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    Clinical Trial Results:
    Use of long acting opioids for pre- and postoperative analgesia in primary total knee arthroplasty. A double-blinded randomized control trial. Tapentadol vs Oxycodon vs Placebo

    Summary
    EudraCT number
    		 2015-000295-94
    Trial protocol
    		 NO  
    Global end of trial date
    28 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2021
    First version publication date
    29 Nov 2021
    Other versions
    Summary report(s)
    		 Summary 121121

    Trial information

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    Trial identification
    Sponsor protocol code
    TPO-150
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02604446
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St. Olavs Hospital, Trondheim, Norway
    Sponsor organisation address
    Olav Kyrrs gate, Trondheim, Norway, 7006
    Public contact
    Head of Clinic, Orthopedic surgery, St. Olavs University Hospital, +47 72823244, knut.hagen@stolav.no
    Scientific contact
    Head of Clinic, Orthopedic surgery, St. Olavs University Hospital, +47 72823244, knut.hagen@stolav.no
    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
    28 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective of the trial is to measure variations in pain relief between three different pain treatments
    Protection of trial subjects
    Before surgery, all patients received acetaminophen tablets 2/ 1.5 g above/below 70 kg, dexamethasone tablets 20/16 mg above/below 70 kg, naproxen 500 mg 1 esomeprazole 20 mg. Acetaminophen, naproxen and esomeprazole were repeated on the day of surgery. After the day of surgery, patients received study medication twice daily, naproxen 500 mg1esomeprazole 20 mg twice daily, and acetaminophen 1000 mg 4 times daily for 6 days. For rescue analgesia, patients in all 3 study groups had the opportunity to take oral oxycodone immediate-release (IR) 5 mg on demand.
    Background therapy
    		 Acetaminophen tablets 2/ 1.5 g above/below 70 kg, dexamethasone tablets 20/16 mg above/below 70 kg, naproxen 500 mg 1 esomeprazole 20 mg. Acetaminophen, naproxen 1 esomeprazole were repeated on the day of surgery. After the day of surgery, patients received study medication twice daily, naproxen 500 mg1esomeprazole 20 mg twice daily, and acetaminophen 1000 mg 4 times daily for 6 days. For rescue analgesia, patients in all 3 study groups had the opportunity to take oral oxycodone immediate-release (IR) 5 mg on demand.
    Evidence for comparator
    		 Opioids are effective drugs for pain relief, with increased efficacy with increased doses. Tapentadol is an analgesic drug that provides analgesia through both the opioid and alpha-2-adrenergic receptors
    Actual start date of recruitment
    01 Sep 2015
    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
    Norway: 149
    Worldwide total number of subjects
    149
    EEA total number of subjects
    149
    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)
    149
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment was done by an anesthesiologist at the preoperative outpatient clinic in the period between September 2015 and February 2019.

    Pre-assignment
    Screening details
    		 Patients scheduled for surgerywith TKA between 18 and 80 years of age were included in the study.

    Period 1
    Period 1 title
    Drug intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind [1]
    Roles blinded
    		 Subject, Monitor, Carer, Assessor
    Blinding implementation details
    Randomization was performed by the Unit for Applied Clinical Research (AKF NTNU). Computer-generated block randomization with block sizes of 30, 30, 30, 21, 21, and 18 was used. The randomization of study drugs was only known by the hospital pharmacy (for emergency unblinding), the monitor unit (AKF NTNU) who generated the list, and the manufacturer of the study drugs. The 3 different study drugs were packed in identical resorbable capsules and swallowed whole. Ward staff did all handling.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo group
    Arm description
    		 Placebo drug x 2 Day of surgery and day 1-6
    Arm type
    		 Placebo

    Investigational medicinal product name
    Tapentadol
    Investigational medicinal product code
    Other name
    Tapentadol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tapentadol 50 mg x 2

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet x 2 in seven days

    Arm title
    		 Tapentadol
    Arm description
    		 tapentadol 50 mg x 2 for seven days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol
    Investigational medicinal product code
    Other name
    Tapentadol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tapentadol 50 mg x 2

    Arm title
    		 Oxycodone
    Arm description
    		 Oxycodone 19 mg x 2 for seven days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    oxycodone
    Investigational medicinal product code
    Other name
    oxycodone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    oxycodone 20 mg x 2 for seven days

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: The randomization of study drugs was only known by the hospital pharmacy (for emergency unblinding), the monitor unit (AKF NTNU) who generated the list, and the manufacturer of the study drugs. The 3 different study drugs were packed in identical resorbable capsules and swallowed whole. Ward staff did all handling of study drugs and other analgesic drugs in the study. All participants, healthcare personnel, and investigators were blinded for the study drug allocation.
    Number of subjects in period 1
    		Placebo group Tapentadol Oxycodone
    Started
    50
    49
    50
    Completed
    50
    49
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo group
    Reporting group description
    		 Placebo drug x 2 Day of surgery and day 1-6

    Reporting group title
    Tapentadol
    Reporting group description
    		 tapentadol 50 mg x 2 for seven days

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone 19 mg x 2 for seven days

    Reporting group values
    		 Placebo group Tapentadol Oxycodone Total
    Number of subjects
    		 50 49 50 149
    Age categorical
    Age
    Units: Subjects
        Adults (18-64 years)
    		 50 49 50 149
    Gender categorical
    Units: Subjects
        Female
    		 7 1 1 9
        Male
    		 43 48 49 140

    End points

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    End points reporting groups
    Reporting group title
    Placebo group
    Reporting group description
    		 Placebo drug x 2 Day of surgery and day 1-6

    Reporting group title
    Tapentadol
    Reporting group description
    		 tapentadol 50 mg x 2 for seven days

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone 19 mg x 2 for seven days

    Primary: Pain at day seven

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    End point title
    		 Pain at day seven
    End point description
    The patients were asked “How much pain do you have now when you move, where 0 is no pain and 10 is the worst pain imaginable.” The primary outcome is reported as area under the pain curve (AUC) and the corresponding mean value of pain for each patient and the groups for the first 7 postoperative days.
    End point type
    Primary
    End point timeframe
    Seven days
    End point values
    		 Placebo group Tapentadol Oxycodone
    Number of subjects analysed
    43 [1]
    45 [2]
    46 [3]
    Units: Area under the curve
        Pain
    528
    427
    508
    Notes
    [1] - 7 without follow-up data
    [2] - 4 without follow-up data
    [3] - 4 without follow-up data
    Statistical analysis title
    		 Kruskal-Wallis
    Statistical analysis description
    For pain on mobilization and pain at rest, AUC was calculated and divided by elapsed time from first to last postoperative measurement fromthe first to the seventh day to yield a measure of mean pain in this period. Mean pain was then compared between the experimental groups using the nonparametric Kruskal–Wallis test.
    Comparison groups
    Placebo group v Tapentadol v Oxycodone
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [4]
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.14
    Variability estimate
    Standard deviation
    Dispersion value
    204
    Notes
    [4] - No statistical difference found between the group for prarimary (or secobdary) outcome (P=12)

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    14 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Placebo group
    Reporting group description
    		 Placebo drug x 2 Day of surgery and day 1-6

    Reporting group title
    Tapentadol
    Reporting group description
    		 tapentadol 50 mg x 2 for seven days

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone 19 mg x 2 for seven days

    Serious adverse events
    		 Placebo group Tapentadol Oxycodone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (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
    		 Placebo group Tapentadol Oxycodone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (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 adverse event occured more frequent than 5%. Constipatiom occured more frequent iin the oxycondone group than the other groups (p=0.02)

    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.
    The sample size of 150 patients was not large enough to rule out a small difference of in pain NRS scores
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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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