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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo controlled, Parallel Group Study of Patiromer for the Enablement of Spironolactone Use for Blood Pressure Control in Patients with Resistant Hypertension and Chronic Kidney Disease: Evaluation of Safety and Efficacy (AMBER)

    Summary
    EudraCT number
    		 2016-002657-38
    Trial protocol
    		 HU   DE   HR   BG  
    Global end of trial date
    27 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RLY5016-207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03071263
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 US IND Number: 75,615
    Sponsors
    Sponsor organisation name
    Relypsa, Inc.
    Sponsor organisation address
    100 Cardinal Way, Redwood City, United States, CA 94063
    Public contact
    Clive Burge, Clinical Support & Regulatory Intelligence, Regulatory Affairs Director. , Vifor Pharma Inc., +1 250 708 4296, Clive.Burge@viforpharma.com
    Scientific contact
    Udo-Michael Göhring, Head of Global Clinical Development, Corporate Strategy, Vifor Pharma Inc., +41 58 851 81 26, Udo-Michael.Goehring@viforpharma.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
    27 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if patiromer treatment of chronic kidney disease (CKD) subjects receiving spironolactone for the treatment of resistant hypertension will result in: • More persistent use of spironolactone through prevention of hyperkalemia • Improved blood pressure control through more persistent use of spironolactone
    Protection of trial subjects
    This study was conducted in accordance with United States (US) Food and Drug Administration (FDA) regulations, the International Council for Harmonisation (ICH) E6 guidelines for Good Clinical Practice (GCP), the Declaration of Helsinki, and IRB or IEC requirements. The study was also conducted in accordance with the European Union (EU) Clinical Trials Directive 2001/20/EC for sites in the EU and all other applicable local and national laws and regulations governing the conduct of human clinical studies. In compliance with GCP guidelines, all subjects were informed of the purpose of the research, the possible risks, and their right to withdraw at any time from the study without prejudice and without jeopardy to their future medical care at the center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Ukraine: 70
    Country: Number of subjects enrolled
    Georgia: 92
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Croatia: 13
    Country: Number of subjects enrolled
    Bulgaria: 30
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 73
    Worldwide total number of subjects
    295
    EEA total number of subjects
    119
    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)
    93
    From 65 to 84 years
    202
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted under the sponsorship of Relypsa, Inc. at 56 sites worldwide.

    Pre-assignment
    Screening details
    		 Purpose of Screening: to ensure that all enrolled subjects were on stable doses of baseline medications, did not have white coat hypertension, could demonstrate proper and reliable use of the home blood pressure monitoring device prior to study treatment, and that they met all study inclusion/exclusion criteria. It consisted of 4 Screening Visits.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Randomization to patiromer or placebo (Day 0) in a 1:1 ratio was performed at the Randomization Visit using the Interactive Web Response System (IWRS), with stratification on the basis of serum potassium and history of diabetes as described previously. All subjects were instructed to begin treatment with assigned patiromer or placebo and spironolactone 25 mg once daily (QD) on the day after randomization to patiromer/placebo (Day 1).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Patiromer
    Arm description
    		 spironolactone + blinded patiromer
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    Veltassa, RLY5016 for Oral Suspension, Patiromer for Oral Suspension
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of patiromer/placebo was 2 packets once daily (QD) taken with food for randomized subjects. Based upon the patiromer/placebo treatment algorithm, patiromer/placebo was increased in 2 packet per day increments for serum potassium >5.1 mEq/L at intervals of at least 1 week. Doses of patiromer/placebo were 2 packets, 4 packets, and 6 packets (maximum dose). Patiromer/placebo was to be decreased by at least 2 packets per day for serum potassium <4.0 mEq/L. The minimum daily dose of patiromer/placebo was 0 packets. All subjects started spironolactone 25 mg QD on Day 1. At the Week 3 visit (or after), the spironolactone dose was increased to 50 mg QD for subjects with AOBP SBP ≥120 mmHg and potassium ≤5.1 mEq/L. For subjects with potassium >5.1 mEq/L, 25 mg daily dose of spironolactone was continued until the first subsequent visit when potassium was ≤5.1 mEq/L (and AOBP SBP ≥120 mmHg), at which time spironolactone was to be increased to 50 mg QD.

    Arm title
    		 Placebo
    Arm description
    		 Spironolactone + Blinded Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of patiromer/placebo was 2 packets once daily (QD) taken with food for randomized subjects. Based upon the patiromer/placebo treatment algorithm, patiromer/placebo was increased in 2 packet per day increments for serum potassium >5.1 mEq/L at intervals of at least 1 week. Doses of patiromer/placebo were 2 packets, 4 packets, and 6 packets (maximum dose). Patiromer/placebo was to be decreased by at least 2 packets per day for serum potassium <4.0 mEq/L. The minimum daily dose of patiromer/placebo was 0 packets. All subjects started spironolactone 25 mg QD on Day 1. At the Week 3 visit (or after), the spironolactone dose was increased to 50 mg QD for subjects with AOBP SBP ≥120 mmHg and potassium ≤5.1 mEq/L. For subjects with potassium >5.1 mEq/L, 25 mg daily dose of spironolactone was continued until the first subsequent visit when potassium was ≤5.1 mEq/L (and AOBP SBP ≥120 mmHg), at which time spironolactone was to be increased to 50 mg QD.

    Number of subjects in period 1
    		Patiromer Placebo
    Started
    147
    148
    Completed
    144
    141
    Not completed
    3
    7
         Adverse event, serious fatal
    -
    1
         Physician decision
    1
    -
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    1
    2
         Subject moved to another city
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Patiromer
    Reporting group description
    		 spironolactone + blinded patiromer

    Reporting group title
    Placebo
    Reporting group description
    		 Spironolactone + Blinded Placebo

    Reporting group values
    		 Patiromer Placebo Total
    Number of subjects
    		 147 148 295
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 49 44 93
        >=65 years
    		 98 104 202
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.8 ( 12.24 ) 68.5 ( 11.13 ) -
    Gender categorical
    Units: Subjects
        Female
    		 71 71 142
        Male
    		 76 77 153
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 7 16 23
        Not Hispanic or Latino
    		 140 131 271
        Unknown or Not Reported
    		 0 1 1
    Race
    Units: Subjects
        White
    		 145 145 290
        Black
    		 2 2 4
        Asian
    		 0 0 0
        Other
    		 0 1 1
    Baseline central laboratory serum potassium
    Units: Subjects
        Baseline serum potassium <4.3 mEq/L
    		 7 17 24
        Baseline serum potassium 4.3-<4.7 mEq/L
    		 55 52 107
        Baseline serum potassium 4.7-5.1 mEq/L
    		 65 65 130
        Baseline serum potassium >5.1 mEq/L
    		 20 14 34
    Antihypertensive Medications at Baseline: Agents Acting on the Renin-Angiotensin System
    Measure Description: Antihypertensive Medications at Baseline by Preferrerd Drug Name for ≥10% of the total subjects. Agents Acting on the Renin-Angiotensin System (AARAS): Perindopril, Valsartan, Losartan.
    Units: Subjects
        Subjects who were on AARAS Drugs
    		 147 147 294
        Subjects who were not on AARAS Drugs
    		 0 1 1
    Antihypertensive Medications at Baseline: Diuretics
    Measure Description: Antihypertensive Medications at Baseline by Preferrerd Drug Name for ≥10% of the total subjects. Diuretics: Indapamide, Hydrochlorothiazide, Furosemide, Torasemide.
    Units: Subjects
        Subjects who were on Diuretic Drugs
    		 146 145 291
        Subjects who were not on Diuretic Drugs
    		 1 3 4
    Antihypertensive Medications at Baseline: Calcium Channel Blockers
    Measure Description: Antihypertensive Medications at Baseline by Preferrerd Drug Name for ≥10% of the total subjects. Calcium Channel Blockers (CCB): Amlodipine, Lercanidipine.
    Units: Subjects
        Subjects who were on CCB drugs
    		 107 106 213
        Subjects who were not on CCB drugs
    		 40 42 82
    Antihypertensive Medications at Baseline: Beta Blocking Agents
    Measure Description: Antihypertensive Medications at Baseline by Preferrerd Drug Name for ≥10% of the total subjects. Beta Blocking Agents (BBA): Bisoprolol, Nebivolol.
    Units: Subjects
        Subjects who were on BBA drugs
    		 87 86 173
        Subjects who were not on BBA drugs
    		 60 62 122
    Antihypertensive Medications at Baseline: Other Antihypertensives
    Measure Description: Antihypertensive Medications at Baseline by Preferrerd Drug Name for ≥10% of the total subjects. Other antihypertensives not listed before (OA): Moxonidine, Rilmenidine, Doxazosin, Clonidine, Prazosin, Urapidil, Dihydralazine, Hydralazine, Reserpine, Terazosin.
    Units: Subjects
        Subjects who were on OA
    		 40 31 71
        Subjects who were not on OA
    		 107 117 224
    Baseline eGFR
    eGFR=Estimated glomerular filtration range. eGFR was calculated using CKD Epidemiology Collaboration (CKD-EPI) formula.
    Units: mL/ min/1.73m^2
        arithmetic mean (standard deviation)
    		 35.37 ( 7.274 ) 36.08 ( 7.597 ) -
    Systolic blood pressure as measured using automated office blood pressure device
    Units: mmHg
        arithmetic mean (standard deviation)
    		 143.3 ( 6.48 ) 144.9 ( 7.01 ) -

    End points

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    End points reporting groups
    Reporting group title
    Patiromer
    Reporting group description
    		 spironolactone + blinded patiromer

    Reporting group title
    Placebo
    Reporting group description
    		 Spironolactone + Blinded Placebo

    Primary: Number of Subjects Remaining on Spironolactone at Week 12

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    End point title
    		 Number of Subjects Remaining on Spironolactone at Week 12
    End point description
    The proportion of subjects remaining on spironolactone at Week 12 will be compared between treatment groups (spironolactone/patiromer versus spironolactone/placebo). Subjects who discontinued from the study early or discontinued study spironolactone prior to Week 12, for any reason, were considered as not having remained on spironolactone until Week 12. Analysis Population Description: Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo.
    End point type
    Primary
    End point timeframe
    At week 12
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    147
    148
    Units: Subjects
        Subjects Remaining on Spironolactone Week 12
    126
    98
        Subjects Not Remaining on Spironolactone Week 12
    21
    50
    Statistical analysis title
    		 Subjects Remaining on Spironolactone at Week 12
    Statistical analysis description
    A sample size of 280 subjects has 90% power to detect a difference between treatment groups of 20% or more in the proportion of subjects remaining on spironolactone at Week 12, at α = 0.05.
    Comparison groups
    Patiromer v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - α-level 0.05. Stratified by baseline potassium category (4.3-<4.7 mEq/L or 4.7-5.1 mEq/L) and history of Type 1 or Type 2 diabetes mellitus (Yes or No) as randomized.

    Secondary: Change in AOBP SBP (Systolic blood pressure as measured using automated office blood pressure device) From Baseline to Week 12 or Last Available AOBP SBP Prior to Addition of Any New BP Medications or Increase From Any Baseline BP Medications

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    End point title
    		 Change in AOBP SBP (Systolic blood pressure as measured using automated office blood pressure device) From Baseline to Week 12 or Last Available AOBP SBP Prior to Addition of Any New BP Medications or Increase From Any Baseline BP Medications
    End point description
    AOBP: Automated Office Blood Pressure SBP: Systolic Blood Pressure BP: Blood Pressure. Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12.
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    144
    141
    Units: mmHg
        arithmetic mean (standard deviation)
    -11.3 ( 14.11 )
    -11.0 ( 15.34 )
    Statistical analysis title
    		 Change in AOBP SBP From Baseline to Week 12
    Statistical analysis description
    Statistical Analysis for Change in AOBP SBP From Baseline to Week 12 or Last Available AOBP SBP Prior to Addition of Any New BP Medications or Increase From Any Baseline BP Medications.
    Comparison groups
    Placebo v Patiromer
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5757 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - Baseline AOBP SBP as a covariate and treatment group, baseline serum potassium (K+ 4.3-<4.7 or 4.7-5.1 mEq/L), and history of Type 1 or Type 2 diabetes mellitus (Yes or No) as factors in the model.

    Other pre-specified: Change in AOBP SBP From Baseline to Week 12 Regardless of Increase in Antihypertensives

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    End point title
    		 Change in AOBP SBP From Baseline to Week 12 Regardless of Increase in Antihypertensives
    End point description
    AOBP SBP: Automated Office Systolic Blood Pressure Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    144
    141
    Units: mmHg
    arithmetic mean (standard deviation)
        Change in AOBP SBP From Baseline to Week 12
    -11.3 ( 14.11 )
    -11.2 ( 15.04 )
    Statistical analysis title
    		 Change in AOBP SBP From Baseline to Week 12
    Statistical analysis description
    Statistical Analysis for Change in AOBP SBP From Baseline to Week 12 Regardless of Increase in Antihypertensives.
    Comparison groups
    Placebo v Patiromer
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.6367 [4]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - The p-value is from a test comparing the difference between two groups in the mean change in AOBP SBP from baseline.
    [4] - Baseline AOBP SBP as a covariate and treatment group, baseline serum potassium (K+ 4.3-<4.7 or 4.7-5.1 mEq/L), and history of Type 1 or Type 2 diabetes mellitus as factors in the model.

    Other pre-specified: Central Serum Potassium Change From Baseline to Week 12 by Baseline Serum Potassium Category

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    End point title
    		 Central Serum Potassium Change From Baseline to Week 12 by Baseline Serum Potassium Category
    End point description
    The two baseline potassium subgroups, 4.3-<4.7 mEq/L versus 4.7-5.1 mEq/L, are based on central laboratory data. If a subject’s serum potassium result is not in one of these two subgroups, the subject’s potassium stratum at randomization was used. Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo. Reported results only include participants with Baseline Serum Potassium values according to the ranges defined below. See attached Table (Central Serum Potassium Change from Baseline to Week 12 by Baseline Serum Potassium) to see the the number of subjects analysed in each categroy.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    144
    140
    Units: mEq/L
    arithmetic mean (standard deviation)
        Baseline Central Serum Potassium 4.3-<4.7 mEq/L
    0.16 ( 0.468 )
    0.40 ( 0.494 )
        Baseline Central Serum Potassium 4.7-<5.1 mEq/L
    -0.09 ( 0.442 )
    0.03 ( 0.468 )
        Overall
    0.02 ( 0.469 )
    0.20 ( 0.514 )
    Attachments
    		 Serum Potassium change from Baseline to Week 12
    No statistical analyses for this end point

    Other pre-specified: Proportion of Subjects With Central Serum Potassium <5.5 mEq/L Over Time

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    End point title
    		 Proportion of Subjects With Central Serum Potassium <5.5 mEq/L Over Time
    End point description
    Baseline Central Serum Potassium: BCSP. Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo. Reported results only include participants with Central Serum Potassium values according to the ranges defined below. Category Titles W= Week See attached Table (Central Serum Potassion Over Time) to see the the number of subjects analysed in each categroy.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    147
    148
    Units: Subjects
        Baseline Serum Potassium 4.3-<4.7 mEq/L ≤W1
    60
    62
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W1-≤W2
    57
    57
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W2-≤W3
    59
    63
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W3-≤W4
    61
    60
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W4-≤W6
    61
    61
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W6-≤W8
    61
    58
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W8-≤W10
    58
    58
        Baseline Serum Potassium 4.3-<4.7 mEq/L >W10-≤W12
    61
    61
        Baseline Serum Potassium 4.7-<5.1 mEq/L ≤W1
    75
    66
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W1-≤W2
    74
    65
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W2-≤W3
    74
    65
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W3-≤W4
    74
    61
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W4-≤W6
    79
    64
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W6-≤W8
    74
    66
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W8-≤W10
    72
    66
        Baseline Serum Potassium 4.7-<5.1 mEq/L >W10-≤W12
    80
    65
        Overall : ≤Week 1
    135
    128
        Overall : > Week 1 and ≤Week 2
    131
    122
        Overall : >Week 2 and ≤Week 3
    133
    128
        Overall : >Week 3 and ≤Week 4
    135
    121
        Overall : >Week 4 and ≤Week 6
    140
    125
        Overall : >Week 6 and ≤Week 8
    135
    124
        Overall : >Week 8 and ≤Week 10
    130
    124
        Overall : >Week 10 and ≤Week 12
    141
    126
    Attachments
    		 Subjects with Serum Potassium <5.5 mEq/L Over Time
    No statistical analyses for this end point

    Other pre-specified: Proportion of Subjects Having Spironolactone Titrations Over Time

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    End point title
    		 Proportion of Subjects Having Spironolactone Titrations Over Time
    End point description
    Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo. Reported results only include the proportion of participants having spironolactone titrations over time according to the classification defined below. See attached Table (Proportion of Subjects Having Spironolactone Titrations over Time) to see the the number of subjects analysed in each categroy.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    147
    148
    Units: Subjects
        Up : ≤Week 1
    0
    0
        Up : >Week 1 and ≤Week 2
    0
    0
        Up : >Week 2 and ≤Week 3
    88
    77
        Up : >Week 3 and ≤Week 4
    27
    21
        Up : >Week 4 and ≤Week 6
    10
    11
        Up : >Week 6 and ≤Week 8
    6
    6
        Up : >Week 8 and ≤Week 10
    6
    7
        Up : >Week 10 and ≤Week 12
    1
    0
        Down : ≤Week 1
    1
    2
        Down : >Week 1 and ≤Week 2
    2
    0
        Down : >Week 2 and ≤Week 3
    2
    2
        Down : >Week 3 and ≤Week 4
    6
    5
        Down : >Week 4 and ≤Week 6
    8
    7
        Down : >Week 6 and ≤Week 8
    5
    8
        Down : >Week 8 and ≤Week 10
    4
    7
        Down : >Week 10 and ≤Week 12
    3
    1
    Attachments
    		 Subjects Having Spironolactone Titrations
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects by Spironolactone Dose Prescribed at Each Visit

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    End point title
    		 Number of Subjects by Spironolactone Dose Prescribed at Each Visit
    End point description
    Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo. QD=Once daily; QOD=Once every other day.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 10
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    147
    148
    Units: Subjects
        50 mg QD : Baseline
    0
    0
        50 mg QD : Week 1
    0
    0
        50 mg QD : Week 2
    0
    0
        50 mg QD : Week 3
    86
    76
        50 mg QD : Week 4
    105
    94
        50 mg QD : Week 6
    106
    96
        50 mg QD : Week 8
    106
    85
        50 mg QD : Week 10
    106
    80
        25 mg QD : Baseline
    147
    148
        25 mg QD : Week 1
    145
    144
        25 mg QD : Week 2
    140
    142
        25 mg QD : Week 3
    49
    57
        25 mg QD : Week 4
    27
    34
        25 mg QD : Week 6
    25
    28
        25 mg QD : Week 8
    26
    24
        25 mg QD : Week 10
    19
    20
        25 mg QOD : Baseline
    0
    0
        25 mg QOD : Week 1
    1
    2
        25 mg QOD : Week 2
    3
    1
        25 mg QOD : Week 3
    3
    2
        25 mg QOD : Week 4
    3
    3
        25 mg QOD : Week 6
    2
    2
        25 mg QOD : Week 8
    1
    4
        25 mg QOD : Week 10
    2
    4
    No statistical analyses for this end point

    Other pre-specified: Shifts in Selected Laboratory Tests From Baseline to End of Treatment

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    End point title
    		 Shifts in Selected Laboratory Tests From Baseline to End of Treatment
    End point description
    The end of treatment value is defined as the last non-missing value on or prior to the last spironolactone dose date (from End of Treatment - Case report form) + 3 days Analysis Population Description Safety Population LLN=Lower limit of the normal range. ULN=Upper limit of the normal range. EoT=End of Treatment
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to End of Treatment
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    146
    147
    Units: Subjects
        Magnesium - Baseline Value <LLN : EoT Value<LLN
    9
    4
        Magnesium - Baseline Value <LLN : EoT Value Normal
    3
    8
        Magnesium - Baseline Value <LLN : EoT Value >ULN
    0
    0
        Magnesium - Baseline Value Normal : EoT Value <LLN
    12
    7
        Magnesium- Baseline Value Normal: EoT Value Normal
    103
    109
        Magnesium - Baseline Value Normal : EoT Value >ULN
    6
    10
        Magnesium - Baseline Value >ULN : EoT Value <LLN
    0
    0
        Magnesium - Baseline Value >ULN : EoT Value Normal
    10
    6
        Magnesium - Baseline Value >ULN : EoT Value >ULN
    3
    3
        Phosphate - Baseline Value <LLN : EoT Value <LLN
    0
    1
        Phosphate - Baseline Value <LLN : EoT Value Normal
    1
    3
        Phosphate - Baseline Value <LLN : EoT Value >ULN
    0
    0
        Phosphate - Baseline Value Normal : EoT Value <LLN
    0
    1
        Phosphate- Baseline Value Normal: EoT Value Normal
    136
    125
        Phosphate - Baseline Value Normal : EoT Value >ULN
    2
    8
        Phosphate - Baseline Value >ULN : EoT Value <LLN
    0
    0
        Phosphate - Baseline Value >ULN : EoT Value Normal
    5
    4
        Phosphate - Baseline Value >ULN : EoT Value >ULN
    2
    5
        Calcium - Baseline Value <LLN : EoT Value <LLN
    2
    4
        Calcium - Baseline Value <LLN : EoT Value Normal
    5
    1
        Calcium - Baseline Value <LLN : EoT Value >ULN
    0
    0
        Calcium - Baseline Value Normal : EoT Value <LLN
    4
    6
        Calcium - Baseline Value Normal : EoT Value Normal
    133
    133
        Calcium - Baseline Value Normal : EoT Value >ULN
    0
    0
        Calcium - Baseline Value >ULN : EoT Value <LLN
    0
    0
        Calcium - Baseline Value >ULN : EoT Value Normal
    2
    1
        Calcium - Baseline Value >ULN : EoT Value >ULN
    0
    2
    No statistical analyses for this end point

    Other pre-specified: Spironolactone Dose Level at End of 12 Weeks of Study Treatment

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    End point title
    		 Spironolactone Dose Level at End of 12 Weeks of Study Treatment
    End point description
    Analysis Population Description Intent-to-Treat population (ITT): The ITT population included all participants who were randomized and who took at least 1 dose of spironolactone and at least 1 dose of patiromer/placebo. Category title: Participants not completing 12W of study treatment: Participants who had not completed 12 weeks of study treatment.
    End point type
    Other pre-specified
    End point timeframe
    12 Weeks of Study Treatment
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    147
    148
    Units: Subjects
        50 mg QD
    102
    76
        25 mg QD
    22
    19
        25 mg QOD
    2
    3
        Participants not completing 12W of study treatment
    21
    50
    No statistical analyses for this end point

    Post-hoc: Number of Subjects Requiring Additional New Antihypertensive Medications or Increases to Baseline Antihypertensive Medications

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    End point title
    		 Number of Subjects Requiring Additional New Antihypertensive Medications or Increases to Baseline Antihypertensive Medications
    End point description
    Row Titles: • AM: Antihypertensive Medication(s) • New AM: Participants who required additional new antihypertensive medication(s) • Increases to baseline AM: Participants who required increases to baseline antihypertensive medication(s) • Addition new (or increase) AM: Participants who required addition of new antihypertensive medication(s) and/or increases to baseline antihypertensive medications • At any time during the study: During study • While on study medication: On medication
    End point type
    Post-hoc
    End point timeframe
    From baseline to Week 12/Early Termination visit
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    147
    148
    Units: Subjects
        New AM : At any time during the study
    0
    3
        New AM : On medication
    0
    1
        Increases to baseline AM: During study
    0
    2
        Increases to baseline AM: On medication
    0
    1
        Addition new (or increases) AM: During study
    0
    4
        Addition new (or increases) AM : On medication
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During Treatment Period (12 weeks); until Follow-up Visit 2 weeks after the Week 12 Visit (or Early Termination Visit).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Patiromer
    Reporting group description
    		 spironolactone + blinded patiromer

    Reporting group title
    Placebo
    Reporting group description
    		 Spironolactone + Blinded Placebo

    Serious adverse events
    		 Patiromer Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 147 (0.68%)
    4 / 148 (2.70%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Aortic rupture
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Humerus fracture
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Patiromer Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 147 (55.10%)
    75 / 148 (50.68%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    9 / 147 (6.12%)
    6 / 148 (4.05%)
         occurrences all number
    9
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 147 (6.12%)
    11 / 148 (7.43%)
         occurrences all number
    9
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 147 (6.12%)
    8 / 148 (5.41%)
         occurrences all number
    9
    9
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    13 / 147 (8.84%)
    10 / 148 (6.76%)
         occurrences all number
    15
    11
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    7 / 147 (4.76%)
    13 / 148 (8.78%)
         occurrences all number
    11
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2016
    • Automated office BP, AOBP, (rather than 7dHBP) to be used for screening, study drug dosing and discontinuation decisions, clinical decision making, and BP analyses • The lower end of the range to define hypertension as measured by AOBP SBP is changed to 135 mmHg • AOBP (automated office BP) – defined as BP measured at the office (i.e., clinical site) using an automatic oscillometric device with the capability of performing automatic multiple measurements after the study staff has left the room (unwitnessed measurement after the subject has been sitting quietly for 5 minutes) • Removed the requirement for evidence of elevated BP during a routine standard of care visit within past 3 months • Changed to allow a single AOBP SBP to be <135 mmHg at either S2 or S3 if AOBP SBP is 135-160 mmHg at the other Screening Visits • Triamterene and amiloride are added to the prohibited medications list • Additional text explaining that a sample size of 290 allows for up to 10 subjects who are randomized but do not receive treatment. Change also removes the statements regarding power for the secondary endpoint • Added ‘After discontinuation of spironolactone and patiromer/placebo, hyperkalemia may be treated using standard of care per the Investigator’s judgment.’ • Added further instructions ‘The site will be notified regarding out-of-range HBP and subject noncompliance with performing HBP.’ • Removed the following urine assessments due to an error: - Calcium - Phosphate - Potassium from 24-hour urine collection - Added leukocyte esterase to urine assessment
    04 Nov 2016
    • Clarified that it is subjects with untreated secondary causes of hypertension that should be excluded • Clarified that BP measurements should be done before BP medications are administered on the morning of the visit • Clarified the order of visit activities

    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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