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    Clinical Trial Results:
    A Mechanism Based Proof of Concept Study of the Effects of Duloxetine in the Treatment of Patients with Osteoarthritic Knee Pain

    Summary
    EudraCT number
    		 2019-003437-42
    Trial protocol
    		 DK  
    Global end of trial date
    01 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2022
    First version publication date
    18 Aug 2022
    Other versions
    Summary report(s)
    		 Published manuscript

    Trial information

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    Trial identification
    Sponsor protocol code
    DULKOA2019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04224584
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University
    Sponsor organisation address
    Fredrik Bajers Vej 7, Aalborg, Denmark, 9220
    Public contact
    Professor, Lars Arendt-Nielsen, +45 9940 8827, LAN@hst.aau.dk
    Scientific contact
    Professor, Lars Arendt-Nielsen, +45 9940 8827, LAN@hst.aau.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
    17 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess which experimental pain mechanisms are modulated by Duloxetine compared to placebo in patients with knee osteoarthritis.
    Protection of trial subjects
    The trial was continuously monitored by the Good Clinical Practice (GCP) Unit of Aalborg University Hospital, externally audited by the Danish Medicines Agency, and was conducted in accordance with The Helsinki Declaration, GCP, and all applicable Danish regulatory requirements. Informed consent was obtained from all participants. All adverse events were monitored continuously .
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Dec 2019
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    0
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited through Synexus/C4Pain, Aalborg, Denmark (a contracting research organization).

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 40
    Number of subjects completed
    		 36

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 4
    Period 1
    Period 1 title
    Treatment period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Duloxetine
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Duloxetin Lilly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment periods included a 2-week titration period (week 1 (7 days): 20 mg/daily, week 2 (7 days): 40 mg/daily), a 14-week full treatment period (week 3-16 (70 days): 60 mg/daily) followed by a 2-week discontinuation period (week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/daily).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment periods included a 2-week titration period (week 1 (7 days): 20 mg/daily, week 2 (7 days): 40 mg/daily), a 14-week full treatment period (week 3-16 (70 days): 60 mg/daily) followed by a 2-week discontinuation period (week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/daily).

    Number of subjects in period 1 [1]
    		Duloxetine Placebo
    Started
    18
    18
    Completed
    13
    14
    Not completed
    5
    4
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    3
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This is a cross-over trial but the system cannot be setup for this. Please see our published results (Open Access) from there trial here: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ejp.1988
    Period 2
    Period 2 title
    Treatment period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Duloxetine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duloxetin Lilly
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment periods included a 2-week titration period (week 1 (7 days): 20 mg/daily, week 2 (7 days): 40 mg/daily), a 14-week full treatment period (week 3-16 (70 days): 60 mg/daily) followed by a 2-week discontinuation period (week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/daily).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment periods included a 2-week titration period (week 1 (7 days): 20 mg/daily, week 2 (7 days): 40 mg/daily), a 14-week full treatment period (week 3-16 (70 days): 60 mg/daily) followed by a 2-week discontinuation period (week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/daily).

    Number of subjects in period 2
    		Duloxetine Placebo
    Started
    14
    13
    Completed
    12
    13
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -

    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
    		 36 36
    Age categorical
    Women and men, 40– 75 years of age, with OA of the knee, who agreed to participate and filled in an informed consent, were included.
    Units: Subjects
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 23 23
    Gender categorical
    Units: Subjects
        Female
    		 23 23
        Male
    		 13 13
    Subject analysis sets

    Subject analysis set title
    38
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients how completed (N=25) the trial are in this analysis.

    Subject analysis sets values
    		 38
    Number of subjects
    25
    Age categorical
    Women and men, 40– 75 years of age, with OA of the knee, who agreed to participate and filled in an informed consent, were included.
    Units: Subjects
        Adults (18-64 years)
    9
        From 65-84 years
    16
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    18
        Male
    7

    End points

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    End points reporting groups
    Reporting group title
    Duloxetine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Duloxetine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    38
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients how completed (N=25) the trial are in this analysis.

    Primary: Pressure pain thresholds

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    End point title
    		 Pressure pain thresholds
    End point description
    End point type
    Primary
    End point timeframe
    Effect of treatment (absolut difference between follow-up and baseline) when comparing the two treatments (placebo vs. duloxetine)
    End point values
    		 Duloxetine Placebo Duloxetine Placebo
    Number of subjects analysed
    13
    14
    12
    13
    Units: kilopascale
        arithmetic mean (standard deviation)
    17.31 ± 6.44
    20.1 ± 7.87
    16.66 ± 6.74
    16.37 ± 7.82
    Attachments
    		 Published manuscript
    Statistical analysis title
    		 Treatment effect of pressure pain thresholds
    Comparison groups
    Duloxetine v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.303
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed at each visit and by contact to the research team.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Duloxetine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Duloxetine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    evere headache, palpitations, and difficulty breathing
    Additional description: One serious adverse event occurred during the duloxetine treatment period where one patient experienced severe headache, palpitations, and difficulty breathing, and the patient was hospitalized for 1 day to ensure safety
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Duloxetine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 32 (100.00%)
    22 / 31 (70.97%)
    Vascular disorders
    Dry mouth
         subjects affected / exposed
    13 / 32 (40.63%)
    7 / 31 (22.58%)
         occurrences all number
    13
    7
    Cardiac disorders
    Fatigue
         subjects affected / exposed
    9 / 32 (28.13%)
    4 / 31 (12.90%)
         occurrences all number
    9
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 32 (43.75%)
    11 / 31 (35.48%)
         occurrences all number
    14
    11

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35638317
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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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