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    Clinical Trial Results:
    Bioavailability study of intranasal sufentanil/ketamine fixed combination in healthy volunteers

    Summary
    EudraCT number
    		 2020-004488-14
    Trial protocol
    		 DK  
    Global end of trial date
    02 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2022
    First version publication date
    21 Oct 2022
    Other versions
    Summary report(s)
    		 PDC-01-0204 CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    PDC01-0204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04807335
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cessatech AS
    Sponsor organisation address
    Kanonbådsvej 2, Copenhagen, Denmark, 1437
    Public contact
    CEO, Cessatech AS, jes.trygved@cessatech.com
    Scientific contact
    CEO, Cessatech AS, jes.trygved@cessatech.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001739-PIP02-16
    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
    15 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the absolute bioavailability of intranasal sufentanil/ketamine in a standardized study set-up with healthy volunteers
    Protection of trial subjects
    None
    Background therapy
    		 None
    Evidence for comparator
    		 The present study investigated bioavailability in a standardised set-up with adult healthy volunteers in accordance with the paediatric investigation plan approved by the European Medicines Agency for the development of a sufentanil/ketamine analgesic spray for treatment of acute pain in children (EMA_001739-PIP02-16)(1). The primary objective for this PK study in adult healthy volunteers was to assess the biopharmaceutical performances (bioavailability) of the sufentanil/ketamine fixed combination compared to currently EU marketed intravenous ketamine and sufentanil products, allowing bridging to data for intravenous sufentanil and ketamine.
    Actual start date of recruitment
    17 Mar 2021
    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: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 15 subjects were included in the study at one site in Denmark during the period 17-Mar-2021 until 02-Jun-2021.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 15
    Number of subjects completed
    		 15

    Period 1
    Period 1 title
    Treatment period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not relevant, open study

    Arms
    Arm title
    		 Ketamine IV
    Arm description
    		 Intravenous (IV) ketamine 10 mg as a single bolus dose
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ketamine solution for injection, 50 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ketamine 10 mg as a single bolus dose

    Number of subjects in period 1
    		Ketamine IV
    Started
    15
    Completed
    15
    Period 2
    Period 2 title
    Treatment period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not relevant, open study

    Arms
    Arm title
    		 Sufentanil IV
    Arm description
    		 Intravenous (IV) sufentanil 10 mcg as a single bolus dose
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sufentanil solution for injection, 5 mcg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sufentanil 10 mcg as a single bolus dose

    Number of subjects in period 2 [1]
    		Sufentanil IV
    Started
    14
    Completed
    14
    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: Cross over study
    Period 3
    Period 3 title
    Treatment period 3
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not relevant, open study

    Arms
    Arm title
    		 CT001
    Arm description
    		 Sufentanil 27 mcg/ml + ketamine 27 mg/ml, nasal spray.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sufentanil 90 mcg/ml + ketamine 90 mg/ml, nasal spray.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    The nasal spray was administer 0.1 ml per spray. The administered intranasal dose was be 27 mcg sufentanil + 27 mg ketamine

    Number of subjects in period 3
    		CT001
    Started
    14
    Completed
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period 1
    Reporting group description
    		 -

    Reporting group values
    		 Treatment period 1 Total
    Number of subjects
    		 15 15
    Age categorical
    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)
    		 28.2 ( 6.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 15 15

    End points

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    End points reporting groups
    Reporting group title
    Ketamine IV
    Reporting group description
    		 Intravenous (IV) ketamine 10 mg as a single bolus dose
    Reporting group title
    Sufentanil IV
    Reporting group description
    		 Intravenous (IV) sufentanil 10 mcg as a single bolus dose
    Reporting group title
    CT001
    Reporting group description
    		 Sufentanil 27 mcg/ml + ketamine 27 mg/ml, nasal spray.

    Primary: Cmax Ketamine IV

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    End point title
    		 Cmax Ketamine IV [1]
    End point description
    End point type
    Primary
    End point timeframe
    One dosing
    Notes
    [1] - 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: Not applicable
    End point values
    		 Ketamine IV
    Number of subjects analysed
    15
    Units: mg/L
        geometric mean (geometric coefficient of variation)
    0.0632 ( 60.0 )
    No statistical analyses for this end point

    Primary: AUC0-t Ketamine IV

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    End point title
    		 AUC0-t Ketamine IV [2]
    End point description
    End point type
    Primary
    End point timeframe
    PK measured from dosing until 48 hours post dose
    Notes
    [2] - 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: Not applicable
    End point values
    		 Ketamine IV
    Number of subjects analysed
    15
    Units: mg/L*h
        geometric mean (geometric coefficient of variation)
    0.0995 ( 20.4 )
    No statistical analyses for this end point

    Primary: Cmax Ketamine IN

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    End point title
    		 Cmax Ketamine IN [3]
    End point description
    End point type
    Primary
    End point timeframe
    PK was measured from dosing until 48 hours post dose
    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: Not applicable
    End point values
    		 CT001
    Number of subjects analysed
    14
    Units: mg/L
        geometric mean (geometric coefficient of variation)
    0.044 ( 39.9 )
    No statistical analyses for this end point

    Primary: AUC0-t Ketamine IN

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    End point title
    		 AUC0-t Ketamine IN [4]
    End point description
    End point type
    Primary
    End point timeframe
    PK was measured form dosing until 48 hours post dose
    Notes
    [4] - 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: Not applicable
    End point values
    		 CT001
    Number of subjects analysed
    14
    Units: mg/L*h
        geometric mean (geometric coefficient of variation)
    0.131 ( 25.8 )
    No statistical analyses for this end point

    Primary: Cmax Sufentanil IV

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    End point title
    		 Cmax Sufentanil IV [5]
    End point description
    End point type
    Primary
    End point timeframe
    PK was measured from dosing until 48 hours post dose
    Notes
    [5] - 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: Not applicable
    End point values
    		 Sufentanil IV
    Number of subjects analysed
    14
    Units: ug/L
        geometric mean (geometric coefficient of variation)
    0.108 ( 86.7 )
    No statistical analyses for this end point

    Primary: AUC0-t Sufentanil IV

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    End point title
    		 AUC0-t Sufentanil IV [6]
    End point description
    End point type
    Primary
    End point timeframe
    PK was measured from dosing until 48 hours post dose
    Notes
    [6] - 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: Not applicable
    End point values
    		 Sufentanil IV
    Number of subjects analysed
    14
    Units: ug/L*h
        geometric mean (geometric coefficient of variation)
    0119 ( 11.1 )
    No statistical analyses for this end point

    Primary: Cmax Sufentanil IN

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    End point title
    		 Cmax Sufentanil IN [7]
    End point description
    End point type
    Primary
    End point timeframe
    PK was measured from dosing until 48 hour post dose.
    Notes
    [7] - 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: Not applicable
    End point values
    		 CT001
    Number of subjects analysed
    14
    Units: ug/L
        geometric mean (geometric coefficient of variation)
    0.0342 ( 41.6 )
    No statistical analyses for this end point

    Primary: AUC0-t Sufentanil IN

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    End point title
    		 AUC0-t Sufentanil IN [8]
    End point description
    End point type
    Primary
    End point timeframe
    PK was measured from dosing until 48 hours after dosing.
    Notes
    [8] - 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: Not applicable
    End point values
    		 CT001
    Number of subjects analysed
    14
    Units: ug/L*h
        geometric mean (geometric coefficient of variation)
    0.127 ( 26.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose until 28 days after last dose.
    Adverse event reporting additional description
    Adverse evets were collected based on study personnel observations during dosing and observation on site and spontaneous reporting from subjects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Ketamine IV
    Reporting group description
    		 Reporting events after treatment period were Ketamine IV was administered.

    Reporting group title
    Sufentanil IV
    Reporting group description
    		 -

    Reporting group title
    Sufentanil/Ketamine IN
    Reporting group description
    		 -

    Serious adverse events
    		 Ketamine IV Sufentanil IV Sufentanil/Ketamine IN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ketamine IV Sufentanil IV Sufentanil/Ketamine IN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 15 (40.00%)
    2 / 14 (14.29%)
    4 / 14 (28.57%)
    Injury, poisoning and procedural complications
    Nerve injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 14 (7.14%)
    2 / 14 (14.29%)
         occurrences all number
    5
    5
    5
    Dizziness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 14 (7.14%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    1
    Presyncope
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 14 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    4
    4
    Psychiatric disorders
    Dissociation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    1

    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.
    None reported
    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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