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    Clinical Trial Results:
    A randomised, multicentre, open-label, cross-over study to investigate the efficacy and safety of Keplat® and Flector® patch in patients with pain caused by Osteoarthritis of the knee

    Summary
    EudraCT number
    		 2013-000334-36
    Trial protocol
    		 HU  
    Global end of trial date
    14 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2020
    First version publication date
    19 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Keplat-HU01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sager Pharma Ltd.
    Sponsor organisation address
    Pasaréti út 122-124, Budapest, Hungary, H-1026
    Public contact
    Rudolf M. Tubbeh, Sager Pharma Ltd., rudy.tubbeh@sagerpharma.hu
    Scientific contact
    Rudolf M. Tubbeh, Sager Pharma Ltd., rudy.tubbeh@sagerpharma.hu
    Sponsor organisation name
    Hisamitsu UK Ltd.
    Sponsor organisation address
    500 Chiswick High Road, London, United Kingdom, W5RG
    Public contact
    Ventsislav Kelchev, Hisamitsu UK Ltd., kelchev@hisamitsu.co.uk
    Scientific contact
    Ventsislav Kelchev, Hisamitsu UK Ltd., kelchev@hisamitsu.co.uk
    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
    31 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to compare effectiveness of Keplat and Flector patches in the treatment of osteoarthritis of the knee. Following evaluations are made: - The pain VAS score of target knee - The tenderness of the knee - Swelling of the knee - Amount of paracetamol tablets - The Patient’s Global assessment - Investigator’s Global Assessment
    Protection of trial subjects
    The Investigator or a person designated by the Investigator did thoroughly explain the purpose and method of the study as well as any expected effects and adverse reactions to the patient before any study specific screening procedures were conducted. The patient were provided with an information sheet and given sufficient time and opportunity to enquire about the details of the trial and to decide whether or not they wished to participate in the study. The patient and the person with whom they discussed the informed consent signed and dated the consent form. The Investigator or a person designated by the Investigator explained that the patient was completely free to refuse to enter the study or to withdraw either spoken or written from it at any time and for any reason. Similarly, the Investigator and/or Sager Pharma were free to withdraw the patient at any time for safety reasons. Any other requirements necessary for the protection of the human rights of the patient were also explained.
    Background therapy
    		 Oral paracetamol was used as rescue medication One tablet of Paracetamol contained 500mg acetaminophen that was manufactured according to the principles of GMP. Paracetamol was obtained from Hungarian market.
    Evidence for comparator
    		 Flector® patch was used as a comparator. Flector® was 10 cm x 14 cm in dimension. The dose of diclofenac epolamine was 1.30% (w/w, excluding the backing material). The sticky side of the patch was applied to a clean, dry skin at the treatment site twice a day in the morning and evening. Flector® was manufactured according to the principles of GMP by Teikoku Seiyaku, in Kagawa, Japan. Flector® was obtained from Hungarian market.
    Actual start date of recruitment
    25 Jun 2013
    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
    Hungary: 108
    Worldwide total number of subjects
    108
    EEA total number of subjects
    108
    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)
    88
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled between June 2013-Mar 2014, in 5 trial centers in Hungary.

    Pre-assignment
    Screening details
    		 Main inclusion criteria: 1. Male or female out-patients aged 45 years and older; 2. Unilateral or bilateral Osteoarthritis of the knee; 3. Oral NSAIDs or Paracetamol or other analgesics on a regular basis; 4. Pain intensity at least 55 mm or more on the 100mm VAS at screening 110 patients were screened, 108 treated, 103 completed the study.

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Keplat
    Arm description
    		 Treated with Keplat patch for 1 week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Keplat
    Investigational medicinal product code
    M02AA10
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    20 mg milligram(s) per day, transdermal use, applied once daily.

    Arm title
    		 Flector
    Arm description
    		 Flector®: Patch containing 1.30% (w/w, excluding the backing material) Diclofenac epolamine (14 cmx 10 cm), twice daily, considered upon the timing of bathing, showering or washing for the week. One patch was applied topically to the skin on one painful area.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Flector
    Investigational medicinal product code
    M02AA15
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Flector®: Patch containing 1.30% (w/w, excluding the backing material) Diclofenac epolamine (14 cm x 10 cm), twice daily, considered upon the timing of bathing, showering or washing for the week. One patch was applied topically to the skin on one painful area.

    Number of subjects in period 1
    		Keplat Flector
    Started
    54
    54
    Completed
    53
    53
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    1
    Period 2
    Period 2 title
    Washout
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Paracetamol treatment only

    Arms
    Arm title
    		 All patients
    Arm description
    		 Paracetamol treatment only
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		All patients
    Started
    106
    Completed
    105
    Not completed
    1
         Adverse event, non-fatal
    1
    Period 3
    Period 3 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1
    Arm description
    		 Flector
    Arm type
    		 Experimental

    Investigational medicinal product name
    Flector
    Investigational medicinal product code
    M02AA15
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Flector®: Patch containing 1.30% (w/w, excluding the backing material) Diclofenac epolamine (14 cm x 10 cm), twice daily, considered upon the timing of bathing, showering or washing for the week. One patch was applied topically to the skin on one painful area.

    Arm title
    		 Arm 2
    Arm description
    		 Keplat
    Arm type
    		 Experimental

    Investigational medicinal product name
    Keplat
    Investigational medicinal product code
    M02AA10
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    20 mg milligram(s) per day, transdermal use, applied once daily.

    Number of subjects in period 3
    		Arm 1 Arm 2
    Started
    53
    52
    Completed
    53
    52
    Period 4
    Period 4 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Arm title
    		 All patients
    Arm description
    		 Follow-up
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		All patients
    Started
    105
    Completed
    105

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 108 108
    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
    Age was collected at visit 1. Descriptive statistics tables were performed.
    Units: years
        arithmetic mean (standard deviation)
    		 62.5 ± 9.2 -
    Gender categorical
    Gender (man or woman) was discrete variable. Descriptive statistics was performed.
    Units: Subjects
        Female
    		 88 88
        Male
    		 20 20
    Height
    Height values were collected at visit 1. Descriptive statistics tables were performed.
    Units: cm
        arithmetic mean (standard deviation)
    		 164.14 ± 8.43 -
    Weight
    Weight values were collected at visit 1. Descriptive statistics tables were performed
    Units: kg
        arithmetic mean (standard deviation)
    		 77.12 ± 12.55 -
    Pain VAS
    Pain VAS values at V1
    Units: NA
        arithmetic mean (standard deviation)
    		 74.9 ± 9.5 -

    End points

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    End points reporting groups
    Reporting group title
    Keplat
    Reporting group description
    		 Treated with Keplat patch for 1 week.

    Reporting group title
    Flector
    Reporting group description
    		 Flector®: Patch containing 1.30% (w/w, excluding the backing material) Diclofenac epolamine (14 cmx 10 cm), twice daily, considered upon the timing of bathing, showering or washing for the week. One patch was applied topically to the skin on one painful area.
    Reporting group title
    All patients
    Reporting group description
    		 Paracetamol treatment only
    Reporting group title
    Arm 1
    Reporting group description
    		 Flector

    Reporting group title
    Arm 2
    Reporting group description
    		 Keplat
    Reporting group title
    All patients
    Reporting group description
    		 Follow-up

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP group included all randomized and completed patient without major protocol deviation (a total of 101 patients). Subgroup for “carry-over effect”: when the difference of patient VAS data between V4 and V2 exhibited more than 30mm, the patient was excluded from this population.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT group included all subjects planned to be treated (all randomized patients). Drop-out patients, patients with missing data or patient with major protocol deviation were included in the analysis (a total of 108 patients).

    Primary: Change in VAS score

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    End point title
    		 Change in VAS score
    End point description
    Treatment efficacy (change in VAS between the treatments): in case of Keplat®: 24.7 mm, in case of Flector®: 23.6 mm. In total, there was 1.1 mm difference between the treatments in favour of Keplat®, but it was not significant.
    End point type
    Primary
    End point timeframe
    Change V2 vs. V3 and V4 vs. V5
    End point values
    		 Keplat Flector
    Number of subjects analysed
    52
    49
    Units: mm
        arithmetic mean (standard deviation)
    -25.2 ± 24.1
    -23.2 ± 22.6
    Statistical analysis title
    		 Treatment efficacy comparing the treatments
    Statistical analysis description
    Cross-over statistics was performed by Generalized Linear model (GLM). The sequence, patients, period and treatment effects were incorporated in the model. For residual effects, thevariables measured at start of treatments were considered as covariates. Test of Hypotheses using the Type III MS for subj(seq) as an Error Term we adapted in GLM procedure.
    Comparison groups
    Keplat v Flector
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 generalised Linear Model
    Confidence interval
    Notes
    [1] - Statistics was performed in aspect the superiority of the Keplat® as it was described in statistical analysis plan; however in the study protocol this was not exactly defined. According study protocol 10 mm of VAS value difference was expected between the Keplat® and Flector®.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    V1-V6
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 SF group included all subjects who apply at least 1 patch during the study (a total of 108 patients).

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 108 (0.93%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Ileus
    Additional description: Reported as severe abdominal pain in the initial report. Event occured during wash-out phase.
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 108 (3.70%)
    Gastrointestinal disorders
    Gastroenteritis
    Additional description: Mild, no relationship. Event occured during Keplat treatment.
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
    Additional description: Mild, probable relationship. Event occured during Flector treatment.
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences all number
    1
    Dyshidrotic eczema
    Additional description: Mild, no relationship. Event occured during wash-out period.
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Joint injury
    Additional description: Moderate, no relationship. Event occured during wash-out period.
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences all number
    0

    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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