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    Clinical Trial Results:
    A trial to compare the effects of nebivolol versus atenolol on various cardiovascular measurements including insulin sensitivity

    Summary
    EudraCT number
    2005-001214-40
    Trial protocol
    GB  
    Global end of trial date
    21 Jan 2009

    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
    cro085
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00125853
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensington Campus, London, United Kingdom, SW7 2AZ
    Public contact
    Professor Neil Poulter, Imperial College London, +44 (0)20 7594 3446, n.poulter@imperial.ac.uk
    Scientific contact
    Professor Neil Poulter, Imperial College London, +44 (0)20 7594 3446, n.poulter@imperial.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
    05 Jul 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jan 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jan 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of nebivolol and atenolol on insulin sensitivity
    Protection of trial subjects
    Bendroflumethiazide 2.5mg daily throughout the whole study period.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Jul 2006
    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 Kingdom: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    27
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The participants were recruited from the Peart-Rose Hypertension clinic at St Mary’s Hospital in West London and from local general practices between 2006 and 2009.

    Pre-assignment
    Screening details
    55 patients with mild-to-moderate essential hypertension were recruited, 54 participants were randomized.

    Period 1
    Period 1 title
    Wash out
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nebivolol_before treatment
    Arm description
    Participants randomized to Nebivolol as a first treatment. Wash-out period participants received Bendroflumethiazide for 4 weeks.
    Arm type
    wash-out

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 4 weeks

    Arm title
    Atenolol_before treatment
    Arm description
    Participants randomized to Atenolol as a first treatment. Wash-out period participants received Bendroflumethiazide for 4 weeks.
    Arm type
    wash-out

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 4 weeks

    Number of subjects in period 1
    Nebivolol_before treatment Atenolol_before treatment
    Started
    27
    27
    Completed
    27
    27
    Period 2
    Period 2 title
    First treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Atenolol
    Arm description
    Participants received Atenolol and Bendroflumethiazide for 8 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 8 weeks

    Investigational medicinal product name
    Atenolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg daily for 8 weeks

    Arm title
    Nebivolol
    Arm description
    participants received Nebivolol and Bendroflumethiazide for 8 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 8 weeks

    Investigational medicinal product name
    Nebivolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 8 weeks

    Number of subjects in period 2
    Atenolol Nebivolol
    Started
    27
    27
    Completed
    27
    27
    Period 3
    Period 3 title
    Wash out
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    All participants
    Arm description
    All participants received Bendroflumethiazide for 4 weeks.
    Arm type
    wash-out

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 4 weeks

    Number of subjects in period 3
    All participants
    Started
    54
    Completed
    44
    Not completed
    10
         Lost to follow-up
    10
    Period 4
    Period 4 title
    Second intervention
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Nebivolol
    Arm description
    Participants received Nebivolol and Bendroflumethiazide for 8 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Nebivolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 8 weeks

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 8 weeks

    Arm title
    Atenolol
    Arm description
    Participants received Atenolol and Bendroflumethiazide for 8 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg daily for 8 weeks

    Investigational medicinal product name
    Atenolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg daily for 8 weeks

    Number of subjects in period 4
    Nebivolol Atenolol
    Started
    20
    24
    Completed
    20
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Wash out
    Reporting group description
    -

    Reporting group values
    Wash out Total
    Number of subjects
    54 54
    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
        geometric mean (standard deviation)
    61.1 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    29 29
        Male
    25 25
    BMI
    Units: kg/m^2
        geometric mean (standard deviation)
    27.2 ± 6.7 -
    Systolic Blood Pressure (SBP)
    Units: mmHg
        geometric mean (standard deviation)
    129.4 ± 13.2 -
    Diastolic Blood Pressure (DBP)
    Units: mmHg
        geometric mean (standard deviation)
    81.3 ± 9 -
    HBa1c
    Units: percentage of glycosylated hemoglobin
        geometric mean (standard deviation)
    5.7 ± 0.7 -
    Total Cholesterol
    Units: mmol/L
        geometric mean (standard deviation)
    5.1 ± 1 -

    End points

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    End points reporting groups
    Reporting group title
    Nebivolol_before treatment
    Reporting group description
    Participants randomized to Nebivolol as a first treatment. Wash-out period participants received Bendroflumethiazide for 4 weeks.

    Reporting group title
    Atenolol_before treatment
    Reporting group description
    Participants randomized to Atenolol as a first treatment. Wash-out period participants received Bendroflumethiazide for 4 weeks.
    Reporting group title
    Atenolol
    Reporting group description
    Participants received Atenolol and Bendroflumethiazide for 8 weeks

    Reporting group title
    Nebivolol
    Reporting group description
    participants received Nebivolol and Bendroflumethiazide for 8 weeks
    Reporting group title
    All participants
    Reporting group description
    All participants received Bendroflumethiazide for 4 weeks.
    Reporting group title
    Nebivolol
    Reporting group description
    Participants received Nebivolol and Bendroflumethiazide for 8 weeks

    Reporting group title
    Atenolol
    Reporting group description
    Participants received Atenolol and Bendroflumethiazide for 8 weeks

    Subject analysis set title
    Atenolol
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants who received Atenolol treatments

    Subject analysis set title
    Nebivolol
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants who received Nebivolol treatments

    Primary: Insulin Sensitivity Index (ISI)

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    End point title
    Insulin Sensitivity Index (ISI)
    End point description
    Patients were asked to fast for a minimum of 12 hours prior to each oral glucose tolerance test (OGTT). Venous blood was withdrawn for insulin and glucose analysis, 15 minutes and immediately prior to, and 30, 60, 90 and 120 minutes following an oral glucose load. For each OGTT, the Insulin Sensitivity Index (ISI) was calculated using the standard method for oral glucose tolerance testing. For each OGTT, the Insulin Sensitivity Index (ISI) was calculated using the standard method for oral glucose tolerance testing.
    End point type
    Primary
    End point timeframe
    Baseline, 15, 30, 60, 90, 120 m following oral glucose load after 8 weeks treatment
    End point values
    Atenolol Nebivolol
    Number of subjects analysed
    44
    44
    Units: factor
        geometric mean (inter-quartile range (Q1-Q3))
    75.47 (50.6 to 144.9)
    81.54 (50.9 to 114.9)
    Statistical analysis title
    Insulin Sensitivity Index (ISI)
    Comparison groups
    Atenolol v Nebivolol
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.6
    Method
    Linear Mixed effect Modelling, adjusted
    Confidence interval
    Notes
    [1] - Linear Mixed effect Modelling, adjusted for baseline values and period effect

    Secondary: 24 Hour Systolic Blood Pressure

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    End point title
    24 Hour Systolic Blood Pressure
    End point description
    The 24-h Ambulatory Blood Pressure Monitoring (ABPM) was recorded at the beginning and end of each beta-blocker treatment period. BP was automatically recorded for 24 h at 30 min intervals. The time periods from 0700h to 2200h and from 2200h to 0700h were defined as daytime and night-time, respectively.
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment
    End point values
    Atenolol Nebivolol
    Number of subjects analysed
    44
    44
    Units: mmHg
        geometric mean (standard deviation)
    117.2 ± 9.2
    121.2 ± 8.2
    Statistical analysis title
    24 Hour Systolic Blood Pressure
    Comparison groups
    Atenolol v Nebivolol
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.06
    Method
    Linear Mixed effect Modelling, adjusted
    Confidence interval
    Notes
    [2] - Linear Mixed effect Model, adjusted for baseline values and period effect

    Secondary: Total Cholesterol

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    End point title
    Total Cholesterol
    End point description
    Fasting blood samples were taken at the beginning and end of each treatment period.
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment
    End point values
    Atenolol Nebivolol
    Number of subjects analysed
    44
    44
    Units: mmol/L
        geometric mean (standard deviation)
    4.9 ± 1.0
    5.1 ± 0.9
    Statistical analysis title
    Total Cholesterol
    Comparison groups
    Atenolol v Nebivolol
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.51
    Method
    Linear Mixed effect Modelling, adjusted
    Confidence interval
    Notes
    [3] - Linear Mixed effect Model, adjusted for baseline values and period effect

    Secondary: HbA1c

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    End point title
    HbA1c
    End point description
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment
    End point values
    Atenolol Nebivolol
    Number of subjects analysed
    44
    44
    Units: percentage of glycosylated hemoglobin
        geometric mean (standard deviation)
    5.7 ± 0.4
    5.7 ± 0.3
    Statistical analysis title
    HbA1c
    Comparison groups
    Atenolol v Nebivolol
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.48
    Method
    Linear Mixed effect Model, adjusted for
    Confidence interval
    Notes
    [4] - Linear Mixed effect Model, adjusted for baseline values and period effect

    Secondary: BMI

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    End point title
    BMI
    End point description
    End point type
    Secondary
    End point timeframe
    After 8 weeks of treatment
    End point values
    Atenolol Nebivolol
    Number of subjects analysed
    44
    44
    Units: kg/m^2
        geometric mean (standard deviation)
    28.0 ± 4.4
    28.3 ± 4.4
    Statistical analysis title
    BMI
    Comparison groups
    Atenolol v Nebivolol
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.09
    Method
    Linear Mixed effect Model, adjusted for
    Confidence interval
    Notes
    [5] - Linear Mixed effect Model, adjusted for baseline values and period effect

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    32 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Atenolol 25mg Daily
    Reporting group description
    -

    Reporting group title
    Nebivolol 2.5mg daily
    Reporting group description
    -

    Serious adverse events
    Atenolol 25mg Daily Nebivolol 2.5mg daily
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 54 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Atenolol 25mg Daily Nebivolol 2.5mg daily
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 54 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse event reported

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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