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    Clinical Trial Results:
    Automated pupillometry and NIRS-EEG to detect signatures of consciousness in acute brain injury after apomorphine and methylphenidate stimulation: A placebo-controlled, randomized, cross-over study

    Summary
    EudraCT number
    		 2021-001453-31
    Trial protocol
    		 DK  
    Global end of trial date
    18 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CONMED3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Copenhagen University Hospital Rigshospitalet
    Sponsor organisation address
    Inge Lehmanns Vej 8, Copenhagen, Denmark, 2100
    Public contact
    Department of Neurology, Copenhagen University Hospital Rigshospitalet, 0045 35456368, daniel.kondziella@regionh.dk
    Scientific contact
    Department of Neurology, Copenhagen University Hospital Rigshospitalet, 0045 35456368, daniel.kondziella@regionh.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
    09 Sep 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To investigate, in a placebo-controlled, randomized, cross-over setting, the potential effects on pupillary function and neurovascular coupling with administrations of 20 mg methylphenidate in patients with acute disorder of consciousness. 2. To investigate, in a placebo-controlled, randomized cross-over setting, the potential effects on pupillary function and neurovascular coupling with subcutaneous injections of 2 mg apomorphine in patients with acute disorder of consciousness.
    Protection of trial subjects
    Subjects’ rights, safety and confidentiality were ensured by compliance with GCP and all regulations. Informed consent was obtained prior to any study procedure. Oversight and monitoring were performed, and legal representatives were involved where required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Aug 2022
    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
    Denmark: 112
    Worldwide total number of subjects
    112
    EEA total number of subjects
    112
    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)
    59
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first subject was enrolled on 12 August 2022, and the last participant’s final visit occurred on 18 November 2023. ICUs were screened daily for consecutive patients eligible for trial participation except for weekends, holidays and other times of leave.

    Pre-assignment
    Screening details
    		 Eligible patients: Adult patients (≥ 18 years), fluent in Danish or English language, with severe acute traumatic or non-traumatic brain injury in a state of coma, vegetative state/unresponsive wakefulness syndrome or minimal consciousness state according to FOUR and SECONDs.

    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, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention (Methylphenidate)
    Arm description
    		 Subjects received one dose of 20 mg methylphenidate tablet suspended in water and administered via a nasogastric tube and we administered subcutaneous placebo injections 0.4 ml of fluid (saline) from a 1 ml syringe.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylphenidat
    Investigational medicinal product code
    29491
    Other name
    Pharmaceutical forms
    Soluble tablet
    Routes of administration
    Nasogastric use
    Dosage and administration details
    20 mg milligrams via a nasogastric tube.

    Arm title
    		 Intervention (Apomorphine)
    Arm description
    		 Subcutaneous injection of 2 mg apomorphine, and 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe administered via a nasogastric tube.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apomorfin
    Investigational medicinal product code
    28426
    Other name
    Pharmaceutical forms
    Injection, Cutaneous solution
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    2 mg milligram administrated with subcutaneous injections.

    Arm title
    		 Placebo (Saline)
    Arm description
    		 Saline as placebo, either administered via a nasogastric tube or subcutaneous injections. We administered 0.4 ml of fluid (saline) from a 1 ml syringe as well as 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Soluble tablet, Cutaneous solution, Injection
    Routes of administration
    Nasogastric use , Solution for injection , Subcutaneous use
    Dosage and administration details
    subcutaneous injection of 0.4 ml of normal saline from a 1 ml syringe, and 8 ml of fluid with a suspended normal saline tablet from a 10 ml gavage syringe administered via a nasogastric tube.

    Number of subjects in period 1
    		Intervention (Methylphenidate) Intervention (Apomorphine) Placebo (Saline)
    Started
    39
    36
    37
    Completed
    39
    36
    37

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention (Methylphenidate)
    Reporting group description
    		 Subjects received one dose of 20 mg methylphenidate tablet suspended in water and administered via a nasogastric tube and we administered subcutaneous placebo injections 0.4 ml of fluid (saline) from a 1 ml syringe.

    Reporting group title
    Intervention (Apomorphine)
    Reporting group description
    		 Subcutaneous injection of 2 mg apomorphine, and 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe administered via a nasogastric tube.

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 Saline as placebo, either administered via a nasogastric tube or subcutaneous injections. We administered 0.4 ml of fluid (saline) from a 1 ml syringe as well as 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe.

    Reporting group values
    		 Intervention (Methylphenidate) Intervention (Apomorphine) Placebo (Saline) Total
    Number of subjects
    		 39 36 37 112
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 22 18 19 59
        From 65-84 years
    		 17 18 18 53
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ( 9.0 ) 62.5 ( 9.3 ) 63.8 ( 9.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 12 11 29
        Male
    		 33 24 26 83

    End points

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    End points reporting groups
    Reporting group title
    Intervention (Methylphenidate)
    Reporting group description
    		 Subjects received one dose of 20 mg methylphenidate tablet suspended in water and administered via a nasogastric tube and we administered subcutaneous placebo injections 0.4 ml of fluid (saline) from a 1 ml syringe.

    Reporting group title
    Intervention (Apomorphine)
    Reporting group description
    		 Subcutaneous injection of 2 mg apomorphine, and 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe administered via a nasogastric tube.

    Reporting group title
    Placebo (Saline)
    Reporting group description
    		 Saline as placebo, either administered via a nasogastric tube or subcutaneous injections. We administered 0.4 ml of fluid (saline) from a 1 ml syringe as well as 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe.

    Primary: Effects of stimulants on pupillary responses during pupillometry

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    End point title
    		 Effects of stimulants on pupillary responses during pupillometry [1]
    End point description
    In a GLMM analysis, comparing the effects of apomorphine and methylphenidate across different treatment sessions (moderate and hard mental arithmetic tasks combined), measuring pupillary responses.
    End point type
    Primary
    End point timeframe
    During a session, collecting data from baseline, and respectively, 15 (T15) and 60 (T60) minutes following drug administration.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The placebo arm serves as the reference group. Treatment effect estimates (e.g., odds ratios with 95% confidence intervals) compare each active treatment to placebo, which by definition does not have an effect estimate itself.
    End point values
    		 Intervention (Methylphenidate) Intervention (Apomorphine)
    Number of subjects analysed
    39
    36
    Units: Pupillary dilations
    number (confidence interval 95%)
        Baseline
    1.29 (0.89 to 1.86)
    1.35 (0.93 to 1.96)
        T15
    0.76 (0.45 to 1.28)
    1.21 (0.73 to 2.02)
        T60
    0.76 (0.46 to 1.26)
    0.75 (0.45 to 1.24)
    Statistical analysis title
    		 GLMM
    Statistical analysis description
    We utilized Generalized Linear Mixed Models (GLMM)29 with Adaptive Gauss-Hermite Quadrature (nAGQ = 100) using the lme4 package in R to evaluate the impact of drug interventions on pupillary responses at different time points (T15 and T60) and across active paradigms. The fixed effects considered were drug interventions (apomorphine, methylphenidate, or placebo) and the assessment times (T0–T60).
    Comparison groups
    Intervention (Methylphenidate) v Intervention (Apomorphine)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%

    Secondary: Clinical arousal effects of stimulants

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    End point title
    		 Clinical arousal effects of stimulants [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed 60 minutes after drug administration
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The placebo arm serves as the reference group. Treatment effect estimates (e.g., odds ratios with 95% confidence intervals) compare each active treatment to placebo, which by definition does not have an effect estimate itself.
    End point values
    		 Intervention (Methylphenidate) Intervention (Apomorphine)
    Number of subjects analysed
    39
    36
    Units: Improved Arousal
        number (confidence interval 95%)
    9.96 (1.36 to 235.8)
    5.04 (0.56 to 120.7)
    Statistical analysis title
    		 GLMM
    Comparison groups
    Intervention (Methylphenidate) v Intervention (Apomorphine)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%

    Secondary: Change toward higher consciousness level categories

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    End point title
    		 Change toward higher consciousness level categories [3]
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed 60 minutes following drug administration
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The placebo arm serves as the reference group. Treatment effect estimates (e.g., odds ratios with 95% confidence intervals) compare each active treatment to placebo, which by definition does not have an effect estimate itself.
    End point values
    		 Intervention (Methylphenidate) Intervention (Apomorphine)
    Number of subjects analysed
    39
    36
    Units: Change in consciousness category
        number (confidence interval 95%)
    3.41 (0.34 to 88)
    5.67 (0.63 to 169.46)
    Statistical analysis title
    		 GLMM
    Comparison groups
    Intervention (Methylphenidate) v Intervention (Apomorphine)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 GLMM
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    TAES were monitored until six half-lives of the active substance with the longest plasma half-life (i.e. methylphenidate, 3 h) had passed. Deaths were reported based on ICU survival status and not limited to the period of active study drug administration.
    Adverse event reporting additional description
    EPR's were screened for adverse events reporting. The process was also externally controlled by staff from the GCP. We observed no adverse events, serious adverse events or suspected unexpected serious adverse reactions related to the study drugs during treatment sessions.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Arm 1
    Reporting group description
    		 Subjects received one dose of 20 mg methylphenidate tablet suspended in water and administered via a nasogastric tube and we administered subcutaneous placebo injections 0.4 ml of fluid (saline) from a 1 ml syringe.

    Reporting group title
    Arm 2
    Reporting group description
    		 Subcutaneous injection of 2 mg apomorphine, and 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe administered via a nasogastric tube.

    Reporting group title
    Arm 3
    Reporting group description
    		 Saline as placebo, either administered via a nasogastric tube or subcutaneous injections. We administered 0.4 ml of fluid (saline) from a 1 ml syringe as well as 8 ml of fluid with a suspended tablet (saline) from a 10 ml gavage syringe.

    Serious adverse events
    		 Arm 1 Arm 2 Arm 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 36 (0.00%)
    0 / 37 (0.00%)
         number of deaths (all causes)
    11
    10
    9
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm 1 Arm 2 Arm 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 36 (0.00%)
    0 / 37 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No SAE's were present in our study.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2022
    Summary of Protocol Amendments a. Revision of Inclusion and Exclusion Criteria: The inclusion and exclusion criteria have been revised to include patients with acute brain injury presenting in coma, unresponsive wakefulness syndrome (UWS), or minimally conscious state (MCS). b. Addition of New Study Sites: Screening and recruitment occur on RH units 6021 and 2143. Additional sites, RH units 4131 and 4141, and the intensive unit at Bispebjerg Hospital (BBH) was added. These amendments are described in Supplementary Protocol Version 2.2, dated 15 December 2022.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/40501148
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