneous (SC) injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 40 mg
    Reporting group description
    		 Subjects received AGT-LRX 40 mg, SC injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 80 mg
    Reporting group description
    		 Subjects received AGT-LRX 80 mg, SC injection once every week up to Day 78.

    Reporting group title
    AGT-LRX 120 mg
    Reporting group description
    		 Subjects received AGT-LRX 120 mg, SC injection once every week up to Day 78.

    Serious adverse events
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 12 (16.67%)
    5 / 26 (19.23%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    1
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal Adenocarcinoma
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Compression Fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypovolaemic Shock
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Failure Chronic
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiorenal Syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure congestive
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo AGT-LRX 40 mg AGT-LRX 80 mg AGT-LRX 120 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 20 (55.00%)
    7 / 12 (58.33%)
    10 / 26 (38.46%)
    6 / 13 (46.15%)
    Vascular disorders
    Blood Pressure Fluctuation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Injection Site Haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection Site Haematoma
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Fibrosis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood Glucose Increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood Potassium Increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Occult Blood Positive
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Limb Injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiorenal Syndrome
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ventricular Extrasystoles
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Headache
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Sciatica
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Normocytic Anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    1
    Gastrointestinal disorders
    Haematochezia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dental Caries
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Peptic Ulcer
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Acute Kidney Injury
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    1
    Infections and infestations
    Pharyngitis Streptococcal
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 12 (8.33%)
    2 / 26 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2021
    The main purpose of amendment 1 was to incorporate changes from the Protocol Clarification Memorandum dated 18 March 2021.
    15 Oct 2021
    The purpose of amendment 2 was to: 1. update the eGFR exclusion criterion to < 30 mL/min/1.73 m2 2. clarify the types of cardiomyopathies that are excluded from the trial 3. clarify the testing needed for HBV at screening 4. update the K+ exclusion criterion to the upper limit of normal of the standard reference range of the study’s central lab (5.1 mmol/L) and update, accordingly, the potassium safety monitoring rule to allow for physiological variability from the upper limit of normal.
    15 Mar 2022
    The purpose of amendment 3 was to: 1. extend the screening period from four to ten weeks 2. include an additional dose cohort (cohort C, 120 mg) or placebo). Based on AGT levels observed at the interim analysis, a decision was made to close enrollment for Cohort A and enroll the remainder of the subjects into Cohort B (approximately n=36) and Cohort C (approximately n=18).

    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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