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    Clinical Trial Results:
    Do ACE inhibitors reduce postural instability in older people?: Towards a novel approach to falls prevention.

    Summary
    EudraCT number
    2013-001677-24
    Trial protocol
    GB  
    Global end of trial date
    30 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Nov 2016
    First version publication date
    17 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012GR06
    Additional study identifiers
    ISRCTN number
    ISRCTN58995463
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Dundee and NHS Tayside
    Sponsor organisation address
    Residency Block, Level 3, Ninewells Hospital, George Pirie, Dundee, United Kingdom, DD1 9SY
    Public contact
    Dr Deepa Sumukadas, University of Dundee, +44 01382 383086, d.sumukadas@dundee.ac.uk
    Scientific contact
    Dr Deepa Sumukadas, University of Dundee, +44 01382 383086, d.sumukadas@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
    26 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to examine the effect of perindopril compared with placebo on the change in standing balance (postural stability) over a 15 week period in older people with falls. Evidence from our group and others suggests that ACE inhibitors (ACEi) have a number of effects that might lead to a reduction in falls risk. These include beneficial effects on muscle function, nerve function, central postural integration and orthostatic hypotension (OH). However ACEi are often stopped in people with falls due to worries about increasing falls through worsening OH. We therefore aimed to study the effect of ACEi on postural stability as an intermediate phenotype for falls risk. Postural stability was measured using a force plate.
    Protection of trial subjects
    Potential participants were given the Participant Information sheet at least 24 hours prior to written informed consent being taken. The trial was explained to them and they were given opportunities to ask questions prior to consent. They were allowed withdraw from the study at any time. At every visit participants were asked about potential adverse events and any adverse events were documented. This information was provided to the DMC for safety assessment. Blood tests and blood pressure was measured at baseline, week 2, 5 and 15 to monitor renal function and blood pressure both of which can be affected by the trial medication. Protocol specified rules of uptitration or down titration of medication and when medication was to be discontinued. Clinical acumen was also employed to ensure participant safety.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Aug 2013
    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: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    0
    From 65 to 84 years
    64
    85 years and over
    16

    Subject disposition

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    Recruitment
    Recruitment details
    From September 2013, 80 participants were recruited from Tayside and Fife. Last participant last visit was 30 September 2015. Participants aged > 65 years with ≥1 self-reported falls in the previous 12 months fulfilling inclusion and exclusion criteria were recruited. Sources were from primary care, secondary care and volunteers from community.

    Pre-assignment
    Screening details
    4289 potential participants were invited to participate . 3793 declined or did not reply, 408 were found ineligible on telephonic pre-screening and 88 attended a screening visit. 80 participants were randomised to receive perindopril or placebo. All usual medication was continued.

    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
    Assessor, Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Perindopril
    Arm description
    Participants were randomised to receive Perindopril or placebo in a 1:1 ratio. Starting dose of 2 mg Perindopril was uptitrated to 4 mg after 2 weeks if tolerated.
    Arm type
    Experimental

    Investigational medicinal product name
    Perindopril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose on randomisation was 2 mg which was uptitrated at 2 weeks to 4 mg if tolerated (Blood pressure and renal function). If 2 mg was tolerated but not 4 mg, participant was kept on 2 mg for the duration of the study.

    Arm title
    Placebo
    Arm description
    Participants were randomised to receive Perindopril or placebo in a 1:1 ratio. The placebo group also received a mock uptitration at 2 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Perindopril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose on randomisation was 2 mg which was uptitrated at 2 weeks to 4 mg if tolerated (Blood pressure and renal function). If 2 mg was tolerated but not 4 mg, participant was kept on 2 mg for the duration of the study.

    Number of subjects in period 1
    Perindopril Placebo
    Started
    40
    40
    Completed
    39
    38
    Not completed
    1
    2
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Perindopril
    Reporting group description
    Participants were randomised to receive Perindopril or placebo in a 1:1 ratio. Starting dose of 2 mg Perindopril was uptitrated to 4 mg after 2 weeks if tolerated.

    Reporting group title
    Placebo
    Reporting group description
    Participants were randomised to receive Perindopril or placebo in a 1:1 ratio. The placebo group also received a mock uptitration at 2 weeks.

    Reporting group values
    Perindopril Placebo Total
    Number of subjects
    40 40 80
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    31 33 64
        85 years and over
    9 7 16
    Age continuous
    Recruited participants aged 65 years or over
    Units: years
        arithmetic mean (standard deviation)
    78.1 ± 7.3 78 ± 7.6 -
    Gender categorical
    Units: Subjects
        Female
    30 30 60
        Male
    10 10 20
    SIMD decile
    Scottish index of multiple deprivation
    Units: Subjects
        1-5
    10 10 20
        6-10
    30 30 60
    Home circumstances
    Units: Subjects
        Home alone
    20 17 37
        Home with family/friends
    17 16 33
        Sheltered housing
    3 7 10
    Walking aid
    Units: Subjects
        None
    20 19 39
        Walking stick
    16 14 30
        Other
    4 7 11
    Hypertension
    Past medical history
    Units: Subjects
        Yes
    16 16 32
        No
    24 24 48
    Ischaemic heart disease
    Past medical history
    Units: Subjects
        Yes
    5 3 8
        No
    35 37 72
    Stroke/TIA
    Past medical history
    Units: Subjects
        Yes
    3 3 6
        No
    37 37 74
    Peripheral vascular disease
    Past medical history
    Units: Subjects
        Yes
    0 1 1
        No
    40 39 79
    Diabetes
    Past medical history
    Units: Subjects
        Yes
    2 2 4
        No
    38 38 76
    COPD
    Past medical history
    Units: Subjects
        Yes
    4 5 9
        No
    36 35 71
    Anaemia
    Past medical history
    Units: Subjects
        Yes
    3 2 5
        No
    37 38 75
    Peripheral neuropathy
    Past medical history
    Units: Subjects
        Yes
    2 7 9
        No
    38 33 71
    Vertigo
    Past medical history
    Units: Subjects
        Yes
    3 4 7
        No
    37 36 73
    Tinnitus
    Past medical history
    Units: Subjects
        Yes
    6 9 15
        No
    34 31 65
    Registered blind
    Past medical history
    Units: Subjects
        Yes
    1 0 1
        No
    39 40 79
    Concomitant betablockers
    Units: Subjects
        Yes
    11 8 19
        No
    29 32 61
    Concomitant thiazides
    Units: Subjects
        Yes
    6 4 10
        No
    34 36 70
    Concomitant calcium channel blockers
    Units: Subjects
        yes
    5 10 15
        No
    35 30 65
    Concomitant sedatives and antipsychotics
    Units: Subjects
        yes
    2 2 4
        No
    38 38 76
    Concomitant opiate based analgesia
    Units: Subjects
        Yes
    10 5 15
        No
    30 35 65
    Height
    Units: metres
        arithmetic mean (standard deviation)
    1.58 ± 0.1 1.59 ± 0.08 -
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    72.5 ± 14 71.9 ± 14.3 -
    Height adjusted muscle mass
    Units: Kg/m
        arithmetic mean (standard deviation)
    13.9 ± 2.9 13.7 ± 3 -
    Height adjusted fat mass
    Units: Kg/m
        arithmetic mean (standard deviation)
    18.9 ± 4.9 18.2 ± 5.8 -

    End points

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    End points reporting groups
    Reporting group title
    Perindopril
    Reporting group description
    Participants were randomised to receive Perindopril or placebo in a 1:1 ratio. Starting dose of 2 mg Perindopril was uptitrated to 4 mg after 2 weeks if tolerated.

    Reporting group title
    Placebo
    Reporting group description
    Participants were randomised to receive Perindopril or placebo in a 1:1 ratio. The placebo group also received a mock uptitration at 2 weeks.

    Primary: Between group change in Anterioposterior sway (eyes closed) from baseline to 15 weeks

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    End point title
    Between group change in Anterioposterior sway (eyes closed) from baseline to 15 weeks
    End point description
    Primary outcome was Difference in static Anteroposterior (AP) sway at 15 weeks between the two groups, adjusted for baseline values. Postural stability was measured using the Advanced Medical Technology Inc. force plate (measuring ground reaction force velocity and pressure distribution). For the static postural stability, participants stood on the force plate with feet slightly apart, eyes open and closed each for 40 seconds and this was repeated 3 times. The sway range was calculated.
    End point type
    Primary
    End point timeframe
    Assessed at baseline and at 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: Millimeter
    arithmetic mean (standard deviation)
        Baseline
    63 ± 33
    64 ± 35
        15 weeks
    59 ± 31
    57 ± 31
    Statistical analysis title
    Between group difference in AP sway
    Statistical analysis description
    Analyses were performed comparing change in outcomes at 15 weeks using ANOVA, adjusted for baseline values of the variable under test. A multivariate model including treatment and any significant co-variables from baseline data gave similar results.
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.59
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7
         upper limit
    12

    Primary: Between group difference in Anterioposterior sway (eyes open) from baseline to 15 weeks

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    End point title
    Between group difference in Anterioposterior sway (eyes open) from baseline to 15 weeks
    End point description
    Difference in static Anteroposterior (AP) sway at 15 weeks between the two groups, adjusted for baseline values. Postural stability was measured using the Advanced Medical Technology Inc. force plate (measuring ground reaction force velocity and pressure distribution). For the static postural stability, participants stood on the force plate with feet slightly apart, eyes open and closed each for 40 seconds and this was repeated 3 times.
    End point type
    Primary
    End point timeframe
    Outcome was measured at baseline and at 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: millimeters
    arithmetic mean (standard deviation)
        Baseline
    53 ± 27
    53 ± 30
        15 weeks
    45 ± 19
    45 ± 28
    Statistical analysis title
    Between group difference in AP sway
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.91
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    7

    Secondary: Between group difference in mediolateral sway (eyes closed) from baseline to 15 weeks

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    End point title
    Between group difference in mediolateral sway (eyes closed) from baseline to 15 weeks
    End point description
    Postural stability was measured using the Advanced Medical Technology Inc. force plate (measuring ground reaction force velocity and pressure distribution). For the static postural stability, participants stood on the force plate with feet slightly apart, eyes open and closed each for 40 seconds and this was repeated 3 times. Sway range in the mediolateral direction was calculated
    End point type
    Secondary
    End point timeframe
    Outcomes were measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        Baseline
    37 ± 40
    44 ± 55
        15 weeks
    34 ± 27
    41 ± 50
    Statistical analysis title
    Change in mediolateral sway
    Statistical analysis description
    Analyses were performed comparing change in outcomes using ANOVA, adjusted for baseline values of the variable under test. The multivariate model including treatment and any significant co-variables gave similar results. Other types of analyses yielded similar results.
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.32
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14
         upper limit
    5

    Secondary: Between group difference in mediolateral sway (eyes open) from baseline to 15 weeks

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    End point title
    Between group difference in mediolateral sway (eyes open) from baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome was measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        Baseline
    37 ± 34
    40 ± 29
        15 weeks
    27 ± 19
    32 ± 27
    Statistical analysis title
    Between group difference in mediolateral sway
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.38
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13
         upper limit
    5

    Secondary: Between group difference in sway velocity (eyes closed) from baseline to 15 weeks

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    End point title
    Between group difference in sway velocity (eyes closed) from baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: mm/s
    arithmetic mean (standard deviation)
        Baseline
    83 ± 19
    86 ± 22
        15 weeks
    81 ± 16
    85 ± 28
    Statistical analysis title
    Between group differrence in sway velocity
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.41
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    3

    Secondary: Between group difference in sway velocity (eyes open) from baseline to 15 weeks

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    End point title
    Between group difference in sway velocity (eyes open) from baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: mm/s
    arithmetic mean (standard deviation)
        Baseline
    79 ± 15
    81 ± 16
        15 weeks
    78 ± 14
    77 ± 20
    Statistical analysis title
    between group difference in sway velocity
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.42
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    6

    Secondary: between group difference in total sway area (eyes closed) baseline to 15 weeks

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    End point title
    between group difference in total sway area (eyes closed) baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: square millimeter
    arithmetic mean (standard deviation)
        Baseline
    2389 ± 6100
    2071 ± 3753
        15 weeks
    1666 ± 3095
    1647 ± 2184
    Statistical analysis title
    Between group difference in total sway area
    Statistical analysis description
    Adjusted for baseline total sway area
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.62
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -150
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -757
         upper limit
    457

    Secondary: Between group difference in total sway area ( eyes open) from baseline to 15 weeks

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    End point title
    Between group difference in total sway area ( eyes open) from baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: square millimeter
    arithmetic mean (standard deviation)
        Baseline
    1311 ± 1558
    1287 ± 1285
        15 weeks
    893 ± 1179
    1064 ± 1536
    Statistical analysis title
    Between group difference in total sway area
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.43
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -179
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -634
         upper limit
    275
    Notes
    [1] - Adjusted for baseline variable

    Secondary: Between group difference in anterioposterior reach

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    End point title
    Between group difference in anterioposterior reach
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: millimeter
    arithmetic mean (standard deviation)
        Baseline
    48 ± 23
    47 ± 21
        15 weeks
    48 ± 30
    45 ± 28
    Statistical analysis title
    Between group difference in forward reach
    Statistical analysis description
    Adjusted for baseline variable
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.62
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9
         upper limit
    16

    Secondary: Between group difference in mediolateral left reach from baseline to 15 weeks

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    End point title
    Between group difference in mediolateral left reach from baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        Baseline
    53 ± 44
    49 ± 40
        15 weeks
    45 ± 27
    36 ± 24
    Statistical analysis title
    Between group difference in left reach
    Statistical analysis description
    Adjusted for baseline variable
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    20

    Secondary: Between group difference in mediolateral right reach from baseline to 15 weeks

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    End point title
    Between group difference in mediolateral right reach from baseline to 15 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measure at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        Baseline
    49 ± 35
    48 ± 42
        15 weeks
    46 ± 44
    42 ± 25
    Statistical analysis title
    Between group difference in right reach
    Statistical analysis description
    Adjusted for baseline variable
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.45
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    18

    Secondary: Falls at baseline

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    End point title
    Falls at baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Reported at baseline - number of falls in 12 months prior to recruitment
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: subjects
        1-2 falls
    14
    19
        3-5 falls
    19
    11
        6-10 falls
    2
    8
        >10 falls
    5
    2
        Median falls (IQR)
    3
    3
    No statistical analyses for this end point

    Secondary: Falls during the study

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    End point title
    Falls during the study
    End point description
    End point type
    Secondary
    End point timeframe
    Number of falls reported in study period
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: subjects
        No falls
    17
    13
        1-2 falls
    10
    18
        3-5 falls
    5
    6
        6-10 falls
    1
    1
        >10 falls
    6
    2
    Statistical analysis title
    Between group difference in falls during the study
    Statistical analysis description
    Number of falls data was skewed so a number of sensitivity analyses were done using different modelling techniques.
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.24
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    4.5
    Notes
    [2] - A number of sensitivity analyses using different modelling techniques were conducted to investigate the difference in falls between the two groups: Mixed model analysis mean difference 1.7 (-1.1 to 4.5, p=0.24); quasi-poisson regression mean difference -0.6 (-1.6 to 0.3, p=0.19); ordinal regression 0.4 (95% CI -0.9 to 1.6; p=0.58). Mixed model analyses are presented in the tables

    Secondary: Between group difference in voluntary muscle strength (QMVC)

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    End point title
    Between group difference in voluntary muscle strength (QMVC)
    End point description
    Isometric quadriceps maximum voluntary contraction strength (QMVC) was measured 3 times in a sitting position with the knee joint at 90 degrees using a Biopac tension dynamometer and output was recorded using a data acquisition system. QMVC was taken as the highest mean force that could be sustained over 1 second.
    End point type
    Secondary
    End point timeframe
    Outcome measure at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: kilogram(s)
    arithmetic mean (standard deviation)
        Baseline
    18.6 ± 9
    19.2 ± 7.5
        15 weeks
    16.8 ± 6.7
    18.5 ± 7.4
    Statistical analysis title
    Between group difference in QMVC
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.11
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    0.3
    Notes
    [3] - Adjusted for baseline variable

    Secondary: Between group difference in Magnetic twitch of quadriceps (TwQ)

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    End point title
    Between group difference in Magnetic twitch of quadriceps (TwQ)
    End point description
    This was used to test non volitional muscle strength and fatigability in participants who had no contraindications to magnetic nerve stimulation. Greatest Twitch tension generated in the Quadriceps (TwQ) using magnetic femoral nerve stimulation with the Magstim 2002 device was recorded. Endurance was tested by repeated QMVC, until force fell to < 70% of baseline maximum QMVC and the number of ‘kicks’ were recorded. Magnetic stimulation was repeated to estimate fatigue immediately and 10 minutes later. Fatigability was further tested by measuring TwQ following a 6 minute walking test (6MW), a valid, reliable test of submaximal endurance capacity in older people.
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: kilogram(s)
    arithmetic mean (standard deviation)
        Baseline rest
    2.7 ± 1.1
    2.8 ± 1.6
        15 weeks rest
    2.9 ± 1.3
    2.6 ± 1.2
        Baseline follwing kicks
    3.1 ± 1.5
    3.6 ± 2
        15 weeks following kicks
    3.5 ± 2.5
    2.9 ± 1.6
        Baseline following 6MW
    2.9 ± 1.2
    2.8 ± 1.5
        15 weeks following 6MW
    3 ± 1.3
    2.8 ± 1.3
    Statistical analysis title
    Between group difference in TwQ at rest
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.04
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1
    Notes
    [4] - Adjusting for baseline variable
    Statistical analysis title
    Between group difference in TwQ following kicks
    Statistical analysis description
    Adjusted for baseline variable
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    1.8
    Statistical analysis title
    Between group difference in TwQ following 6MW
    Statistical analysis description
    Adjusted for baseline variable
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.35
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.7

    Secondary: Between group difference in 6minute walking distance

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    End point title
    Between group difference in 6minute walking distance
    End point description
    End point type
    Secondary
    End point timeframe
    Outcome measured at baseline and 15 weeks
    End point values
    Perindopril Placebo
    Number of subjects analysed
    40
    40
    Units: meters
    arithmetic mean (standard deviation)
        Baseline
    336 ± 94
    330 ± 113
        15 weeks
    338 ± 104
    351 ± 111
    Statistical analysis title
    Between group difference in 6MW distance
    Statistical analysis description
    Adjusted for baseline variable
    Comparison groups
    Perindopril v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.41
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29
         upper limit
    12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the study
    Adverse event reporting additional description
    At each visit participants were asked about any adverse events and these were recorded in the Adverse event log
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Perindopril
    Reporting group description
    Active arm receiving perindopril - adverse events occurring during the study

    Reporting group title
    Placebo
    Reporting group description
    Placebo arm - adverse events occurring during the study

    Serious adverse events
    Perindopril Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
    Additional description: Fall associated with dizziness admitted to hospital
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture ankle
    Additional description: Had stroke - and fell fracturing ankle
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Menieres disease
    Additional description: Dizziness and fall admitted to hospital
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
    Additional description: Breast abscess
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         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
    Perindopril Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 40 (90.00%)
    38 / 40 (95.00%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    23 / 40 (57.50%)
    27 / 40 (67.50%)
         occurrences all number
    156
    95
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 40 (2.50%)
         occurrences all number
    3
    1
    Rhinitis
         subjects affected / exposed
    6 / 40 (15.00%)
    7 / 40 (17.50%)
         occurrences all number
    6
    7
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Ligament injury
    Additional description: Ligament sprain
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2013
    Change to the protocol to add an extra inclusion criteria, namely to add that participants must have been assessed at a Medicine for the Elderly (MFE) clinic within the past 18 months. This is to ensure that all participants have received standard treatment currently recommended for their falls risk. This will ensure that they are not recruited under the misperception that participating in this study is a substitute for standard care.
    26 Mar 2014
    Amendment included several points: 1.A brief participant information sheet (BPIS) created 2.New Patient Information Sheet to replace the original Patient Information Sheet with a table of visits and tests added for ease of reference. 3. Heading on the poster, and PIS’s altered to ‘Falls Research Study’. 4.To send only the new brief PIS to potential participants initially. When these potential participants have contacted the study team to discuss the study further they will be sent a full Patient Information Sheet in advance of their screening visit to give them further details on the trial. 5. To distribute posters and brief PISs to community settings . 6. Additional information in Participant Information Sheet regarding contact details for participants if they become unwell during the study and advice on what to do if feeling unwell on study medications. 7. Following a redesign in services, people who fall were referred from different sources to a Falls Coordinator We therefore extended recruitment through this Falls service. 8. Use of 24 hour BP monitor in participants with high screening BP in case there was a white coat effect 9. Measure postural BP at home visits as per DMC suggestion 10. Extend recruitment to NHS Fife in addition to NHS Tayside
    26 Nov 2014
    Protocol: We have added that we wish to use the national SHARE registry as a potential source of recruitment - this database has Tayside and Fife volunteers who have given prior consent to be approached for clinical research projects which could be a useful source of recruitment. To the PIS: We added the new number for NHS 24 and put the NHS Tayside logo on the PIS. We have had a recent Data Monitoring Committee and they specifically requested that we give consideration to spelling out clearly in the PIS that if a participant experiences diarrhoea or vomiting they are to stop study meds immediately. Addition of new invitation letter to patients who have been seen on the wards as part of the Medicine for the Elderly (MFE) services.

    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.
    Please note that issues with AE resolution reporting were identified by an MHRA inspection in July 2016, data were reanalyzed after correction of errors - hence date of final analysis is 26/10/16 and report posting is beyond a year from end of trial
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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