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    Clinical Trial Results:
    A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel Group Study of Patiromer for the Management of Hyperkalemia in Subjects Receiving Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications for the Treatment of Heart Failure (DIAMOND)

    Summary
    EudraCT number
    		 2018-005030-38
    Trial protocol
    		 PL   CZ   NL   ES   HU   DE   BG   GB   BE   IT  
    Global end of trial date
    02 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Sep 2022
    First version publication date
    10 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PAT-CR-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03888066
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number : 075615
    Sponsors
    Sponsor organisation name
    Vifor Pharma, Inc.
    Sponsor organisation address
    200 Cardinal Way, Redwood City, United States, CA 94063
    Public contact
    DIAMOND Clinical Study Team, Vifor Pharma, Inc., 001 8447359772, Diamond_Information@viforpharma.com
    Scientific contact
    DIAMOND Clinical Study Team, Vifor Pharma, Inc., 001 8447359772, Diamond_Information@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
    02 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of patiromer on serum potassium (K+) in heart failure (HF) participants compared with placebo.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki including amendments in force up to and including the time the study was conducted. The study was conducted in compliance with the International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), Committee for Proprietary Medicinal Products Guideline (CPMP/ICH/135/95), compliant with the EU Clinical Trial Directive (Directive 2001/20/EC) and/or the Code of Federal Regulations (CFR) for informed consent and protection of subject rights (21 CFR, Parts 50 and 56), and in accordance with United States Food and Drug Administration (FDA) regulations. Prior to initiation of the study, the protocol, the subject information sheet, and the informed consent form (ICF) were reviewed and approved by Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs), operating in accord with current regulations.
    Background therapy
    		 Subjects receiving angiotensin-aldosterone system inhibitor (RAASi) medications for the treatment of heart failure with reduced ejection fraction (HFrEF). During the Treatment Phase, subjects randomized to either patiromer or placebo continued the doses of RAASi medications optimized at the end of the Run-in Phase.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Apr 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 80
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 91
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Argentina: 32
    Country: Number of subjects enrolled
    Brazil: 16
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Georgia: 257
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Russian Federation: 79
    Country: Number of subjects enrolled
    Serbia: 8
    Country: Number of subjects enrolled
    Ukraine: 156
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    878
    EEA total number of subjects
    245
    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)
    350
    From 65 to 84 years
    505
    85 years and over
    23

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 From a total of 1642 subjects screened, 1195 of these subjects entered Run-in Phase.A total of 1168 subjects received patiromer during Run-in Phase, and 878 of these subjects were randomized to receive patiromer or placebo during the Treatment Phase.

    Period 1
    Period 1 title
    Treatment Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The Run-in Phase was single blinded for the subject. The Treatment Phase was double-blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Patiromer
    Arm description
    		 Randomized subjects who received continued treatment with patiromer during the Treatment Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patiromer
    Investigational medicinal product code
    Other name
    Veltassa®
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The same number of packets as established for patiromer at the end of the Run-in Phase but were to be up- or down-titrated depending on local serum K+ levels. During the Run-in Phase, patiromer was to be taken at a starting oral dose of 1 packet/day (8.4 g/day) either with or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).

    Arm title
    		 Placebo
    Arm description
    		 Randomized subjects who discontinued treatment with patiromer of the Run-in-Phase and received placebo during the Treatment Phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    microcrystalline cellulose
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    The same number of packets as established for patiromer at the end of the Run-in Phase but were to be up- or down-titrated depending on local serum K+ levels. During the Run-in Phase, patiromer was to be taken at a starting oral dose of 1 packet/day (8.4 g/day) either with or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).

    Number of subjects in period 1
    		Patiromer Placebo
    Started
    439
    439
    Completed
    360
    367
    Not completed
    79
    72
         Sponsor's decision
    1
    -
         Physician decision
    20
    13
         Consent withdrawn by subject
    21
    25
         Treatment discontinuation
    2
    2
         Adverse event, non-fatal
    27
    21
         Early study termination
    -
    1
         End of study visit not completed/delayed
    1
    3
         Lost to follow-up
    1
    -
         Delayed visit and insufficient study drug
    6
    6
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Patiromer
    Reporting group description
    		 Randomized subjects who received continued treatment with patiromer during the Treatment Phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized subjects who discontinued treatment with patiromer of the Run-in-Phase and received placebo during the Treatment Phase.

    Reporting group values
    		 Patiromer Placebo Total
    Number of subjects
    		 439 439 878
    Age categorical
    Units: Subjects
        <65 years
    		 181 169 350
        ≥65 years
    		 258 270 528
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.6 ( 10.0 ) 67.1 ( 9.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 112 126 238
        Male
    		 327 313 640

    End points

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    End points reporting groups
    Reporting group title
    Patiromer
    Reporting group description
    		 Randomized subjects who received continued treatment with patiromer during the Treatment Phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomized subjects who discontinued treatment with patiromer of the Run-in-Phase and received placebo during the Treatment Phase.

    Subject analysis set title
    All subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomized to patiromer or placebo arm.

    Subject analysis set title
    All subjects - For reporting purposes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomized to patiromer or placebo arm. As adviced in the EudraCT Q&A, in order to report a statistical analysis related to a specific endpoint it is required to define at least two comparison groups. For the secondary endpoints Hyperkalemia-related Hard Outcomes Endpoints & RAASi Use Score there were no comparison groups since the results were reported for all subjects (N=878). Due to this fact, a workaround needs to be performed for reporting their statistical analyses. It is adviced to create an additional “Subject analysis set” and then select both comparison groups in each “Endpoint definition” section.

    Primary: Changes in serum K+ levels from Baseline

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    End point title
    		 Changes in serum K+ levels from Baseline
    End point description
    Adjusted mean changes in serum K+ from Baseline.
    End point type
    Primary
    End point timeframe
    From Day 1/Baseline to the End of Study visit
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    439
    439
    Units: mEq/l
        least squares mean (standard error)
    0.029 ( 0.019 )
    0.127 ( 0.019 )
    Statistical analysis title
    		 Difference in adjusted mean changes (SE)
    Comparison groups
    Patiromer v Placebo
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.097
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.128
         upper limit
    		 -0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.015

    Secondary: Time to First Hyperkalemia Event with Serum K+ Level >5.5 mEq/l

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    End point title
    		 Time to First Hyperkalemia Event with Serum K+ Level >5.5 mEq/l
    End point description
    Time to the first event of hyperkalemia with a serum K+ value >5.5 mEq/l calculated as CIF Estimate (95% CI) from the measured values. CIF = cumulative incidence function Number of subjects with Hyperkalemia was n=61 (13.9%) for Patiromer and n=85 (19.4%) for Placebo
    End point type
    Secondary
    End point timeframe
    From Day 1/Baseline to week 90
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    439
    439
    Units: CIF estimate
    number (confidence interval 95%)
        Week 1
    0.02 (0.01 to 0.04)
    0.04 (0.03 to 0.06)
        Week 2
    0.04 (0.02 to 0.06)
    0.08 (0.06 to 0.11)
        Week 6
    0.05 (0.03 to 0.07)
    0.10 (0.08 to 0.13)
        Week 18
    0.08 (0.06 to 0.12)
    0.14 (0.11 to 0.18)
        Week 30
    0.13 (0.10 to 0.17)
    0.20 (0.15 to 0.24)
        Week 42
    0.17 (0.12 to 0.22)
    0.24 (0.19 to 0.29)
        Week 54
    0.21 (0.15 to 0.27)
    0.29 (0.23 to 0.35)
        Week 66
    0.25 (0.18 to 0.32)
    0.34 (0.26 to 0.42)
        Week 78
    0.30 (0.22 to 0.40)
    0.34 (0.26 to 0.42)
        Week 90
    0.34 (0.23 to 0.44)
    0.34 (0.26 to 0.42)
    Statistical analysis title
    		 Hazard Ratio patiromer vs placebo
    Statistical analysis description
    HR = Hazard Ratio The HR for the time to first hyperkalemia event for patiromer vs placebo was calculated. HR and p-value come from a Cox proportional regression model adjusted for geographic region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR.
    Comparison groups
    Patiromer v Placebo
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.87
    Notes
    [1] - The treatment difference between patiromer vs placebo was statistically significant.

    Secondary: Durable Enablement to Stay on MRA Target Dose

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    End point title
    		 Durable Enablement to Stay on MRA Target Dose
    End point description
    MRA=mineralocorticoid receptor antagonist; CIF=cumulative incidence function Time to reduction of the MRA dose below target dose calculated as CIF Estimate (95% CI) from the measured values. Note: The reduction below the MRA target dose must last for at least 14 days (or less if at the end of study) to confirm this endpoint. Number of subjects with MRA reduction was n=61 (13.9%) for Patiromer and n=83 (18.9%) for Placebo.
    End point type
    Secondary
    End point timeframe
    From Day 1/Baseline to week 102)
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    439
    439
    Units: CIF estimate
    number (confidence interval 95%)
        Week 1
    0.02 (0.01 to 0.04)
    0.04 (0.03 to 0.07)
        Week 2
    0.03 (0.02 to 0.05)
    0.08 (0.06 to 0.11)
        Week 6
    0.06 (0.04 to 0.08)
    0.12 (0.09 to 0.15)
        Week 18
    0.10 (0.08 to 0.14)
    0.15 (0.12 to 0.19)
        Week 30
    0.14 (0.10 to 0.18)
    0.19 (0.15 to 0.23)
        Week 42
    0.16 (0.12 to 0.21)
    0.23 (0.18 to 0.28)
        Week 54
    0.19 (0.14 to 0.24)
    0.26 (0.20 to 0.32)
        Week 66
    0.22 (0.16 to 0.29)
    0.27 (0.21 to 0.33)
        Week 78
    0.27 (0.20 to 0.35)
    0.29 (0.22 to 0.36)
        Week 90
    0.27 (0.20 to 0.35)
    0.29 (0.22 to 0.36)
    Statistical analysis title
    		 Hazard Ratio patiromer vs placebo
    Statistical analysis description
    HR = Hazard Ratio The HR for the time to first hyperkalemia event for patiromer vs placebo was calculated. HR and p-value come from a Cox proportional regression model adjusted for geographic region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR
    Comparison groups
    Patiromer v Placebo
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.87
    Notes
    [2] - The treatment difference between patiromer vs placebo was statistically significant.

    Secondary: Investigator-reported Events of Hyperkalemia

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    End point title
    		 Investigator-reported Events of Hyperkalemia
    End point description
    Subject’s follow-up is from the date of the first dose of randomized study medication up to the subject’s end of study date or 24 Jun 2021, whichever comes first. Annualized event rate per 100 subject-years= The total number of events for all subjects in the treatment group divided by the total subject-years of follow-up in that treatment group multiplied by 100.
    End point type
    Secondary
    End point timeframe
    From Day 1/Baseline to the End of Study visit
    End point values
    		 Patiromer Placebo
    Number of subjects analysed
    439
    439
    Units: Number (n)
    number (not applicable)
        Number of Hyperkalemia AEs,
    225
    316
        Number of subjects with at least 1 event
    137
    198
        Number of subjects with more than 1 event
    54
    74
        Number of events per subject n=0
    302
    241
        Number of events per subject n=1
    83
    124
        Number of events per subject n=2
    36
    43
        Number of events per subject n ≥ 3
    18
    31
        Total subject-years of follow-up
    273.1
    275.6
        Annualized event rate per 100 subject-years
    82.38
    114.65
    Statistical analysis title
    		 NBMAC Annualized event RR patiromer vs placebo
    Statistical analysis description
    NBMAC=Negative binomial model adjusted for covariates; RR=Rate Ratio NBMAC adjusted for geographical region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR. Rate ratio less than 1 favors patiromer.
    Comparison groups
    Patiromer v Placebo
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative binomial model adjusted for cov
    Parameter type
    		 Annualized event rate ratio
    Point estimate
    0.658
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.534
         upper limit
    		 0.81

    Secondary: Hyperkalemia-related Hard Outcomes Endpoints

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    End point title
    		 Hyperkalemia-related Hard Outcomes Endpoints
    End point description
    Analyzed using Win Ratio approach with the following hierarchical components: 1. Time to CV death 2. Total number of CV hospitalizations 3. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/l 4. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/l 5. Total number of hyperkalemia events with serum K+ >5.0 mEq/l MHTE=More hyperkalemia toxicity events MHE= More hyperkalemia events
    End point type
    Secondary
    End point timeframe
    From Day 1/Baseline to the End of Study visit
    End point values
    		 All subjects All subjects - For reporting purposes
    Number of subjects analysed
    878
    878
    Units: Number
        CV death-placebo
    3491
    3491
        CV death-patiromer
    4609
    4609
        More CV hospitalizations-placebo
    4539
    4539
        More CV hospitalizations-patiromer
    4178
    4178
        MHTE with serum K+>6.5-placebo
    419
    419
        MHTE with serum K+>6.5-patiromer
    401
    401
        MHE with serum K+>6.0-6.5-placebo
    4283
    4283
        MHE with serum K+>6.0-6.5-patiromer
    1446
    1446
        MHE with serum K+>5.0-6.0-placebo
    55633
    55633
        MHE with serum K+>5.0-6.0-patiromer
    34156
    34156
        None of the above
    79566
    79566
        Total number of pairs
    192721
    19272
    Statistical analysis title
    		 Win ratio for composite
    Statistical analysis description
    Subjects analyzed n=1756 refers to the sum of the two comparison groups below. Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/losser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.
    Comparison groups
    All subjects v All subjects - For reporting purposes
    Number of subjects included in analysis
    1756
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Win Ratio
    Parameter type
    		 Win Ratio
    Point estimate
    1.526
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.231
         upper limit
    		 1.906
    Statistical analysis title
    		 Win ratio CV death and hospitalization
    Statistical analysis description
    Subjects analyzed n=1756 refers to the sum of the two comparison groups below. Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/losser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.
    Comparison groups
    All subjects - For reporting purposes v All subjects
    Number of subjects included in analysis
    1756
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.744
    Method
    		 Win Ratio
    Parameter type
    		 Win Ratio
    Point estimate
    0.914
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.526
         upper limit
    		 1.578

    Secondary: RAASi Use Score

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    End point title
    		 RAASi Use Score
    End point description
    RAASi use score (0 to 8 points) analyzed using the Win Ratio approach for each pair of subjects with the following additive components: 1. All-cause death 2. Occurrence of a CV hospitalization 3. HF medication use and dose for i) an ACEi/ARB/ARNi, ii) a MRA, and iii) a beta-blocker Each subject in each comparison can have 0-8 points and all subjects are compared using this score at the respective appropriate follow-up time point. RAASi = renin-angiotensin-aldosterone system inhibitor; ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; ARNi=angiotensin receptor/neprilysin inhibitor; MRA=mineralocorticoid receptor antagonist.
    End point type
    Secondary
    End point timeframe
    From Day 1/Baseline to the End of Study visit
    End point values
    		 All subjects All subjects - For reporting purposes
    Number of subjects analysed
    878
    878
    Units: Number
        Number of wins-patiromer
    62073
    62073
        Number of wins-placebo
    49733
    49733
        Number of ties
    80915
    80915
        Total number of pairs
    192721
    192721
    Statistical analysis title
    		 Win ratio for composite
    Statistical analysis description
    Subjects analyzed n=1756 refers to the sum of the two comparison groups below. Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/losser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.
    Comparison groups
    All subjects v All subjects - For reporting purposes
    Number of subjects included in analysis
    1756
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 Win Ratio
    Parameter type
    		 Win Ratio
    Point estimate
    1.248
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.003
         upper limit
    		 1.564

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Phase
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Patiromer Continued
    Reporting group description
    		 Randomized subjects who received continued treatment with patiromer during the Treatment Phase.

    Reporting group title
    Placebo (withdraw patiromer)
    Reporting group description
    		 Randomized subjects who discontinued treatment with patiromer of the Run-in-Phase and received placebo during the Treatment Phase.

    Serious adverse events
    		 Patiromer Continued Placebo (withdraw patiromer)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 439 (12.30%)
    58 / 439 (13.21%)
         number of deaths (all causes)
    24
    18
         number of deaths resulting from adverse events
    24
    18
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancoast's tumour
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 439 (0.00%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    10 / 439 (2.28%)
    10 / 439 (2.28%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 10
         deaths causally related to treatment / all
    0 / 10
    0 / 10
    Death
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord dysfunction
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ultrasound pancreas abnormal
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular procedure complication
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    9 / 439 (2.05%)
    15 / 439 (3.42%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 18
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Angina unstable
         subjects affected / exposed
    3 / 439 (0.68%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    2 / 439 (0.46%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 439 (0.23%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 439 (0.23%)
    4 / 439 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    2 / 439 (0.46%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 439 (0.00%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 439 (0.46%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         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
    Muscle atrophy
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 439 (1.14%)
    6 / 439 (1.37%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    COVID-19
         subjects affected / exposed
    2 / 439 (0.46%)
    3 / 439 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 439 (0.00%)
    2 / 439 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 439 (0.23%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 439 (0.23%)
    0 / 439 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 439 (0.00%)
    1 / 439 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Patiromer Continued Placebo (withdraw patiromer)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    320 / 439 (72.89%)
    325 / 439 (74.03%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    15 / 439 (3.42%)
    13 / 439 (2.96%)
         occurrences all number
    17
    14
    Hypertension
         subjects affected / exposed
    8 / 439 (1.82%)
    2 / 439 (0.46%)
         occurrences all number
    8
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 439 (1.14%)
    8 / 439 (1.82%)
         occurrences all number
    5
    9
    Oedema peripheral
         subjects affected / exposed
    2 / 439 (0.46%)
    5 / 439 (1.14%)
         occurrences all number
    2
    5
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    6 / 439 (1.37%)
    0 / 439 (0.00%)
         occurrences all number
    6
    0
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    6 / 439 (1.37%)
    2 / 439 (0.46%)
         occurrences all number
    7
    2
    Acute respiratory failure
         subjects affected / exposed
    5 / 439 (1.14%)
    0 / 439 (0.00%)
         occurrences all number
    6
    0
    Dyspnoea
         subjects affected / exposed
    4 / 439 (0.91%)
    5 / 439 (1.14%)
         occurrences all number
    4
    7
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    15 / 439 (3.42%)
    10 / 439 (2.28%)
         occurrences all number
    19
    14
    Blood creatinine increased
         subjects affected / exposed
    2 / 439 (0.46%)
    5 / 439 (1.14%)
         occurrences all number
    2
    5
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    10 / 439 (2.28%)
    10 / 439 (2.28%)
         occurrences all number
    11
    11
    Atrial fibrillation
         subjects affected / exposed
    5 / 439 (1.14%)
    3 / 439 (0.68%)
         occurrences all number
    6
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 439 (2.05%)
    11 / 439 (2.51%)
         occurrences all number
    9
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 439 (2.51%)
    5 / 439 (1.14%)
         occurrences all number
    11
    6
    Iron deficiency anaemia
         subjects affected / exposed
    9 / 439 (2.05%)
    7 / 439 (1.59%)
         occurrences all number
    9
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 439 (4.33%)
    15 / 439 (3.42%)
         occurrences all number
    20
    15
    Constipation
         subjects affected / exposed
    11 / 439 (2.51%)
    5 / 439 (1.14%)
         occurrences all number
    13
    5
    Abdominal pain upper
         subjects affected / exposed
    2 / 439 (0.46%)
    5 / 439 (1.14%)
         occurrences all number
    2
    5
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    5 / 439 (1.14%)
    8 / 439 (1.82%)
         occurrences all number
    7
    8
    Renal impairment
         subjects affected / exposed
    5 / 439 (1.14%)
    7 / 439 (1.59%)
         occurrences all number
    5
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 439 (2.28%)
    6 / 439 (1.37%)
         occurrences all number
    11
    6
    Arthralgia
         subjects affected / exposed
    6 / 439 (1.37%)
    3 / 439 (0.68%)
         occurrences all number
    6
    3
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    7 / 439 (1.59%)
    1 / 439 (0.23%)
         occurrences all number
    8
    1
    COVID-19
         subjects affected / exposed
    6 / 439 (1.37%)
    6 / 439 (1.37%)
         occurrences all number
    6
    8
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 439 (0.00%)
    6 / 439 (1.37%)
         occurrences all number
    0
    6
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    197 / 439 (44.87%)
    238 / 439 (54.21%)
         occurrences all number
    335
    412
    Hypokalaemia
         subjects affected / exposed
    66 / 439 (15.03%)
    47 / 439 (10.71%)
         occurrences all number
    75
    53
    Hypomagnesaemia
         subjects affected / exposed
    19 / 439 (4.33%)
    22 / 439 (5.01%)
         occurrences all number
    20
    25
    Hyperglycaemia
         subjects affected / exposed
    10 / 439 (2.28%)
    3 / 439 (0.68%)
         occurrences all number
    11
    3
    Diabetes mellitus
         subjects affected / exposed
    7 / 439 (1.59%)
    5 / 439 (1.14%)
         occurrences all number
    7
    5
    Iron deficiency
         subjects affected / exposed
    6 / 439 (1.37%)
    2 / 439 (0.46%)
         occurrences all number
    6
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 439 (0.00%)
    5 / 439 (1.14%)
         occurrences all number
    0
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2019
    Version 1.0 to Version 1.1 - Global amendment
    19 Oct 2020
    Version 2.0 - Global amendment
    23 Jun 2021
    Version 4.0 - Final version submitted worldwide.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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