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    Clinical Trial Results:
    Dose response study of Patient Controlled Analgesia (PCA) of S-ketamine in orthopaedic spine surgery patients

    Summary
    EudraCT number
    		 2016-002887-14
    Trial protocol
    		 FI  
    Global end of trial date
    01 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2020
    First version publication date
    25 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Turku
    Sponsor organisation address
    Kiinamyllynkatu 4-8, Turku, Finland,
    Public contact
    Turku Clinical Research Centre, Turku University Hospital, turkucrc@tyks.fi
    Scientific contact
    Turku Clinical Research Centre, Turku University Hospital, turkucrc@tyks.fi
    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
    15 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This randomized, double-blinded, controlled study is aimed to study the dose-response using combining adjunct S-ketamine with oxycodone in intravenous PCA bolus dosing in patients scheduled for posterolateral lumbar spine fusion with bilateral transpedicular screw instrumentation.
    Protection of trial subjects
    Normal in-house operating theater routines
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2015
    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
    Finland: 107
    Worldwide total number of subjects
    107
    EEA total number of subjects
    107
    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)
    89
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One hundred and seven adult patients scheduled for elective posterolateral lumbar spine fusion with bilateral transpedicular screw instrumentation under general anesthesia were recruited between February 2017 and October 2019 of of 231 eligible patients

    Pre-assignment
    Screening details
    		 Patients were pre-screened by a preoperative care nurse, and the potentially eligible subjects were directed to investigators for further screening and information.

    Period 1
    Period 1 title
    Study clinical phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer
    Blinding implementation details
    An independent statistician created a computer-generated randomization list that was sent to the local hospital pharmacies, which took care of assignment. The pharmacy delivered coded PCA reservoirs with no other markings to the operation room on the day of each surgery to ensure double-blinding. Patients, researchers, and clinical staff were blinded to group allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 G1: Placebo arm
    Arm description
    		 G1, oxycodone 1 mg ml-1 alone. The starting dose of (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) in the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).
    Arm type
    		 Placebo

    Investigational medicinal product name
    oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone.

    Arm title
    		 G2: S-Ketamine 0.25 mg/ml group
    Arm description
    		 G2, oxycodone 1 mg ml-1 with 0.25 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone.

    Investigational medicinal product name
    S-ketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone - 0.25 mg/ml S-ketamine (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland; Ketanest-S 5 mg ml-1, Pfizer Manufacturing Belgium NV, Puurs, Belgium) ) in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Arm title
    		 G3: S-ketamine, 0.5 mg/ml
    Arm description
    		 G3, oxycodone 1 mg ml-1 with 0.5 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) with S-ketamine in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone.

    Investigational medicinal product name
    S-ketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone - 0.5 mg/ml S-ketamine (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland; Ketanest-S 5 mg ml-1, Pfizer Manufacturing Belgium NV, Puurs, Belgium) ) in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Arm title
    		 G4: S-ketamine, 0.5 mg/ml
    Arm description
    		 G4, oxycodone 1 mg ml-1 with 0.75 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) with S-ketamine in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone.

    Investigational medicinal product name
    S-ketamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The starting dose of oxycodone - 0.75 mg/ml S-ketamine (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland; Ketanest-S 5 mg ml-1, Pfizer Manufacturing Belgium NV, Puurs, Belgium) ) in the PCA solution was 2 mg, and the lockout interval was five minutes. When NRS was 4 or lower, the PCA oxycodone dose was decreased to 1 mg oxycodone. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Number of subjects in period 1
    		G1: Placebo arm G2: S-Ketamine 0.25 mg/ml group G3: S-ketamine, 0.5 mg/ml G4: S-ketamine, 0.5 mg/ml
    Started
    25
    27
    26
    29
    Clinical phase ended
    25
    26
    25
    26
    Completed
    25
    25
    25
    25
    Not completed
    0
    2
    1
    4
         Consent withdrawn by subject
    -
    -
    1
    1
         operation postponed
    -
    1
    -
    -
         Lost to follow-up
    -
    1
    -
    1
         Operation cancelled
    -
    -
    -
    1
         Operation changed
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study clinical phase
    Reporting group description
    		 -

    Reporting group values
    		 Study clinical phase Total
    Number of subjects
    		 107 107
    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
        median (full range (min-max))
    		 60 (28 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 49 49
        Male
    		 58 58
    Ethnic group
    Units: Subjects
        caucasian
    		 107 107

    End points

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    End points reporting groups
    Reporting group title
    G1: Placebo arm
    Reporting group description
    		 G1, oxycodone 1 mg ml-1 alone. The starting dose of (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) in the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Reporting group title
    G2: S-Ketamine 0.25 mg/ml group
    Reporting group description
    		 G2, oxycodone 1 mg ml-1 with 0.25 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Reporting group title
    G3: S-ketamine, 0.5 mg/ml
    Reporting group description
    		 G3, oxycodone 1 mg ml-1 with 0.5 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Reporting group title
    G4: S-ketamine, 0.5 mg/ml
    Reporting group description
    		 G4, oxycodone 1 mg ml-1 with 0.75 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Primary: cumulatice oxycodone consumption

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    End point title
    		 cumulatice oxycodone consumption
    End point description
    End point type
    Primary
    End point timeframe
    24 hours from the end of surgery when PCA was initiated
    End point values
    		 G1: Placebo arm G2: S-Ketamine 0.25 mg/ml group G3: S-ketamine, 0.5 mg/ml G4: S-ketamine, 0.5 mg/ml
    Number of subjects analysed
    25
    25
    25
    25
    Units: milligram(s)/24 hours
        arithmetic mean (standard deviation)
    81.9 ( 47.6 )
    74.1 ( 30.7 )
    74.7 ( 31.8 )
    61.3 ( 32.3 )
    Statistical analysis title
    		 comparison of oxycodone consumption
    Comparison groups
    G1: Placebo arm v G2: S-Ketamine 0.25 mg/ml group v G3: S-ketamine, 0.5 mg/ml v G4: S-ketamine, 0.5 mg/ml
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 97.5
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Follow-up (72 hours after the start of patient controlled analgesia)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    G1: Placebo arm
    Reporting group description
    		 G1, oxycodone 1 mg ml-1 alone. The starting dose of (Oxycodone Orion 10 mg ml-1, Orion Pharma, Espoo, Finland) in the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Reporting group title
    G2: S-Ketamine 0.25 mg/ml group
    Reporting group description
    		 G2, oxycodone 1 mg ml-1 with 0.25 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Reporting group title
    G3: S-ketamine, 0.5 mg/ml
    Reporting group description
    		 G3, oxycodone 1 mg ml-1 with 0.5 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Reporting group title
    G4: S-ketamine, 0.5 mg/ml
    Reporting group description
    		 G4, oxycodone 1 mg ml-1 with 0.75 mg/ml S-ketamine. The starting dose of the patient conrolled analgesia (PCA) solution was 2 mg, and the lockout interval was five minutes. When pain (measured with numerical rating scale) was 4 or lower, the PCA oxycodone dose was decreased to 1 mg. The study-PCA dosing continued for 24 hours from the end of surgery, after which the PCA cassette was changed to only an oxycodone-containing solution (G1).

    Serious adverse events
    		 G1: Placebo arm G2: S-Ketamine 0.25 mg/ml group G3: S-ketamine, 0.5 mg/ml G4: S-ketamine, 0.5 mg/ml
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 G1: Placebo arm G2: S-Ketamine 0.25 mg/ml group G3: S-ketamine, 0.5 mg/ml G4: S-ketamine, 0.5 mg/ml
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    7 / 25 (28.00%)
    6 / 25 (24.00%)
    5 / 25 (20.00%)
    Nervous system disorders
    Nightmare
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 25 (16.00%)
    4 / 25 (16.00%)
    3 / 25 (12.00%)
         occurrences all number
    4
    4
    4
    3
    Immune system disorders
    Pruritus
         subjects affected / exposed
    4 / 25 (16.00%)
    7 / 25 (28.00%)
    4 / 25 (16.00%)
    1 / 25 (4.00%)
         occurrences all number
    4
    7
    4
    1
    Gastrointestinal disorders
    postoperative nausea and vomiting
    alternative dictionary used: MedDRA 10
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 25 (12.00%)
    6 / 25 (24.00%)
    5 / 25 (20.00%)
         occurrences all number
    4
    3
    6
    5

    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
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