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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer’s disease (AD)

    Summary
    EudraCT number
    		 2016-002976-28
    Trial protocol
    		 ES   DE   BE   FI   IS   PT   NL   GB   FR   IT  
    Global end of trial date
    26 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Apr 2021
    First version publication date
    12 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCNP520A2202J
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03131453
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Novartis Pharma AG, Clinical Disclosure Office, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Novartis Pharma AG, Clinical Disclosure Office, 41 613241111, Novartis.email@Novartis.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
    26 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objectives of the trial were to demonstrate the effect of CNP520 vs. placebo on time to diagnosis of mild cognitive impairment (MCI) due to AD or dementia due to AD, whichever occurs first during the course of the study and to demonstrate the effect of CNP520 vs. placebo on cognition using API Preclinical Composite Cognitive Battery (APCC). The study was terminated early due to unexpected, mild, early worsening in measures of cognitive function, increased brain volume loss, and greater mean body weight loss on CNP520 compared to placebo. Treatment was stopped due to an early signal of potential harm to study participants, which was studied through the off-treatment follow-up period which demonstrated reversibility of the findings. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Aug 2017
    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
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Iceland: 129
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Japan: 28
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 158
    Country: Number of subjects enrolled
    United States: 645
    Worldwide total number of subjects
    1144
    EEA total number of subjects
    214
    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)
    201
    From 65 to 84 years
    943
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 8970 participants were screened. One patient in the CNP520 50 mg arm was mis-randomized and not included in Number started.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CNP520 50 mg
    Arm description
    		 50 mg capsule taken orally once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    CNP520
    Investigational medicinal product code
    CNP520
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    CNP520 50 mg administered orally once daily

    Arm title
    		 CNP520 15 mg
    Arm description
    		 15 mg capsule taken orally once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    CNP520
    Investigational medicinal product code
    CNP520
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    CNP520 15 mg administered orally once daily

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo to 15 and 50 mg CNP520 taken orally once daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo of CNP520 50 mg or 15mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally once daily

    Number of subjects in period 1
    		CNP520 50 mg CNP520 15 mg Placebo
    Started
    455
    233
    456
    Completed
    0
    0
    0
    Not completed
    455
    233
    456
         Consent withdrawn by subject
    18
    7
    13
         Physician decision
    1
    -
    1
         Study terminated by Sponsor
    424
    222
    438
         Adverse event, non-fatal
    10
    3
    3
         Technical problems
    1
    -
    -
         Protocol deviation
    -
    1
    -
         Lost to follow-up
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CNP520 50 mg
    Reporting group description
    		 50 mg capsule taken orally once daily

    Reporting group title
    CNP520 15 mg
    Reporting group description
    		 15 mg capsule taken orally once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to 15 and 50 mg CNP520 taken orally once daily

    Reporting group values
    		 CNP520 50 mg CNP520 15 mg Placebo Total
    Number of subjects
    		 455 233 456 1144
    Age Categorical
    Units: participants
        <=64
    		 76 45 80 201
        65-69
    		 181 82 162 425
        >70
    		 198 106 214 518
    Sex: Female, Male
    Units:
        Female
    		 284 148 288 720
        Male
    		 171 85 168 424
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 416 213 422 1051
        Black
    		 7 1 5 13
        Asian
    		 18 12 22 52
        Native American
    		 3 2 1 6
        Pacific Islander
    		 2 1 0 3
        Other
    		 4 2 0 6
        Unknown
    		 5 2 6 13
    Baseline API Preclinical Composite Cognitive Battery (APCC)
    APCC is a composite score derived from RBANS (Repeatable Battery for Assessment of Neurological Status), MMSE(Mini-Mental State Examination) and the Raven's Progressive Matrices; scores are 0-100 and higher scores=better cognitive performance.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 74.6 ( 6.68 ) 75.8 ( 6.81 ) 74.9 ( 7.16 ) -
    Baseline Battery for Assessment of Neurological Status (RBANS)
    RBANS is a tool to detect/characterize neurocognitive dementia changes in 5 neurocognitive domains; scores are from 40-160 and higher scores=better cognitive functioning.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 100.5 ( 11.96 ) 102.0 ( 12.09 ) 100.7 ( 12.42 ) -
    Baseline Clinical Dementia Rating Sum of Boxes (CDR-SOB)
    CDR-SOB measures cognition and functioning in 6 domains; scores are from 0-18 and higher scores indicate greater disease severity
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 0.19 ( 0.389 ) 0.16 ( 0.358 ) 0.14 ( 0.358 ) -

    End points

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    End points reporting groups
    Reporting group title
    CNP520 50 mg
    Reporting group description
    		 50 mg capsule taken orally once daily

    Reporting group title
    CNP520 15 mg
    Reporting group description
    		 15 mg capsule taken orally once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo to 15 and 50 mg CNP520 taken orally once daily

    Primary: Time to Event (diagnosis of mild cognitive impairment or dementia, due to Alzheimer's disease (AD))

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    End point title
    		 Time to Event (diagnosis of mild cognitive impairment or dementia, due to Alzheimer's disease (AD)) [1]
    End point description
    Time-to-event (TTE) was defined as the first confirmed diagnosis of MCI due to Alzheimer's disease (AD) or dementia due to AD (whichever occurred first). An event was identified when adjudication by the progression adjudication committee (PAC) was triggered either by an investigator diagnosis or an increase in the Clinical Dementia Rating (CDR) global score. An event had to be confirmed by the PAC at two consecutive visits. In case no confirmed event was observed for a participant, the observation was censored, and the censoring date was defined as the last date where the diagnostic classification was assessed. Time to censoring date was calculated from day of randomization. The Study was terminated and only confirmed events collected up to the data cut-off point were counted. Due to the early termination of the studies, only a small number of events following the above definition were observed.
    End point type
    Primary
    End point timeframe
    Baseline to end of exposure for a maximum of 617 days (premature termination)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No analysis done
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: percentage of participants
    number (confidence interval 95%)
        Week 26 n=6,1,3
    0.99 (0.96 to 1.00)
    1.00 (0.999 to 99.999)
    1.00 (0.97 to 1.00)
        Week 52 n=6,1,3
    0.97 (0.94 to 0.99)
    0.99 (0.92 to 1.00)
    0.99 (0.96 to 1.00)
        Week 78 n=6,1,3
    0.97 (0.94 to 0.99)
    0.99 (0.92 to 1.00)
    0.97 (0.88 to 0.99)
    No statistical analyses for this end point

    Primary: Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score

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    End point title
    		 Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score [2]
    End point description
    APCC is a composite score derived from the specific scores from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE) and the Raven's Progressive Matrices. The APCC score is a weighted score with ranges from from 0 to 100 where higher scores correspond to better cognitive performance.
    End point type
    Primary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No analysis done
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: Total scores
    arithmetic mean (standard deviation)
        Week 26 n=160,79,162
    -3.1 ( 5.20 )
    -2.9 ( 5.00 )
    -1.7 ( 4.44 )
        Last on-treatment n=269,144,275
    -2.2 ( 4.88 )
    -0.8 ( 4.67 )
    -1.3 ( 5.21 )
        Last off-treatment n=255,124,260
    -0.8 ( 4.56 )
    -0.8 ( 4.38 )
    -0.8 ( 4.64 )
    No statistical analyses for this end point

    Secondary: Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score

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    End point title
    		 Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score
    End point description
    The CDR was obtained through semi-structured interviews of participants and informants, and cognitive functioning was rated on a 5-point scale of functioning in six domains: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. The CDR global score ranged from zero to three, while the CDR-SOB was the sum of the ratings from the six domains, ranging from 0 to 18 with a minimum increment of 0.5. Higher scores indicated greater disease severity
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 26 n=160,78,160
    0.17 ( 0.606 )
    0.20 ( 0.451 )
    0.08 ( 0.385 )
        Last on-treatment n=265,144,267
    0.15 ( 0.557 )
    0.08 ( 0.449 )
    0.10 ( 0.468 )
        Last off-treatment n=254,117,256
    0.09 ( 0.525 )
    0.07 ( 0.401 )
    0.10 ( 0.565 )
    No statistical analyses for this end point

    Secondary: Change in the Total and Index scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

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    End point title
    		 Change in the Total and Index scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
    End point description
    Repeatable Battery for the Assessment of Neurological Status (RBANS) is a clinical tool designed to detect and characterize the earliest neurocognitive changes associated with dementia. The RBANS generates age-adjusted index scores for five neurocognitive domains: Immediate Memory, Visuospatial/Constructional, Language, Attention and Delayed Memory, which are used to calculate a Total Scale Index score. Index scores and total score range from 40 to 160 and a higher score indicates better cognitive functioning.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last-off treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: scores
    arithmetic mean (standard deviation)
        Total Week 26 n=162,81,162
    -5.8 ( 8.54 )
    -6.3 ( 8.58 )
    -3.4 ( 8.35 )
        Total Last on-treatment n=356,183,353
    -3.4 ( 8.66 )
    -3.5 ( 8.87 )
    -0.5 ( 8.88 )
        Total Last off-treatment n=259,125,265
    -1.3 ( 8.12 )
    -2.4 ( 9.55 )
    -1.9 ( 8.56 )
        Immediate memory - Week 26 n=162,81,162
    -9.8 ( 11.85 )
    -9.7 ( 12.10 )
    -5.2 ( 11.26 )
        Immediate memory - Last on-treatment n=347,183,353
    -5.9 ( 13.01 )
    -4.0 ( 13.54 )
    -1.1 ( 13.04 )
        Immediate memory- Last off-treatment n=259,125,266
    -3.1 ( 12.50 )
    -4.8 ( 13.52 )
    -3.0 ( 13.00 )
        Visuospatial Week 26 n=162,81,162
    -5.6 ( 15.11 )
    -5.4 ( 15.51 )
    -2.6 ( 15.26 )
        Visuospatial Last on-treatment n=347,183,353
    -3.7 ( 14.90 )
    -3.8 ( 15.14 )
    -1.2 ( 13.95 )
        Visuospatial Last off-treatment n=259,125,266
    -1.5 ( 14.87 )
    -0.7 ( 14.37 )
    -1.2 ( 14.56 )
        Language Week 26 n=162,81,162
    -0.8 ( 11.48 )
    -1.8 ( 11.05 )
    -3.1 ( 11.07 )
        Language Last on-treatment n=347,183,353
    -0.3 ( 11.95 )
    -1.7 ( 11.69 )
    -1.3 ( 12.58 )
        Language Last off-treatment n=259,125,265
    -1.0 ( 10.93 )
    -2.0 ( 12.68 )
    -3.4 ( 11.47 )
        Attention Week 26 n=162,81,162
    0.1 ( 11.19 )
    -0.1 ( 10.37 )
    0.1 ( 10.56 )
        Attention Last on-treatment n=347,183,353
    0.0 ( 11.30 )
    0.0 ( 10.68 )
    0.7 ( 10.99 )
        Attention Last off-treatment n=259,125,265
    1.6 ( 11.59 )
    1.7 ( 10.65 )
    1.1 ( 9.81 )
        Delayed memory - Week 26 n=162,81,162
    -5.5 ( 11.54 )
    -5.0 ( 11.68 )
    -2.1 ( 11.69 )
        Delayed memory - Last on-treatment n=346,183,353
    -3.0 ( 11.58 )
    -2.8 ( 10.56 )
    0.8 ( 11.43 )
        Delayed memory - Last off-treatment n=259,125,265
    -1.0 ( 10.91 )
    -2.5 ( 10.34 )
    -0.5 ( 10.57 )
    No statistical analyses for this end point

    Secondary: Change in the Everyday Cognition scale (ECog-Subject) total scores

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    End point title
    		 Change in the Everyday Cognition scale (ECog-Subject) total scores
    End point description
    Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: Total scores
    arithmetic mean (standard deviation)
        Week 26 n=155,78,157
    0.9 ( 7.90 )
    0.2 ( 5.52 )
    0.5 ( 6.76 )
        Last on-treatment n=266,143,268
    1.6 ( 8.03 )
    0.4 ( 5.62 )
    0.7 ( 8.25 )
        Last off-treatment n=249,122,255
    -0.1 ( 6.49 )
    0.0 ( 7.02 )
    0.1 ( 7.47 )
    No statistical analyses for this end point

    Secondary: Change in the Everyday Cognition scale (ECog-Informant) total scores

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    End point title
    		 Change in the Everyday Cognition scale (ECog-Informant) total scores
    End point description
    Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: Total scores
    arithmetic mean (standard deviation)
        Week 26 n=153,76,153
    -0.3 ( 7.55 )
    1.7 ( 7.77 )
    -1.2 ( 6.10 )
        Last on-treatment n=252,138,255
    0.5 ( 7.58 )
    0.7 ( 8.49 )
    0.2 ( 7.00 )
        Last off-treatment n=223,113,239
    0.5 ( 6.97 )
    0.0 ( 6.74 )
    1.2 ( 9.36 )
    No statistical analyses for this end point

    Secondary: Number of participants with newly occurring safety MRI abnormalities (ARIA-E, ARIA-H,white matter disease and any other MRI abnormalities)

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    End point title
    		 Number of participants with newly occurring safety MRI abnormalities (ARIA-E, ARIA-H,white matter disease and any other MRI abnormalities)
    End point description
    Safety MRI included sequences necessary for ascertainment of possible ARIA-E (Amyloid Related Imaging Abnormality‑Edema), ARIA-H (Amyloid Related Imaging Abnormality- Hemorrhage, including superficial siderosis and microhemorrhages), assessment of recent infarcts and white matter integrity examination (White matter disease worsening) and a general assessment of brain abnormalities.
    End point type
    Secondary
    End point timeframe
    Baseline up to study termination approximately 617 days
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: participants
        Presence of ARIA-H
    0
    0
    0
        Questionable presence of ARIA-E
    1
    0
    2
        White matter disease worsening: 1-3 increase
    4
    2
    3
        White matter disease worsening: 4- - >8 increase
    0
    0
    0
        White matter disease worsening >8
    0
    0
    0
        Any other MRI abnormalities
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Annualized percent change on volume of brain regions

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    End point title
    		 Annualized percent change on volume of brain regions
    End point description
    Annualized % change from baseline in volume of specific brain regions of interest (ROIs): hippocampus, lateral ventricles, and total brain. Annualized percentage change was calculated as (percentage per participant / time interval (in days)) x 365.25. Time interval (in days) was derived as date of current MRI assessment on study drug - date of baseline MRI assessment + 1.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: Percentage of volume change
    arithmetic mean (standard deviation)
        Week 26 n=169,83,169
    -1.1016 ( 1.03196 )
    -0.9348 ( 0.85477 )
    -0.5552 ( 1.21385 )
        Last on-treatment n=179,85,182
    -1.0427 ( 0.93751 )
    -0.9205 ( 0.75633 )
    -0.5378 ( 1.09542 )
        Last off-treatment n=72,44,81
    -0.6984 ( 0.73644 )
    -0.9188 ( 0.94516 )
    -0.5811 ( 0.75412 )
    No statistical analyses for this end point

    Secondary: Change in CSF levels of Amyloid Beta 40 (Aβ40)

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    End point title
    		 Change in CSF levels of Amyloid Beta 40 (Aβ40)
    End point description
    Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    97
    49
    90
    Units: ng/mL
    arithmetic mean (standard deviation)
        AB40 Last on-treatment n=1,0,1
    -7.320 ( 999.9 )
    999.9 ( 999.9 )
    -0.760 ( 999.9 )
        AB40 Last off-treatment n=16,5,13
    -1.492 ( 1.9263 )
    0.804 ( 1.9220 )
    -1.172 ( 1.7408 )
    No statistical analyses for this end point

    Secondary: Change in CSF levels of Amyloid Beta 42 (Aβ42)

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    End point title
    		 Change in CSF levels of Amyloid Beta 42 (Aβ42)
    End point description
    Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    96
    48
    90
    Units: pg/mL
    arithmetic mean (standard deviation)
        AB42 Last on-treatment n=1,0,1
    -366.200 ( 999.9 )
    999.9 ( 999.9 )
    -61.300 ( 999.9 )
        AB42 Last off-treatment n=16,5,13
    20.431 ( 74.5595 )
    -68.660 ( 62.8505 )
    21.246 ( 104.3395 )
    No statistical analyses for this end point

    Secondary: Change in neurofibrillary tangle burden as measured by standardized uptake ratio (SUVR) of PET scans with tau radiotracer (where available)

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    End point title
    		 Change in neurofibrillary tangle burden as measured by standardized uptake ratio (SUVR) of PET scans with tau radiotracer (where available)
    End point description
    To demonstrate the effects of CNP520 vs placebo on Alzheimer’s Disease-related biomarkers
    End point type
    Secondary
    End point timeframe
    Baseline to Months 24 and 60
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: standardized uptake ratio
        number (not applicable)
    Notes
    [3] - No available data
    [4] - No available data
    [5] - No available data
    No statistical analyses for this end point

    Secondary: Change in amyloid deposition as measured by standardized uptake ratio (SUVR) of positron emission tomography (PET) scan with amyloid radiotracer

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    End point title
    		 Change in amyloid deposition as measured by standardized uptake ratio (SUVR) of positron emission tomography (PET) scan with amyloid radiotracer
    End point description
    To demonstrate the effects of CNP520 vs placebo on Alzheimer’s Disease-related biomarkers
    End point type
    Secondary
    End point timeframe
    Baseline to Months 24 and 60
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    Units: standardized uptake ratio
        number (not applicable)
    Notes
    [6] - Only baseline amyloid PET scans are available
    [7] - Only baseline amyloid PET scans are available
    [8] - Only baseline amyloid PET scans are available
    No statistical analyses for this end point

    Secondary: Change in CSF levels of total tau and phosphorylated tau

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    End point title
    		 Change in CSF levels of total tau and phosphorylated tau
    End point description
    Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    98
    49
    92
    Units: pg/mL
    arithmetic mean (standard deviation)
        Total tau - Last on-treatment n=1,0,1
    40.000 ( 999.9 )
    999.9 ( 999.9 )
    -12.600 ( 999.9 )
        Total tau - Last off-treatment n=16,5,13
    -22.119 ( 28.6218 )
    -3.320 ( 21.1548 )
    -3.238 ( 23.4442 )
        Phosphorylated tau - Last on-treatment n=1,0,1
    -2.360 ( 999.9 )
    999.9 ( 999.9 )
    -0.550 ( 999.9 )
        Phosphorylated tau - Last off-treatment n=16,5,13
    -1.849 ( 2.3397 )
    -0.852 ( 2.7005 )
    0.065 ( 1.3032 )
    No statistical analyses for this end point

    Secondary: Change in Neurofilaments

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    End point title
    		 Change in Neurofilaments
    End point description
    Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26, Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    226
    103
    230
    Units: pg/mL
    arithmetic mean (standard deviation)
        Week 26 n=33,17,38
    0.622 ( 4.5576 )
    0.901 ( 4.6732 )
    -5.731 ( 40.9042 )
        Last on-treatment n=33,15,40
    0.932 ( 4.2494 )
    0.041 ( 3.4144 )
    -5.771 ( 39.8254 )
        Last off-treatment n=5,2,1
    -2.764 ( 3.0981 )
    7.350 ( 9.5884 )
    3.880 ( 999.9 )
    No statistical analyses for this end point

    Secondary: Number of suicidal ideation or behavior events

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    End point title
    		 Number of suicidal ideation or behavior events
    End point description
    Prospective suicidality assessment was performed with the use of Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire using a detailed branched logic algorithm evaluating participant’s suicidality ideation and behavior. Answer “yes” on item 4 or 5 of the Suicidal Ideation section or “yes” on any item of the Suicidal Behavior section was considered positive.
    End point type
    Secondary
    End point timeframe
    Baseline up to study termination approximately 617 days
    End point values
    		 CNP520 50 mg CNP520 15 mg Placebo
    Number of subjects analysed
    455
    233
    456
    Units: events
        Any suicidal ideation n=13,3,9
    25
    6
    12
        Any suicidal behavior n=1,0,1
    1
    999
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
    Adverse event reporting additional description
    Frequency threshold was 2.5 (system will not accept decimal)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    CNP520 50 mg
    Reporting group description
    		 CNP520 50 mg

    Reporting group title
    CNP520 15 mg
    Reporting group description
    		 CNP520 15 mg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 CNP520 50 mg CNP520 15 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 455 (3.30%)
    9 / 233 (3.86%)
    15 / 456 (3.29%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chordoma
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic lung injury
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 455 (0.44%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 455 (0.22%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 455 (0.00%)
    0 / 233 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 455 (0.00%)
    1 / 233 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 455 (0.22%)
    0 / 233 (0.00%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 CNP520 50 mg CNP520 15 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 455 (30.11%)
    62 / 233 (26.61%)
    89 / 456 (19.52%)
    Investigations
    Weight decreased
         subjects affected / exposed
    19 / 455 (4.18%)
    3 / 233 (1.29%)
    7 / 456 (1.54%)
         occurrences all number
    19
    3
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 455 (2.42%)
    7 / 233 (3.00%)
    5 / 456 (1.10%)
         occurrences all number
    14
    7
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 455 (3.08%)
    7 / 233 (3.00%)
    8 / 456 (1.75%)
         occurrences all number
    16
    7
    8
    Headache
         subjects affected / exposed
    12 / 455 (2.64%)
    8 / 233 (3.43%)
    15 / 456 (3.29%)
         occurrences all number
    13
    9
    16
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    32 / 455 (7.03%)
    12 / 233 (5.15%)
    16 / 456 (3.51%)
         occurrences all number
    40
    15
    18
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    18 / 455 (3.96%)
    7 / 233 (3.00%)
    3 / 456 (0.66%)
         occurrences all number
    19
    7
    3
    Anxiety
         subjects affected / exposed
    21 / 455 (4.62%)
    4 / 233 (1.72%)
    8 / 456 (1.75%)
         occurrences all number
    23
    5
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 455 (2.42%)
    6 / 233 (2.58%)
    11 / 456 (2.41%)
         occurrences all number
    14
    6
    13
    Back pain
         subjects affected / exposed
    14 / 455 (3.08%)
    2 / 233 (0.86%)
    4 / 456 (0.88%)
         occurrences all number
    14
    2
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 455 (1.32%)
    7 / 233 (3.00%)
    4 / 456 (0.88%)
         occurrences all number
    6
    7
    4
    Nasopharyngitis
         subjects affected / exposed
    22 / 455 (4.84%)
    9 / 233 (3.86%)
    11 / 456 (2.41%)
         occurrences all number
    27
    11
    11
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 455 (3.96%)
    5 / 233 (2.15%)
    16 / 456 (3.51%)
         occurrences all number
    19
    6
    17
    Urinary tract infection
         subjects affected / exposed
    8 / 455 (1.76%)
    8 / 233 (3.43%)
    7 / 456 (1.54%)
         occurrences all number
    13
    8
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Nov 2017
    Updated from GLP embryo-fetal development studies : CNP520 was not genotoxic nor teratogenic therefore male contraception was no longer required. Updated: a pooled concentration-effect analysis of ECG QT data from Phase 1 and Phase 2a studies, revealed that there was no relevant QT prolongation by CNP520 and therefore concomitant medications associated with Torsades de Pointes were allowed. Included tau PET at screening, month 24 and month 60, to assess neurofibrillary tangles burden as a secondary endpoint.
    18 Dec 2018
    This amendment primarily addressed proactive actions required to enhance the ongoing monitoring of CNP520. The changes to the protocol were required to reflect the USM action plan from 13 Nov 2018: an additional cognitive assessment with RBANS at the 3 Month visit, as well as the NPI-Q at 3 and 6 months and every 6 months thereafter was added. Other changes to the protocol included: Potential lower dose regimen options targeting less than 60% reduction of CSF Aβ. Such dose regimen modification (DRM process) could be activated upon DMC recommendation after review of CNP520 data and/or in light of new data on either CNP520 or other BACE inhibitors. Incorporation of changes required by local health authorities and clarifications of different administrative aspects of the protocol.
    07 Jan 2020
    Modified treatment epoch (period )completion (TEC) visit • The following assessments were no longer required: MRI, PET and lumbar puncture for CSF samples. 2. Modified end of study visit: • Timing was changed from 3 Month post TEC visit to 6 Month post TEC visit: Simplified assessments required at this visit included: AEs and SAEs, RBANS, CDRSOB, volumetric MRI, blood sample for biomarkers.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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