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    Clinical Trial Results:
    A Multicenter, Randomized, Open-Label, Dose Ranging Study to Evaluate the Efficacy and Safety of RLY5016 in the Treatment of Hyperkalemia in Patients with Hypertension and Diabetic Nephropathy Receiving ACEI and/or ARB Drugs, with or without Spironolactone

    Summary
    EudraCT number
    		 2011-000165-12
    Trial protocol
    		 HU   DE   AT   SI  
    Global end of trial date
    17 Jun 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2016
    First version publication date
    11 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RLY5016-205
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01371747
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Relypsa, Inc.
    Sponsor organisation address
    100 Cardinal Way, Redwood City, United States, 94063
    Public contact
    Medical Information, Relypsa, Inc., medinfo@relypsa.com
    Scientific contact
    Medical Information, Relypsa, Inc., medinfo@relypsa.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
    10 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine the optimal starting dose of RLY5016 in treating hyperkalemia in patients with hypertension and diabetic nephropathy receiving ACEI and/or ARB drugs, with or without spironolactone
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 All subjects were on ACEI and/or ARB drugs with or without spironolactone.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 50
    Country: Number of subjects enrolled
    Georgia: 181
    Country: Number of subjects enrolled
    Croatia: 24
    Country: Number of subjects enrolled
    Serbia: 36
    Country: Number of subjects enrolled
    Slovenia: 15
    Worldwide total number of subjects
    306
    EEA total number of subjects
    89
    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)
    123
    From 65 to 84 years
    183
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening serum potassium ≤ 5 mEq/L (milliequivalent) entered Run-in: Cohort 1 stopped ACEI/ARB (angiotensin-converting enzyme inhibitor/angiotensin receptor blockers), started losartan; Cohort 2 started spironolactone; Run-in (Cohorts 1 and 2) or screening (Cohort 3) > 5 mEq/L entered study.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Stratum 1: 8.4 g/d patiromer
    Arm description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 8.4 g/day patiromer starting dose, orally, as a divided dose twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    RLY5016 for Oral Suspension
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 8.4 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Arm title
    		 Stratum 1: 16.8 g/d Patiromer
    Arm description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    RLY5016 for Oral Suspension
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Arm title
    		 Stratum 1: 25.2 g/d Patiromer
    Arm description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    RLY5016 for Oral Suspension
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Arm title
    		 Stratum 2: 16.8 g/d Patiromer
    Arm description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    RLY5016 for Oral Suspension
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Arm title
    		 Stratum 2: 25.2 g/d Patiromer
    Arm description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    RLY5016 for Oral Suspension
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Arm title
    		 Stratum 2: 33.6 g/d Patiromer
    Arm description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 33.6 g/day patiromer starting dose, orally, as a divided dose twice a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    RLY5016 for Oral Suspension
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 33.6 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Number of subjects in period 1 [1]
    		Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Started
    74
    73
    73
    26
    28
    30
    Completed
    56
    51
    50
    17
    21
    16
    Not completed
    18
    22
    23
    9
    7
    14
         Adverse event, serious fatal
    1
    -
    4
    1
    2
    -
         Non-Compliance
    3
    4
    3
    -
    -
    1
         Consent withdrawn by subject
    6
    11
    5
    2
    2
    4
         Physician decision
    -
    -
    -
    -
    1
    -
         Low Serum Potassium Results
    1
    1
    1
    1
    -
    3
         Adverse event, non-fatal
    4
    2
    7
    2
    2
    2
         Other Reasons
    2
    1
    1
    -
    -
    1
         High Serum Potassium Results
    1
    1
    1
    2
    -
    2
         Abnormal Renal Function
    -
    2
    -
    1
    -
    1
         Protocol deviation
    -
    -
    1
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 306 participants were randomized and stratified by baseline serum potassium (2 randomized participants in Stratum 1 did not receive any study drug: 1 participant withdrew consent and 1 participant was randomized in error and was withdrawn from the study); 304 participants were analyzed for safety.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Stratum 1: 8.4 g/d patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 8.4 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 1: 16.8 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 1: 25.2 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 2: 16.8 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 2: 25.2 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 2: 33.6 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 33.6 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer Total
    Number of subjects
    		 74 73 73 26 28 30 304
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 28 29 28 12 12 13 122
        From 65-84 years
    		 46 44 45 14 16 17 182
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 67 (46 to 80) 70 (37 to 79) 68 (40 to 79) 66.5 (56 to 76) 68.5 (39 to 80) 65 (44 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 29 26 26 8 13 10 112
        Male
    		 45 47 47 18 15 20 192

    End points

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    End points reporting groups
    Reporting group title
    Stratum 1: 8.4 g/d patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 8.4 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 1: 16.8 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 1: 25.2 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.0 - 5.5 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 2: 16.8 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 16.8 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 2: 25.2 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 25.2 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Reporting group title
    Stratum 2: 33.6 g/d Patiromer
    Reporting group description
    		 Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L randomized to 33.6 g/day patiromer starting dose, orally, as a divided dose twice a day.

    Primary: Least Squares Mean Change in Serum Potassium From Baseline to Week 4 or Time of First Titration for Each Individual Starting Dose Group

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    End point title
    		 Least Squares Mean Change in Serum Potassium From Baseline to Week 4 or Time of First Titration for Each Individual Starting Dose Group [1]
    End point description
    Least square mean changes from Baseline to Week 4/first titration were derived from parallel lines ANCOVA model with randomized starting dose and baseline serum potassium value as covariates. Individual dose group was compared to its baseline values.
    End point type
    Primary
    End point timeframe
    Baseline to Week 4 or First Titration which could occur at any scheduled study visit after patiromer initiation.
    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: Individual dose group was compared to its baseline values. P-Value <0.001; method: ANCOVA
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    73
    72
    72
    26
    27
    30
    Units: mEq/L
        least squares mean (standard error)
    -0.35 ± 0.066
    -0.51 ± 0.067
    -0.55 ± 0.067
    -0.87 ± 0.134
    -0.97 ± 0.132
    -0.92 ± 0.125
    No statistical analyses for this end point

    Secondary: Least Squares Mean Change in Serum Potassium From Baseline to Week 8 or Time of First Titration for Each Individual Starting Dose Group

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    End point title
    		 Least Squares Mean Change in Serum Potassium From Baseline to Week 8 or Time of First Titration for Each Individual Starting Dose Group
    End point description
    Least squares mean changes from Baseline to Week 8/first titration were derived from parallel lines ANCOVA model with randomized starting dose and baseline serum potassium value as covariates. Individual dose group was compared to its baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8 or First Titration which could occur at any scheduled study visit after patiromer initiation.
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    73
    72
    72
    26
    27
    30
    Units: mEq/L
        least squares mean (standard error)
    -0.35 ± 0.07
    -0.47 ± 0.07
    -0.54 ± 0.07
    -0.88 ± 0.142
    -0.95 ± 0.139
    -0.91 ± 0.132
    No statistical analyses for this end point

    Secondary: Least Squares Mean Change in Serum Potassium From Baseline to Day 3 During the Treatment Initiation Period for Each Individual Starting Dose Group

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    End point title
    		 Least Squares Mean Change in Serum Potassium From Baseline to Day 3 During the Treatment Initiation Period for Each Individual Starting Dose Group
    End point description
    Least squares mean changes from Baseline to Day 3 were derived from parallel lines ANCOVA model with randomized starting dose and baseline serum potassium value as covariates. Individual dose group was compared to its baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 3
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    68
    63
    69
    25
    26
    30
    Units: mEq/L
        least squares mean (standard error)
    -0.26 ± 0.048
    -0.28 ± 0.05
    -0.31 ± 0.047
    -0.65 ± 0.086
    -0.59 ± 0.084
    -0.53 ± 0.079
    No statistical analyses for this end point

    Secondary: Mean Change in Serum Potassium From Baseline to Week 52 During the Long-term Maintenance Period for Each Individual Starting Dose Group

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    End point title
    		 Mean Change in Serum Potassium From Baseline to Week 52 During the Long-term Maintenance Period for Each Individual Starting Dose Group
    End point description
    Mean Change in Serum Potassium From Baseline to Week 52 During the Long-term Maintenance Period for Each Individual Starting Dose Group. Individual dose group was compared to its baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    50
    49
    44
    15
    19
    15
    Units: mEq/L
        arithmetic mean (standard deviation)
    -0.54 ± 0.465
    -0.44 ± 0.44
    -0.5 ± 0.417
    -1 ± 0.466
    -0.96 ± 0.414
    -1.17 ± 0.569
    No statistical analyses for this end point

    Secondary: Mean Change in Serum Potassium From Week 52 or Last Patiromer Dose (if Occurred Before Week 52) to Follow-up Visits Plus 7 Days

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    End point title
    		 Mean Change in Serum Potassium From Week 52 or Last Patiromer Dose (if Occurred Before Week 52) to Follow-up Visits Plus 7 Days
    End point description
    Mean Change in Serum Potassium From Week 52 or Last Patiromer Dose (if Occurred Before Week 52) to Follow-up Visits Plus 7 Days. Individual dose group was compared to its baseline values.
    End point type
    Secondary
    End point timeframe
    Week 52 or Last Patiromer Dose (if Occurred before Week 52) to Following up Visit Plus 7 Days
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    52
    52
    50
    20
    17
    20
    Units: mEq/L
        arithmetic mean (standard deviation)
    0.36 ± 0.567
    0.22 ± 0.424
    0.3 ± 0.508
    0.41 ± 0.66
    0.39 ± 0.331
    0.58 ± 0.557
    No statistical analyses for this end point

    Secondary: Proportion of Participants Achieving Serum Potassium Levels Within 3.5 to 5.5 mEq/L at Week 8 for Each Individual Starting Dose Group

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    End point title
    		 Proportion of Participants Achieving Serum Potassium Levels Within 3.5 to 5.5 mEq/L at Week 8 for Each Individual Starting Dose Group
    End point description
    Proportion of Participants Achieving Serum Potassium Levels Within 3.5 to 5.5 mEq/L at Week 8 for Each Individual Starting Dose Group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    63
    65
    64
    24
    24
    22
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (94.3 to 100)
    100 (94.5 to 100)
    98.4 (91.6 to 100)
    91.7 (73 to 99)
    95.8 (78.9 to 99.9)
    95.5 (77.2 to 99.9)
    No statistical analyses for this end point

    Secondary: Time to First Serum Potassium Measurement of 4.0 - 5.0 mEq/L During Treatment Initiation Period for Each Individual Starting Dose Group

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    End point title
    		 Time to First Serum Potassium Measurement of 4.0 - 5.0 mEq/L During Treatment Initiation Period for Each Individual Starting Dose Group
    End point description
    Time to First Serum Potassium Measurement of 4.0 - 5.0 mEq/L During Treatment Initiation Period for Each Individual Starting Dose Group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    72
    72
    73
    26
    28
    30
    Units: days
        median (confidence interval 95%)
    4 (4 to 5)
    4 (4 to 6)
    4 (4 to 5)
    8 (4 to 9)
    7.5 (4 to 8)
    8 (4 to 8)
    No statistical analyses for this end point

    Secondary: Proportions of Participants Achieving Serum Potassium Levels Within 3.8 to 5.0 mEq/L at Week 52 for Each Individual Starting Dose Group

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    End point title
    		 Proportions of Participants Achieving Serum Potassium Levels Within 3.8 to 5.0 mEq/L at Week 52 for Each Individual Starting Dose Group
    End point description
    Proportions of Participants Achieving Serum Potassium Levels Within 3.8 to 5.0 mEq/L at Week 52 for Each Individual Starting Dose Group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    58
    63
    59
    22
    24
    20
    Units: percentage of participants
        number (confidence interval 95%)
    86.3 (73.7 to 94.3)
    81.6 (68 to 91.2)
    88.9 (75.9 to 96.3)
    86.7 (59.5 to 98.3)
    89.5 (66.9 to 98.7)
    93.3 (68.1 to 99.8)
    No statistical analyses for this end point

    Secondary: Proportion of Participants Achieving Serum Potassium Levels Within 4.0 to 5.0 mEq/L at Week 8 for Each Individual Starting Dose Group

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    End point title
    		 Proportion of Participants Achieving Serum Potassium Levels Within 4.0 to 5.0 mEq/L at Week 8 for Each Individual Starting Dose Group
    End point description
    Proportion of Participants Achieving Serum Potassium Levels Within 4.0 to 5.0 mEq/L at Week 8 for Each Individual Starting Dose Group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Stratum 1: 8.4 g/d patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Number of subjects analysed
    63
    65
    64
    24
    24
    22
    Units: percentage of participants
        number (confidence interval 95%)
    95.2 (86.7 to 99)
    90.8 (81 to 96.5)
    81.3 (69.5 to 89.9)
    79.2 (57.8 to 92.9)
    91.7 (73 to 99)
    77.3 (54.6 to 92.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 28 days after end of treatment or last patiromer dose, whichever was earlier.
    Adverse event reporting additional description
    Randomized participants who received at least one dose of trial medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Stratum 1: 8.4 g/d Patiromer
    Reporting group description
    		 -

    Reporting group title
    Stratum 1: 16.8 g/d Patiromer
    Reporting group description
    		 -

    Reporting group title
    Stratum 1: 25.2 g/d Patiromer
    Reporting group description
    		 -

    Reporting group title
    Stratum 2: 16.8 g/d Patiromer
    Reporting group description
    		 -

    Reporting group title
    Stratum 2: 25.2 g/d Patiromer
    Reporting group description
    		 -

    Reporting group title
    Stratum 2: 33.6 g/d Patiromer
    Reporting group description
    		 -

    Serious adverse events
    		 Stratum 1: 8.4 g/d Patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 74 (12.16%)
    10 / 73 (13.70%)
    10 / 73 (13.70%)
    6 / 26 (23.08%)
    5 / 28 (17.86%)
    4 / 30 (13.33%)
         number of deaths (all causes)
    1
    2
    6
    1
    4
    1
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Diabetic vascular disorder
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    3 / 73 (4.11%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 26 (3.85%)
    2 / 28 (7.14%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy toxic
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerotic gangrene
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Stratum 1: 8.4 g/d Patiromer Stratum 1: 16.8 g/d Patiromer Stratum 1: 25.2 g/d Patiromer Stratum 2: 16.8 g/d Patiromer Stratum 2: 25.2 g/d Patiromer Stratum 2: 33.6 g/d Patiromer
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 74 (37.84%)
    29 / 73 (39.73%)
    29 / 73 (39.73%)
    14 / 26 (53.85%)
    14 / 28 (50.00%)
    22 / 30 (73.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 74 (6.76%)
    7 / 73 (9.59%)
    2 / 73 (2.74%)
    4 / 26 (15.38%)
    2 / 28 (7.14%)
    4 / 30 (13.33%)
         occurrences all number
    6
    9
    2
    5
    2
    5
    Hypotension
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    1 / 26 (3.85%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    2
    1
    4
    0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 73 (5.48%)
    2 / 73 (2.74%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
         occurrences all number
    2
    4
    2
    0
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    1
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 73 (2.74%)
    4 / 73 (5.48%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    4
    0
    1
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 74 (8.11%)
    5 / 73 (6.85%)
    1 / 73 (1.37%)
    3 / 26 (11.54%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    6
    7
    1
    4
    1
    1
    Constipation
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 73 (4.11%)
    4 / 73 (5.48%)
    2 / 26 (7.69%)
    1 / 28 (3.57%)
    5 / 30 (16.67%)
         occurrences all number
    6
    5
    4
    3
    1
    5
    Renal and urinary disorders
    Renal failure chronic
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 73 (5.48%)
    2 / 73 (2.74%)
    2 / 26 (7.69%)
    3 / 28 (10.71%)
    6 / 30 (20.00%)
         occurrences all number
    5
    4
    2
    2
    3
    6
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 73 (0.00%)
    4 / 73 (5.48%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    5
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 73 (4.11%)
    2 / 73 (2.74%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    6
    3
    4
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 73 (1.37%)
    2 / 73 (2.74%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    2
    1
    1
    2
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    2 / 26 (7.69%)
    1 / 28 (3.57%)
    3 / 30 (10.00%)
         occurrences all number
    1
    1
    2
    2
    1
    5
    Hypomagnesaemia
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 73 (6.85%)
    6 / 73 (8.22%)
    2 / 26 (7.69%)
    4 / 28 (14.29%)
    5 / 30 (16.67%)
         occurrences all number
    4
    7
    7
    2
    5
    5
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 73 (2.74%)
    1 / 73 (1.37%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    1
    2
    1
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    3
    1
    0
    3
    0
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2011
    Added Long-Term Maintenance Period and Long-Term Maintenance Titration Algorithm Added Weekly Maintenance Visits Added Mandatory Safety Visits (previously called Mandatory Safety Follow-up Visits) Added New Secondary Objective Increased Patient Sample Size Added RLY5016 Dose Group to Stratum 2 Added New Cohort for Hyperkalemic Patients (Cohort 3) Revised Allocation of Patients to Cohorts Clarified Re-Screening Procedures, Revised Description of Run-In Period, and Added Unscheduled Visit for Cohort 1 and 2 Screening/Enrollment Failures Revised Eligibility Criteria (IC #7; EC #2, 3, 17) Revised Eligibility Criteria (IC #5) Revised Eligibility Criteria (IC #4) Revised Eligibility Criteria (IC #3, 4; EC #2, 13) Deleted Exclusion Criterion Updated Study Variables Revised Follow-up Period and Treatment Discontinuation Added Allowed Medications during the Long-Term Maintenance Period Clarified Allowed and Prohibited Concomitant Medications Updated Clinical Experience Updated Rationale for Study Design Expanded Summary of Known and Potential Benefits and Risks Clarified Serum Potassium Collection Procedure Revised Withdrawal Criteria Added Clarifications to Study Procedures Updated Statistical Methods and Data Analysis Revised Appendix A - Schedule of Events Revised Appendix B - Listing of Laboratory Assays Revised or Added Titration and Follow-up Flowcharts in Appendices C−F
    23 Mar 2012
    Added Investigational Sites Removed Enrollment Limits Revised Eligibility Criteria (IC #3) Revised Eligibility Criteria (IC #7; Added EC #4) Added Exclusion Criteria (EC #5-7) Clarified Exclusion Criteria (Renumbered EC #10) Clarified Exclusion Criteria (Renumbered EC #17) Clarified Wording for Timing of Long-Term Maintenance Visits Added Run-in Period Other Antihypertensive Treatment Usage Clarified Exact Timing of RLY5016 Dosing When Dose is Adjusted (Treatment Initiation and Long-Term Maintenance Periods) Revised Blood Pressure Control Guidelines During the Treatment Initiation and Long-Term Maintenance Periods Revised Other Antihypertensive Treatment Usage During the Treatment Initiation Period Clarified Serum Potassium and Blood Pressure Monitoring and Control Procedures (Long-Term Maintenance Titration Algorithm) Inserted Rules for Withdrawal for Non-Responders (Long-Term Maintenance Titration Algorithm) Revised Concomitant Medication Usage During the Long-Term Maintenance Period Added Survival Follow-up Contact for Patients that Early Terminate (Telephone Calls) Revised Withdrawal Criteria Deleted Reference to “Study Manual” Clarified Exact Timing of Spironolactone and Losartan Initiation Revised Prohibited Concomitant Medication Text Revised Allowed Concomitant Medication Text Added New Criteria for Rescreening of Patients Added Serum Magnesium to New Confirmatory Local Lab Test at Screening (Cohort 3 only) Revised Appendix A - Schedule of Events Revised Appendix F – End of Treatment / Early Termination Flowchart

    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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