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    Clinical Trial Results:
    Pharmacodynamic interactions between remifentanil and dexmedetomidine (PIRAD)

    Summary
    EudraCT number
    		 2017-000945-37
    Trial protocol
    		 NL  
    Global end of trial date
    23 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Mar 2022
    First version publication date
    23 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PIRAD-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03143972
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Medical Center Groningen
    Sponsor organisation address
    Hanzeplein 1, Groningen, Netherlands,
    Public contact
    spanjersberg, umcg, r.spanjersberg@umcg.nl
    Scientific contact
    spanjersberg, umcg, r.spanjersberg@umcg.nl
    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
    24 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Our objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth, measured by hypnotic and analgesic endpoints such as modified observer’s assessment of alertness and sedation scale (MOAA/S), response to electrical stimuli, response to laryngoscopy and electroencephalogram (EEG) derived indices. These effects will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling
    Protection of trial subjects
    A complete anaesthesia work station including a ventilator, were present in the study room. The study team included a board certified anaesthetist and nurse anaesthetist ensured the safety of our volunteers. Volunteers were well informed in advance, local anesthesia was given before inserting the arterial canula. We ensured someone was present in the room at all times so volunteers could indicate problems at all times.
    Background therapy
    		 NA
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    28 Jun 2017
    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
    Netherlands: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    27
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We recruited healthy volunteers through an online advertisement on www.medians.nl, approved by the ethical committee. We recruited between 25-5-2017 and 31-1-2018 in the Netherlands.

    Pre-assignment
    Screening details
    		 Screened: 48 Included: 35 (including replacement of 5 drop-outs before second session) Reasons for drop-out: failure of arterial cannula placement (n=3), withdrawal after 1st session by participant (n=1), withdrawal after 1st session by physician due to too much anxiety of volunteer during 1st session (n=1)

    Period 1
    Period 1 title
    Dexmedetomidine
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dexmedetomidine
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexmedetomidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Volunteers received dexmedetomidine via target-controlled infusion (Supplemental Digital Content 2, http://links.lww.com/ALN/C13). This target-controlled infusion was based on the pharmacokinetic model developed by Hannivoort (Hannivoort LN, Eleveld DJ, Proost JH et al.: Development of an optimized pharmacokinetic model of dexmedetomidine using target-controlled infusion in healthy volunteers. Anesthesiology 2015; 123:357–67) expanded with an equilibration rate constant (ke0) for the effect site of the MOAA/S estimated in the pharmacodynamic model by Colin (Colin PJ, Hannivoort LN, Eleveld DJ, et al: Dexmedetomidine pharmacokinetic–pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation. Br J Anaesth 2017; 119:200–10). To avoid hypertensive reactions, the infusion of dexmedetomidine was limited to 6 μg · kg−1 · h−1 for the first three infusion steps and was increased to 10 μg · kg−1 · h−1 for the two highest targets of 5 and 8 ng/ml.

    Number of subjects in period 1
    		Dexmedetomidine
    Started
    30
    Completed
    30
    Period 2
    Period 2 title
    Remifentanil
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Remifentanil
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    remifentanil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A computer-controlled infusion, based on the pharmacokinetic–pharmacodynamic model developed by Eleveld et al. (Eleveld DJ, Proost JH, Vereecke H, Absalom AR, Olofsen E, Vuyk J, Struys MMRF: An allometric model of remifentanil pharmacokinetics and pharmacodynamics.Anesthesiology 2017; 126:1005–18) was used to target remifentanil effect-site concentrations.

    Number of subjects in period 2
    		Remifentanil
    Started
    30
    Completed
    30
    Period 3
    Period 3 title
    Interaction
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Interaction
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexmedetomidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Volunteers received dexmedetomidine via target-controlled infusion (Supplemental Digital Content 2, http://links.lww.com/ALN/C13). This target-controlled infusion was based on the pharmacokinetic model developed by Hannivoort (Hannivoort LN, Eleveld DJ, Proost JH et al.: Development of an optimized pharmacokinetic model of dexmedetomidine using target-controlled infusion in healthy volunteers. Anesthesiology 2015; 123:357–67) expanded with an equilibration rate constant (ke0) for the effect site of the MOAA/S estimated in the pharmacodynamic model by Colin (Colin PJ, Hannivoort LN, Eleveld DJ, et al: Dexmedetomidine pharmacokinetic–pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation. Br J Anaesth 2017; 119:200–10). To avoid hypertensive reactions, the infusion of dexmedetomidine was limited to 6 μg · kg−1 · h−1 for the first three infusion steps and was increased to 10 μg · kg−1 · h−1 for the two highest targets of 5 and 8 ng/ml.

    Investigational medicinal product name
    remifentanil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A computer-controlled infusion, based on the pharmacokinetic–pharmacodynamic model developed by Eleveld et al. (Eleveld DJ, Proost JH, Vereecke H, Absalom AR, Olofsen E, Vuyk J, Struys MMRF: An allometric model of remifentanil pharmacokinetics and pharmacodynamics.Anesthesiology 2017; 126:1005–18) was used to target remifentanil effect-site concentrations.

    Number of subjects in period 3 [1]
    		Interaction
    Started
    29
    Completed
    29
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: During the remifentanil period, one participant experienced thorax rigidity (known side effect of remifentanil). This person completed the remifentanil period, but did not enter the interaction period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dexmedetomidine
    Reporting group description
    		 -

    Reporting group values
    		 Dexmedetomidine Total
    Number of subjects
    		 30 30
    Age categorical
    Our total of 30 volunteers completing both study sessions were stratified into three age categories (18 to 34, 35 to 49, and 50 to 70 yr) with five males and five females in each category. Volunteers ranged from 18 to 67 yrs of age.
    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)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        All Subjects (18-70 years)
    		 30 30
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 15 15

    End points

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    End points reporting groups
    Reporting group title
    Dexmedetomidine
    Reporting group description
    		 -
    Reporting group title
    Remifentanil
    Reporting group description
    		 -
    Reporting group title
    Interaction
    Reporting group description
    		 -

    Subject analysis set title
    All subjects (18-70 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects within the study

    Primary: Tolerance of laryngoscopy

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    End point title
    		 Tolerance of laryngoscopy
    End point description
    End point type
    Primary
    End point timeframe
    At the end of each infusion step
    End point values
    		 Interaction All subjects (18-70 years)
    Number of subjects analysed
    29
    29 [1]
    Units: yes / no
        tolerant
    12
    12
        non-tolerant
    17
    17
    Attachments
    		 Response surface - Tolerance of laryngoscopy
    Notes
    [1] - One person experienced thoraxi rigidity in period two, and did not enter period 3.
    Statistical analysis title
    		 non-linear mixed effects modeling
    Statistical analysis description
    non-linear mixed effects modeling was used to describe exposure-response relationships of either drug alone (dexmedetomidine / remifentanil) and in combination (interaction).
    Comparison groups
    Interaction v All subjects (18-70 years)
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 nonlinear mixed effects modeling
    Parameter type
    		 EC50
    Point estimate
    35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 25
         upper limit
    		 54
    Notes
    [2] - nonlinear mixed-effects modeling

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    As per protocol, all adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded. Serious adverse events will be reported to ethical comittee by PI through webportal ToetsingOnline
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Not applicable
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    All subjects-all periods
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects-all periods
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 All subjects-all periods
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    30 / 30 (100.00%)
         occurrences all number
    40
    Hypertension
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Bradycardia
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    6
    Syncope
    Additional description: orthostatic syncope
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 30 (36.67%)
         occurrences all number
    13
    Vomiting
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
    Additional description: thoracic rigidity (known complication of remifentanil)
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Respiratory depression
         subjects affected / exposed
    25 / 30 (83.33%)
         occurrences all number
    40

    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.
    Results are not interpretable in this online format. Please read article for results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31425170
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