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    Clinical Trial Results:
    RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, MULTI-CENTER REGISTRATION TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF TTP488 IN PATIENTS WITH MILD ALZHEIMER'S DISEASE RECEIVING ACETYLCHOLINESTERASE INHIBITORS AND/OR MEMANTINE

    Summary
    EudraCT number
    		 2016-002005-19
    Trial protocol
    		 GB   IE  
    Global end of trial date
    01 Jun 2018

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TTP488-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02080364
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 US IND : 68, 445, CTA Control #: 181266
    Sponsors
    Sponsor organisation name
    vTv Therapeutics LLC
    Sponsor organisation address
    3980 Premier Dr., High Point, United States, 27265
    Public contact
    Ann Gooch, vTv THERAPEUTICS LLC, 1 3368410300, AGOOCH@VTVTHERAPEUTICS.COM
    Scientific contact
    Ann Gooch, vTv THERAPEUTICS LLC, 1 3368410300, AGOOCH@VTVTHERAPEUTICS.COM
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of azeliragon on cognitive [Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] and global function [Clinical Dementia Rating Scale Sum of Boxes (CDR-sb)] measures in patients with mild AD.
    Protection of trial subjects
    Safety surveillance was performed regularly by the medical monitor (blinded) and the Independent Data Monitoring Committee as a protection for trial subjects. Safety surveillance of the accumulating safety data was performed by the medical monitors monthly in a blinded fashion. Safety surveillance review included review of adverse events, lab results and alerts, ECG results and alerts, MRI findings, and protocol deviations. In addition, an external Independent Data Monitoring Committee was responsible for the review of all available safety data. The primary function of the IDMC was to monitor the study and recommend to the Sponsor whether to amend safety monitoring procedures, modify the protocol or consent, terminate the study, or continue the study as designed in order to safeguard the well-being of subjects already in the study and those yet to be recruited.
    Background therapy
    		 All subjects enrolled in TTP488-301 were required to be on a stable dose of a background cholinesterase inhibitor and/or memantine.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2015
    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: 48
    Country: Number of subjects enrolled
    Ireland: 16
    Country: Number of subjects enrolled
    United States: 662
    Country: Number of subjects enrolled
    Canada: 84
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    South Africa: 46
    Worldwide total number of subjects
    880
    EEA total number of subjects
    64
    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)
    115
    From 65 to 84 years
    654
    85 years and over
    111

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The A-Study was conducted from March 2015 through April 2018 in the United States and Canada. The B-Study was conducted from September 2016 through June 2018 in the United States, Canada, United Kingdom, Ireland, South Africa, Australia and New Zealand.

    Pre-assignment
    Screening details
    		 A total of 1733 subjects underwent screening procedures for determination of eligibility for participation across the A- and B- Studies.

    Pre-assignment period milestones
    Number of subjects started
    		 1733 [1]
    Number of subjects completed
    		 880

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen failure: 853
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1733 subjects started the screening process worldwide; however, 880 subjects completed the screening process as eligible subjects to participate in the study. Therefore 880 subjects are captured as the worldwide enrollment number.
    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azeliragon - A Study
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azeliragon
    Investigational medicinal product code
    Other name
    TTP488
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Drug supplies consisted of a 5 mg azeliragon and matching placebo formulation supplied as a Size 2 hard gelatin capsule in a double-blind fashion. Treatment began in the clinic at the baseline visit immediately following randomization. Participants were to be instructed to take one capsule per day by mouth for the duration of the treatment period.

    Arm title
    		 Placebo - A Study
    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
    One capsule by mouth once daily. May be administered without regards to meals.

    Arm title
    		 Azeliragon - B Study
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azeliragon
    Investigational medicinal product code
    Other name
    TTP488
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Drug supplies consisted of a 5 mg azeliragon and matching placebo formulation supplied as a Size 2 hard gelatin capsule in a double-blind fashion. Treatment began in the clinic at the baseline visit immediately following randomization. Participants were to be instructed to take one capsule per day by mouth for the duration of the treatment period.

    Arm title
    		 Placebo - B Study
    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
    One capsule by mouth once daily. May be administered without regards to meals.

    Number of subjects in period 1
    		Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study
    Started
    197
    208
    247
    228
    Completed
    195
    206
    246
    228
    Not completed
    2
    2
    1
    0
         Other
    -
    1
    1
    -
         Protocol deviation
    2
    1
    -
    -
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Azeliragon - A Study
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azeliragon
    Investigational medicinal product code
    Other name
    TTP488
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Drug supplies consisted of a 5 mg azeliragon and matching placebo formulation supplied as a Size 2 hard gelatin capsule in a double-blind fashion. Treatment began in the clinic at the baseline visit immediately following randomization. Participants were to be instructed to take one capsule per day by mouth for the duration of the treatment period.

    Arm title
    		 Placebo - A Study
    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
    One capsule by mouth once daily. May be administered without regards to meals.

    Arm title
    		 Azeliragon - B Study
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azeliragon
    Investigational medicinal product code
    Other name
    TTP488
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Drug supplies consisted of a 5 mg azeliragon and matching placebo formulation supplied as a Size 2 hard gelatin capsule in a double-blind fashion. Treatment began in the clinic at the baseline visit immediately following randomization. Participants were to be instructed to take one capsule per day by mouth for the duration of the treatment period.

    Arm title
    		 Placebo - B Study
    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
    One capsule by mouth once daily. May be administered without regards to meals.

    Arm title
    		 Azeliragon- A+B Study
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azeliragon
    Investigational medicinal product code
    Other name
    TTP488
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Drug supplies consisted of a 5 mg azeliragon and matching placebo formulation supplied as a Size 2 hard gelatin capsule in a double-blind fashion. Treatment began in the clinic at the baseline visit immediately following randomization. Participants were to be instructed to take one capsule per day by mouth for the duration of the treatment period.

    Arm title
    		 Placebo - A+B Study
    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
    One capsule by mouth once daily. May be administered without regards to meals.

    Number of subjects in period 2
    		Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study Azeliragon- A+B Study Placebo - A+B Study
    Started
    195
    206
    246
    228
    441
    434
    Completed
    148
    157
    9
    4
    157
    161
    Not completed
    47
    49
    237
    224
    284
    273
         Consent withdrawn by subject
    16
    16
    15
    10
    31
    26
         Adverse event, non-fatal
    10
    15
    11
    14
    21
    29
         Other
    14
    12
    21
    16
    35
    28
         Study Terminated by Sponsor
    -
    -
    180
    183
    180
    183
         Lost to follow-up
    2
    3
    5
    -
    7
    3
         Protocol deviation
    5
    3
    5
    1
    10
    4

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Azeliragon - A Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - A Study
    Reporting group description
    		 -

    Reporting group title
    Azeliragon - B Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - B Study
    Reporting group description
    		 -

    Reporting group values
    		 Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study Total
    Number of subjects
    		 197 208 247 228 880
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.3 ( 9.14 ) 74.6 ( 7.94 ) 74.7 ( 8.56 ) 74.0 ( 8.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 97 91 107 107 402
        Male
    		 98 115 139 121 473
        Not recorded
    		 2 2 1 0 5
    Race
    Units: Subjects
        White
    		 179 194 231 220 824
        Black or African American
    		 8 9 8 5 30
        Asian
    		 5 2 6 3 16
        Hawaiian or other Pacific Islander
    		 2 0 1 0 3
        American Indian or Alaska Native
    		 0 1 0 0 1
        Multiple
    		 1 0 0 0 1
        Not recorded
    		 2 2 1 0 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 27 23 8 15 73
        Not Hispanic or Latino
    		 168 183 238 213 802
        Not collected
    		 2 2 1 0 5
    Apo E4 status
    Units: Subjects
        Heterozygous
    		 83 79 115 105 382
        Homozygous
    		 15 27 31 18 91
        Non-carrier
    		 95 98 96 99 388
        Not collected
    		 4 4 5 6 19
    Education Level
    Units: Subjects
        High School
    		 61 65 86 79 291
        Other (trainings, certifications)
    		 15 14 8 6 43
        Some college
    		 32 33 34 31 130
        Associate's Degree
    		 17 14 14 21 66
        Bachelor's Degree
    		 44 39 64 55 202
        Master's Degree
    		 21 26 29 25 101
        Doctoral Degree
    		 5 15 11 11 42
        Not recorded
    		 2 2 1 0 5
    Background AD Medication
    Units: Subjects
        Memantine
    		 12 16 19 22 69
        Acetylcholinesterase inhibitor
    		 117 124 156 145 542
        Both Memantine and Acetylcholinesterase inhibitor
    		 65 66 71 60 262
        Not recorded
    		 3 2 1 1 7
    Years since AD diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 2.4 ( 2.4 ) 2.3 ( 2.4 ) 2.0 ( 1.9 ) 1.9 ( 1.9 ) -
    Baseline MMSE
    Units: points
        arithmetic mean (standard deviation)
    		 23.5 ( 2.6 ) 23.2 ( 2.5 ) 23.3 ( 2.5 ) 23.4 ( 2.7 ) -
    Baseline ADAS-cog
    Units: points
        arithmetic mean (standard deviation)
    		 15.3 ( 5.2 ) 15.6 ( 5.5 ) 17.0 ( 5.6 ) 16.1 ( 5.3 ) -
    Baseline CDR-Sum of Boxes
    Units: points
        arithmetic mean (standard deviation)
    		 4.1 ( 1.7 ) 4.1 ( 1.6 ) 4.6 ( 1.6 ) 4.5 ( 1.6 ) -
    Baseline ADCS-ADL
    Units: points
        arithmetic mean (standard deviation)
    		 67.8 ( 7.3 ) 67.5 ( 8.4 ) 66.3 ( 8.2 ) 67.2 ( 7.6 ) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) includes all randomized subjects who receive any study medication.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set (SAF) includes all subjects who receive any study medication.

    Subject analysis sets values
    		 Full Analysis Set Safety Analysis Set
    Number of subjects
    829
    875
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    74.4 ( 8.53 )
    74.7 ( 8.80 )
    Gender categorical
    Units: Subjects
        Female
    380
    402
        Male
    449
    473
        Not recorded
    Race
    Units: Subjects
        White
    778
    824
        Black or African American
    30
    30
        Asian
    16
    16
        Hawaiian or other Pacific Islander
    3
    3
        American Indian or Alaska Native
    1
    1
        Multiple
    1
    1
        Not recorded
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    69
    73
        Not Hispanic or Latino
    760
    802
        Not collected
    Apo E4 status
    Units: Subjects
        Heterozygous
    364
    382
        Homozygous
    84
    91
        Non-carrier
    368
    388
        Not collected
    Education Level
    Units: Subjects
        High School
    278
    291
        Other (trainings, certifications)
    39
    43
        Some college
    124
    130
        Associate's Degree
    60
    66
        Bachelor's Degree
    189
    202
        Master's Degree
    98
    101
        Doctoral Degree
    41
    42
        Not recorded
    Background AD Medication
    Units: Subjects
        Memantine
    313
    331
        Acetylcholinesterase inhibitor
    762
    804
        Both Memantine and Acetylcholinesterase inhibitor
    248
    262
        Not recorded
    Years since AD diagnosis
    Units: years
        arithmetic mean (standard deviation)
    2.1 ( 2.2 )
    2.1 ( 2.2 )
    Baseline MMSE
    Units: points
        arithmetic mean (standard deviation)
    23.4 ( 2.6 )
    23.3 ( 2.6 )
    Baseline ADAS-cog
    Units: points
        arithmetic mean (standard deviation)
    16.0 ( 5.5 )
    16.0 ( 5.4 )
    Baseline CDR-Sum of Boxes
    Units: points
        arithmetic mean (standard deviation)
    4.3 ( 1.6 )
    4.3 ( 1.6 )
    Baseline ADCS-ADL
    Units: points
        arithmetic mean (standard deviation)
    67.0 ( 7.9 )
    67.4 ( 8.0 )

    End points

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    End points reporting groups
    Reporting group title
    Azeliragon - A Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - A Study
    Reporting group description
    		 -

    Reporting group title
    Azeliragon - B Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - B Study
    Reporting group description
    		 -
    Reporting group title
    Azeliragon - A Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - A Study
    Reporting group description
    		 -

    Reporting group title
    Azeliragon - B Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - B Study
    Reporting group description
    		 -

    Reporting group title
    Azeliragon- A+B Study
    Reporting group description
    		 -

    Reporting group title
    Placebo - A+B Study
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) includes all randomized subjects who receive any study medication.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set (SAF) includes all subjects who receive any study medication.

    Primary: Change from Baseline in the ADAS-cog

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    End point title
    		 Change from Baseline in the ADAS-cog
    End point description
    Change from Baseline in ADAS-cog Total Score - MMRM
    End point type
    Primary
    End point timeframe
    Baseline to Month 18 (Study A) Baseline to Month 12 (Study B) [B-study results reported for data collected through announcement of A-study results and termination of B-Study.]
    End point values
    		 Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study
    Number of subjects analysed
    138
    151
    118 [1]
    121 [2]
    Units: Points
        least squares mean (standard error)
    3.8 ( 0.51 )
    3.1 ( 0.49 )
    3.4 ( 0.46 )
    2.5 ( 0.46 )
    Notes
    [1] - Excludes data from visits after announcement of A-Study topline results and termination of B-Study
    [2] - Excludes data from visits after announcement of A-Study topline results and termination of B-Study
    Statistical analysis title
    		 A-Study Change from Baseline in ADAS-cog
    Statistical analysis description
    The primary analysis will be done on change from baseline in ADAS-cog and on change from baseline in CDR-sb. The primary analysis will use the ITT methodology and a main-effects model with analysis of covariance (ANCOVA) at endpoint with multiple imputations (MI) for coping with missing data, with 100 invocations (acknowledging that more invocations are needed with more missing data). Monte Carlo methods are planned.
    Comparison groups
    Placebo - A Study v Azeliragon - A Study
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3386
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 B-Study Change from Baseline in ADAS-cog
    Comparison groups
    Azeliragon - B Study v Placebo - B Study
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1992
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Change from Baseline in the CDR-sb

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    End point title
    		 Change from Baseline in the CDR-sb
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Month 18 (Study A) Baseline to Month 12 (Study B) [B-study results reported for data collected through announcement of A-study results and termination of B-Study.]
    End point values
    		 Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study
    Number of subjects analysed
    140
    150
    117
    120
    Units: points
        arithmetic mean (standard deviation)
    1.4 ( 2.23 )
    1.4 ( 1.85 )
    1.3 ( 1.87 )
    0.7 ( 1.40 )
    Statistical analysis title
    		 Primary Efficacy Analysis
    Statistical analysis description
    The primary analysis will be done on change from baseline in ADAS-cog and on change from baseline in CDR-sb. The primary analysis will use the ITT methodology and a main-effects model with analysis of covariance (ANCOVA) at endpoint with multiple imputations (MI) for coping with missing data, with 100 invocations (acknowledging that more invocations are needed with more missing data). Monte Carlo methods are planned.
    Comparison groups
    Azeliragon - A Study v Placebo - A Study
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9394
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change from Baseline in hippocampal volume at Month 18

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    End point title
    		 Change from Baseline in hippocampal volume at Month 18
    End point description
    Percent of Total Hippocampal Atrophy to Intracranial Volume
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Azeliragon- A+B Study Placebo - A+B Study
    Number of subjects analysed
    112
    116
    Units: Percent
        least squares mean (standard error)
    -0.016 ( 0.001 )
    -0.014 ( 0.001 )
    Statistical analysis title
    		 Key Secondary
    Statistical analysis description
    LS Means and standard errors are based on an ANCOVA model with change from baseline as the response variable and effects for treatment and baseline stratum and a covariate of baseline included in the model.
    Comparison groups
    Azeliragon- A+B Study v Placebo - A+B Study
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1792
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - LS Means and standard errors are based on an ANCOVA model with change from baseline as the response variable and effects for treatment and baseline stratum and a covariate of baseline included in the model.

    Secondary: Change from Baseline in ADCS-ADL total score

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    End point title
    		 Change from Baseline in ADCS-ADL total score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18 (Study A) Baseline to Month 12 (Study B) [B-study results reported for data collected through announcement of A-study results and termination of B-Study.]
    End point values
    		 Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study
    Number of subjects analysed
    141
    152
    121
    122
    Units: points
        arithmetic mean (standard deviation)
    -5.1 ( 8.63 )
    -3.2 ( 8.92 )
    -5.4 ( 8.85 )
    -2.8 ( 7.83 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in MMSE

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    End point title
    		 Change from Baseline in MMSE
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18 (Study A) Baseline to Month 12 (Study B) [B-study results reported for data collected through announcement of A-study results and termination of B-Study.]
    End point values
    		 Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study
    Number of subjects analysed
    142
    153
    121
    121
    Units: points
        arithmetic mean (standard deviation)
    -2.1 ( 3.55 )
    -2.0 ( 3.25 )
    -2.1 ( 3.25 )
    -1.8 ( 3.29 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in NPI total score

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    End point title
    		 Change from Baseline in NPI total score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18 (Study A) Baseline to Month 12 (Study B) [B-study results reported for data collected through announcement of A-study results and termination of B-Study.]
    End point values
    		 Azeliragon - A Study Placebo - A Study Azeliragon - B Study Placebo - B Study
    Number of subjects analysed
    142
    152
    121
    122
    Units: points
        arithmetic mean (standard deviation)
    -0.2 ( 9.77 )
    1.3 ( 11.53 )
    2.3 ( 11.24 )
    0 ( 10.67 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting will commence as soon as the study participant has been dosed and continue through their last study visit.
    Adverse event reporting additional description
    Note: Non-serious adverse events reported here include all adverse events (including serious adverse events).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Azeliragon - Study A+B
    Reporting group description
    		 -

    Reporting group title
    Placebo - Study A+B
    Reporting group description
    		 -

    Serious adverse events
    		 Azeliragon - Study A+B Placebo - Study A+B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 441 (15.87%)
    67 / 434 (15.44%)
         number of deaths (all causes)
    4
    5
         number of deaths resulting from adverse events
    4
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         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
    Chest pain
         subjects affected / exposed
    2 / 441 (0.45%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 441 (0.45%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 441 (0.00%)
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 441 (0.68%)
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 441 (0.23%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 441 (0.23%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 441 (0.00%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 441 (0.00%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 441 (0.68%)
    5 / 434 (1.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 441 (0.00%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    4 / 441 (0.91%)
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    2 / 441 (0.45%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 441 (0.00%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 441 (1.13%)
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 441 (0.23%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 441 (0.00%)
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 434 (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: 2%
    Non-serious adverse events
    		 Azeliragon - Study A+B Placebo - Study A+B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    320 / 441 (72.56%)
    324 / 434 (74.65%)
    Investigations
    Weight decreased
         subjects affected / exposed
    17 / 441 (3.85%)
    13 / 434 (3.00%)
         occurrences all number
    17
    13
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    51 / 441 (11.56%)
    58 / 434 (13.36%)
         occurrences all number
    62
    62
    Laceration
         subjects affected / exposed
    10 / 441 (2.27%)
    11 / 434 (2.53%)
         occurrences all number
    10
    13
    Contusion
         subjects affected / exposed
    8 / 441 (1.81%)
    9 / 434 (2.07%)
         occurrences all number
    9
    13
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 441 (2.27%)
    14 / 434 (3.23%)
         occurrences all number
    10
    14
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 441 (1.81%)
    12 / 434 (2.76%)
         occurrences all number
    11
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 441 (4.08%)
    15 / 434 (3.46%)
         occurrences all number
    19
    15
    Headache
         subjects affected / exposed
    15 / 441 (3.40%)
    19 / 434 (4.38%)
         occurrences all number
    16
    19
    Syncope
         subjects affected / exposed
    11 / 441 (2.49%)
    9 / 434 (2.07%)
         occurrences all number
    12
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 441 (2.95%)
    14 / 434 (3.23%)
         occurrences all number
    16
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 441 (3.85%)
    20 / 434 (4.61%)
         occurrences all number
    18
    22
    Nausea
         subjects affected / exposed
    14 / 441 (3.17%)
    10 / 434 (2.30%)
         occurrences all number
    14
    10
    Constipation
         subjects affected / exposed
    10 / 441 (2.27%)
    8 / 434 (1.84%)
         occurrences all number
    10
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 441 (2.95%)
    9 / 434 (2.07%)
         occurrences all number
    13
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    21 / 441 (4.76%)
    20 / 434 (4.61%)
         occurrences all number
    21
    20
    Agitation
         subjects affected / exposed
    15 / 441 (3.40%)
    17 / 434 (3.92%)
         occurrences all number
    17
    18
    Anxiety
         subjects affected / exposed
    11 / 441 (2.49%)
    15 / 434 (3.46%)
         occurrences all number
    12
    15
    Insomnia
         subjects affected / exposed
    11 / 441 (2.49%)
    7 / 434 (1.61%)
         occurrences all number
    11
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 441 (2.27%)
    15 / 434 (3.46%)
         occurrences all number
    11
    15
    Musculoskeletal pain
         subjects affected / exposed
    10 / 441 (2.27%)
    5 / 434 (1.15%)
         occurrences all number
    10
    5
    Arthralgia
         subjects affected / exposed
    9 / 441 (2.04%)
    14 / 434 (3.23%)
         occurrences all number
    9
    16
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    45 / 441 (10.20%)
    35 / 434 (8.06%)
         occurrences all number
    47
    36
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 441 (4.54%)
    16 / 434 (3.69%)
         occurrences all number
    23
    17
    Nasopharyngitis
         subjects affected / exposed
    19 / 441 (4.31%)
    23 / 434 (5.30%)
         occurrences all number
    19
    24
    Bronchitis
         subjects affected / exposed
    10 / 441 (2.27%)
    15 / 434 (3.46%)
         occurrences all number
    10
    15
    Pneumonia
         subjects affected / exposed
    9 / 441 (2.04%)
    7 / 434 (1.61%)
         occurrences all number
    9
    7
    Sinusitis
         subjects affected / exposed
    9 / 441 (2.04%)
    9 / 434 (2.07%)
         occurrences all number
    9
    9
    Influenza
         subjects affected / exposed
    7 / 441 (1.59%)
    12 / 434 (2.76%)
         occurrences all number
    7
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 441 (1.13%)
    9 / 434 (2.07%)
         occurrences all number
    5
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2016
    Investigator Brochure Version 10.1 dated 15 Aug 2016 included changes to the reference safety information based upon feedback from MHRA during CTA review.
    21 Feb 2018
    TTP488-301 Protocol Amendment 7 & IB Version 11 1. Remove restriction for drugs known to be strong CYP3A4 inhibitors based on completed drug drug interaction study showing no clinically relevant interaction between azeliragon and a strong CYP3A4 inhibitor. The recent Investigator’s Brochure (IB) update (Version 11 dated 09 Aug 2017) includes the completed drug-drug interaction study justifying this change. 2. Add Follow-up visit to occur 3 months after last dose of study drug for those participants who discontinue the study early. This visit will allow a final safety follow-up assessment off treatment for participants who discontinue prior to the Month 18 Visit. 3. Modify the MRI and PET analyses to be unblinded to time sequence. MRI and PET trained technicians remain blinded to subject treatment assignment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Apr 2018
    On 10 April 2018, TTP488-301 Investigators were instructed to contact their STEADFAST Part B participants and caregivers as soon as possible to inform them that the study was being stopped due to lack of efficacy based upon Part A topline results. Part B Participants were informed to immediately discontinue dosing and return for an Early Termination Visit as soon as possible, and a Follow‐up visit at 6 weeks following the last dose of study medication.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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