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    Clinical Trial Results:
    A single-center, open-label, single-arm, 13-week study to evaluate the efficacy, safety and tolerability of ORY-2001 in aggression in Alzheimer’s Disease (AD) – REIMAGINE-AD

    Summary
    EudraCT number
    		 2019-001436-54
    Trial protocol
    		 ES  
    Global end of trial date
    17 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2023
    First version publication date
    23 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL06-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
    Carrer de Sant Ferran, 74, CORNELLA DE LLOBREGAT, Spain, 08940
    Public contact
    Michael Ropacki, Chief Medical Officer CNS, Oryzon Genomics S.A., Oryzon Genomics S. A., 34 93 515 13 13, mropacki@oryzon.com
    Scientific contact
    Michael Ropacki, Chief Medical Officer CNS, Oryzon Genomics S.A., Oryzon Genomics S. A., 34 93 515 13 13, mropacki@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
    12 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of ORY-2001 in aggression in an AD population
    Protection of trial subjects
    In accordance with European Union RGPD 2016/679 of 27 April, 2016 the data were processed in accordance with the specifications outlined by the local law to ensure that requirements regarding personal data protection are met. If an external organization processed data on behalf of Oryzon, a contractual procedure was signed between Oryzon and the external organization to ensure compliance with the above-mentioned legislation. If applicable, the participation of patients in this study was reported to the appropriate local data protection agencies, in accordance with European Union RGPD 2016/679 of 27 April 2016 and Country-specific guidelines and laws (Spanish Organic Law 3/2018 of 5 December).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    1
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 It was planned that approximately 15 patients were screened in one single center to obtain a total of 8-12 subjects. A total of 13 patients were screened and 12 subjects were included in the study.

    Pre-assignment
    Screening details
    		 This Phase IIa study was a single center, open-label, single arm study with a 1-week Screening Period and no study related procedures, including any screening procedures, were performed before the PI had obtained written informed consent from the patient and/or his/her legal representative and the close relative/caregiver.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment arm
    Arm description
    		 1.2 mg dose of vafidemstat five times in week (fiw).
    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
    Vafidemstat was administered daily for 5 days, at a dose of 1.2 mg/day.

    Number of subjects in period 1 [1]
    		Treatment arm
    Started
    12
    Completed
    7
    Not completed
    5
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    1
         Protocol deviation
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 12 subjects were enrolled however 5 did not complet the study treatment period due to the reasons described.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 1.2 mg dose of vafidemstat five times in week (fiw).

    Reporting group values
    		 Treatment arm Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 11 11
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.83 ( 7.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 1.2 mg dose of vafidemstat five times in week (fiw).

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all patients who received at least one dose of the study IMP

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients who received at least one dose of the IMP and have completed at least one of the primary endpoints (NPI-A/A, CMAI, CGI-A/A) in Baseline Visit (Week 1-Day 1) and any other post-Baseline Visit.

    Subject analysis set title
    PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol Set 1 (PPS) until Visit 4: All randomized patients of the FAS who have completed the assessment of at least one primary endpoint (NPI-A/A, CMAI, CGI-A/A) at Visit 4 (Week 8), and who were deemed to have no major protocol violations until Week 24 that could interfere with the objectives of this study. This is a subpopulation of the FAS.

    Subject analysis set title
    PPS2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol Set 2 (PPS2) until Visit 8: All randomized patients of the FAS who have completed the assessment of at least one primary endpoint (NPI-A/A, CMAI, CGI-A/A) at Visit 8 (Week 24), and who were deemed to have no major protocol violations until Week 24 that could interfere with the objectives of this study. This is a subpopulation of the FAS. Two subjects continued the study treatment for an additional 24-weeks, for a total of up to 48 weeks.

    Primary: Change from baseline in NPI-4 A/A

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    End point title
    		 Change from baseline in NPI-4 A/A [1]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 8 and to week 24
    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: It is a single-arm study, comparisons were made within that single-arm comparing baseline and end-of-treatment data.
    End point values
    		 FAS PPS PPS2
    Number of subjects analysed
    12
    10
    7
    Units: Subscale scores
    arithmetic mean (standard deviation)
        NPI-A/A Subscale scores
    12.17 ( 6.25 )
    6.5 ( 4.65 )
    2.29 ( 3.40 )
    No statistical analyses for this end point

    Primary: Change from baseline in the Cohen-Mansfield Agitation inventory (CMAI)

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    End point title
    		 Change from baseline in the Cohen-Mansfield Agitation inventory (CMAI) [2]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 8 and to week 24
    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: It is a single-arm study, comparisons were made within that single-arm comparing baseline and end-of-treatment data.
    End point values
    		 FAS PPS PPS2
    Number of subjects analysed
    12
    10
    7
    Units: CMAI score
    arithmetic mean (standard deviation)
        CMAI score
    54.58 ( 14.58 )
    52.50 ( 11.17 )
    39.29 ( 6.45 )
    No statistical analyses for this end point

    Primary: Change from baseline in the Clinical Global Impression – Improvement Agitation/Aggression (CGI- I A/A)

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    End point title
    		 Change from baseline in the Clinical Global Impression – Improvement Agitation/Aggression (CGI- I A/A) [3]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 8 and to week 24
    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: It is a single-arm study, comparisons were made within that single-arm comparing baseline and end-of-treatment data.
    End point values
    		 FAS PPS PPS2
    Number of subjects analysed
    12
    10
    7
    Units: CGI-I A/A score
    arithmetic mean (standard deviation)
        CGI-I-A/A
    4.00 ( 0.00 )
    3.60 ( 1.78 )
    1.86 ( 0.90 )
    No statistical analyses for this end point

    Primary: Change over time in the CGI- I A/A

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    End point title
    		 Change over time in the CGI- I A/A [4]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 8 and to week 24
    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: It is a single-arm study, comparisons were made within that single-arm comparing baseline and end-of-treatment data.
    End point values
    		 PPS PPS2
    Number of subjects analysed
    10 [5]
    7 [6]
    Units: CGI- I A/A score
    arithmetic mean (standard deviation)
        CGI-I-A/A score (absolute change)
    -0.40 ( 1.78 )
    -2.14 ( 0.90 )
    Notes
    [5] - Change: Visit 4 - Visit 1 (week 8 - week 1)
    [6] - Change: Visit 8 - Visit 1 (week 24 - week 1)
    No statistical analyses for this end point

    Primary: Change over time in the NPI-4 A/A

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    End point title
    		 Change over time in the NPI-4 A/A [7]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 8 and to week 24
    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: It is a single-arm study, comparisons were made within that single-arm comparing baseline and end-of-treatment data.
    End point values
    		 PPS PPS2
    Number of subjects analysed
    10 [8]
    7 [9]
    Units: Subscale score
    arithmetic mean (standard deviation)
        NPI-A/A Subscale score
    -4.00 ( 8.01 )
    -9.71 ( 5.85 )
    Notes
    [8] - Change: Visit 4 - Visit 1 (week 8 - week 1)
    [9] - Change: Visit 8 - Visit 1 (week 24 - week 1)
    No statistical analyses for this end point

    Primary: Change over time in the CMAI

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    End point title
    		 Change over time in the CMAI [10]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 8 and to week 24
    Notes
    [10] - 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: It is a single-arm study, comparisons were made within that single-arm comparing baseline and end-of-treatment data.
    End point values
    		 PPS PPS2
    Number of subjects analysed
    10 [11]
    7 [12]
    Units: CMAI score
    arithmetic mean (standard deviation)
        Total CMAI score (absolute change)
    -0.7 ( 16.63 )
    -16.71 ( 17.58 )
    Notes
    [11] - Change: Visit 4 - Visit 1 (week 8 - week 1)
    [12] - Change: Visit 8 - Visit 1 (week 24 - week 1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24-week treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 1.2 mg dose of vafidemstat five times in week (fiw).

    Serious adverse events
    		 Treatment arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 12 (8.33%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 12 (75.00%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood creatine increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hematocrit decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Protein C increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Edema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Behaviour disorder
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Oral infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2019
    Protocol v2.0: Extended-treatment period
    30 Jan 2020
    Protocol v3.0: Extended-treatment period

    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.
    Small sample size and open study design. A larger, randomized, double-blind, placebo-controlled trial is needed to confirm study results and demonstrate vafidemstat’s potential efficacy in treating agitation and aggression in moderate-to-severe AD.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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