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    Clinical Trial Results:
    Memory, Ageing, and the Cholinergic System a combined fMRI and PET study

    Summary
    EudraCT number
    		 2008-008896-32
    Trial protocol
    		 DE  
    Global end of trial date
    07 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2020
    First version publication date
    14 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MACS(Uni-Koeln-1260)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universität zu Köln
    Sponsor organisation address
    Albertus-Magnus-Platz, Köln, Germany, 50937
    Public contact
    Univeritätsklinikum Köln Klinik und Poliklinik für Neurologie AG Altern und Demenz, Univeritätsklinikum Köln Klinik und Poliklinik für Neurologie, 049 0221-478-97493, oezguer.onur@uk-koeln.de
    Scientific contact
    Univeritätsklinikum Köln Klinik und Poliklinik für Neurologie AG Altern und Demenz, Univeritätsklinikum Köln Klinik und Poliklinik für Neurologie, 049 0221-478-97493, oezguer.onur@uk-koeln.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We want to investigate the effects of cholinergic stimulation on brain activity underlying memory in healthy older subjects and patients with mild cognitive impairment (MCI). In a double-blind, placebo-controlled crossover design we want to administer rivastigmine or placebo prior to measuring brain activity during memory paradigm using fMRI. We expect that cholinergic stimulation will enhance cognitive performance and the underlying brain activity in patients with MCI more than in healthy older controls. Therefore we will test whether there is a group difference between healthy subjects and MCI patients in the correlation of regional MP4A-PET activity (visualising the cerebral cholinergic system) and brain activity underlying memory and attention functions. We will furthermore investigate whether the effect of cholinergic stimulation (using rivastigmine) is dependent on the MP4A-PET activity and whether there is a group difference.
    Protection of trial subjects
    Paticipants remained under observation for an additional hour after the MRI measurements on the visits when they received trial medication. If experiencing severe nausea after application of the trial medication, participants received antiemetics. Participants were instructed not to drive motor vehicles for the remained of the day after receiving trial medication.
    Background therapy
    		 Participants continued to take their regular medication (antihypertensives, thyroid medication, etc.) during the course of the trial. None of the participants were taking centrally acting medications, other than the trial medication, during the course of the trial.
    Evidence for comparator
    		 Participants received rivastigmine and placebo in a double-blind cross-over design. The placebo was given to account for the placebo effect.
    Actual start date of recruitment
    21 May 2012
    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
    Germany: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    12
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the Memory Clinic at the Dept. of Neurology of the University Hospital of Cologne from may 2012 until march 2014. Control participants were recruited from the public using flyers during the same time period.

    Pre-assignment
    Screening details
    		 Cognitively normal volunteers and patients with mild cognitive impairment (MCI) and CSF and/or imaging findings indicative of Alzheimer's disease were screened. Exclusion criteria were other major medical, neurological or psychiatric conditions, contraindications to MRI and centrally acting medication.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Experimental
    Arm description
    		 Application of a single dose of rivastigmine 3mg p.o. and placebo in a double blind cross-over design
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivastigmine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3mg of Rivastigmine p.o. as single dose

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    single capsule of placebo applied p.o.

    Number of subjects in period 1
    		Experimental
    Started
    42
    Completed
    37
    Not completed
    5
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
         incidental MRI finding
    1
         MRI contraindication
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 Application of a single dose of rivastigmine 3mg p.o. and placebo in a double blind cross-over design

    Reporting group values
    		 Experimental Total
    Number of subjects
    		 42 42
    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)
    		 12 12
        From 65-84 years
    		 30 30
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 25 25
    Subject analysis sets

    Subject analysis set title
    Control group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Cognitively normal controls, that completed experiment under rivastigmine and placebo, with complete imaging data.

    Subject analysis set title
    MCI patients
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MCI patients, that completed experiment under rivastigmine and placebo, with complete imaging data.

    Subject analysis set title
    all participants
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    16 control participants and 14 MCI patients

    Subject analysis sets values
    		 Control group MCI patients all participants
    Number of subjects
    16
    14
    30
    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)
    7
    5
    12
        From 65-84 years
    9
    9
    18
        85 years and over
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    7
    7
    14
        Male
    9
    7
    16

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 Application of a single dose of rivastigmine 3mg p.o. and placebo in a double blind cross-over design

    Subject analysis set title
    Control group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Cognitively normal controls, that completed experiment under rivastigmine and placebo, with complete imaging data.

    Subject analysis set title
    MCI patients
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    MCI patients, that completed experiment under rivastigmine and placebo, with complete imaging data.

    Subject analysis set title
    all participants
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    16 control participants and 14 MCI patients

    Primary: Effect of cholinergic stimulation on memory-related activation of the fusiform gyrus

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    End point title
    		 Effect of cholinergic stimulation on memory-related activation of the fusiform gyrus
    End point description
    End point type
    Primary
    End point timeframe
    during the functional MRI measurements - 30 min duration - about 2 hours after the application of the trial medication
    End point values
    		 Control group MCI patients
    Number of subjects analysed
    16
    14
    Units: parameter estimates
        arithmetic mean (standard deviation)
    -7.65 ( 10.85 )
    6.38 ( 13.76 )
    Statistical analysis title
    		 Group comparison
    Statistical analysis description
    The significance of the group difference in the change of neural activation after application of rivastigmine is assessed.
    Comparison groups
    MCI patients v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.004
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Effect of cholinergic stimulation on memory-related activation of the posterior cingulate

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    End point title
    		 Effect of cholinergic stimulation on memory-related activation of the posterior cingulate
    End point description
    End point type
    Primary
    End point timeframe
    duration of the functional MRI measurements - (30min duration - about 2 hours after the application of the trial medication)
    End point values
    		 Control group MCI patients
    Number of subjects analysed
    16
    14
    Units: parameter estimates
        arithmetic mean (standard deviation)
    12.95 ( 14.08 )
    -4.22 ( 10.72 )
    Statistical analysis title
    		 Group comparison
    Statistical analysis description
    The significance of the group difference in the change of neural activation after application of rivastigmine is assessed.
    Comparison groups
    Control group v MCI patients
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Effect of rivastigmine on task performance

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    End point title
    		 Effect of rivastigmine on task performance
    End point description
    End point type
    Secondary
    End point timeframe
    duration of the memory task, about 30 min duration, 2 hours after application of the trial medication
    End point values
    		 Control group MCI patients
    Number of subjects analysed
    16
    14
    Units: d-prime
        arithmetic mean (standard deviation)
    0.184 ( 0.444 )
    0.08 ( 0.439 )
    Statistical analysis title
    		 ANOVA
    Statistical analysis description
    The group by treatment effect is examined.
    Comparison groups
    MCI patients v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.114
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Group comparison of difference in treatment effect (rivastigmine).
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    Group comparison of difference in treatment effect (rivastigmine), adjusted for change in well-being and hippocampal atrophy.
    Comparison groups
    MCI patients v Control group
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    P-value
    		 = 0.026
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported if taking place during the time between the application of the first dose of trial medication and 24 hours after application of the last dose of trial medication.
    Adverse event reporting additional description
    Participants were interviewed 7 days after each application of trial medication to find out if adverse events had taken place.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1-17.1
    Reporting groups
    Reporting group title
    control participants
    Reporting group description
    		 -

    Reporting group title
    MCI patients
    Reporting group description
    		 -

    Serious adverse events
    		 control participants MCI patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 control participants MCI patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 16 (37.50%)
    5 / 14 (35.71%)
    Vascular disorders
    Elevated blood pressure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Orthostatic dysregulation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 14 (14.29%)
         occurrences all number
    3
    2
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Granulocyte count
    Additional description: Finding in routine blood sample. Neutrophils decreased, eosinophils increased. Minor deviations, no treatment indicated.
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 16 (31.25%)
    4 / 14 (28.57%)
         occurrences all number
    5
    4
    Psychiatric disorders
    Psychomotor agitation
    Additional description: Transient. No persistent impairment. No hospitalization necessary.
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Endocrine disorders
    free T4 decreased
    Additional description: minor deviation, normal TSH, no treatment indicated
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Sprained ankle
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Lumbar disk prolapse
    Additional description: Treatment by general practitioner with local injections. No persistent impairment.
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Elevated serum lipids
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jul 2010
    Unclassifiable and unclassified events are also considered as side-effects of the trial medication to increase patient safety. Contact list was updated.
    02 Mar 2011
    Radiation safety officer was updated. Trial time frame was updated. Change in randomisation protocol - this is now performed by the Insitute for medical statistics of the University of Cologne Neuropsychological testing battery was modified.
    03 Aug 2012
    Contacts updated. The first MRI is now performed before the PET-scan to avoid unnecessary radiation exposure. Adjustment of fMRI protocol to reduce demand on participants. Update of exclusion criteria to reflect the rivastigmine investigators brochure of April 2012. Added lab for analysis of serum rivastigmine to protocol. Time frame for reporting of adverse events was rephrased more clearly. Procedure for SAE follow-up was explicitly defined. Procedure for the annual safety report was updated to reflect ICH-Guideline E2F.
    22 Mar 2013
    Adjusted exclusion criteria to allow participation of individuals that had previously undergone exams by nuclear medicine or radiotherapy. MR-compatible implants are no longer an exclusion criterion. Several minor changes to the protocol to improve detection of AE's, including a telephone interview 7 days after the final trial medication. Inclusion and exclusion criteria are listed in the consent form.

    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. Single dose of rivastigmine (3mg) orally.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29309600
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