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    Clinical Trial Results:
    Does oral sodium bicarbonate therapy improve function and quality of life in older patients with chronic kidney disease and low-grade acidosis? A multicentre randomized placebo controlled trial

    Summary
    EudraCT number
    		 2011-005271-16
    Trial protocol
    		 GB  
    Global end of trial date
    28 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Mar 2019
    First version publication date
    09 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2010NE02
    Additional study identifiers
    ISRCTN number
    		 ISRCTN09486651
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MREC: 12/ES/0023
    Sponsors
    Sponsor organisation name
    Tayside Academic Health Science Centre
    Sponsor organisation address
    Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
    Public contact
    Margaret Band, Tayside Clinical Trials Unit, +44 01382383993, m.band@dundee.ac.uk
    Scientific contact
    Margaret Band, Tayside Clinical Trials Unit, +44 01382383993, m.band@dundee.ac.uk
    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 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether oral bicarbonate therapy improves physical function and health-related quality of life compared to placebo in older people with Chronic Kidney Disease (CKD) and mild acidosis
    Protection of trial subjects
    Nil specific to this intervention. Regular clinical review and telephone contact to detect adverse events.
    Background therapy
    		 Usual care
    Evidence for comparator
    		 Placebo used as comparator
    Actual start date of recruitment
    01 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 300
    Worldwide total number of subjects
    300
    EEA total number of subjects
    300
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    26
    From 65 to 84 years
    256
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants recruited from 27 UK centres between May 2013 and February 2017

    Pre-assignment
    Screening details
    		 410 screened. Reasons for ineligibility: serum bicarbonate >21mmol/L (n=81). eGFR >30ml/min/1.73m2 (n=37). Uncontrolled hypertension (n=9). Commenced on sodium bicarbonate at screening (n=4). other medical contraindication (n=6). Unable to comply with study requirements (n=1). Did not wish to continue after screening visit (n=3)

    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
    		 Investigator, Monitor, Data analyst, Carer, Subject, Assessor
    Blinding implementation details
    Matching placebo used; identical bottles, allocated by web-based randomisation system. Dummy uptitration used to ensure masking during dose escalation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bicarbonate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Bicarbonate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg three times a day, titrated up to 1 gram three times a day after 3 months if serum bicarbonate <22mmol/L

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet three times a day; uptitrated to 2 tablets 3 times a day after 3 months if serum bicarbonate <22mmol/L

    Number of subjects in period 1
    		Bicarbonate Placebo
    Started
    152
    148
    Completed
    81
    80
    Not completed
    71
    68
         Adverse event, serious fatal
    15
    11
         Physician decision
    2
    4
         Consent withdrawn by subject
    33
    35
         Adverse event, non-fatal
    5
    5
         Miscellaneous
    1
    4
         Lost to follow-up
    2
    -
         Truncated follow up
    13
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bicarbonate
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Bicarbonate Placebo Total
    Number of subjects
    		 152 148 300
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.9 ( 7.6 ) 74.0 ( 6.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 42 44 86
        Male
    		 110 104 214
    Mean eGFR
    Estimated glomerular filtration rate derived via MDRD4 equation
    Units: ml/min/1.73m2
        arithmetic mean (standard deviation)
    		 19.7 ( 6.5 ) 18.2 ( 6.4 ) -
    Serum bicarbonate
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 20.6 ( 2.6 ) 20.1 ( 2.5 ) -
    Short Physical Performance Battery
    Units: Units
        arithmetic mean (standard deviation)
    		 8.0 ( 2.4 ) 8.1 ( 2.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Bicarbonate
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Short Physical Performance Battery at 12 months

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    End point title
    		 Short Physical Performance Battery at 12 months
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Bicarbonate Placebo
    Number of subjects analysed
    116
    104
    Units: Units
        arithmetic mean (standard deviation)
    8.3 ( 2.5 )
    8.8 ( 2.2 )
    Statistical analysis title
    		 Between-group difference
    Comparison groups
    Bicarbonate v Placebo
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.15
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.1
    Notes
    [1] - Adjusted for baseline SPPB, age, sex and CKD category

    Secondary: EQ5D-3L

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    End point title
    		 EQ5D-3L
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Bicarbonate Placebo
    Number of subjects analysed
    81
    80
    Units: units
        arithmetic mean (standard deviation)
    0.72 ( 0.24 )
    0.75 ( 0.19 )
    Statistical analysis title
    		 EQ5D repeated measures between group comparison
    Comparison groups
    Bicarbonate v Placebo
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.06
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0
    Notes
    [2] - Adjusted for baseline EQ5D, age,sex and CKD category

    Secondary: Serum bicarbonate

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    End point title
    		 Serum bicarbonate
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Bicarbonate Placebo
    Number of subjects analysed
    81
    80
    Units: mmol/L
        arithmetic mean (standard deviation)
    22.9 ( 4.1 )
    22.5 ( 3.3 )
    Statistical analysis title
    		 Repeated measures between-groups analysis
    Comparison groups
    Bicarbonate v Placebo
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.6
    Notes
    [3] - Adjusted for baseline bicarbonate, age, sex and CKD stage

    Secondary: eGFR

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    End point title
    		 eGFR
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Bicarbonate Placebo
    Number of subjects analysed
    81
    80
    Units: ml/min/1.73m2
        arithmetic mean (standard deviation)
    19.5 ( 10.2 )
    18.0 ( 8.2 )
    Statistical analysis title
    		 Repeated measures between groups analysis
    Comparison groups
    Bicarbonate v Placebo
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.39
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 2
    Notes
    [4] - Adjusted for baseline eGFR, age and sex

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening visit to last visit (24 months or point of dropout)
    Adverse event reporting additional description
    Note that total number of AEs was 457 in the bicarbonate arm, and 400 in the placebo arm. Majority of AEs spread across multiple preferred terms and hence not reaching the 5% reporting threshold
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Bicarbonate
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Bicarbonate Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 152 (3.95%)
    6 / 148 (4.05%)
         number of deaths (all causes)
    15
    11
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Adverse drug reaction
         subjects affected / exposed
    0 / 152 (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
    Myopathy toxic
         subjects affected / exposed
    0 / 152 (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
    General disorders and administration site conditions
    Ill-defined disorder
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 152 (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
    Intestinal perforation
         subjects affected / exposed
    0 / 152 (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
    Volvulus
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 152 (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 haematoma
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 148 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 152 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bicarbonate Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 152 (30.26%)
    46 / 148 (31.08%)
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    23 / 152 (15.13%)
    24 / 148 (16.22%)
         occurrences all number
    23
    24
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    23 / 152 (15.13%)
    24 / 148 (16.22%)
         occurrences all number
    23
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jan 2015
    Series of amendments to relax the inclusion/exclusion criteria. Protocol as published reflects the final amended protocol used for the trial. See: Witham MD et al. Trials. 2015 Aug 1;16:326. doi: 10.1186/s13063-015-0843-6.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26231610
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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
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