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    Clinical Trial Results:
    Serum-monitoring of anti-dementia drugs, and the relevance to side-effects, clinical efficacy and compliance

    Summary
    EudraCT number
    		 2017-002707-10
    Trial protocol
    		 DK  
    Global end of trial date
    16 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Oct 2024
    First version publication date
    09 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SJ-596
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04117178
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Neurology ZUH
    Sponsor organisation address
    Vestermarksvej 4000, Roskilde, Denmark,
    Public contact
    RVD, Regional Dementia Research Centre, Dept of Neurology, 0045 47322800, phh@regionsjaelland.dk
    Scientific contact
    RVD, Regional Dementia Research Centre, Dept of Neurology, 0045 47322800, suh-neu@regionsjaelland.dk
    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
    02 Sep 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether serum-monitoring of anti-dementia drugs may reduce side-effects and improve clinical efficacy and patient compliance. NOTA BENE: two fictonal (male 'in utero') study participants (from Åland Islands) have been added to this report because the webside does not allow for validation without this ridiculous amendment.
    Protection of trial subjects
    the trial was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. Both the regional scientific ethics committee (Videnskabsetisk komité for Region Sjælland, file no.: SJ-596) and the Danish Medicines Agency approved the trial . The trial protocol was approved by the local data supervisory authority (Datatilsynet Region Sjælland, approval no.: REG-007-2018). The Good Clinical Practice (GCP) unit of Copenhagen monitored the study externally and conducted regular site inspections.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2020
    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
    Denmark: 132
    Country: Number of subjects enrolled
    Åland Islands: 2
    Worldwide total number of subjects
    134
    EEA total number of subjects
    132
    Number of subjects enrolled per age group
    In utero
    2
    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)
    16
    From 65 to 84 years
    105
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 132 participants were enrolled from February 12th, 2020, to February 24th, 2022. Of the 132 participants, 25 were registered as drop-outs either due to participant decision to withdraw or if treatment was changed to an anti-dementia drug not investigated in the trial (galanmantine, rivastigmine).

    Pre-assignment
    Screening details
    		 Patients attending the study site for patient visits were screened according to the inlcusion and exclusion criteria. Elegibile patients were offered trial participation during the visit where the diagnosis and treatment options were presented.

    Period 1
    Period 1 title
    Single-blinded RCT (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Assessor of clinical end points blinded to group allocation of participants. Also, the statistical analysis was done in a blinded manner.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control group
    Arm description
    		 Standard of care
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Standard care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    participants had their treatment titrated according to the standard of care at the study site. Hence, participants scheduled for donepezil were prescribed 5 mg./d for 4 weeks and then if well-tolerated the dose was increased to 10 mg./d. Participants scheduled for memantine were initially prescribed 5 mg./d, with a gradual dose-increase of 5 mg. the following weeks to a maximum of 20 mg./d.

    Arm title
    		 Intervention group
    Arm description
    		 Dosing of donepezil or memantine based on therapeutic drug monitoring
    Arm type
    		 Experimental

    Investigational medicinal product name
    TDM based dosing
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the IG, the PI adjusted treatment at the 6 months visit according to the serum concentration of the study drug in addition to relevant clinical information identical to that of the CG. We presumed that the lower limit of the TRR for serum donepezil (S-donepezil) was 50ng/mL. Accordingly, for participants in the IG, if the 10 mg/d dosage was well-tolerated and the serum concentration was below the 50ng/mL threshold we increased to daily dose to 15 or 20 mg/d. We applied the same procedure for treatment with memantine, with the lower limit set at serum memantine (S-memantine) 90 ng/mL. The maximum allowed daily dose in the study was 20 mg/d and 30 mg/d for donepezil and memantine respectively.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The assessor of clinical endpoints was blinded to group allocation
    Number of subjects in period 1
    		Control group Intervention group
    Started
    65
    67
    Completed
    49
    58
    Not completed
    17
    10
         Adverse event, serious fatal
    2
    2
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    11
    4
         test
    1
    1
    Joined
    1
    1
         test
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 Standard of care

    Reporting group title
    Intervention group
    Reporting group description
    		 Dosing of donepezil or memantine based on therapeutic drug monitoring

    Reporting group values
    		 Control group Intervention group Total
    Number of subjects
    		 66 68 134
    Age categorical
    Intervention group mean age: 74.4 Control group mean age: 76.0
    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
    Units: years
        arithmetic mean (standard deviation)
    		 76.0 ( 7.9 ) 74.4 ( 8.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 37 21 58
        Male
    		 29 47 76

    End points

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    End points reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 Standard of care

    Reporting group title
    Intervention group
    Reporting group description
    		 Dosing of donepezil or memantine based on therapeutic drug monitoring

    Primary: Mean change on Addenbrooke's Cognitive Exam from baseline to 12-month follow-up

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    End point title
    		 Mean change on Addenbrooke's Cognitive Exam from baseline to 12-month follow-up
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to 12-month follow-up
    End point values
    		 Control group Intervention group
    Number of subjects analysed
    49 [1]
    58 [2]
    Units: ACE
        arithmetic mean (standard deviation)
    -0.27 ( 3.19 )
    -0.90 ( 3.56 )
    Notes
    [1] - Due to dropout the number of subjects at 12 month was 49
    [2] - Due to withdrawal 58 subjects were assessed at 12 months
    Statistical analysis title
    		 Linear regression models with GEE
    Statistical analysis description
    We assessed the clinical outcomes at 12 months follow-up in linear regression models. Clinical outcomes were assessed using linear regression models comparing the difference between the baseline effect (difference in outcome between the randomization arms at study start) and the 12-month follow-up effect (difference in outcome between the randomization arms at the 12-month follow-up). We used generalized estimating equations (GEE) to accommodate for repeated measurements on the same study partic
    Comparison groups
    Control group v Intervention group
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Confidence interval

    Primary: Change on MMSE

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    End point title
    		 Change on MMSE [3]
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to 12 month follow-up
    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 was presumed that at least 50% of serum concentrations would be out of the recommended range without TDM based dose optimization and that the use of TDM based dose optimization would result in at least 75% of participants reaching a serum concentration within the TRR. Hence 55 participants were needed in each group with a significance level of 5% and a power of 80% in a Z-test for absolute difference in proportions.
    End point values
    		 Control group Intervention group
    Number of subjects analysed
    49 [4]
    58 [5]
    Units: score
        arithmetic mean (standard deviation)
    -0.27 ( 3.19 )
    -0.90 ( 3.56 )
    Notes
    [4] - Due to dropout the number of subjects at 12 months was 49
    [5] - Due to dropout the number of subjects at 12 months was 58
    No statistical analyses for this end point

    Secondary: Change on Geriatric Depression Scale

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    End point title
    		 Change on Geriatric Depression Scale
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 12 month follow-up
    End point values
    		 Control group Intervention group
    Number of subjects analysed
    49 [6]
    58 [7]
    Units: score
        arithmetic mean (standard deviation)
    -0.57 ( 2.47 )
    0.79 ( 2.55 )
    Notes
    [6] - Due to dropout the number of subjects at 12 months was 49
    [7] - Due to dropout the number of subjects at 12 months was 58
    No statistical analyses for this end point

    Secondary: Change on Neuropsychiatric Inventory

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    End point title
    		 Change on Neuropsychiatric Inventory
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 12 month follow-up
    End point values
    		 Control group Intervention group
    Number of subjects analysed
    49 [8]
    58 [9]
    Units: score
        arithmetic mean (standard deviation)
    2.40 ( 6.34 )
    1.30 ( 3.18 )
    Notes
    [8] - Due to dropout the number of subjects at 12 months was 49
    [9] - Due to dropout the number of subjects at 12 months was 58
    No statistical analyses for this end point

    Secondary: Change on Disability Assessment in Dementia

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    End point title
    		 Change on Disability Assessment in Dementia
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 12 month follow-up
    End point values
    		 Control group Intervention group
    Number of subjects analysed
    49 [10]
    58 [11]
    Units: score
        arithmetic mean (standard deviation)
    -0.07 ( 0.13 )
    -0.10 ( 0.16 )
    Notes
    [10] - Due to dropout the number of subjects at 12 months was 49
    [11] - Due to dropout the number of subjects at 12 months was 49
    No statistical analyses for this end point

    Secondary: Change on Clinical Global Impression Scale Improvement

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    End point title
    		 Change on Clinical Global Impression Scale Improvement
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to 12 month follow-up
    End point values
    		 Control group Intervention group
    Number of subjects analysed
    49 [12]
    58 [13]
    Units: score
        arithmetic mean (standard deviation)
    4.68 ( 1.06 )
    4.62 ( 0.95 )
    Notes
    [12] - Due to dropout the number of subjects at 12 months was 49
    [13] - Due to dropout the number of subjects at 12 months was 58
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to 12 month follow-up
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 medicine prod. info
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Intervention group
    Reporting group description
    		 Participants in intervention group

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 Intervention group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 67 (10.45%)
    6 / 65 (9.23%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cerebral metastases
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Donepezil overdose
    Additional description: Non-fatal serious adverse reaction. Hospitalized. No treatment necessary.
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Sugery for hip fracture
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    syncope
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    headache
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychosis
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Antebrachium fracture
    Additional description: Fracture due to fall. Surgery performed.
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 67 (68.66%)
    42 / 65 (64.62%)
    General disorders and administration site conditions
    Non-related, non serious adverse events
    Additional description: various minor non-related events
         subjects affected / exposed
    46 / 67 (68.66%)
    42 / 65 (64.62%)
         occurrences all number
    46
    42

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    This study did not support general usage of TDM based dose optimization for donepezil and memantine in dementia, albeit important study limitations and caveats to the external validity of the results apply.
    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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