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    Clinical Trial Results:
    Vigilance regulation as predictor of response to Psychostimulants in adult patients with ADHD

    Summary
    EudraCT number
    		 2015-000488-15
    Trial protocol
    		 DE  
    Global end of trial date
    16 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2020
    First version publication date
    11 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leipzig
    Sponsor organisation address
    Ritterstr. 26, Leipzig, Germany,
    Public contact
    OA Dr. med. Maria Strauß, Department of Psychiatry of University of Leipzig, +49 3419724304, Maria.Strauss@medizin.uni-leipzig.de
    Scientific contact
    OA Dr. med. Maria Strauß, Department of Psychiatry of University of Leipzig, +49 3419724304, Maria.Strauss@medizin.uni-leipzig.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
    23 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective of the trial is the investigation, if an unstable vigilance regulation in the EEG prior to medication (measured on VIGALL classification) predicates the response of therapy with methylphenidate in ADHD. The therapeutic target is a >30%-reduction of CAARS (CAARS-S:L - Conners’ Adult ADHD Rating Scales-Self-Report: Long Version).
    Protection of trial subjects
    Each patient is closely monitored with regard to safety during the course of the study. This includes, in addition to the recording of adverse events, the collection of data for each visit the vital signs. In addition, laboratory tests and ECG are performed before the start and at the end of the intervention.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2016
    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: 121
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    121
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 first patient in: 29-APR-2016; last patient out: 16-AUG-2018 recruitment in 7 univiersity hospitals in Germany

    Pre-assignment
    Screening details
    		 - outpatients with clinically defined ADHD according to the DSM-IV were recruited at the ADHD outpatient clinic for adults - diagnoses were confirmed by a psychiatrist and psychologist based on mental status examination, clinical history, structured clinical interviews and rating scales/questionnaires

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

    Arms
    Arm title
    		 methylphenidate
    Arm description
    		 all patients received methylphenidate
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylphenidate
    Investigational medicinal product code
    Other name
    Medikinet adult (10 mg, 20 mg, 30 mg, 40 mg)
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    - 20 mg as an initial dose (all patients) - dose increased each week by 20 mg/day up to a target dose - target dose depended on body weight: 40 mg daily (weight< 55 kg) / 60 mg daily (weight 55-69 kg) / 80 mg daily (weight>=70 kg) over a course of up to 4 weeks. - after titration target dose continued for 4 weeks.

    Number of subjects in period 1
    		methylphenidate
    Started
    121
    Completed
    112
    Not completed
    9
         Baseline EEG unavailable
    6
         Baseline CAARS unavailable
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 121 121
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 121 121
    Gender categorical
    Units: Subjects
        Female
    		 40 40
        Male
    		 81 81
    Subject analysis sets

    Subject analysis set title
    Full analysis set unstable
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects registered and who provided valid baseline EEG and CAARS data and showed unstable brain arousal

    Subject analysis set title
    Full analysis set stable
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects registered and who provided valid baseline EEG and CAARS data and showed stable brain arousal

    Subject analysis sets values
    		 Full analysis set unstable Full analysis set stable
    Number of subjects
    52
    60
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    52
    60
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    14
    23
        Male
    38
    37

    End points

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    End points reporting groups
    Reporting group title
    methylphenidate
    Reporting group description
    		 all patients received methylphenidate

    Subject analysis set title
    Full analysis set unstable
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects registered and who provided valid baseline EEG and CAARS data and showed unstable brain arousal

    Subject analysis set title
    Full analysis set stable
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects registered and who provided valid baseline EEG and CAARS data and showed stable brain arousal

    Primary: association between brain arousal regulation and success of the therapy

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    End point title
    		 association between brain arousal regulation and success of the therapy
    End point description
    The primary endpoint is the association between brain arousal regulation and success of the therapy. Brain arousal regulation is based on the Vigilance Algorithm Leipzig (VIGALL 2.1) and categorized to be stable or unstable based on the arousal stability score, also call the “Labilitätsindex” (Strauß et al. 2018). Scores 1–5 are considered “unstable” and 6–11 stable. Success of the therapy is defined as a >30% reduction in the total CAARS-S:L T-score from the “DSM-ADHS” 4 weeks after the titration phase compared to the baseline value.
    End point type
    Primary
    End point timeframe
    4 weeks after the titration phase
    End point values
    		 methylphenidate Full analysis set unstable Full analysis set stable
    Number of subjects analysed
    121
    52
    60
    Units: patients
    121
    52
    60
    Statistical analysis title
    		 primary end point analysis
    Comparison groups
    Full analysis set unstable v Full analysis set stable
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 29

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from the start time of the first administration of the IMP until the final visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    overall adverse events
    Reporting group description
    		 -

    Serious adverse events
    		 overall adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 121 (1.65%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 overall adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 121 (66.12%)
    Cardiac disorders
    Heart racing
         subjects affected / exposed
    5 / 121 (4.13%)
         occurrences all number
    8
    Tachycardia
         subjects affected / exposed
    5 / 121 (4.13%)
         occurrences all number
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 121 (15.70%)
         occurrences all number
    23
    Vertigo
         subjects affected / exposed
    6 / 121 (4.96%)
         occurrences all number
    6
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    10 / 121 (8.26%)
         occurrences all number
    14
    Nausea
         subjects affected / exposed
    5 / 121 (4.13%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    3 / 121 (2.48%)
         occurrences all number
    5
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    12 / 121 (9.92%)
         occurrences all number
    13
    Sleep disorder
         subjects affected / exposed
    7 / 121 (5.79%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 121 (6.61%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2015
    Amendment 1 before start of recruitment: specification of inclusion and exclusion criteria, specification of concomitant medication
    13 Nov 2017
    extension of recruitment period; changes in SmPC

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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