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    Clinical Trial Results:
    Efficacy and Safety of oral Alitretinoin (Toctino®) in the Treatment of Patients with Cutaneous Lupus Erythematosus: A Multicentre, Open-Label, Prospective Pilot Study

    Summary
    EudraCT number
    		 2010-024131-16
    Trial protocol
    		 DE  
    Global end of trial date
    30 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UKM10_0019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Münster
    Sponsor organisation address
    Albert-Schweitzer-Campus 1, Münster, Germany, 48149
    Public contact
    Prof. Dr. Annegret Kuhn, Universitätsklinikum Münster , kuhnan@uni-muenster.de
    Scientific contact
    Prof. Dr. Annegret Kuhn, Universitätsklinikum Münster , kuhnan@uni-muenster.de
    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
    14 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the therapeutic effect of alitretinoin (Toctino®) in the treatment of Cutaneous Lupus Erythematosus (CLE) with respect to proportion of responders based on the Revised Cutaneous Lupus Disease Area and Severity Index (RCLASI) activity score for skin lesions at baseline and after 24 weeks of treatment or at the latest assessment for patients who withdrew prematurely (Last Observation Carried Forward, LOCF).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines in Good Clinical Practice. The study was not started before the competent ethics committee had given a favorable opinion. Written informed consent was obtained from all patients and the study was only conducted as approved by the Ethics committee and the competent authority. Amendments were only implemented after approval.
    Background therapy
    		 Throughout the trial, daily use of sunscreen (sun protection factor, SPF≥50) was recommended to all patients. The management of CLE could involve the use of topical medications, such as topical steroids, or systemic rescue medications, such as antimalarials.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Dec 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    6
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from 2 dermatology clinics in Germany. The recruitment period was from December 2011 to April 2013.

    Pre-assignment
    Screening details
    		 7 patients with a clinically and histologically confirmed diagnosis of CLE refractory to topical corticosteroids were included in the study.

    Pre-assignment period milestones
    Number of subjects started
    		 7
    Number of subjects completed
    		 5

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Patient did not meet the inclusion criteria: 1
    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Alitretinoin
    Arm description
    		 Patients who received study treatment with alitretinoin (Toctino®).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Toctino®
    Investigational medicinal product code
    Other name
    Alitretinoin
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated for 24 weeks with alitretinoin (Toctino®). Study treatment started with 30 mg alitretinoin per day. The daily dose was reduced to 10 mg alitretinoin if adverse reactions such as hyperlipidemia or severe headaches occurred.

    Number of subjects in period 1 [1]
    		Alitretinoin
    Started
    5
    Completed
    2
    Not completed
    3
         Non-Compliance
    1
         Adverse event, non-fatal
    1
         Lack of efficacy
    1
    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: 7 patients were enrolled in the study and assessed for eligibility. Because one patient did not meet the inclusion criteria and one patient withdrew consent before start of treatment, only 5 patients entered the baseline period.

    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
    		 5 5
    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)
    		 4 4
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Alitretinoin
    Reporting group description
    		 Patients who received study treatment with alitretinoin (Toctino®).

    Subject analysis set title
    Visit (Baseline)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Examination visit before starting alitretinoin treatment.

    Subject analysis set title
    Visit (last)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Last examination visit of patients treated with alitretinoin.

    Primary: RCLASI activity score for skin lesions

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    End point title
    		 RCLASI activity score for skin lesions [1]
    End point description
    Efficacy of alitretinoin on disease severity as evaluated by RCLASI activity score for skin lesions.
    End point type
    Primary
    End point timeframe
    Week 0, 2, 4, 8, 12, 16, 20, 24 and 28
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was terminated prematurely. Since not enough patients were included, no statistical analysis of the results was performed.
    End point values
    		 Visit (Baseline) Visit (last)
    Number of subjects analysed
    5
    4
    Units: Activity score
        arithmetic mean (standard deviation)
    12.8 ± 4.1
    10.3 ± 4.3
    No statistical analyses for this end point

    Secondary: RCLASI activity score total

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    End point title
    		 RCLASI activity score total
    End point description
    Efficacy of alitretinoin on disease severity as evaluated by total RCLASI activity score.
    End point type
    Secondary
    End point timeframe
    Week 0, 2, 4, 8, 12, 16, 20, 24 and 28
    End point values
    		 Visit (Baseline) Visit (last)
    Number of subjects analysed
    5
    4
    Units: Activity score
        arithmetic mean (standard deviation)
    12.8 ± 4.1
    11.3 ± 4.1
    No statistical analyses for this end point

    Secondary: RCLASI damage score total

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    End point title
    		 RCLASI damage score total
    End point description
    Efficacy of alitretinoin on disease severity as evaluated by total RCLASI damage score.
    End point type
    Secondary
    End point timeframe
    Week 0, 2, 4, 8, 12, 16, 20, 24 and 28
    End point values
    		 Visit (Baseline) Visit (last)
    Number of subjects analysed
    5
    4
    Units: Activity score
        arithmetic mean (standard deviation)
    2.0 ± 2.0
    2.3 ± 1.7
    No statistical analyses for this end point

    Secondary: VAS score for itch

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    End point title
    		 VAS score for itch
    End point description
    Efficacy of alitretinoin on disease severity as evaluated by patient assessment score VAS (Visual Analogue Scale) for itch.
    End point type
    Secondary
    End point timeframe
    Week 0, 2, 4, 8, 12, 16, 20, 24 and 28
    End point values
    		 Visit (Baseline) Visit (last)
    Number of subjects analysed
    5
    3
    Units: VAS score
        arithmetic mean (standard deviation)
    3.5 ± 2.2
    2.2 ± 3.8
    No statistical analyses for this end point

    Secondary: VAS score for pain

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    End point title
    		 VAS score for pain
    End point description
    Efficacy of alitretinoin on disease severity as evaluated by patient assessment score VAS for pain.
    End point type
    Secondary
    End point timeframe
    Week 0, 2, 4, 8, 12, 16, 20, 24 and 28
    End point values
    		 Visit (Baseline) Visit (last)
    Number of subjects analysed
    5
    3
    Units: VAS score
        arithmetic mean (standard deviation)
    0 ± 0
    1.8 ± 3.2
    No statistical analyses for this end point

    Secondary: PAGI Score

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    End point title
    		 PAGI Score
    End point description
    Efficacy of alitretinoin on disease severity as evaluated by patient assessment score PAGI (Patient Assessment of Global Improvement).
    End point type
    Secondary
    End point timeframe
    Week 0, 2, 4, 8, 12, 16, 20, 24 and 28
    End point values
    		 Visit (Baseline) Visit (last)
    Number of subjects analysed
    4
    3
    Units: PAGI score
        arithmetic mean (standard deviation)
    0 ± 0.8
    0 ± 1.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time of informed consent until the final study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Safety group
    Reporting group description
    		 Patients who received at least one dose of alitretinoin (Toctino®).

    Serious adverse events
    		 Safety group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Nervous system disorders
    Head discomfort
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 May 2013
    - Exclusion criteria were amended. Patients with hereditary myopathy in patient and family history as well as patients with known rhabdomyolysis in patient history (e.g. musculous-toxic complications in association with statin and fibrate therapy) should not participate in the study. - In patients with clinical suspicion of myalgia and/ or myopathia, creatine kinase should be determined. If the level was significantly increased, the patient should be excluded from the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Apr 2013
    Only 7 patients could be enrolled in the study within 18 months and it was not expected that more patients or even all 30 patients would be recruited in the near future. Therefore, recruitment of patients was interrupted on April 11, 2013, and on April 30, 2014, the study was officially terminated.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated prematurely because only 7 patients could be enrolled in the study (only 5 patients started study treatment).
    For support, Contact us.
    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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