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    Clinical Trial Results:
    A multi-centre, randomised, double-blind, parallel-group phase III study to investigate the efficacy, safety, and tolerability of a generic calcipotriol-betamethasone ointment formulation compared to Daivobet® and vehicle in the treatment of adult patients with chronic stable plaque psoriasis

    Summary
    EudraCT number
    		 2013-002861-20
    Trial protocol
    		 BG   PL  
    Global end of trial date
    25 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2016
    First version publication date
    14 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lek Pharmaceuticals d.d.
    Sponsor organisation address
    Verovškova 57, Ljubljana, Slovenia, 1526
    Public contact
    Head of Clinical Development, Lek Pharmaceuticals d.d., +386 15803385,
    Scientific contact
    Head of Clinical Development, Lek Pharmaceuticals d.d., +386 15803385 ,
    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 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that topical treatment with the generic calcipotriol-betamethasone ointment formulation is therapeutically equivalent to the originator product Daivobet® ointment in the treatment of chronic stable plaque psoriasis as determined by the percentage reduction in modified Psoriasis Area and Severity Index (PASI).
    Protection of trial subjects
    Safety assessments included adverse events (AEs), local tolerance, safety laboratory parameters (including determination of albumin-corrected calcium), vital signs, physical examination and cortisol measurement. This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jan 2014
    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
    Poland: 187
    Country: Number of subjects enrolled
    Bulgaria: 257
    Worldwide total number of subjects
    444
    EEA total number of subjects
    444
    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)
    404
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 multi-centre, randomised, double-blind, parallel-group, study in male and female patients

    Pre-assignment
    Screening details
    		 Patients underwent a screening phase with a maximum duration of 2 weeks prior to the baseline visit. Of 483 screened patients 445 were randomized.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 test
    Arm description
    		 test product
    Arm type
    		 Experimental

    Investigational medicinal product name
    calcipotriol-betamethasone
    Investigational medicinal product code
    Other name
    Calcipotriol-Betamethasone Sandoz
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Strength: 50 μg/g, 0.5 mg/g. Topical cutaneous application once daily.

    Arm title
    		 reference
    Arm description
    		 reference product
    Arm type
    		 Active comparator

    Investigational medicinal product name
    calcipotriol-betamethasone
    Investigational medicinal product code
    Other name
    Daivobet®
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Strength: 50 μg/g, 0.5 mg/g. Topical cutaneous application once daily.

    Arm title
    		 vehicle
    Arm description
    		 placebo/vehicle product
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Topical cutaneous application once daily.

    Number of subjects in period 1
    		test reference vehicle
    Started
    194
    201
    49
    Completed
    188
    198
    48
    Not completed
    6
    3
    1
         Consent withdrawn by subject
    3
    1
    -
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    2
    -
    -
         not able to continue due to long travel
    -
    1
    -
         Protocol deviation
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    test
    Reporting group description
    		 test product

    Reporting group title
    reference
    Reporting group description
    		 reference product

    Reporting group title
    vehicle
    Reporting group description
    		 placebo/vehicle product

    Reporting group values
    		 test reference vehicle Total
    Number of subjects
    		 194 201 49 444
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 174 185 45 404
        From 65-84 years
    		 20 16 4 40
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.18 ( 14.19 ) 45.57 ( 14.23 ) 48.39 ( 12.96 ) -
    Gender categorical
    Units: Subjects
        Female
    		 84 88 22 194
        Male
    		 110 113 27 250

    End points

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    End points reporting groups
    Reporting group title
    test
    Reporting group description
    		 test product

    Reporting group title
    reference
    Reporting group description
    		 reference product

    Reporting group title
    vehicle
    Reporting group description
    		 placebo/vehicle product

    Primary: Mean percent change from baseline in modified Psoriasis Area and Severity Index (PASI) score, per protocol set

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    End point title
    		 Mean percent change from baseline in modified Psoriasis Area and Severity Index (PASI) score, per protocol set
    End point description
    End point type
    Primary
    End point timeframe
    baseline (score at randomization), end of week 4
    End point values
    		 test reference vehicle
    Number of subjects analysed
    171
    186
    41
    Units: % change LS mean
        least squares mean (confidence interval 95%)
    81.3 (78.13 to 84.46)
    75.51 (72.53 to 78.5)
    48.97 (42.86 to 55.08)
    Statistical analysis title
    		 therapeutic equivalence compared to reference
    Statistical analysis description
    For the primary efficacy outcome measure, mean percent change in modified PASI score between baseline and end of week 4 of the double-blind treatment phase, an analysis of covariance (ANCOVA) was carried out using treatment and centre as factors and baseline PASI score as a covariate.
    Comparison groups
    test v reference
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.69
         upper limit
    		 9.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.08
    Statistical analysis title
    		 superiority of the test product to its vehicle
    Statistical analysis description
    This analysis was intended to provide supportive evidence and was considered descriptive.
    Comparison groups
    test v vehicle
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.58
         upper limit
    		 39.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.43

    Primary: Mean percent change from baseline in modified Psoriasis Area and Severity Index (PASI) score, full analysis set

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    End point title
    		 Mean percent change from baseline in modified Psoriasis Area and Severity Index (PASI) score, full analysis set
    End point description
    End point type
    Primary
    End point timeframe
    baseline, end of week 4
    End point values
    		 test reference vehicle
    Number of subjects analysed
    193
    201
    49
    Units: % change LS mean
        least squares mean (confidence interval 95%)
    79.87 (76.87 to 82.88)
    75.1 (72.17 to 78.02)
    48.39 (42.66 to 54.12)
    Statistical analysis title
    		 therapeutic equivalence compared to reference
    Comparison groups
    test v reference
    Number of subjects included in analysis
    394
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 8.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.03
    Statistical analysis title
    		 superiority of the test product to its vehicle
    Comparison groups
    test v vehicle
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.12
         upper limit
    		 37.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.24

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded by the investigator at each visit until the end of the double-blind phase and at follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    test
    Reporting group description
    		 patients treated with test medication

    Reporting group title
    reference
    Reporting group description
    		 patients treated with reference drug

    Reporting group title
    vehicle
    Reporting group description
    		 patients receiving placebo/vehicle formulation

    Serious adverse events
    		 test reference vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 194 (0.52%)
    2 / 201 (1.00%)
    0 / 49 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 test reference vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 194 (5.15%)
    17 / 201 (8.46%)
    8 / 49 (16.33%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 201 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    1 / 49 (2.04%)
         occurrences all number
    0
    1
    1
    Vascular disorders
    Venous insufficiency
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 201 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1
    Application site pain
         subjects affected / exposed
    2 / 194 (1.03%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    2
    1
    0
    Application site pruritus
         subjects affected / exposed
    1 / 194 (0.52%)
    1 / 201 (0.50%)
    2 / 49 (4.08%)
         occurrences all number
    1
    1
    2
    Influenza like illness
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Pain
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    1 / 194 (0.52%)
    2 / 201 (1.00%)
    2 / 49 (4.08%)
         occurrences all number
    1
    2
    2
    Miliaria
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    3 / 49 (6.12%)
         occurrences all number
    0
    1
    3
    Psoriasis
         subjects affected / exposed
    2 / 194 (1.03%)
    2 / 201 (1.00%)
    0 / 49 (0.00%)
         occurrences all number
    2
    2
    0
    Rash macular
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    1 / 49 (2.04%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 201 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 201 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 201 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 201 (0.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 201 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 201 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2014
    Amendment was prepared as it became known after finalizing and submitting the study protocol to the regulatory authorities of both countries that the product needed for performing the planned adrenocorticotropic hormone (ACTH) challenge test was at that time not available in Europe due to manufacturing problems. An alternative test had to be introduced to replace the ACTH challenge test, i.e. measurement of cortisol excreted into urine over a period of 24 hours.

    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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    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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