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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
    2016-001568-12
    Trial protocol
    BG  
    Global end of trial date
    04 May 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Feb 2020
    First version publication date
    08 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    16-02/CalciBet-S
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Project number (CRO): CDD16001
    Sponsors
    Sponsor organisation name
    Dermapharm AG
    Sponsor organisation address
    Lil-Dagover Ring 7, Gruenwald, Germany, 82031
    Public contact
    Clinical Research Department, Dermapharm AG, Clinicaltrials.Dermapharm@dermapharm.com
    Scientific contact
    Clinical Research Department, Dermapharm AG, Clinicaltrials.Dermapharm@dermapharm.com
    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
    16 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2017
    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
    The study was conducted in accordance with the principles of ICH GCP, the declaration of Helsinki, as well as all other applicable local ethical and legal requirements. The reference product Daivobet® ointment is already registered and commercially available for years in Europe. For the purpose of approval the efficacy and safety of this drug has already been proven in clinical trials. The test drug had not been tested in clinical trials before. One possible risk have resulted from the theoretical assumption of lack of efficacy. In addition a certain, although small proportion of patients were treated with placebo. Any patient with lack of efficacy and/or deterioration of symptoms could stop treatment with study drug at any moment based on the clinical judgement of the investigator. In addition to this every patient could withdraw from the study on his/ her own request and without giving reasons. The planned procedures within the trial represented no special risk to the patients as, apart of blood sampling for laboratory evaluations, there were no further invasive procedures planned.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Oct 2016
    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
    Bulgaria: 439
    Worldwide total number of subjects
    439
    EEA total number of subjects
    439
    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)
    375
    From 65 to 84 years
    64
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Multi-centric study in Bulgaria; first volunteer enrolled: 17-Nov-2016; date of last completion: 04-May- 2017

    Pre-assignment
    Screening details
    Diagnosis and main criteria for inclusion: male or female patients ≥ 18 years of age; clinical diagnosis of chronic stable (at least 6 months) plaque psoriasis amenable to topical treatment; psoriasis affecting less than 30% of the body surface area (BSA); a modified PASI score of ≥ 5 to ≤ 15 at baseline.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The study medications was masked to look the same. The test, reference, and vehicle ointment formulations were almost identical in smell and appearance. The investigators and the staff at clinical sites, patients, as well as CRO and sponsor personnel involved in the monitoring or conduct of the study were blinded to the drug codes, except in the case of an emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Test product
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Calcipotriol Combi Ointment
    Investigational medicinal product code
    D05AX52
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    once daily, maximum daily dose of 15 g ointment

    Arm title
    Reference product
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Daivobet 50 μg/g + 0.5 mg/g Ointment
    Investigational medicinal product code
    D05AX52
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    once daily, maximum daily dose of 15 g ointment

    Arm title
    Vehicle
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Test product vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    once daily, maximum daily dose of 15 g ointment

    Number of subjects in period 1
    Test product Reference product Vehicle
    Started
    194
    195
    50
    Completed
    191
    192
    48
    Not completed
    3
    3
    2
         Protocol deviation
    2
    1
    1
         Non-compliance
    -
    -
    1
         Adverse event, non-fatal
    -
    1
    -
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    -

    Reporting group values
    Treatment period Total
    Number of subjects
    439 439
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    375 375
        From 65-84 years
    64 64
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    193 193
        Male
    246 246

    End points

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    End points reporting groups
    Reporting group title
    Test product
    Reporting group description
    -

    Reporting group title
    Reference product
    Reporting group description
    -

    Reporting group title
    Vehicle
    Reporting group description
    -

    Primary: Primary endpoint

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    End point title
    Primary endpoint
    End point description
    Percent change of modified PASI to baseline after 4 weeks of treatment - ANCOVA and 95% confidence intervals of treatment diffs., FAS, LOCF applied
    End point type
    Primary
    End point timeframe
    Baseline to end of week 4
    End point values
    Test product Reference product Vehicle
    Number of subjects analysed
    193
    195
    50
    Units: % change of mean
        least squares mean (confidence interval 95%)
    71.81 (68.53 to 75.09)
    68.96 (65.71 to 72.21)
    46.55 (40.84 to 52.27)
    Statistical analysis title
    Therapeutic equivalence
    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, analysis of covariance (ANCOVA) was carried out using treatment and centre as factors and baseline PASI score as a covariate. The decision of therapeutic equivalence was based on two one-sided tests against the lower and the upper limit of the equivalence range, each with a local one-sided type I error rate of α=0.025.
    Comparison groups
    Test product v Reference product
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    2.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.12
         upper limit
    6.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.02
    Statistical analysis title
    Superiority of test product to vehicle
    Statistical analysis description
    The analysis was intended to provide supportive evidence with regard to assay sensitivity.
    Comparison groups
    Test product v Vehicle
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Superiority of reference product to vehicle
    Statistical analysis description
    This analysis was intended to provide supportive evidence with regard to assay sensitivity.
    Comparison groups
    Reference product v Vehicle
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval

    Secondary: Change at the end of week 1

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    End point title
    Change at the end of week 1
    End point description
    Percent change of modified PASI to baseline after 1 week of treatment - ANCOVA and 95% confidence intervals of treatment diffs., FAS, LOCF applied
    End point type
    Secondary
    End point timeframe
    Baseline to end of week 1
    End point values
    Test product Reference product Vehicle
    Number of subjects analysed
    193
    195
    50
    Units: % change of mean
        least squares mean (confidence interval 95%)
    29.22 (26.84 to 31.60)
    27.93 (25.57 to 30.29)
    20.10 (15.95 to 24.25)
    Statistical analysis title
    Therapeutic equivalence
    Comparison groups
    Test product v Reference product
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    4.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.47
    Statistical analysis title
    Superiority of test product to vehicle
    Comparison groups
    Test product v Vehicle
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Superiority of reference product to vehicle
    Comparison groups
    Reference product v Vehicle
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    ANCOVA
    Confidence interval

    Secondary: Mean percent change in BSA at the end of treatment

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    End point title
    Mean percent change in BSA at the end of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to end of week 4
    End point values
    Test product Reference product Vehicle
    Number of subjects analysed
    193
    195
    50
    Units: % change of mean
        least squares mean (confidence interval 95%)
    46.33 (41.14 to 51.52)
    45.49 (40.33 to 50.65)
    28.55 (18.35 to 38.75)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to the end of follow-up.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Test product
    Reporting group description
    all patients who have administered the test medication at least once

    Reporting group title
    Reference product
    Reporting group description
    All patients who had administered the reference product at least once

    Reporting group title
    Vehicle
    Reporting group description
    All patients who have administered the vehicle product at least once.

    Serious adverse events
    Test product Reference product Vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 194 (0.52%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Spinal operation
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    0 / 50 (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
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    Test product Reference product Vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 194 (2.58%)
    4 / 195 (2.05%)
    3 / 50 (6.00%)
    Investigations
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Renal colic
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 195 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Contact dermatitis
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 194 (0.00%)
    2 / 195 (1.03%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Psoriasis
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Dyslipidaemia
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 195 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 195 (0.51%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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