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    Clinical Trial Results:
    A multicentre, multinational, randomised, double-blind, placebo-controlled, 3-arm, 24-week parallel-group study to evaluate the safety, tolerability and preliminary efficacy of ORY-2001 in patients with mild-moderate Alzheimer's Disease. ETHERAL Study

    Summary
    EudraCT number
    2017-004893-32
    Trial protocol
    ES   FR   GB  
    Global end of trial date
    28 Aug 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Mar 2022
    First version publication date
    19 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL03-ORY-2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Oryzon Genomics S.A.
    Sponsor organisation address
    C/Sant Ferran 74, Cornellà de Llobregat, Spain, 08940
    Public contact
    Clinical Operations, Oryzon Genomics S.A., 34 935151313, sgutierrez@oryzon.com
    Scientific contact
    Clinical Operations, Oryzon Genomics S.A., 34 935151313, sgutierrez@oryzon.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
    21 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of two doses of vafidemstat (ORY-2001) in subjects with mild-moderate Alzheimer's Disease
    Protection of trial subjects
    Subjects were free to discontinue their participation in the study at any time. An independent Data Monitoring Committee (DMC) reviewed unblinded safety data throughout the study. All subjects, except for those who withdraw consent, completed a Safety Follow-up Visit 30 days after last dose of vafidemstat. For subjects who withdrew their consent, a safety assessment conducted by a physician outside the scope of this study was also recommended 4 weeks after treatment discontinuation.
    Background therapy
    AChEI (donepezil, rivastigmine, or galantamine)
    Evidence for comparator
    Placebo was the comparator in the Treatment period. No comparator was used during the Extension period.
    Actual start date of recruitment
    02 Apr 2018
    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
    Spain: 52
    Country: Number of subjects enrolled
    United Kingdom: 55
    Country: Number of subjects enrolled
    France: 10
    Worldwide total number of subjects
    117
    EEA total number of subjects
    62
    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)
    18
    From 65 to 84 years
    92
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 17 centers in France (n=3), Spain (n=6) and The United Kingdom (n=8) recruited subjects in this study, whereas 16 centers enrolled subjects.

    Pre-assignment
    Screening details
    A Screening Period for up to 4 weeks before the Treatment Period was allowed. Randomization was stratified by cognitive impairment severity at the Screening Visit (MMSE score: 16-19 vs. 20-26). A total of 218 subjects were screened and 117 subjects were randomized and treated.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    Initially, all patients were randomised in a 2:2:1 ratio. After Amendment No. 3, patients were randomised in a 1:1:2 ratio from the 41st patient onwards (i.e. 85 patients). Blinding was only to be broken for serious, unexpected, and related AEs that required immediate medical treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Vafidemstat 0.6 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with 0.6 mg ORY-2001 drug substance without addition of excipients, and by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Arm title
    Vafidemstat 1.2 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with 1.2 mg ORY-2001 drug substance without addition of excipients, and by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with cellulose microcristalline by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Number of subjects in period 1
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo
    Started
    38
    34
    45
    Completed
    31
    28
    38
    Not completed
    7
    6
    7
         Consent withdrawn by subject
    2
    2
    2
         Physician decision
    -
    1
    1
         Adverse event, non-fatal
    2
    2
    3
         Other
    1
    1
    -
         Protocol deviation
    2
    -
    1
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    During the Extension Period, subjects in the placebo arm during the Treatment Period were re-allocated in one of the two different dose levels of vafidemstat in a 1:1 ratio. This Extension Period was considered open as all subjects were under active treatment and the results were unblinded after the last subject last visit in the Treatment Period. However, IMP labelling remained blinded during the Extension Period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Early Start 0.6 mg
    Arm description
    Treatment with vafidemstat 0.6 mg during Treatment Period and Extension Period
    Arm type
    Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with 0.6 mg ORY-2001 drug substance without addition of excipients, and by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Arm title
    Early Start 1.2 mg
    Arm description
    Treatment with vafidemstat 1.2 mg during Treatment Period and Extension Period
    Arm type
    Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with 1.2 mg ORY-2001 drug substance without addition of excipients, and by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Arm title
    Delayed Start 0.6 mg
    Arm description
    Treated with Placebo during Treatment Period, and treated with vafidemstat 0.6 mg during Extension Period
    Arm type
    Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with 0.6 mg ORY-2001 drug substance without addition of excipients, and by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Arm title
    Delayed Start 1.2 mg
    Arm description
    Treated with Placebo during Treatment Period, and treated with vafidemstat 1.2 mg during Extension Period
    Arm type
    Experimental

    Investigational medicinal product name
    Vafidemstat
    Investigational medicinal product code
    ORY-2001
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Swedish orange coloured size 3 capsules (hydroxypropyl methylcellulose shells) loaded directly with 1.2 mg ORY-2001 drug substance without addition of excipients, and by means of Xcelodose® filling technology. The subjects were instructed to take orally one capsule of IMP fiw, e.g. once-a-day from Monday to Friday (in the morning)

    Number of subjects in period 2 [1]
    Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg
    Started
    29
    27
    18
    19
    Completed
    25
    23
    17
    16
    Not completed
    4
    4
    1
    3
         Consent withdrawn by subject
    1
    -
    -
    1
         Adverse event, non-fatal
    3
    4
    1
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 97 subjects completed the Treatment Period and 93 subjects constituted the Extension Period SAF2 population. Out of the 4 subjects completing the Treatment Period but not continuing in the Extension Period, 3 discontinued the study due to and AE (1 subject of each the ES 0.6 mg, ES 1.2 mg and DS 0.6 mg groups), and 1 discontinued due to withdrawal by subject (ES 0.6 mg group).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vafidemstat 0.6 mg
    Reporting group description
    -

    Reporting group title
    Vafidemstat 1.2 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Total
    Number of subjects
    38 34 45 117
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Only the FAS population results are available
    Units: years
        arithmetic mean (standard deviation)
    72.5 ± 8.0 71.9 ± 8.0 73.5 ± 6.1 -
    Gender categorical
    Units: Subjects
        Female
    25 18 24 67
        Male
    13 16 21 50
    Subject analysis sets

    Subject analysis set title
    SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population includes all subjects who received at least one dose of the study IMP. Safety summaries were performed on the safety set

    Subject analysis set title
    FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set includes all randomized subjects who received at least one dose of the IMP and completed at least one test assessing the clinical domains of AD (CMAI, AES-C, ADAS-Cog14, CSDD, Cogstate, MMSE or CDR) with an available score, for at least one visit after baseline

    Subject analysis set title
    PPS1
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects of the FAS who completed at least one test assessing the clinical domains of AD (CMAI, AES-C, ADAS-Cog14, CSDD, Cogstate, MMSE or CDR) with available scores at Week 24, and who were deemed to have no major protocol violations until Week 24 that could interfere with the objectives of this study

    Subject analysis set title
    SAF2
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This safety population includes all subjects who received at least one dose of the study IMP from visit 10 until visit 17 or EoS (after visit 10). Safety summaries for Extension period were performed based on the safety set 2

    Subject analysis set title
    PPS2
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects of the FAS who completed at least one test assessing the clinical domains of AD (CMAI, AES-C, ADAS-Cog14, CSDD, Cogstate, MMSE or CDR) with available scores at Week 48, and who were deemed to have no major protocol violations until Week 48 that could interfere with the objectives of this study

    Subject analysis sets values
    SAF FAS PPS1 SAF2 PPS2
    Number of subjects
    117
    115
    96
    93
    66
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Only the FAS population results are available
    Units: years
        arithmetic mean (standard deviation)
    ±
    72.7 ± 7.3
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    67
    65
        Male
    50
    50

    End points

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    End points reporting groups
    Reporting group title
    Vafidemstat 0.6 mg
    Reporting group description
    -

    Reporting group title
    Vafidemstat 1.2 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -
    Reporting group title
    Early Start 0.6 mg
    Reporting group description
    Treatment with vafidemstat 0.6 mg during Treatment Period and Extension Period

    Reporting group title
    Early Start 1.2 mg
    Reporting group description
    Treatment with vafidemstat 1.2 mg during Treatment Period and Extension Period

    Reporting group title
    Delayed Start 0.6 mg
    Reporting group description
    Treated with Placebo during Treatment Period, and treated with vafidemstat 0.6 mg during Extension Period

    Reporting group title
    Delayed Start 1.2 mg
    Reporting group description
    Treated with Placebo during Treatment Period, and treated with vafidemstat 1.2 mg during Extension Period

    Subject analysis set title
    SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population includes all subjects who received at least one dose of the study IMP. Safety summaries were performed on the safety set

    Subject analysis set title
    FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set includes all randomized subjects who received at least one dose of the IMP and completed at least one test assessing the clinical domains of AD (CMAI, AES-C, ADAS-Cog14, CSDD, Cogstate, MMSE or CDR) with an available score, for at least one visit after baseline

    Subject analysis set title
    PPS1
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects of the FAS who completed at least one test assessing the clinical domains of AD (CMAI, AES-C, ADAS-Cog14, CSDD, Cogstate, MMSE or CDR) with available scores at Week 24, and who were deemed to have no major protocol violations until Week 24 that could interfere with the objectives of this study

    Subject analysis set title
    SAF2
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This safety population includes all subjects who received at least one dose of the study IMP from visit 10 until visit 17 or EoS (after visit 10). Safety summaries for Extension period were performed based on the safety set 2

    Subject analysis set title
    PPS2
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All randomized subjects of the FAS who completed at least one test assessing the clinical domains of AD (CMAI, AES-C, ADAS-Cog14, CSDD, Cogstate, MMSE or CDR) with available scores at Week 48, and who were deemed to have no major protocol violations until Week 48 that could interfere with the objectives of this study

    Primary: Number of TEAEs

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    End point title
    Number of TEAEs [1]
    End point description
    Overall number of TEAEs. TEAEs reported during the Treatment Period are summarized here for the 3 applicable groups in the SAF population. TEAEs reported during the Extension Period are summarized here for the 4 applicable groups in the SAF2 population.
    End point type
    Primary
    End point timeframe
    Up to Week 24 (Treatment Period) and from Week 24 to Week 48 (Extension Period)
    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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: TEAEs
    139
    156
    131
    63
    65
    18
    58
    426
    204
    No statistical analyses for this end point

    Primary: Number of Severe TEAEs

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    End point title
    Number of Severe TEAEs [2]
    End point description
    Severe TEAEs reported during the Treatment Period are summarized here for the 3 applicable groups in the SAF population. Severe TEAEs reported during the Extension Period are summarized here for the 4 applicable groups in the SAF2 population.
    End point type
    Primary
    End point timeframe
    Up to Week 24 (Treatment Period) and from Week 24 to Week 48 (Extension Period)
    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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: Severe TEAEs
    2
    3
    5
    5
    1
    2
    3
    10
    11
    No statistical analyses for this end point

    Primary: Incidence of TEAEs

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    End point title
    Incidence of TEAEs [3]
    End point description
    TEAEs reported during the Treatment Period are summarized here for the 3 applicable groups in the SAF population. TEAEs reported during the Extension Period are summarized here for the 4 applicable groups in the SAF2 population.
    End point type
    Primary
    End point timeframe
    Up to Week 24 (Treatment Period) and from Week 24 to Week 48 (Extension Period)
    Notes
    [3] - 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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: TEAEs per subject-years of follow-up
        arithmetic mean (standard deviation)
    9.23 ± 8.04
    11.99 ± 12.26
    7.51 ± 8.30
    5.27 ± 4.34
    8.20 ± 11.79
    3.56 ± 7.13
    7.00 ± 5.00
    9.37 ± 9.64
    6.14 ± 7.89
    No statistical analyses for this end point

    Primary: Change in vital signs

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    End point title
    Change in vital signs [4]
    End point description
    The analysis of vital signs did not reveal any relevant clinically significant trend.
    End point type
    Primary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period)
    Notes
    [4] - 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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    117
    93
    No statistical analyses for this end point

    Primary: Change in ECG parameters

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    End point title
    Change in ECG parameters [5]
    End point description
    The analysis of ECG did not reveal any relevant clinically significant trend.
    End point type
    Primary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period)
    Notes
    [5] - 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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    117
    93
    No statistical analyses for this end point

    Primary: Change in clinical laboratory parameters

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    End point title
    Change in clinical laboratory parameters [6]
    End point description
    The analysis of laboratory parameters for hematology and biochemistry did not reveal any relevant clinically significant trend.
    End point type
    Primary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period)
    Notes
    [6] - 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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    117
    93
    No statistical analyses for this end point

    Primary: Concomitant medications

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    End point title
    Concomitant medications [7]
    End point description
    End point type
    Primary
    End point timeframe
    Up to Week 24 (Treatment Period) and from Baseline to Week 48 (Extension Period)
    Notes
    [7] - 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: N/A
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg SAF SAF2
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    117
    93
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    117
    93
    No statistical analyses for this end point

    Secondary: Cohen-Mansfield Agitation Inventory (CMAI) score

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    End point title
    Cohen-Mansfield Agitation Inventory (CMAI) score
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Secondary: Apathy Evaluation Scale - Clinician (AES-C) score

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    End point title
    Apathy Evaluation Scale - Clinician (AES-C) score
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Secondary: Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score

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    End point title
    Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 12, Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Secondary: Computerised Cognitive Test battery (Cogstate) score

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    End point title
    Computerised Cognitive Test battery (Cogstate) score
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 12, Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Secondary: Mini-Mental State Examination (MMSE) score

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    End point title
    Mini-Mental State Examination (MMSE) score
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Secondary: Clinical Dementia Rating Scale (CDR) scores

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    End point title
    Clinical Dementia Rating Scale (CDR) scores
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Secondary: Cornell Scale for Depression in Dementia (CSDD) score

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    End point title
    Cornell Scale for Depression in Dementia (CSDD) score
    End point description
    Over the 24-week Treatment Period, no improvements across secondary endpoints were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Other pre-specified: Cerebrospinal Fluid Biomarkers (PD)

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    End point title
    Cerebrospinal Fluid Biomarkers (PD)
    End point description
    The analysis of CSF biomarkers showed no treatment differences in any CSF parameters over the Treatment Period, except for YKL-40, which results in a statistical difference between study arms (p=0.0104). ANCOVA-Least square Means shows that placebo treatment leads to an increase of the CSF levels of YKL-40 at Week 24 compared to baseline (p=0.0006) due to inflammatory progression, while vafidemstat treatment impedes this increase and no differences from baseline were observed at both treatment arms. No differences between study arms were observed in YKL-40 biomarker during the Extension Period once all groups were assigned to vafidemstat treatment although the YKL-40 levels were reduced in all arms to similar levels observed in the vafidemstat-treated subjects during the Treatment Period.
    End point type
    Other pre-specified
    End point timeframe
    Change from screening to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Other pre-specified: Magnetic Resonance Imaging (MRI) parameters

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    End point title
    Magnetic Resonance Imaging (MRI) parameters
    End point description
    The MRI parameters showed similar trends across the 3 studied groups over the Treatment Period, only observing a statistically significant effect of the treatment in the superior lateral ventricle LH and RH volumes % of intracranial volume (icv), and the superior lateral ventricles normative percentile. The MRI values showed similar trends across the 4 studied groups over the full study period, only observing a statistically significant effect of the treatment in the superior lateral ventricle LH volume % of icv and the cerebellum RH volume % of icv.
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Other pre-specified: Dependence Scale score

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    End point title
    Dependence Scale score
    End point description
    Over the 24-week Treatment Period, no improvements in the Dependence Scale score were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Other pre-specified: EuroQOL five dimensions questionnaire (EQ-5D-5L) score

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    End point title
    EuroQOL five dimensions questionnaire (EQ-5D-5L) score
    End point description
    Over the 24-week Treatment Period, no improvements in the EQ-5D-5L score were observed in the vafidemstat treatment groups compared to placebo. Consistent results were observed during the overall trial (48-weeks).
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to Week 12, Week 24 (Treatment Period) and Week 48 (Extension Period) Change over time
    End point values
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg FAS
    Number of subjects analysed
    38
    34
    45
    29
    27
    18
    19
    115
    Units: Subjects
    38
    34
    45
    29
    27
    18
    19
    115
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 24 (Treatment Period) and from Week 24 to Week 48 (Extension Period)
    Adverse event reporting additional description
    The described ‘Non-serious adverse events’ results comprise all the TEAEs (serious+non-serious). TEAEs reported during the Treatment Period are summarized here for the 3 applicable groups in the SAF population. TEAEs reported during the Extension Period are summarized here for the 4 applicable groups in the SAF2 population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Vafidemstat 0.6 mg
    Reporting group description
    Only TEAEs reported during Treatment Period (up to Week 24)

    Reporting group title
    Vafidemstat 1.2 mg
    Reporting group description
    Only TEAEs reported during Treatment Period (up to Week 24)

    Reporting group title
    Placebo
    Reporting group description
    Only TEAEs reported during Treatment Period (up to Week 24)

    Reporting group title
    Early Start 0.6 mg
    Reporting group description
    Only TEAEs reported during Extension Period (Week 24 to Week 48)

    Reporting group title
    Early Start 1.2 mg
    Reporting group description
    Only TEAEs reported during Extension Period (Week 24 to Week 48)

    Reporting group title
    Delayed Start 0.6 mg
    Reporting group description
    Only TEAEs reported during Extension Period (Week 24 to Week 48)

    Reporting group title
    Delayed Start 1.2 mg
    Reporting group description
    Only TEAEs reported during Extension Period (Week 24 to Week 48)

    Serious adverse events
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 34 (11.76%)
    4 / 45 (8.89%)
    3 / 29 (10.34%)
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Coronary Artery Stenosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    2 / 45 (4.44%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper Gastrointestinal Hemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Vafidemstat 0.6 mg Vafidemstat 1.2 mg Placebo Early Start 0.6 mg Early Start 1.2 mg Delayed Start 0.6 mg Delayed Start 1.2 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 38 (97.37%)
    32 / 34 (94.12%)
    37 / 45 (82.22%)
    23 / 29 (79.31%)
    24 / 27 (88.89%)
    10 / 18 (55.56%)
    16 / 19 (84.21%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 34 (5.88%)
    2 / 45 (4.44%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    4
    2
    2
    1
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 34 (2.94%)
    5 / 45 (11.11%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    5
    0
    0
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 34 (5.88%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    1
    1
    1
    1
    2
    Delusion
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    3
    Confusional state
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 34 (5.88%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    2
    0
    0
    1
    0
    1
    Disorientation
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 34 (2.94%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 34 (5.88%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    1
    1
    1
    1
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 34 (11.76%)
    1 / 45 (2.22%)
    2 / 29 (6.90%)
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    8
    1
    3
    2
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 34 (14.71%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    5
    0
    1
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 34 (5.88%)
    2 / 45 (4.44%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    1
    2
    2
    0
    1
    2
    1
    Blood pressure increased
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 34 (2.94%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    1
    1
    1
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 34 (0.00%)
    2 / 45 (4.44%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    2
    0
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 34 (2.94%)
    2 / 45 (4.44%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    2
    0
    2
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 34 (5.88%)
    5 / 45 (11.11%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    7
    3
    5
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 34 (8.82%)
    4 / 45 (8.89%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    3
    6
    2
    1
    0
    1
    Contusion
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 34 (0.00%)
    3 / 45 (6.67%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    4
    1
    0
    0
    1
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 34 (8.82%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    4
    2
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 34 (5.88%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    0 / 19 (0.00%)
         occurrences all number
    2
    6
    1
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 34 (0.00%)
    2 / 45 (4.44%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    2
    1
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 34 (2.94%)
    2 / 45 (4.44%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Hypertension
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 34 (2.94%)
    2 / 45 (4.44%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    1
    2
    1
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 34 (2.94%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    1
    1
    1
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 34 (5.88%)
    3 / 45 (6.67%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    5
    1
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 34 (2.94%)
    2 / 45 (4.44%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 34 (2.94%)
    3 / 45 (6.67%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    3
    1
    0
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 34 (5.88%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    2 / 27 (7.41%)
    1 / 18 (5.56%)
    1 / 19 (5.26%)
         occurrences all number
    0
    2
    0
    1
    2
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 34 (11.76%)
    1 / 45 (2.22%)
    3 / 29 (10.34%)
    1 / 27 (3.70%)
    1 / 18 (5.56%)
    4 / 19 (21.05%)
         occurrences all number
    5
    4
    1
    3
    1
    1
    4
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 34 (5.88%)
    2 / 45 (4.44%)
    2 / 29 (6.90%)
    4 / 27 (14.81%)
    1 / 18 (5.56%)
    4 / 19 (21.05%)
         occurrences all number
    1
    2
    2
    2
    4
    1
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 34 (11.76%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    5
    1
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 34 (0.00%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    0 / 18 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 34 (8.82%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
    0 / 18 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    3
    0
    0
    2
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2018
    The main protocol modifications emerged after thorough review of the statistical considerations in order not to underestimate the true treatment effect in comparison to the placebo. These considerations included an increase of the sample size from 90 randomized subjects to 125 randomized subjects, and a switch in the randomization scheme from a 2:2:1 (vafidemstat 0.6 mg/day:vafidemstat 1.2 mg/day:placebo) to a 1:1:2 scheme. Specifically, the ETHERAL trial started with a randomization scheme of 2:2:1 between two doses of vafidemstat (0.6 and 1.2 mg) and placebo during the first 6 months treatment period. However, for the following reasons a randomization ratio of 1:1:2 led to a more informative study: 1. Preclinical studies suggested that both doses should have similar therapeutic effect. If the safety and efficacy profiles of the two vafidemstat arms were similar, then a comparison of the pooled vafidemstat arms vs. the placebo group could be more powerful with a 1:1:2 allocation ratio. This combined comparison analysis was finally not performed 2. The placebo group subjects were actually under the standard of care and were expected to have an improvement. A larger proportion of subjects assigned to the placebo group and with re-allocation in the extension period allowed a more efficient within subject comparison within the placebo 3. In case future investigations with vafidemstat were carried out with a Bayesian design, with room to borrow information from previous studies, having a more balanced vafidemstat to placebo assignment in the current study may be more efficient Other changes made to the protocol were: • Planned dates of the last subject first visit (from 3Q 2018 to 1Q 2019) and the last subject last visit (from 3Q 2019 to 1Q 2020) • Accountability of the AChEI (concomitant chronic medication used by all the subjects), from being tracked in the same way of the Investigational Medical Product to being tracked as the other concomitant medications
    07 Jan 2019
    Protocol modifications have emerged from a thorough review, where the introduction of some modifications was implemented in order to clarify items that were not previously explained with sufficient detail. The following modifications were performed: • Clarification in definition of fertile female for the inclusion criterion number 12 • Clarification of exclusion criteria number 7 and 8 • Amendment of exclusion criterion number 11 to facilitate recruitment by accommodating the wash-out period to the common criteria in clinical trials • Clarification of window period between visits • Clarification of the blood extractions to be taken during the study • Addition of two Cogstate practice assessments before baseline • Clarification of the subjects re-screened • Clarification of two criteria for removing subjects from therapy or assessment • Clarification of information given to the subject about the storage and handling of Investigational Medicinal Product • Clarification of the treatment compliance • Clarification of the order of the efficacy assessments and the administration of the Investigational Medicinal Product • Clarification of when a clinical laboratory abnormality should be documented as an adverse event
    29 Apr 2019
    The following modifications were performed: • Inclusion of an exploratory objective, and the corresponding endpoints, to document APOE genotype in the study’s participants as well as examine any associated treatment differences. Finally, none of the planned APOE genotype relationship analyses were performed • Clarification of the Extension Period as an open period because all subjects will be on active treatment and results will be unblinded after the last subject last visit in the 24 week double blind placebo-controlled Treatment Period • Inclusion of an optional blood sample test at any point throughout the study, although baseline collection is recommended, for APOE genotyping • Amendment of inclusion criterion number 10: AD treatment-naïve subjects as eligible participants in the study (only in centers located in France and UK) • Clarification of AChEI compliance assessment as only would apply to subjects with AChEI at the Screening Visit • Amendment of withdrawal criterion about changes in the concomitant medication to make it apply to both AD treatment-naïve subjects and subjects with AChEI at the Screening Visit • Amendment of the statistical issues due to the inclusion of the APOE genotyping, and AD treatment-naïve subjects as eligible participants This protocol amendment also included changes in the study administrative structure

    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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