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    Clinical Trial Results:
    Reducing pathology in Alzheimer’s Disease through Angiotensin taRgeting. The RADAR Trial. A phase II, two arm, double-blind, placebo-controlled, randomised trial to evaluate the effect of losartan on brain tissue changes in patients diagnosed with Alzheimer’s disease.

    Summary
    EudraCT number
    		 2012-003641-15
    Trial protocol
    		 GB  
    Global end of trial date
    31 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2021
    First version publication date
    21 Aug 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2625
    Additional study identifiers
    ISRCTN number
    		 ISRCTN93682878
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    North Bristol NHS Research and Innovation
    Sponsor organisation address
    Southmead Hospital, Southmead Road, Bristol, United Kingdom,
    Public contact
    Clinical Trials Manager, North Bristol NHS Trust, +44 (0117) 32 38602, helen.lewis@nbt.nhs.uk
    Scientific contact
    Clinical Trials Manager, North Bristol NHS Trust, +44 (0117) 32 38602, helen.lewis@nbt.nhs.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
    01 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To what extent does angiotensin II signalling blockade by losartan reduce MRI-based measures of brain atrophy (wasting) in Alzheimer's Disease? Angiotensin II is a small molecule that is already well known for being responsible for the contraction of blood vessels which in turn increases blood pressure. More recent evidence over the last decades has come to light of how angiotensin II is also very promiscuous in biochemical terms. Angiotensin II (or Ang II) is very involved in processes that increase inflammation; it inhibits the release of the chemical acetylcholine which is vital for memory formation in the brain; it is heavily involved with how cells regulate calcium levels which in turn can impact on levels of cell death and the activation of other mechanisms that also damage cells. All of these facets are characteristics of the detrimental processes that are all very active in the brain of patients with Alzheimer's disease.
    Protection of trial subjects
    An open label phase of the trial was conducted to ensure participant drug toloerability. Safety bloods were taken during the trial to monitor participant safety.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 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: 211
    Worldwide total number of subjects
    211
    EEA total number of subjects
    211
    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)
    37
    From 65 to 84 years
    168
    85 years and over
    6

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were identified from AD clinic lists, primary care and from the 'Join Dementia Research' portal. Potential participants were sent; letter of invitation, Patient Information Sheet, Companion Information sheet and a reply slip. Response dependent participants were phoned for eligibility check and to make consenting/screening appointment

    Pre-assignment
    Screening details
    		 Pre-screening phase: early eligibility assessment (medication records, brief telephone assessment) Screening visit: eligibility assessment (MMSE, blood tests) Open label phase (including washout period): drug tolerabity (BP, blood for safety tests, record AEs)

    Period 1
    Period 1 title
    Baseline visit
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention - Losartan
    Arm description
    		 We used a maximum dose of over-encapsulated 100mg of losartan which was titrated directly from over-encapsulated 25 mg losartan that was initially given for 7 days and, reflecting standard clinical practice
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Control - placebo
    Arm description
    		 The placebo used in this study was similarly over-encapsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Number of subjects in period 1
    		Intervention - Losartan Control - placebo
    Started
    105
    106
    Completed
    105
    106
    Period 2
    Period 2 title
    3 month
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention - Losartan
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Control - placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placeob
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Number of subjects in period 2
    		Intervention - Losartan Control - placebo
    Started
    105
    106
    Completed
    105
    106
    Period 3
    Period 3 title
    6 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention - Losartan
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Control - placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Number of subjects in period 3
    		Intervention - Losartan Control - placebo
    Started
    105
    106
    Completed
    105
    106
    Period 4
    Period 4 title
    9 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention - Losartan
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Control - placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Number of subjects in period 4
    		Intervention - Losartan Control - placebo
    Started
    105
    106
    Completed
    105
    106
    Period 5
    Period 5 title
    12 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention - Losartan
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Control - placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Number of subjects in period 5
    		Intervention - Losartan Control - placebo
    Started
    105
    106
    Completed
    105
    106
    Period 6
    Period 6 title
    12 months hypertension
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention - hypertensive
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Intervention - normatensive
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Losartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Following randomisation, patients followed the same titration pattern as was followed in the open label phase of 25mg for 7 days then 100mg as a maintenance dosage with a 14-day monitoring and dispensing follow-up visit within the randomised phase

    Arm title
    		 Control - hypertensive
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Arm title
    		 Control - normatensive
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo used in this study was similarly capsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK.

    Number of subjects in period 6 [1]
    		Intervention - hypertensive Intervention - normatensive Control - hypertensive Control - normatensive
    Started
    37
    47
    43
    44
    Completed
    37
    47
    43
    44
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The numbers reflect subgroups within arms rather than preceding periods

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 We used a maximum dose of over-encapsulated 100mg of losartan which was titrated directly from over-encapsulated 25 mg losartan that was initially given for 7 days and, reflecting standard clinical practice

    Reporting group title
    Control - placebo
    Reporting group description
    		 The placebo used in this study was similarly over-encapsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK

    Reporting group values
    		 Intervention - Losartan Control - placebo Total
    Number of subjects
    		 105 106 211
    Age categorical
    Units: Subjects
        <70
    		 39 39 78
        70-79
    		 39 42 81
        >79
    		 27 25 52
    Gender categorical
    Units: Subjects
        Female
    		 45 39 84
        Male
    		 60 67 127
    Ethnicity
    Units: Subjects
        White
    		 104 106 210
        Other
    		 1 0 1
    Hypertensive
    Units: Subjects
        Yes
    		 47 50 97
        No
    		 58 56 114
    Taking anti-dementia drug
    Units: Subjects
        Yes
    		 100 102 202
        No
    		 5 4 9
    Schelten's score
    Units: Subjects
        Absent/Low
    		 62 62 124
        Moderate/Sever
    		 43 44 87
    Years of education
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 12 (10 to 16) 12 (11 to 16) -
    Time since diagnosis
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 1.38 (0.64 to 2.29) 1.10 (0.69 to 2.43) -
    Total brain volume
    Units: ml
        arithmetic mean (standard deviation)
    		 1022 ( 99 ) 1036 ( 111 ) -
    Total intracranial volume
    Units: ml
        arithmetic mean (standard deviation)
    		 1440 ( 140 ) 1459 ( 146 ) -
    Lateral ventricular volume
    Units: ml
        median (inter-quartile range (Q1-Q3))
    		 48 (35 to 69) 47 (35 to 64) -
    Total hippocampal volume
    Units: ml
        arithmetic mean (standard deviation)
    		 5.2 ( 0.9 ) 5.0 ( 1.0 ) -
    Left hippocampal volume
    Units: ml
        arithmetic mean (standard deviation)
    		 2.5 ( 0.5 ) 2.5 ( 0.5 ) -
    Right hippocampal volume
    Units: ml
        arithmetic mean (standard deviation)
    		 2.6 ( 0.5 ) 2.6 ( 0.5 ) -
    NPI
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    		 8 (3 to 18) 6 (2 to 15) -
    BADLS
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    		 7 (2 to 13) 5 (2 to 9) -
    DEMQOL
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    		 96 (87 to 102) 96 (85 to 102) -
    DEMQOL-PROXY
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    		 91 (82 to 100) 92 (83 to 99) -
    Sitting systolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Sitting diastolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Standing systolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Mean Systolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Standing diastolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Mean Diastolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    ADAS-COG
    Units: instrument score
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    MMSE
    Units: instrument score
        arithmetic mean (standard deviation)
    		 ( ) 22 ( 3 ) -
    Subject analysis sets

    Subject analysis set title
    Reduced N BL BP 1 - Intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incomplete N of baseline blood pressure measures

    Subject analysis set title
    Reduced N BL BP 1 - Control
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incomplete set of baseline blood pressure measures

    Subject analysis set title
    Reduced N BL BP 2 - Intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete baseline BP measures

    Subject analysis set title
    Reduced N BL BP 2 - Control
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete set of baseline blood pressure measures

    Subject analysis set title
    Reduced N BL ADAS - Intervention
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    incomplete baseline adas-cog instrument

    Subject analysis set title
    Reduced N BL ADAS - Control
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete baseline adas-cog instrument

    Subject analysis set title
    Reduced N BL MMSE - Intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete baseline MMSE instrument

    Subject analysis sets values
    		 Reduced N BL BP 1 - Intervention Reduced N BL BP 1 - Control Reduced N BL BP 2 - Intervention Reduced N BL BP 2 - Control Reduced N BL ADAS - Intervention Reduced N BL ADAS - Control Reduced N BL MMSE - Intervention
    Number of subjects
    85
    85
    83
    84
    103
    104
    103
    Age categorical
    Units: Subjects
        <70
        70-79
        >79
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity
    Units: Subjects
        White
        Other
    Hypertensive
    Units: Subjects
        Yes
        No
    Taking anti-dementia drug
    Units: Subjects
        Yes
        No
    Schelten's score
    Units: Subjects
        Absent/Low
        Moderate/Sever
    Years of education
    Units: years
        median (inter-quartile range (Q1-Q3))
    Time since diagnosis
    Units: years
        median (inter-quartile range (Q1-Q3))
    Total brain volume
    Units: ml
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Total intracranial volume
    Units: ml
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Lateral ventricular volume
    Units: ml
        median (inter-quartile range (Q1-Q3))
    Total hippocampal volume
    Units: ml
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Left hippocampal volume
    Units: ml
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Right hippocampal volume
    Units: ml
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    NPI
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    BADLS
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    DEMQOL
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    DEMQOL-PROXY
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    Sitting systolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    138 ( 14 )
    138 ( 15 )
    ( )
    ( )
    ( )
    ( )
    ( )
    Sitting diastolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    77 ( 9 )
    78 ( 9 )
    ( )
    ( )
    ( )
    ( )
    ( )
    Standing systolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    ( )
    ( )
    137 ( 17 )
    134 ( 17 )
    ( )
    ( )
    ( )
    Mean Systolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    ( )
    ( )
    138 ( 13 )
    136 ( 15 )
    ( )
    ( )
    ( )
    Standing diastolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    ( )
    ( )
    80 ( 12 )
    79 ( 9 )
    ( )
    ( )
    ( )
    Mean Diastolic BP
    Units: mmHG
        arithmetic mean (standard deviation)
    ( )
    ( )
    79 ( 9 )
    78 ( 8 )
    ( )
    ( )
    ( )
    ADAS-COG
    Units: instrument score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    20 ( 8 )
    19 ( 7 )
    ( )
    MMSE
    Units: instrument score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    22 ( 4 )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 We used a maximum dose of over-encapsulated 100mg of losartan which was titrated directly from over-encapsulated 25 mg losartan that was initially given for 7 days and, reflecting standard clinical practice

    Reporting group title
    Control - placebo
    Reporting group description
    		 The placebo used in this study was similarly over-encapsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 -

    Reporting group title
    Control - placebo
    Reporting group description
    		 -
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 -

    Reporting group title
    Control - placebo
    Reporting group description
    		 -
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 -

    Reporting group title
    Control - placebo
    Reporting group description
    		 -
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 -

    Reporting group title
    Control - placebo
    Reporting group description
    		 -
    Reporting group title
    Intervention - hypertensive
    Reporting group description
    		 -

    Reporting group title
    Intervention - normatensive
    Reporting group description
    		 -

    Reporting group title
    Control - hypertensive
    Reporting group description
    		 -

    Reporting group title
    Control - normatensive
    Reporting group description
    		 -

    Subject analysis set title
    Reduced N BL BP 1 - Intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incomplete N of baseline blood pressure measures

    Subject analysis set title
    Reduced N BL BP 1 - Control
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Incomplete set of baseline blood pressure measures

    Subject analysis set title
    Reduced N BL BP 2 - Intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete baseline BP measures

    Subject analysis set title
    Reduced N BL BP 2 - Control
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete set of baseline blood pressure measures

    Subject analysis set title
    Reduced N BL ADAS - Intervention
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    incomplete baseline adas-cog instrument

    Subject analysis set title
    Reduced N BL ADAS - Control
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete baseline adas-cog instrument

    Subject analysis set title
    Reduced N BL MMSE - Intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    incomplete baseline MMSE instrument

    Primary: Mean brain volume at 12 months

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    End point title
    		 Mean brain volume at 12 months
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    1002 ( 98 )
    1018 ( 111 )
    Statistical analysis title
    		 Adjusted difference in mean brain volume at 12m
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.136
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.46
         upper limit
    		 0.89

    Secondary: 12 month BSI

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    End point title
    		 12 month BSI
    End point description
    brain volume change from baseline to 12 months as measured by the boundary shift interval
    End point type
    Secondary
    End point timeframe
    baseline to 12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    20.0 ( 10.8 )
    19.1 ( 10.3 )
    Statistical analysis title
    		 Adjusted difference in mean BSI
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.411
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.72
         upper limit
    		 4.19

    Secondary: Mean MMSE at 12 months

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    End point title
    		 Mean MMSE at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    95
    97
    Units: instrument score
        arithmetic mean (standard deviation)
    19 ( 6 )
    19 ( 6 )
    Statistical analysis title
    		 Adjusted difference in mean MMSE at 12m
    Comparison groups
    Control - placebo v Intervention - Losartan
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 0.78

    Secondary: NPI at 12 months

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    End point title
    		 NPI at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    92
    99
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    8 (3 to 18)
    8 (3 to 17)
    Statistical analysis title
    		 Adjusted ratio of geometric mean NPI 12 months
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Regression, Linear
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.13

    Secondary: BADLS at 12 months

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    End point title
    		 BADLS at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    94
    100
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    10 (3 to 17)
    7 (3 to 14)
    Statistical analysis title
    		 Adjusted ratio of BADLS 12 month geometric means
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 Regression, Linear
    Parameter type
    		 ratio of geometric means
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.21

    Secondary: DEMQOL at 12 months

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    End point title
    		 DEMQOL at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    91
    95
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    96 (87 to 105)
    94 (85 to 101)
    Statistical analysis title
    		 Adjusted ratio of 12 month DEMQOL geometric means
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74
    Method
    		 Regression, Linear
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.09

    Secondary: DEMQOL-PROXY at 12 months

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    End point title
    		 DEMQOL-PROXY at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    92
    98
    Units: instrument score
        median (inter-quartile range (Q1-Q3))
    93 (83 to 99)
    93 (82 to 100)
    Statistical analysis title
    		 Adjusted difference of 12m DEMQOL-PROXY means
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 4.28

    Secondary: 12 month ADAS-COG

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    End point title
    		 12 month ADAS-COG
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    90
    92
    Units: instrument score
        arithmetic mean (standard deviation)
    23 ( 12 )
    24 ( 12 )
    Statistical analysis title
    		 Adjusted difference in 12 m ADAS-COG mean
    Comparison groups
    Control - placebo v Intervention - Losartan
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.71
         upper limit
    		 1.66

    Secondary: White Matter Hyperintensity at 12 months

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    End point title
    		 White Matter Hyperintensity at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    54
    51
    Units: ml
        median (inter-quartile range (Q1-Q3))
    11992 (2548 to 24039)
    9793 (4788 to 20263)
    Statistical analysis title
    		 Ratio of geometric means of 12 month WMH
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.697
    Method
    		 Regression, Linear
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.05

    Other pre-specified: Compliance sensitivity analysis

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    End point title
    		 Compliance sensitivity analysis
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    79
    87
    Units: ml
        arithmetic mean (standard deviation)
    1002 ( 100 )
    1019 ( 113 )
    Statistical analysis title
    		 CACE analysis
    Statistical analysis description
    CACE analysis based on treatment compliance status
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.106
    Method
    		 2SLS IV regression
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.14
         upper limit
    		 0.69

    Other pre-specified: 12m brain volume by hypertensive status

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    End point title
    		 12m brain volume by hypertensive status
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Intervention - hypertensive Intervention - normatensive Control - hypertensive Control - normatensive
    Number of subjects analysed
    37
    47
    43
    44
    Units: ml
        arithmetic mean (standard deviation)
    998 ( 101 )
    1044 ( 97 )
    1009 ( 114 )
    1029 ( 112 )
    Statistical analysis title
    		 Treatment effect moderation of hypertensive status
    Statistical analysis description
    primary analysis repeated including an interaction between treatment allocation and hypertensive status
    Comparison groups
    Intervention - hypertensive v Intervention - normatensive v Control - hypertensive v Control - normatensive
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.509
    Method
    		 Regression, Linear
    Parameter type
    		 difference in adjusted mean difference
    Point estimate
    -2.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.43
         upper limit
    		 5.19

    Other pre-specified: MI sensitivity analysis of primary outcome (brain volume)

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    End point title
    		 MI sensitivity analysis of primary outcome (brain volume)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    105
    106
    Units: ml
        arithmetic mean (standard error)
    1003 ( 10 )
    1017 ( 10 )
    Statistical analysis title
    		 repeat primary analysis on multiply imputed data
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.77
         upper limit
    		 3.25

    Post-hoc: 12 month lateral ventricular volume

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    End point title
    		 12 month lateral ventricular volume
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        median (inter-quartile range (Q1-Q3))
    51 (40 to 78)
    50 (40 to 67)
    Statistical analysis title
    		 Ratio of geometric means of 12m LVV
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.443
    Method
    		 Regression, Linear
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.01

    Post-hoc: LVV BSI

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    End point title
    		 LVV BSI
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    83
    86
    Units: ml
        median (inter-quartile range (Q1-Q3))
    5 (3 to 8)
    5 (3 to 7)
    Statistical analysis title
    		 Adjusted difference in mean LVV BSI
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 0.56

    Post-hoc: 12m left hippocampal volume

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    End point title
    		 12m left hippocampal volume
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    2.5 ( 0.5 )
    2.4 ( 0.5 )
    Statistical analysis title
    		 Adjusted difference in mean 12m LHV
    Comparison groups
    Control - placebo v Intervention - Losartan
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.337
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.03

    Post-hoc: LHV BSI

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    End point title
    		 LHV BSI
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    0.11 ( 0.08 )
    0.11 ( 0.06 )
    Statistical analysis title
    		 Adjusted difference in mean LHV BSI
    Comparison groups
    Control - placebo v Intervention - Losartan
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.385
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.01

    Post-hoc: 12m right hippocampal volume

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    End point title
    		 12m right hippocampal volume
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    2.6 ( 0.5 )
    2.5 ( 0.5 )
    Statistical analysis title
    		 Adjusted difference in mean 12m RHV
    Comparison groups
    Control - placebo v Intervention - Losartan
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.112
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.003
         upper limit
    		 0.03

    Post-hoc: RHV BSI

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    End point title
    		 RHV BSI
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    0.11 ( 0.08 )
    0.12 ( 0.06 )
    Statistical analysis title
    		 Adjusted difference in mean RHV BSI
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.231
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.01

    Post-hoc: 12m total hippocampal volume

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    End point title
    		 12m total hippocampal volume
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    84
    87
    Units: ml
        arithmetic mean (standard deviation)
    5.0 ( 0.9 )
    4.9 ( 0.9 )
    Statistical analysis title
    		 Adjusted difference in mean 12m THV
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.144
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.05

    Post-hoc: 12m Schelten's

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    End point title
    		 12m Schelten's
    End point description
    End point type
    Post-hoc
    End point timeframe
    12 months
    End point values
    		 Intervention - Losartan Control - placebo
    Number of subjects analysed
    91
    98
    Units: number of people
        no atrophy
    14
    9
        only widening of choroid fissure
    36
    28
        also widening of temporal horn of lateral ventricl
    21
    43
        moderate loss of hippocampal volume
    19
    18
        severe volume loss of hippocampus
    1
    0
    Statistical analysis title
    		 Difference in 12m Schelten's score
    Comparison groups
    Intervention - Losartan v Control - placebo
    Number of subjects included in analysis
    189
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 ordinal logistic regression
    Parameter type
    		 proportional odds ratio
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.68

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    baseline to 12 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NA
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Intervention - Losartan
    Reporting group description
    		 We used a maximum dose of over-encapsulated 100mg of losartan which was titrated directly from over-encapsulated 25 mg losartan that was initially given for 7 days and, reflecting standard clinical practice

    Reporting group title
    Control - placebo
    Reporting group description
    		 The placebo used in this study was similarly over-encapsulated and made to match both doses and sourced from St. Mary’s Pharmaceutical Unit [SMPU], Cardiff, UK

    Serious adverse events
    		 Intervention - Losartan Control - placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 105 (20.95%)
    20 / 106 (18.87%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Elective surgery (throat biopsy)
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         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
    Ankle swelling (oedema)
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persistent nausea, dizziness and headache
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility problems and unable to get out of bath
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose of dementia medication
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Collapse
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Collapse without loss of consciousness
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Found slumped on sofa unable to sit up, visual hallucinations
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vivid delusions and aggressive outburst
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Temp admission to Dementia Assessment Unit
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    fall
         subjects affected / exposed
    2 / 105 (1.90%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fainting
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Participant died. Admitted with femur fracture, dehydration and anaemia. Unrelated to trial
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    prolonged syncopal episode
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fainting and bradycardia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    seizure
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain pathology
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Admission 3 days Right sided chest pain. Discharged with anticoagulant meds.
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation and prolapse
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomach pain and breathing difficulty
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention and diarrhoea and vomiting
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Collapse Raised ALT 100 (0-55)
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grossly raised AST serum level
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Safety bloods results outside of the safety range
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (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
    Rash around armpits and right side of the abdomen
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    development of diabetes
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Participant died pancreatic cancer
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Hospital admission knee pain. Arthritis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Hospital admission. Sepsis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis left leg
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis left leg flare up
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recurrent bronchitis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizzy spell, tremor and cold hands. Discharged with antibiotics.
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention - Losartan Control - placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 105 (76.19%)
    84 / 106 (79.25%)
    General disorders and administration site conditions
    AE
         subjects affected / exposed
    80 / 105 (76.19%)
    84 / 106 (79.25%)
         occurrences all number
    80
    84

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2013
    Revisions for clarity, consistency with SOPs and MRE recommendations
    18 Jul 2013
    Addition of information pertaining to pilot imaging procedures
    28 Nov 2013
    Change to minimisation details and eligibility criteria
    07 Oct 2014
    Remove severe hippocampal atrophy as exclusion criteria
    03 Dec 2015
    Change to MMSE inclusion criteria
    03 Mar 2016
    Inclusion of an embedded qualitative component
    27 Jul 2017
    Inclusion of additional pre-screening tools, and clarification to consent wording
    11 Oct 2017
    Amendment to the blood pressure range exclusion criteria

    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.
    This study may still be underpowered, or the intervention may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes or may not have crossed the blood brain barrier as much as expected.
    For support, Contact us.
    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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