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    Clinical Trial Results:
    CLINICAL EFFICACY AND SAFETY OF TAZAROTENE CREAM 0.05% IN THE INITIAL AND MAINTENANCE THERAPIES OF LAMELLAR ICHTHYOSIS (LI)

    Summary
    EudraCT number
    		 2010-022284-35
    Trial protocol
    		 IT   SE   DE   FR   AT  
    Global end of trial date
    03 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2016
    First version publication date
    13 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R00002 CR 301 (ORF)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Orfagen
    Sponsor organisation address
    3, avenue Hubert Curien, Toulouse CEDEX 1, France, 31035
    Public contact
    Clinical project manager, Orfagen, info@orfagen.com
    Scientific contact
    Clinical project manager, Orfagen, info@orfagen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000510-PIP02-10
    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
    03 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the long-term clinical efficacy and safety of Tazarotene 0.05% cream in LI patients in real-life setting conditions.
    Protection of trial subjects
    - plasmatic bone markers monitoring - IDMC/Data Safety Management Board (quartely meeting)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Tunisia: 6
    Country: Number of subjects enrolled
    Algeria: 44
    Worldwide total number of subjects
    91
    EEA total number of subjects
    41
    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)
    10
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    59
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After a wash-out of at least 7 days (period with no application f treatment, except the standard moisturizer), patients with moderate to severe ichthyosis and who fulfilled all the inclusion criteria were enrolled in the study

    Period 1
    Period 1 title
    Period I (84 days)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tazarotene 0.05%
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    R0002 CR 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1mg/cm² using the finger tip technique. Application every other day on lesional areas excluding face, neck, scalp, palms, soles and genital areas.

    Arm title
    		 Urea cream
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Urea cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1mg/cm² using the finger tip technique. Application every other day on lesional areas excluding face, neck, scalp, palms, soles and genital areas.

    Number of subjects in period 1
    		Tazarotene 0.05% Urea cream
    Started
    42
    49
    Completed
    37
    47
    Not completed
    5
    2
         Consent withdrawn by subject
    4
    1
         Lost to follow-up
    1
    1
    Period 2
    Period 2 title
    Period II (84 days)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Tazarotene 0.05%
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    R0002CR 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1mg/cm² using the finger tip technique. Recommended frequency of application: every other day excluding genital areas

    Number of subjects in period 2
    		Tazarotene 0.05%
    Started
    84
    Completed
    82
    Not completed
    2
         Consent withdrawn by subject
    1
         Lost to follow-up
    1
    Period 3
    Period 3 title
    Period III (up to 56 days)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tazarotene 0.05%
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    R0002 CR 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1mg/cm² using the finger tip technique. Recommended frequency of application: every other day excluding genital areas

    Arm title
    		 Vehicle
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1mg/cm² using the finger tip technique. Recommended frequency of application: every other day excluding genital areas

    Number of subjects in period 3 [1]
    		Tazarotene 0.05% Vehicle
    Started
    35
    35
    Completed
    30
    25
    Not completed
    5
    10
         Relapse
    4
    8
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Patients with non persisting lesions at the end of Period II only could enter Period III.
    Period 4
    Period 4 title
    Children Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Follow-up without treatment
    Arm description
    		 Post treatment follow-up for children who entered at least Period I
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4 [2]
    		Follow-up without treatment
    Started
    22
    Completed
    10
    Not completed
    12
         upon sponsor request
    10
         Lost to follow-up
    1
         Protocol deviation
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Post treatment long term safety for children who entered at least period I and who agreed to perform this follow-up.
    Period 5
    Period 5 title
    Period IV
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Tazarotene 0.05%
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    R0002CR 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1mg/cm² using the finger tip technique. Recommended frequency of application: every other day excluding genital areas.

    Number of subjects in period 5 [3]
    		Tazarotene 0.05%
    Started
    4
    Completed
    0
    Not completed
    16
         Study ended by sponsor
    16
    Joined
    12
         Extension after Period III
    12
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Study extension in order to maintain an optimal follow-up procedure, following patients' request to benefit from R0002CR 0.05% cream: 4 patients after children follow-up end, 12 patients after Period III end.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tazarotene 0.05%
    Reporting group description
    		 -

    Reporting group title
    Urea cream
    Reporting group description
    		 -

    Reporting group values
    		 Tazarotene 0.05% Urea cream Total
    Number of subjects
    		 42 49 91
    Age categorical
    Units: Subjects
        9 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29.2 ± 16.9 25.2 ± 13 -
    Gender categorical
    Units: Subjects
        Female
    		 22 22 44
        Male
    		 20 27 47

    End points

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    End points reporting groups
    Reporting group title
    Tazarotene 0.05%
    Reporting group description
    		 -

    Reporting group title
    Urea cream
    Reporting group description
    		 -
    Reporting group title
    Tazarotene 0.05%
    Reporting group description
    		 -
    Reporting group title
    Tazarotene 0.05%
    Reporting group description
    		 -

    Reporting group title
    Vehicle
    Reporting group description
    		 -
    Reporting group title
    Follow-up without treatment
    Reporting group description
    		 Post treatment follow-up for children who entered at least Period I
    Reporting group title
    Tazarotene 0.05%
    Reporting group description
    		 -

    Primary: Response to treatment at day 84 compared to Baseline

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    End point title
    		 Response to treatment at day 84 compared to Baseline
    End point description
    Response to test treatment at the end of Period I (Day 84): treatment response was defined as a score of 0 to 2 for scaling and roughness using a 5-point severity scale combined with a reduction from baseline of the score of at least 2 grades for scaling only. Patients with premature switch from Period I to Period II were classified as non-responders.
    End point type
    Primary
    End point timeframe
    Baseline - End of Period I (day 84 visit)
    End point values
    		 Tazarotene 0.05% Urea cream
    Number of subjects analysed
    20 [1]
    27 [2]
    Units: patients
    5
    2
    Notes
    [1] - efficacy analysis on ITT population from centers without GCP violation
    [2] - efficacy analysis on ITT population from centers without GCP violation
    Statistical analysis title
    		 Primary efficacy parameter
    Comparison groups
    Urea cream v Tazarotene 0.05%
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.119
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study beginning to study end
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Urea Group
    Reporting group description
    		 TEAE that occured when patients received urea treatment.

    Reporting group title
    Tazarotene group
    Reporting group description
    		 TEAE that occured when patients received tazarotene treatment.

    Reporting group title
    Vehicle group
    Reporting group description
    		 TEAE that occured when patients received vehicle.

    Reporting group title
    No treatment
    Reporting group description
    		 TEAE that occured when patients did not received study treatment.

    Serious adverse events
    		 Urea Group Tazarotene group Vehicle group No treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 84 (2.38%)
    0 / 35 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 84 (1.19%)
    0 / 35 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip surgery
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 84 (1.19%)
    0 / 35 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Urea Group Tazarotene group Vehicle group No treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 49 (51.02%)
    63 / 84 (75.00%)
    8 / 35 (22.86%)
    1 / 21 (4.76%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 84 (2.38%)
    0 / 35 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 49 (16.33%)
    29 / 84 (34.52%)
    1 / 35 (2.86%)
    1 / 21 (4.76%)
         occurrences all number
    8
    41
    1
    1
    Erythema
         subjects affected / exposed
    2 / 49 (4.08%)
    20 / 84 (23.81%)
    0 / 35 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    23
    0
    0
    Skin irritation
         subjects affected / exposed
    0 / 49 (0.00%)
    10 / 84 (11.90%)
    0 / 35 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    12
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 49 (6.12%)
    7 / 84 (8.33%)
    1 / 35 (2.86%)
    0 / 21 (0.00%)
         occurrences all number
    3
    9
    1
    0
    Influenza
         subjects affected / exposed
    3 / 49 (6.12%)
    3 / 84 (3.57%)
    2 / 35 (5.71%)
    0 / 21 (0.00%)
         occurrences all number
    3
    3
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2012
    To provide recommandations concerning the allocation of the treatment units for patients who may request more amount of drug.
    25 Jan 2012
    Implementation of a Children Follow-up Period (postponement of study end: prolongation for 1 year)
    22 Nov 2012
    Implementation of the Period IV: Study extension with treatment for patient wishing to continue to apply the Tazarotene cream

    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
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