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    Clinical Trial Results:
    EXploratory PLatform trial on Anti-INflammatory agents in Alzheimer’s Disease (EXPLAIN-AD): A randomized, placebo-controlled, multicenter platform study to evaluate the efficacy, safety, tolerability and pharmacokinetics of various anti-inflammatory agents in patients with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease

    Summary
    EudraCT number
    		 2020-003966-38
    Trial protocol
    		 FI   IS  
    Global end of trial date
    07 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2025
    First version publication date
    21 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CADPT06A12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04795466
    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
    07 Mar 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the effects of each individual agent vs placebo on cognition in early Alzheimer's Disease using the Neuropsychological Test Battery (NTB) score at 24 weeks.
    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. Symptomatic treatments for AD (such as ChEIs or memantine) could be continued, in addition to the investigational treatment; however, dosage should not be adjusted in the 3 months preceding baseline and for the duration of the study. Following randomization, the investigator had to avoid initiating a symptomatic treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2021
    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
    Finland: 4
    Country: Number of subjects enrolled
    Iceland: 12
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    34
    EEA total number of subjects
    16
    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)
    4
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 10 sites in 4 different countries

    Pre-assignment
    Screening details
    		 There was a screening period (Day -60 to Day -8), followed by a baseline period of 7 days (Day -7 to Day -1), before first treatment. 34 participants were enrolled and received study treatment (safety analysis set). One participant was misdiagnosed with AD and was excluded from pharmacodynamic analysis set.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Canakinumab
    Arm description
    		 Canakinumab 150 mg SC once every 4 weeks for the first 2 doses followed by 300 mg SC once every 4 weeks for the subsequent 4 doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canakinumab
    Investigational medicinal product code
    ACZ885
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Canakinumab 150 mg SC once every 4 weeks for the first 2 doses followed by 300 mg SC once every 4 weeks for the subsequent 4 doses.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo subcutaneous injections
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo sub-cutaneous injections

    Number of subjects in period 1
    		Canakinumab Placebo
    Started
    16
    18
    Pharmacodynamic analysis set
    15
    18
    Completed
    10
    16
    Not completed
    6
    2
         Physician decision
    1
    -
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Canakinumab 150 mg SC once every 4 weeks for the first 2 doses followed by 300 mg SC once every 4 weeks for the subsequent 4 doses.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo subcutaneous injections

    Reporting group values
    		 Canakinumab Placebo Total
    Number of subjects
    		 16 18 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 2 3 5
        From 65-84 years
    		 14 15 29
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 71 ( 6.53 ) 72.4 ( 6.71 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 3 8 11
        Male
    		 13 10 23
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 16 18 34
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 16 18 34
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Canakinumab
    Reporting group description
    		 Canakinumab 150 mg SC once every 4 weeks for the first 2 doses followed by 300 mg SC once every 4 weeks for the subsequent 4 doses.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo subcutaneous injections

    Primary: Change from baseline in cognition as measured by the Neuropsychological Test Battery (NTB) z-scores

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    End point title
    		 Change from baseline in cognition as measured by the Neuropsychological Test Battery (NTB) z-scores
    End point description
    NTB is a composite of multiple neuropsychological tests that provide a thorough assessment of the cognitive domains affected by early Alzheimer's Disease (AD), in particular, memory, executive function, attention and verbal fluency. 5 out of 9 NTB components were administered in the study, Rey Auditory Verbal Learning Test (RAVLT) immediate and delayed scores, Wechsler Memory Scale Digit Span, Controlled Word Association Test (COWAT) and Category Fluency Test (CFT). For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging all resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.
    End point type
    Primary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: z-score change from baseline
        least squares mean (standard error)
    0.225 ( 0.116 )
    0.156 ( 0.0905 )
    Statistical analysis title
    		 NTB Total z-score - day 171
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6386
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    0.069
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.178
         upper limit
    		 0.316
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1442

    Secondary: Change from baseline in memory as measured by the total composite NTB memory z-score

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    End point title
    		 Change from baseline in memory as measured by the total composite NTB memory z-score
    End point description
    Total Neuropsychological Test Battery memory composite score is a "memory function" score composed of the NTB RAVLT immediate and delayed scores. For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging the two resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: z-score change from baseline
        least squares mean (standard error)
    0.461 ( 0.1382 )
    0.463 ( 0.1062 )
    Statistical analysis title
    		 Memory function - day 171
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9917
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.002
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.296
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1739

    Secondary: Change from baseline in executive function as measured by the total composite NTB executive function z-score

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    End point title
    		 Change from baseline in executive function as measured by the total composite NTB executive function z-score
    End point description
    The total Neuropsychological Test Battery executive function composite score is an "executive function" score composed of the NTB Wechsler Memory Scale Digit Span, COWAT, and CFT. For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging the two resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: z-score change from baseline
        least squares mean (standard error)
    0.111 ( 0.1492 )
    -0.075 ( 0.1251 )
    Statistical analysis title
    		 Executive function- day 171
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.351
    Method
    		 Mixed models analysis
    Parameter type
    		 least squares mean difference
    Point estimate
    0.186
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.148
         upper limit
    		 0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1958

    Secondary: Change from baseline in digit symbol substitution test (DSST) score - CANTAB

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    End point title
    		 Change from baseline in digit symbol substitution test (DSST) score - CANTAB
    End point description
    The DSST is an attention-demanding component of the Wechsler Adult Intelligence Scale-IV. The DSST score is the number of digits coded correctly in a fixed amount of time. The DSST has a minimum of "0" correct responses and does not have a maximum; a higher number on the DSST represents better performance The test was administered using CANTAB web based testing
    End point type
    Secondary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: DSST score change from baseline
        least squares mean (standard error)
    1.96 ( 1.37 )
    2.45 ( 1.13 )
    Statistical analysis title
    		 DSST - day 171
    Comparison groups
    Canakinumab v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.787
    Method
    		 Mixed models analysis
    Parameter type
    		 Repeated measures analysis
    Point estimate
    -0.49
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.56
         upper limit
    		 2.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8

    Secondary: Change from baseline in neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) total score

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    End point title
    		 Change from baseline in neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) total score
    End point description
    Neuropsychiatric Inventory (NPI) total score is globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials. NPI covers twelve neuropsychiatric domains. For each domain there are four scores, frequency (rated 1-4), severity (rated 1-3), domain total score (frequency x severity) and caregiver distress score (rated 0-5). The NPI total score was calculated by adding 12 domain total scores together, and ranges from 0 to 144, with higher values indicating greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: NPI total score change from Baseline
        arithmetic mean (standard deviation)
    -1.4 ( 7.76 )
    2.9 ( 8.68 )
    No statistical analyses for this end point

    Secondary: Change from baseline in neuropsychiatric symptoms associated distress as measured by the Neuropsychiatric Inventory caregiver distress (NPI-D) score

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    End point title
    		 Change from baseline in neuropsychiatric symptoms associated distress as measured by the Neuropsychiatric Inventory caregiver distress (NPI-D) score
    End point description
    Neuropsychiatric Inventory (NPI) total score is globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials. NPI covers twelve neuropsychiatric domains. For each domain there are four scores, frequency (rated 1-4), severity (rated 1-3), domain total score (frequency x severity) and caregiver distress score (rated 0-5). The caregiver distress score (NPI-D) was calculated by adding together the scores of the 12 individual NPI distress questions, and ranges from 0 to 60, with higher values indicating greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: NPI-D score change from Baseline
        arithmetic mean (standard deviation)
    -2.7 ( 7.70 )
    1.2 ( 5.74 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Mean eNeuropsychiatric at home caregiver assessment score

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    End point title
    		 Change from baseline in Mean eNeuropsychiatric at home caregiver assessment score
    End point description
    Neuropsychiatric Inventory (NPI) total score is globally recognized and the most frequently used assessment of neuropsychiatric symptoms in AD trials. NPI covers twelve neuropsychiatric domains. For each domain there are four scores, frequency (rated 1-4), severity (rated 1-3), domain total score (frequency x severity) and caregiver distress score (rated 0-5). The eNeuropsychiatric at-home assessment was calculated the same way as the in-clinic NPI by adding the12 domain total scores together. The eNeuropsychiatric at-home assessments were completed more frequently than the single time-point in-clinic NPI assessment and the scores averaged. It ranges from 0 to 144, with higher values indicating greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline, day 85
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    12
    Units: eNeuropsychiatric change from Baseline
        arithmetic mean (standard deviation)
    0.983 ( 3.7904 )
    -1.094 ( 1.7083 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Everyday Cognition scale (ECog) total score

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    End point title
    		 Change from baseline in Everyday Cognition scale (ECog) total score
    End point description
    Everyday Cognition (ECog) scale measures cognitively-relevant everyday abilities and is comprised of 39 items covering six cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. Each item is scored on a 4 point scale (1=better or no change compared to 10 years earlier, 2=questionable/occasionally worse, 3=consistently a little worse, 4=consistently much worse). An "I don't know" response is also included, in that case the item is not included in the calculation. The total ECog score is calculated as the sum of all 39 items, and ranges from 0 to 156. Lower total ECog scores indicate better performance.
    End point type
    Secondary
    End point timeframe
    Baseline and day 171
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    10
    16
    Units: ECog total score change from Baseline
        arithmetic mean (standard deviation)
    1.2 ( 14.26 )
    3.4 ( 11.79 )
    No statistical analyses for this end point

    Secondary: Change from baseline in eCognitive testing scores - SWM between errors

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    End point title
    		 Change from baseline in eCognitive testing scores - SWM between errors
    End point description
    Spatial Working Memory (SWM) is a test of the subject’s ability to retain spatial information and to manipulate remembered items in working memory. A trial begins with several colored squares (boxes) being shown on the screen. The overall aim is that the subject should find a blue ‘token’ in each of the boxes and use them to fill up an empty column. The subject must touch each box in turn until one opens with a blue ‘token’ inside (a search). Returning to an empty box already sampled on this search is an error. SWM between errors is the number of times the subject incorrectly revisits a box in which a token has previously been found. It starts at 0 without a maximum limit with higher scores indicating a worse outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, day 85
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    9
    12
    Units: SWMBE score change from baseline
        arithmetic mean (standard deviation)
    -1.56 ( 6.018 )
    -1.83 ( 4.910 )
    No statistical analyses for this end point

    Secondary: Change from baseline in eCognitive testing scores - MTS proportional slowing 8-2 patterns

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    End point title
    		 Change from baseline in eCognitive testing scores - MTS proportional slowing 8-2 patterns
    End point description
    Match to Sample Visual Search (MTS) assesses attention and visual searching, with a speed accuracy trade-off. The participant is shown a complex visual pattern in the middle of the screen. After a brief delay, a varying number of similar patterns are shown in a circle of boxes around the edge of the screen. Only one of these patterns matches the pattern in the center of the screen, and the participant must indicate which it is by selecting it. MTS proportional slowing 8-2 patterns is the difference in mean time between presentation of the response stimulus options and the subject selecting the correct box on their first attempt on the 8 pattern assessment trials compared to the 2 pattern assessment trials. It starts at 0 without a maximum limit, and with higher scores indicating a worse outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, day 85
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    9
    12
    Units: Change from baseline in milliseconds
        arithmetic mean (standard deviation)
    143.780 ( 2871.0641 )
    77.573 ( 2824.3325 )
    No statistical analyses for this end point

    Secondary: Change from baseline in eCognitive testing scores - SWM strategy

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    End point title
    		 Change from baseline in eCognitive testing scores - SWM strategy
    End point description
    Spatial Working Memory (SWM) is a test of the subject’s ability to retain spatial information and to manipulate remembered items in working memory. A trial begins with several colored squares (boxes) being shown on the screen. The overall aim is that the subject should find a blue ‘token’ in each of the boxes and use them to fill up an empty column. The subject must touch each box in turn until one opens with a blue ‘token’ inside (a search). Returning to an empty box already sampled on this search is an error. SWM Strategy is the number of times a subject begins a new search pattern from the same box they started with previously. If they always begin a search from the same starting point, we infer that the subject is employing a planned strategy for finding the tokens. SMW strategy ranges from 3 to 26, a low score indicates high strategy use, they always begin the search from the same box, and a high score indicates that they are beginning their searches from many different boxes.
    End point type
    Secondary
    End point timeframe
    Baseline, day 85
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    9
    12
    Units: SWM strategy change from baseline
        arithmetic mean (standard deviation)
    -0.28 ( 1.149 )
    -0.92 ( 1.459 )
    No statistical analyses for this end point

    Secondary: Change from baseline in eCognitive testing scores - PAL first attempt memory score

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    End point title
    		 Change from baseline in eCognitive testing scores - PAL first attempt memory score
    End point description
    Pair associated learning (PAL): tests participants’ visual memory/new learning using patterns randomly displayed in boxes on a screen. Participants are to touch the box where patterns first appeared. PAL first attempt memory score is the number of times a subject choses the correct box on their first attempt when recalling the pattern locations. Ranges from 0 to 20 with higher score indicates a better outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, day 85
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    9
    12
    Units: PAL score change from baseline
        arithmetic mean (standard deviation)
    -0.17 ( 2.716 )
    0.08 ( 3.059 )
    No statistical analyses for this end point

    Secondary: Change from baseline in microglia activation as measured by Positron-Emission Tomography-Translocator Protein 18kDa - microglia activation

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    End point title
    		 Change from baseline in microglia activation as measured by Positron-Emission Tomography-Translocator Protein 18kDa - microglia activation
    End point description
    Positron-Emission Tomography-Translocator Protein 18kDa-microglia activation (PET TSPO) is considered a marker of central inflammation (a marker for activated microglia and astrocytes) and the signal strength has been shown to correlate with worsening clinical severity in participants with MCI or AD, measures of cognition and various clinical scores. Relative % change from baseline in volume of distribution (Vt) of the radio tracer for TSPO after treatment. Since only one participant completed day 85 PET TSPO, no data is reported here in order to protect and maintain participant privacy/confidentiality.
    End point type
    Secondary
    End point timeframe
    Baseline and day 85
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [1] - No data is reported here in order to protect and maintain participant privacy/confidentiality.
    [2] - No data is reported here in order to protect and maintain participant privacy/confidentiality.
    No statistical analyses for this end point

    Secondary: Serum pharmacokinetic concentrations of Canakinumab

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    End point title
    		 Serum pharmacokinetic concentrations of Canakinumab [3]
    End point description
    Serum pharmacokinetic pre-dose concentrations of CanakinumabConcentrations below the LLOQ were reported as “zero”.
    End point type
    Secondary
    End point timeframe
    Baseline, day29, day 57, day 8, day 141, day 171
    Notes
    [3] - 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: Pharmacokinetic concentration of the active drug can only be reported for the active drug per definition. We cannot report concentrations of placebo arm.
    End point values
    		 Canakinumab
    Number of subjects analysed
    16
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=14)
    0.0 ( 0.00 )
        Day 29 (n=16)
    8921.3 ( 2721.47 )
        Day 57 (n=13)
    14230.8 ( 4712.07 )
        Day 85 (n=12)
    26575.0 ( 10216.93 )
        Day 141 (n=11)
    34000.0 ( 11288.67 )
        Day 171 (n=10)
    33170.0 ( 6825.45 )
    No statistical analyses for this end point

    Secondary: Total target (IL-1 beta) concentration in serum and CSF

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    End point title
    		 Total target (IL-1 beta) concentration in serum and CSF
    End point description
    Serum and CSF samples were obtained and evaluated for total target concentrations (the sum of free and drug-bound target) as a pharmacodynamic (PD) marker for target engagement.
    End point type
    Secondary
    End point timeframe
    Baseline, day 29, day 57, day 85, day 141, day 171 for serum concentrations and Baseline and day 85 for CSF concentrations
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    15
    18
    Units: pg/mL
    arithmetic mean (standard deviation)
        Serum - Baseline (n=13 /n=18)
    0.000 ( 0.0000 )
    0.000 ( 0.0000 )
        Serum - Day 29 (n=15 /n=18)
    12.632 ( 4.4949 )
    0.000 ( 0.0000 )
        Serum - Day 57 (n=13 /n=17)
    20.818 ( 10.2918 )
    0.000 ( 0.0000 )
        Serum - Day 85 (n=11 /n=16)
    23.291 ( 5.2984 )
    0.000 ( 0.0000 )
        Serum - Day 141 (n=11 /n=16)
    44.473 ( 58.3963 )
    0.000 ( 0.0000 )
        Serum - Day 171 (n=10 /n=16)
    28.460 ( 18.4483 )
    0.000 ( 0.0000 )
        CSF - Baseline (n=15 /n=18)
    0.000 ( 0.0000 )
    0.000 ( 0.0000 )
        CSF - Day 85 (n=12 /n=15)
    0.000 ( 0.0000 )
    0.023 ( 0.0883 )
    No statistical analyses for this end point

    Secondary: Number of participants with anti-agent antibodies in serum

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    End point title
    		 Number of participants with anti-agent antibodies in serum [4]
    End point description
    Number of participants with anti-agent antibodies in serum. Immunogenicity (IG) was assessed in serum of all participants treated with biotherapeutic drug.
    End point type
    Secondary
    End point timeframe
    Baseline, day 85, day 171
    Notes
    [4] - 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: Anti-agent antibodies can only be reported for participants receiving the active drug.
    End point values
    		 Canakinumab
    Number of subjects analysed
    16
    Units: Participants
        Baseline|POSITIVE
    0
        Baseline|NEGATIVE
    16
        Day 85|POSITIVE
    0
        Day 85|NEGATIVE
    12
        Day 171|POSITIVE
    0
        Day 171|NEGATIVE
    10
    No statistical analyses for this end point

    Secondary: Number of participants who experience adverse events and serious adverse events

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    End point title
    		 Number of participants who experience adverse events and serious adverse events
    End point description
    Clinically significant abnormalities of laboratory values, physical findings, electrocardiogram findings and other safety assessments were recorded as adverse events if the findings meet the defined criteria for adverse events. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5. For CTCAE, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 140 days post last dose (day 281)
    End point values
    		 Canakinumab Placebo
    Number of subjects analysed
    16
    18
    Units: Participants
        Participants with at least one AE
    14
    16
        Participants with grade 1 AEs
    14
    16
        Participants with grade 2 AEs
    6
    6
        Participants with grade 3 AEs
    1
    0
        Participants with study drug related AEs
    4
    5
        Participants with serious AEs
    2
    1
        AEs leading to drug discont.
    3
    1
        Treatment related AEs leading to drug discont.
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to approximately 140 days post last dose (day 281)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    ACZ885
    Reporting group description
    		 ACZ885

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 ACZ885 Total Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 34 (8.82%)
    1 / 18 (5.56%)
         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)
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (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
    Nervous system disorders
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (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
    Streptococcal infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ACZ885 Total Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 16 (81.25%)
    29 / 34 (85.29%)
    16 / 18 (88.89%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 16 (25.00%)
    5 / 34 (14.71%)
    1 / 18 (5.56%)
         occurrences all number
    4
    5
    1
    Flushing
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Immune system disorders
    Sensitisation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Procedural anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Persecutory delusion
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Irritability
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Confusional state
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 34 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    2
    2
    0
    Anxiety
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Investigations
    White blood cells urine positive
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Weight decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Lipase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 34 (8.82%)
    2 / 18 (11.11%)
         occurrences all number
    1
    4
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 34 (8.82%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Post lumbar puncture syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Immunisation reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Fall
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    2
    2
    0
    Contusion
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Scratch
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 34 (5.88%)
    2 / 18 (11.11%)
         occurrences all number
    0
    3
    3
    Intention tremor
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Syncope
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Pancreatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Diverticulum
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Abdominal tenderness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 34 (5.88%)
    2 / 18 (11.11%)
         occurrences all number
    0
    3
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Eczema
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Acne
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 34 (8.82%)
    1 / 18 (5.56%)
         occurrences all number
    2
    3
    1
    Acute kidney injury
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Back pain
         subjects affected / exposed
    2 / 16 (12.50%)
    4 / 34 (11.76%)
    2 / 18 (11.11%)
         occurrences all number
    2
    4
    2
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 34 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    2
    2
    0
    Otitis externa
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 34 (2.94%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 34 (5.88%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 34 (8.82%)
    2 / 18 (11.11%)
         occurrences all number
    1
    4
    3
    Vaginal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Viral infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 34 (2.94%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2021
    The purpose of this amendment is to address comments from the Medicines and Healthcare Products Regulatory Agency (MHRA) including: 1. Revisions to clinically important infection-related safety language in alignment with the administration of immunomodulatory agents; 2. Revisions to female contraception requirement to reflect unknown risks to fetal development in immunomodulatory agents.
    01 Aug 2021
    The rationale for this protocol amendment is three-fold: 1. To reflect logistical changes in the study execution prior to enrolling participants 2. To increase the duration of the study when monoclonal antibodies are administered 3. Address previous requests from The Finnish Medicines Agency (FIMEA) and US Food and Drug Administration (FDA) received during the review of the original clinical trial submission. Minor changes were made to some sections of the protocol for additional clarity and better understanding of the study.
    01 Mar 2022
    The rationale for this protocol amendment is to update Inclusion/Exclusion section to better specify excluded medications or timing around previous exposure to prohibited medications; and, to more clearly specify the intended population to be studied in the EXPLAIN-AD trial. In addition, this amendment provides an update to SAE section regarding covid-19 in order to align with evolving state of pandemic. Minor changes were made to some sections of the protocol for additional clarity and better understanding of the study.
    04 Sep 2022
    The rationale for this protocol amendment is to update Inclusion/Exclusion section to better clarify the targeted participant population based on eligibility with the intention to not unnecessarily exclude participants that are suitable for this trial.

    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.
    None reported
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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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