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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, two-cohort parallel group study to evaluate the efficacy of CAD106 and CNP520 in participants at risk for the onset of clinical symptoms of Alzheimer’s disease

    Summary
    EudraCT number
    		 2015-002715-15
    Trial protocol
    		 BE   ES   FI   NL   DE  
    Global end of trial date
    30 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2021
    First version publication date
    14 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAPI015A2201J
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02565511
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 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
    30 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The first primary objective of the trial was to demonstrate the effects of CAD106 and CNP520 vs. respective placebo on Time-to-event (TTE), with event defined as a diagnosis of MCI due to AD or dementia due to AD, whichever occured first during the course of the study. The second primary objective was to demonstrate the effects of CAD106 and CNP520 vs. respective placebo on cognition as measured by the change from Baseline to Month 60 in the APCC test. The study was terminated due to unexpected changes in cognitive function, brain volume loss, and body weight loss. Cohort II (CNP520) treatment was stopped and evaluated through an off-treatment follow-up period. After the decision to terminate Cohort II of the study (CNP520), treatment with CAD106 (Cohort I) was also terminated.
    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
    10 Mar 2016
    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
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    United Kingdom: 47
    Country: Number of subjects enrolled
    United States: 346
    Worldwide total number of subjects
    477
    EEA total number of subjects
    55
    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)
    158
    From 65 to 84 years
    319
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 713 participants were screened. Three subjects were mis-randomized and not included in the subject disposition for Cohort II (2 in CNP520 and 1 in CNP520 placebo).

    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
    		 Cohort I (CI) CAD106
    Arm description
    		 CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
    Arm type
    		 Experimental

    Investigational medicinal product name
    CAD106
    Investigational medicinal product code
    CAD106
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 month prior to completion of the Treatment Epoch.

    Arm title
    		 Cohort I (CI) CAD106 Placebo
    Arm description
    		 Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
    Arm type
    		 Placebo

    Investigational medicinal product name
    CAD106 Placebo
    Investigational medicinal product code
    CAD106
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 month prior to completion of the Treatment Epoch.

    Arm title
    		 Cohort II (CII) CNP520
    Arm description
    		 CNP520 (50 mg) capsules taken once daily orally
    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 capsule taken orally once a day for the duration of the Treatment Epoch

    Arm title
    		 Cohort II (CII) CNP520 Placebo
    Arm description
    		 Placebo to CNP520 capsules taken once daily orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    CNP520 Placebo
    Investigational medicinal product code
    CNP520
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    CNP520 Placebo capsule taken orally once a day for the duration of the Treatment Epoch

    Number of subjects in period 1
    		Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Started
    42
    23
    249
    163
    Completed
    0
    0
    0
    0
    Not completed
    42
    23
    249
    163
         Consent withdrawn by subject
    3
    -
    12
    5
         Physician decision
    -
    -
    -
    1
         Study terminated by Sponsor
    35
    22
    233
    155
         Adverse event, non-fatal
    -
    -
    1
    1
         Protocol deviation
    -
    -
    3
    -
         Lost to follow-up
    4
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort I (CI) CAD106
    Reporting group description
    		 CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter

    Reporting group title
    Cohort I (CI) CAD106 Placebo
    Reporting group description
    		 Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter

    Reporting group title
    Cohort II (CII) CNP520
    Reporting group description
    		 CNP520 (50 mg) capsules taken once daily orally

    Reporting group title
    Cohort II (CII) CNP520 Placebo
    Reporting group description
    		 Placebo to CNP520 capsules taken once daily orally

    Reporting group values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo Total
    Number of subjects
    		 42 23 249 163 477
    Age Categorical
    Units: participants
        <=64 years
    		 20 9 77 52 158
        65-69 years
    		 18 7 116 65 206
        >70 years
    		 4 7 56 46 113
    Sex: Female, Male
    Units: participants
        Female
    		 27 17 129 102 275
        Male
    		 15 6 120 61 202
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 41 22 241 162 466
        Black
    		 1 1 1 0 3
        Asian
    		 0 0 4 0 4
        Pacific Islander
    		 0 0 1 0 1
        Other
    		 0 0 1 0 1
        Unknown
    		 0 0 1 1 2
    API Preclinical Composite Cognitive Battery (APCC)
    APCC (API Preclinical Compo site Cognitive Battery) 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 indicate better cognitive performance.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 78.0 ( 5.53 ) 79.0 ( 6.76 ) 29.0 ( 1.17 ) 28.9 ( 1.33 ) -
    Repeatable Battery for Assessment of Neurological Status (RBANS)
    RBANS is a tool to detect/characterize neurocognitive dementia changes in 5 neurocognitive domains; scores are 40-160 and higher scores indicate better cognitive functioning.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 104.4 ( 12.03 ) 108.7 ( 12.83 ) 102.6 ( 12.22 ) 103.2 ( 12.03 ) -
    Clinical Dementia Rating Sum of Boxes (CDR-SOB)
    Clinical Dementia Rating Sum of Boxes (CDR-SOB) measures cognition and functioning in 6 domains; scores are : 0-18 and higher scores indicate greater disease severity
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 0.10 ( 0.276 ) 0.04 ( 0.209 ) 0.16 ( 0.404 ) 0.15 ( 0.417 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort I (CI) CAD106
    Reporting group description
    		 CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter

    Reporting group title
    Cohort I (CI) CAD106 Placebo
    Reporting group description
    		 Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter

    Reporting group title
    Cohort II (CII) CNP520
    Reporting group description
    		 CNP520 (50 mg) capsules taken once daily orally

    Reporting group title
    Cohort II (CII) CNP520 Placebo
    Reporting group description
    		 Placebo to CNP520 capsules taken once daily orally

    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
    Event was defined as the first confirmed diagnosis of MCI due to Alzheimer's disease (AD) or dementia due to AD (whichever occurred first) after adjudication by the progression adjudication committee (PAC) as 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. 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 study only a small number of events were observed and time-to-event could not be analyzed. Kaplan-Meyer (KM) estimates were provided to estimate probability that a subject would have an event prior to the specified visit.
    End point type
    Primary
    End point timeframe
    Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
    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
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: proportion of participants
    number (confidence interval 95%)
        Week 26 n=41,22,193, 126
    1.00 (1.00 to 1.00)
    1.00 (1.00 to 1.00)
    0.98 (0.95 to 0.99)
    0.98 (0.94 to 0.99)
        Week 52 n=40,22,95,63
    1.00 (1.00 to 1.00)
    1.00 (1.00 to 1.00)
    0.93 (0.88 to 0.96)
    0.95 (0.90 to 0.98)
        Week 78 n=37,21,18,9
    0.97 (0.83 to 1.00)
    1.00 (1.00 to 1.00)
    0.88 (0.79 to 0.93)
    0.85 (0.63 to 0.94)
        Week 104 n=22,15,5,2
    0.97 (0.83 to 1.00)
    1.00 (1.00 to 1.00)
    0.88 (0.79 to 0.93)
    0.85 (0.63 to 0.94)
    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
    CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and 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
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: Total scores
    arithmetic mean (standard deviation)
        Week 26 n=41,23,154,105
    -1.1 ( 4.10 )
    -2.0 ( 3.90 )
    -3.3 ( 4.54 )
    -1.0 ( 4.65 )
        Week 52 n=41,22,64,36
    0.9 ( 4.24 )
    1.4 ( 3.36 )
    0.3 ( 4.27 )
    2.2 ( 6.11 )
        Week 78 n=27, 18,7,8
    0.2 ( 4.15 )
    -0.7 ( 5.48 )
    -4.1 ( 4.14 )
    2.4 ( 4.23 )
        Week 104 n=17,9,3,0
    -1.4 ( 4.67 )
    0.3 ( 4.00 )
    -6.7 ( 3.95 )
    9.999 ( 9.999 )
        CI-Last post BL assessment n=41,23,0,0
    0.0 ( 4.62 )
    0.1 ( 3.87 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII - Last on treatment n=0,0,179,125
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.7 ( 4.81 )
    0.1 ( 4.58 )
        CII-Last off treatment n=0,0,166,90
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -0.1 ( 4.72 )
    0.2 ( 4.56 )
    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
    CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 26 n=41,23,153,105
    -0.04 ( 0.234 )
    0.00 ( 0.000 )
    0.04 ( 0.361 )
    0.00 ( 0.336 )
        Week 52 n=41,23,64,36
    -0.01 ( 0.237 )
    0.02 ( 0.104 )
    -0.02 ( 0.281 )
    -0.08 ( 0.541 )
        Week 78 n=27,18,7,7
    -0.04 ( 0.237 )
    0.03 ( 0.118 )
    0.14 ( 0.802 )
    -0.14 ( 0.244 )
        Week 104 n=17,9,3,0
    0.15 ( 0.460 )
    0.06 ( 0.167 )
    -0.17 ( 0.764 )
    9.999 ( 9.999 )
        CI Last post baseline assessment n=41,23,0,0
    0.04 ( 0.343 )
    0.00 ( 0.302 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Last on-treatment n=0,0,174,122
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    0.06 ( 0.505 )
    0.03 ( 0.410 )
        CII Last off-treatment n=0,0,156,90
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    0.05 ( 0.464 )
    -0.01 ( 0.519 )
    No statistical analyses for this end point

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

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    End point title
    		 Change in the Total 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
    CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: scores
    arithmetic mean (standard deviation)
        Total Week 26 n=41,23,154,105
    -5.1 ( 7.25 )
    -3.0 ( 7.51 )
    -4.1 ( 8.58 )
    -2.6 ( 7.83 )
        Total Week 52 n=41,22,64,37
    -1.2 ( 7.82 )
    4.5 ( 7.10 )
    -0.1 ( 7.91 )
    1.4 ( 8.06 )
        Total Week 78 n=27,18,7,8
    -2.1 ( 7.69 )
    -4.0 ( 7.82 )
    -12.1 ( 7.40 )
    -4.8 ( 5.99 )
        Total Week 104 n=17,9,3,0
    -1.4 ( 6.74 )
    -3.0 ( 8.34 )
    -7.7 ( 15.57 )
    9.999 ( 9.999 )
        Total CI Last post baseline assessment n=41,23,0,0
    -1.0 ( 9.27 )
    0.4 ( 7.20 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        Total CII Last on-treatment n=0,0,209,141
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -2.7 ( 8.65 )
    -0.2 ( 9.22 )
        Total CII Last off-treatment n=0,0,169,93
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.5 ( 9.20 )
    -0.6 ( 8.83 )
    No statistical analyses for this end point

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

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    End point title
    		 Change in the 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
    CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: scores
    arithmetic mean (standard deviation)
        Immediate memory - Week 26 n=41,23,154,105
    -8.6 ( 10.68 )
    -3.8 ( 11.16 )
    -7.4 ( 13.11 )
    -3.7 ( 12.15 )
        Immediate memory - Week 52 n=41,22,64,37
    1.3 ( 10.81 )
    4.8 ( 8.68 )
    0.6 ( 13.55 )
    5.1 ( 11.73 )
        CI Immediate memory-Last post BL asses n=41,23,0,0
    -1.1 ( 13.11 )
    1.1 ( 14.52 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Immediate memory-Last on-treat n=0,0,209,141
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -3.7 ( 14.43 )
    0.6 ( 13.54 )
        CII Immediate memory-Last off-treat n=0,0,169,93
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -3.2 ( 13.76 )
    -2.0 ( 11.90 )
        Visuospatial Week 26 n=41,23,154,105
    -6.5 ( 15.21 )
    0.7 ( 12.39 )
    -3.5 ( 14.98 )
    -2.4 ( 13.00 )
        Visuospatial Week 52 n=41,22,64,37
    -6.5 ( 14.59 )
    3.0 ( 15.09 )
    -1.4 ( 14.29 )
    -4.8 ( 12.60 )
        CI Visuospatial Last post BL assess n=41,23,0,0
    -4.7 ( 13.91 )
    1.9 ( 12.72 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Visuospatial Last on-treat n=0,0,209,141
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -3.5 ( 14.59 )
    -2.6 ( 14.92 )
        CII Visuospatial Last off-treatment n=0,0,169,93
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.2 ( 15.13 )
    -0.8 ( 15.18 )
        Language Week 26 n=41,23,154,105
    -1.4 ( 12.91 )
    -2.8 ( 11.42 )
    -0.1 ( 12.05 )
    -1.5 ( 11.87 )
        Language Week 52 n=41,22,64,37
    2.6 ( 10.29 )
    2.0 ( 11.51 )
    -0.3 ( 12.88 )
    0.8 ( 9.72 )
        CI Language Last post BL assess n=41,23,0,0
    1.9 ( 13.00 )
    -4.5 ( 12.86 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Language Last on-treat n=0,0,209,141
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -0.1 ( 12.07 )
    -0.1 ( 11.93 )
        CII Language Last off-treatment n=0,0,169,93
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.0 ( 13.19 )
    -1.8 ( 11.25 )
        Attention Week 26 n=41,23,154,105
    1.8 ( 9.40 )
    -0.6 ( 14.19 )
    -0.7 ( 10.42 )
    -0.6 ( 11.67 )
        Attention Week 52 n=41,22,64,37
    0.9 ( 10.80 )
    -0.5 ( 13.09 )
    -0.2 ( 10.02 )
    2.7 ( 10.77 )
        CI Attention Last post BL assess n=41,23,0,0
    2.0 ( 12.91 )
    2.0 ( 10.25 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Attention Last on-treat n=0,0,209,141
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    0.1 ( 10.80 )
    0.8 ( 11.20 )
        CII-Attention Last off-treat n=0,0,169,93
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    1.0 ( 1.64 )
    1.2 ( 11.07 )
        Delayed memory - Week 26 n=41,23,154,105
    -3.8 ( 7.83 )
    -2.7 ( 7.64 )
    -3.8 ( 11.20 )
    -2.6 ( 8.85 )
        Delayed memory - Week 52 n=41,22,64,37
    -2.0 ( 8.01 )
    3.2 ( 6.23 )
    2.3 ( 9.09 )
    0.6 ( 11.73 )
        CI Delayed memory-Last post BL assess n=41,23,0,0
    -1.0 ( 10.20 )
    1.3 ( 8.44 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Delayed memory-Last on-treat n=0,0,209,141
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -2.5 ( 10.61 )
    0.4 ( 10.28 )
        CII Delayed memory Last off-treat n=0,0,169,93
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.1 ( 10.75 )
    1.1 ( 11.28 )
    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
    CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: Total scores
    arithmetic mean (standard deviation)
        Week 26
    -1.0 ( 2.94 )
    2.3 ( 4.80 )
    1.8 ( 6.03 )
    0.6 ( 6.45 )
        Week 52
    0.6 ( 5.23 )
    0.4 ( 2.99 )
    2.7 ( 6.16 )
    0.2 ( 5.01 )
        CI Last post baseline assessment
    0.6 ( 5.02 )
    1.6 ( 4.07 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Last on-treatment
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    2.6 ( 7.81 )
    0.9 ( 6.48 )
        CII Last off-treatment
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    1.6 ( 6.77 )
    0.8 ( 6.13 )
    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. Cohort I=C I and Cohort II=C II.
    End point type
    Secondary
    End point timeframe
    CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: Total scores
    arithmetic mean (standard deviation)
        Week 26 n=37,23,142,95
    -0.4 ( 4.21 )
    -1.0 ( 4.87 )
    0.1 ( 6.84 )
    -0.7 ( 8.69 )
        Week 52 n=37,22,57,29
    -0.2 ( 3.15 )
    -0.3 ( 5.12 )
    1.4 ( 5.18 )
    -0.2 ( 9.59 )
        CI Last post baseline assessment
    -1.1 ( 4.23 )
    -1.0 ( 4.88 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        CII Last on-treatment n=0,0,160,113
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    1.3 ( 8.76 )
    0.1 ( 9.12 )
        CII Last off-treatment n=0,0,143,77
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    1.4 ( 8.49 )
    -0.5 ( 10.10 )
    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 since baseline) and a general assessment of brain abnormalities. Assessment of cerebral amyloid angiopathy (CAA) is included in the overall safety MRI findings results. Presence of ARIA-H is >4 microhemorrhages (new hemosiderin deposits < 10 mm)
    End point type
    Secondary
    End point timeframe
    Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: participants
        Questionable presence of ARIA-E
    0
    0
    0
    1
        Presence of ARIA-E
    1
    0
    0
    2
        ARIA-E - If present, the worst Severity=moderate
    1
    0
    0
    2
        Presence of ARIA-H
    2
    0
    6
    2
        White matter disease worsening: 1-3 increase
    0
    2
    6
    1
        White matter disease worsening: 4 - 8 increase
    0
    0
    0
    0
        White matter disease worsening >8 increase
    0
    0
    0
    0
        Any other MRI abnormalities
    2
    1
    0
    0
    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): whole brain (WB), hippocampus (Hip), and lateral ventricles (LV). 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
    CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    201
    135
    Units: Percentage of volume change
    arithmetic mean (standard deviation)
        WB Week 26 n=35,23,145,104
    -0.7570 ( 1.33114 )
    -0.6044 ( 1.29608 )
    -0.9318 ( 1.06843 )
    -0.4616 ( 1.00537 )
        WB Week 52 n=37,22,63,40
    -0.5144 ( 0.66578 )
    -0.3395 ( 0.75810 )
    -0.6590 ( 0.64838 )
    -0.4227 ( 0.58778 )
        WB CI Last post baseline assessment n=40,23,0,0
    -0.4645 ( 0.57503 )
    -0.5321 ( 0.46526 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        WB CII Last on-treatment n=0,0,148,108
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -0.8268 ( 0.94889 )
    -0.5181 ( 0.92086 )
        WB CII Last off-treatment n=0,0,36,23
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -0.6748 ( 0.62542 )
    -0.3317 ( 0.62616 )
        Hip Week 26 n=35,23,145,104
    -1.3262 ( 2.35453 )
    -0.9245 ( 2.81731 )
    -1.6603 ( 2.65529 )
    -0.8817 ( 2.06227 )
        Hip Week 52 n=37,22,63,40
    -1.0376 ( 1.44310 )
    -0.7780 ( 1.81604 )
    -1.2438 ( 1.79988 )
    -0.9567 ( 1.42941 )
        Hip CI Last post baseline assessment n=40,23,0,0
    -1.0801 ( 1.38061 )
    -1.0477 ( 1.33603 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        Hip CII Last on-treatment n=0,0,148,108
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.4790 ( 2.36526 )
    -0.9984 ( 1.85655 )
        Hip CII Last off-treatment n=0,0,36,23
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -1.9375 ( 2.03593 )
    -1.0498 ( 1.66596 )
        LV Week 26 n=35,23,145,104
    4.1848 ( 5.77286 )
    2.5581 ( 7.54667 )
    4.5176 ( 5.59748 )
    3.9735 ( 4.23237 )
        LV Week 52 n=37,22,63,40
    4.2060 ( 3.92877 )
    2.8232 ( 5.04358 )
    3.3854 ( 3.71214 )
    2.9059 ( 3.18734 )
        LV CI Last post baseline assessment n=40,23,0,0
    4.0543 ( 3.75310 )
    3.5427 ( 3.53772 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        LV CII Last on-treatment n=0,0,148,108
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    4.3588 ( 5.07839 )
    4.0308 ( 3.64102 )
        LV CII Last off-treatment n=0,0,36,23
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    3.9617 ( 2.61831 )
    2.6052 ( 3.54903 )
    No statistical analyses for this end point

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

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    End point title
    		 Change in cerebrospinal fluid (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 last assessment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [3] - No post baseline data available
    [4] - No post baseline data available
    [5] - No post baseline data available
    [6] - No post baseline data available
    No statistical analyses for this end point

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

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    End point title
    		 Change in cerebrospinal fluid (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 last assessment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: pg/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [7] - No post baseline data available
    [8] - No post baseline data available
    [9] - No post baseline data available
    [10] - No post baseline data available
    No statistical analyses for this end point

    Secondary: Change in cerebrospinal fluid (CSF) levels of total tau and phosphorylated tau

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    End point title
    		 Change in cerebrospinal fluid (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 last assessment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    Units: pg/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [11] - No post baseline data available
    [12] - No post baseline data available
    [13] - No post baseline data available
    [14] - No post baseline data available
    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 CAD106 and CNP520 vs placebo on tau pathology in the brain
    End point type
    Secondary
    End point timeframe
    Baseline to last assessment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: SUVR
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [15] - No post baseline data available
    [16] - No post baseline data available
    [17] - No post baseline data available
    [18] - No post baseline data available
    No statistical analyses for this end point

    Secondary: Cohort I : Annualized change in amyloid deposition as measured by centiloids of positron emission tomography (PET) scan with amyloid radiotracer

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    End point title
    		 Cohort I : Annualized change in amyloid deposition as measured by centiloids of positron emission tomography (PET) scan with amyloid radiotracer [19]
    End point description
    To demonstrate the effects of CAD106 vs placebo on Alzheimer’s Disease-related biomarkers
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately Week 104
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only available for CAD106
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo
    Number of subjects analysed
    42
    23
    Units: Centiloids
        arithmetic mean (standard deviation)
    -0.911 ( 5.6596 )
    8.367 ( 6.6805 )
    No statistical analyses for this end point

    Secondary: Change in Serum Neurofilaments

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    End point title
    		 Change in Serum 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 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: pg/mL
    arithmetic mean (standard deviation)
        Week 26
    1.44 ( 3.165 )
    -3.89 ( 13.058 )
    0.644 ( 3.4879 )
    0.362 ( 6.7547 )
        Week 52
    2.63 ( 5.716 )
    -6.09 ( 16.542 )
    1.921 ( 4.0515 )
    -4.852 ( 14.2270 )
        C I Last post baseline assessment
    1.77 ( 4.643 )
    -3.31 ( 12.858 )
    9.999 ( 9.999 )
    9.999 ( 9.999 )
        C II Last on-treatment
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    0.647 ( 3.5357 )
    0.280 ( 6.8289 )
        C II Last off-treatment
    9.999 ( 9.999 )
    9.999 ( 9.999 )
    -0.004 ( 3.7102 )
    -2.145 ( 2.6799 )
    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 to end of exposure for a maximum of 1455 days for CI and 907 days for CII
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    42
    23
    249
    163
    Units: events
        Any suicidal ideation
    2
    1
    12
    4
        Any suicidal behavior
    0
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Cohort I : change in cognition as measured by APCC and CDR-SOB scores and antibody response

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    End point title
    		 Cohort I : change in cognition as measured by APCC and CDR-SOB scores and antibody response
    End point description
    End point type
    Secondary
    End point timeframe
    Month 6 to Month 60
    End point values
    		 Cohort I (CI) CAD106 Cohort I (CI) CAD106 Placebo Cohort II (CII) CNP520 Cohort II (CII) CNP520 Placebo
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    Units: scores
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [20] - No post baseline data available
    [21] - No post baseline data available
    [22] - No post baseline data available
    [23] - No post baseline data available
    No statistical analyses for this end point

    Secondary: Cohort I: Peak concentration (Cmax) of CAD106 induced Abeta-specific antibody titers

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    End point title
    		 Cohort I: Peak concentration (Cmax) of CAD106 induced Abeta-specific antibody titers [24]
    End point description
    Cmax is the maximum Titer Concentration of any post-baseline 'on treatment' visit. A visit is considered as 'on treatment' if visit date is within {last injection + 180 days}. - Geometric mean and CI’s are back-transformed from the estimates for Log mean and CI’s.
    End point type
    Secondary
    End point timeframe
    Week 9, 13, 15, 26 and quarterly thereafter (trough values)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Outcome objectiive only for CAD106
    End point values
    		 Cohort I (CI) CAD106
    Number of subjects analysed
    41
    Units: units/mL
        geometric mean (confidence interval 95%)
    128.76 (99.05 to 167.37)
    No statistical analyses for this end point

    Secondary: Cohort I: Area under the concentration curve (AUC) of CAD106 induced Abeta-specific antibody titers

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    End point title
    		 Cohort I: Area under the concentration curve (AUC) of CAD106 induced Abeta-specific antibody titers [25]
    End point description
    AUC is calculated based on 'on treatment' visit only.(missing values for peak visits were linearly interpolated for calculation; missing values for trough visits were imputed by average of non-missing trough values.).
    End point type
    Secondary
    End point timeframe
    Week 9, 13, 15, 26 and quarterly thereafter (trough values)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Outcome objective only for CAD106
    End point values
    		 Cohort I (CI) CAD106
    Number of subjects analysed
    42
    Units: integral
        number (confidence interval 95%)
    34999.89 (22992.17 to 53278.68)
    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 plus 31 days of washout period for a maximum duration of 1455 days for CI and 907 days for CII
    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
    Cohort I @CAD106
    Reporting group description
    		 Cohort I @CAD106

    Reporting group title
    Cohort I @Placebo
    Reporting group description
    		 Cohort I @Placebo

    Reporting group title
    Cohort II @CNP520 50 mg
    Reporting group description
    		 Cohort II @CNP520 50 mg

    Reporting group title
    Cohort II @Placebo
    Reporting group description
    		 Cohort II @Placebo

    Serious adverse events
    		 Cohort I @CAD106 Cohort I @Placebo Cohort II @CNP520 50 mg Cohort II @Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 42 (9.52%)
    3 / 23 (13.04%)
    8 / 249 (3.21%)
    7 / 163 (4.29%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Feeling jittery
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Cohort I @CAD106 Cohort I @Placebo Cohort II @CNP520 50 mg Cohort II @Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 42 (85.71%)
    21 / 23 (91.30%)
    106 / 249 (42.57%)
    76 / 163 (46.63%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    3
    0
    0
    2
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemangioma of liver
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    0
    1
    Uterine leiomyoma
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Fatigue
         subjects affected / exposed
    11 / 42 (26.19%)
    1 / 23 (4.35%)
    3 / 249 (1.20%)
    1 / 163 (0.61%)
         occurrences all number
    13
    1
    3
    1
    Influenza like illness
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    10 / 42 (23.81%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    12
    0
    0
    0
    Injection site pruritus
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Injection site reaction
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Malaise
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    7 / 42 (16.67%)
    1 / 23 (4.35%)
    4 / 249 (1.61%)
    0 / 163 (0.00%)
         occurrences all number
    15
    2
    4
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 23 (0.00%)
    5 / 249 (2.01%)
    2 / 163 (1.23%)
         occurrences all number
    3
    0
    5
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    4 / 249 (1.61%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Throat irritation
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 23 (4.35%)
    19 / 249 (7.63%)
    5 / 163 (3.07%)
         occurrences all number
    2
    1
    19
    6
    Anxiety
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    11 / 249 (4.42%)
    0 / 163 (0.00%)
         occurrences all number
    0
    0
    13
    0
    Insomnia
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 23 (4.35%)
    4 / 249 (1.61%)
    9 / 163 (5.52%)
         occurrences all number
    2
    1
    4
    10
    Irritability
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    2 / 249 (0.80%)
    0 / 163 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lumbar puncture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    9 / 249 (3.61%)
    2 / 163 (1.23%)
         occurrences all number
    0
    0
    9
    2
    Weight decreased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    7 / 249 (2.81%)
    1 / 163 (0.61%)
         occurrences all number
    0
    0
    7
    1
    Weight increased
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    2
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    2 / 249 (0.80%)
    4 / 163 (2.45%)
         occurrences all number
    0
    1
    2
    4
    Contusion
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    3 / 163 (1.84%)
         occurrences all number
    4
    0
    1
    4
    Fall
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 23 (4.35%)
    8 / 249 (3.21%)
    4 / 163 (2.45%)
         occurrences all number
    7
    1
    10
    4
    Injection related reaction
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Mallet finger
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Meniscus injury
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pelvic fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Congenital, familial and genetic disorders
    Type V hyperlipidaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 23 (8.70%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Atrial flutter
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    0
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cerebral cyst
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    7 / 249 (2.81%)
    1 / 163 (0.61%)
         occurrences all number
    0
    0
    7
    1
    Headache
         subjects affected / exposed
    7 / 42 (16.67%)
    0 / 23 (0.00%)
    6 / 249 (2.41%)
    9 / 163 (5.52%)
         occurrences all number
    9
    0
    7
    9
    Lethargy
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    2 / 249 (0.80%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Paraesthesia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    2 / 249 (0.80%)
    0 / 163 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Presyncope
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Radiculopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    3 / 249 (1.20%)
    0 / 163 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    0
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 23 (8.70%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    0
    1
    Constipation
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 23 (0.00%)
    7 / 249 (2.81%)
    2 / 163 (1.23%)
         occurrences all number
    5
    0
    9
    2
    Diarrhoea
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 23 (4.35%)
    6 / 249 (2.41%)
    3 / 163 (1.84%)
         occurrences all number
    3
    1
    7
    3
    Eosinophilic oesophagitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    5 / 249 (2.01%)
    4 / 163 (2.45%)
         occurrences all number
    2
    0
    5
    4
    Pancreatic cyst
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Salivary gland disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    2 / 163 (1.23%)
         occurrences all number
    2
    0
    2
    3
    Nail disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 23 (0.00%)
    10 / 249 (4.02%)
    5 / 163 (3.07%)
         occurrences all number
    0
    0
    14
    6
    Urticaria
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypercalciuria
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Thyroid mass
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 23 (4.35%)
    6 / 249 (2.41%)
    7 / 163 (4.29%)
         occurrences all number
    4
    1
    7
    7
    Back pain
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 23 (0.00%)
    7 / 249 (2.81%)
    6 / 163 (3.68%)
         occurrences all number
    5
    0
    7
    6
    Exostosis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Foot deformity
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    5 / 249 (2.01%)
    1 / 163 (0.61%)
         occurrences all number
    2
    0
    6
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    3 / 163 (1.84%)
         occurrences all number
    2
    0
    1
    4
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Myalgia
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 23 (13.04%)
    3 / 249 (1.20%)
    0 / 163 (0.00%)
         occurrences all number
    3
    3
    3
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    0
    1
    Pain in extremity
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 23 (8.70%)
    6 / 249 (2.41%)
    5 / 163 (3.07%)
         occurrences all number
    5
    2
    6
    6
    Rotator cuff syndrome
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    2
    1
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    1
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 23 (8.70%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Bronchitis
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    8 / 163 (4.91%)
         occurrences all number
    2
    1
    1
    9
    Cellulitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    0
    1
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dacryocanaliculitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    1
    1
    Influenza
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 23 (8.70%)
    3 / 249 (1.20%)
    0 / 163 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 23 (8.70%)
    10 / 249 (4.02%)
    2 / 163 (1.23%)
         occurrences all number
    4
    2
    12
    2
    Pharyngitis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 23 (4.35%)
    1 / 249 (0.40%)
    0 / 163 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    2
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 23 (4.35%)
    5 / 249 (2.01%)
    8 / 163 (4.91%)
         occurrences all number
    3
    1
    6
    12
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 42 (16.67%)
    3 / 23 (13.04%)
    11 / 249 (4.42%)
    11 / 163 (6.75%)
         occurrences all number
    8
    4
    11
    13
    Urinary tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 23 (8.70%)
    5 / 249 (2.01%)
    4 / 163 (2.45%)
         occurrences all number
    0
    2
    5
    5
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 23 (0.00%)
    0 / 249 (0.00%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 23 (8.70%)
    4 / 249 (1.61%)
    0 / 163 (0.00%)
         occurrences all number
    1
    2
    4
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2015
    This amendment addressed the Special Protocol Assessment comments received from the US Food and Drug Administration (FDA) on 18-Sep-2015.
    30 Sep 2016
    This amendment addressed the activation of Cohort II (CNP520 and matching placebo). The amendment also included some clarifications of the protocol following feedback from Investigators, health authorities and ethics committees on the previous version.
    30 Jun 2017
    This amendment included: The consolidation of the changes required by the UK Health Authority (MHRA) dated 24 January 2017 and the German Health Authorities (BfArM and PEI) dated 17 February 2017; Allowance for PET tracer other than 18F-florbetapir (e.g. 18F-flutemetamol and 18F-florbetaben) or substitution with Aβ measurement from cerebrospinal fluid (CSF) sampling if amyloid PET scan/tracer is unavailable; Prioritization of cohort recruitment for Cohort II defined by 1:4 ratio for Cohort I:Cohort II until Cohort II was fully recruited in order to enable a concurrent read-out of Cohort II and the parallel study with CNP520 (CCNP520A2202J – Generation Study 2); A randomization halt to Cohort I was introduced to mitigate the risk that a large number of participants are exposed to CAD106 prior to the futility analysis on CNS activity. Additionally, feedback from Investigators, other health authorities and ethics committees in other countries and updates for consistency with Study CCNP520A2202J were incorporated.
    30 Nov 2017
    This amendment included: Alignment with recent CNP520 IB update (Edition 4 released 25-Aug-2017) reflecting new data from which eliminated need for male contraception, no relevant QT prolongation by CNP520 therefore current cardiac monitoring was adequate, inclusion of tau PET assessments to neurofibrillary tangle burden, randomization halt to Cohort to mitigate risk to patients prior to futility analysis regarding CNS activitiy.
    18 Dec 2018
    This amendment followed a Letter to Investigators issued on November 13, 2018 and included the changes implemented according to USM plan as required for participant safety monitoring. (per ICH GCP 3.3.7; 4.5.4. and European Commission guidance (2010/C 82/01) 3.9); dose regimen modification.
    30 Jan 2020
    This amendment documents, for completeness, the changes regarding follow-up of participants after early termination of the study according to the Investigators Notifications distributed between July-2019 and December-2019. The changes related to discontinuation of treatment with CNP520 were already formally communicated via an Urgent Safety Measure (USM) dated 11-Jul-2019.

    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, of which EMA is aware, 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.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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