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    Clinical Trial Results:
    A Randomised Controlled Trial of Adjunctive Systemic Therapy for Vulval Erosive Lichen Planus

    Summary
    EudraCT number
    		 2014-000547-32
    Trial protocol
    		 GB  
    Global end of trial date
    10 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Mar 2017
    First version publication date
    09 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Lenton Lane, Nottingham, United Kingdom, NG7 2NR
    Public contact
    CI, Kim Thomas, +44 01158468632, kim.thomas@nottingham.ac.uk
    Scientific contact
    CI, Kim Thomas, +44 01158468632, kim.thomas@nottingham.ac.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
    17 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess whether the addition of systemic therapies are better than topical treatment (in conjunction with a short course of oral corticosteroids) in treating patients with ELPV that has not responded to standard first-line topical therapy. The trial will be statistically powered to assess whether the additional systemic therapy is more effective than the control treatment, it will not be powered to assess which of the three additional therapies is the most effective.
    Protection of trial subjects
    An individual participant will stop treatment (but continue follow up) if: - they have poor ongoing control of disease despite good adherence to the treatment regimen and optimising topical clobetasol propionate 0.05% use and the clinician feels it is unethical to continue; or - side effects indicate that the participant should not carry on with the designated treatment regimen. Please note - Specifically for patients taking mycophenolate mofetil if neutropenia develops (absolute neutrophil count < 1.3 x 10^3) treatment should be discontinued. If participants stop the study treatment they will continue to be followed up. Participants may stop the trial early either at their own request or at the Investigator’s discretion (for example due to severe secondary infection, pregnancy and development of malignancy). If possible data will continue to be collected. The participants will be made aware that this will not affect their future care. Participants will be made aware (via the information sheet and consent form) that should they stop the trial, data collected to date cannot be erased and will still be used in the final analysis. Participants who are randomised but are subsequently found to be ineligible will be replaced and will not be included in the intention to treat analysis. Participants who are randomised but choose not to start their medication (i.e. change their mind re: participation) will be followed up and will be included in the intention to treat analysis.
    Background therapy
    		 None. All participants receive clobetasol as per usual care.
    Evidence for comparator
    		 First-line therapy in the UK is with a super-potent topical steroid, usually clobetasol propionate 0.05% [16, 17]. Non-randomised studies, mainly retrospective case series, have suggested that super-potent topical steroids can be an effective first-line therapy [10, 12, 18, 19]. However, in the only prospective published case series [10], one-third of patients responded poorly to super-potent topical steroids. Evidence to date suggests that super-potent topical steroids are a reasonable first-line therapeutic choice and qualitative work has shown that they are ingrained into clinical practice as an initial therapy for ELPV [20]. The rationale for using clobetasol propionate 0.05% in all groups is determined from collaboration with the British Society for the Study of vulThere is no agreement for which second-line agents should be used [7, 17], despite the fact that one-third of patients fail first-line therapy. Most second-line therapies are used based upon expert opinion. Systemic agents described in case series and case reports consist of: • oral corticosteroids • systemic immunosuppressants including azathioprine, ciclosporin, methotrexate and mycophenolate mofetil • systemic antibiotics, particularly tetracyclines • hydroxychloroquine • oral retinoids • other anti-inflammatory agents including griseofulvin (an oral anti-fungal agent), colchicine (an agent traditionally used to treat gout) and dapsone. vovaginal disease (BSSVD) and limited case series studies in the literature.
    Actual start date of recruitment
    01 May 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
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place over 14 months (1st June 2014 to 31st July 2015) at 12 United Kingdom National Health Service hospital outpatient departments. Follow-up was for 12 months.

    Pre-assignment
    Screening details
    		 Women aged 18 or over with a clinical diagnosis of moderate to severe ELPV, despite treatment for three-months with clobetasol propionate 0.05%, were included. A vulval biopsy that excluded malignant/pre-malignant disease must have been documented. Participants had to agree to clinical photographs being taken and, if relevant, agree to use effectiv

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control group
    Arm description
    		 standard care of topical clobetasol propionate 0.05% plus a short course of oral prednisolone. N.B Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon. This is in conjunction with an initial reducing course of oral prednisolone (20mg per day to reduce by 5mg per week over 4 weeks until stop (i.e. 20mg/day for 1 week, then 15mg/day for 1 week, then 10mg/day for 1 week, then 5mg/day for 1 week then stop)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clobetasol prorionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    reducing course of oral prednisolone (20mg per day to reduce by 5mg per week over 4 weeks until stop (i.e. 20mg/day for 1 week, then 15mg/day for 1 week, then 10mg/day for 1 week, then 5mg/day for 1 week then stop)

    Arm title
    		 Research arm 1
    Arm description
    		 Oral hydroxychloroquine (up to 200mg twice daily) PLUS topical clobetasol propionate 0.05%% in the same regimen as in the control group. The exact dose will be decided by the treating physician according to clinical requirement. Oral hydroxychloroquine shoRuld be used as per usual practice following national guidelines including appropriate safety monitoring.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clobetasol prorionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon.

    Arm title
    		 Research arm 2
    Arm description
    		 Oral methotrexate (starting at 5mg weekly titrated upwards over 3-4 months to a ceiling dose of 25mg weekly) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral methotrexate should be used as per usual practice following national guidelines including appropriate safety monitoring.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clobetasol prorionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon.

    Investigational medicinal product name
    methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral methotrexate (starting at 5mg weekly titrated upwards over 3-4 months to a ceiling dose of 25mg weekly) . Oral methotrexate should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Arm title
    		 Research arm 3
    Arm description
    		 Oral mycophenolate mofetil (starting at 500mg OD titrated upwards over 3-4 months to a ceiling dose of 3g/day) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral mycophenolate mofetil should be used as per usual practice following national guidelines including appropriate safety monitoring.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clobetasol prorionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon.

    Investigational medicinal product name
    Mycophenolate mofetil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    : Oral mycophenolate mofetil (starting at 500mg OD titrated upwards over 3-4 months to a ceiling dose of 3g/day) . Oral mycophenolate mofetil should be used as per usual practice following national guidelines including appropriate safety monitoring

    Number of subjects in period 1
    		Control group Research arm 1 Research arm 2 Research arm 3
    Started
    5
    6
    4
    5
    Completed
    3
    4
    3
    2
    Not completed
    2
    2
    1
    3
         Adverse event, non-fatal
    -
    -
    -
    2
         Lost to follow-up
    1
    1
    -
    -
         failed to start treatment
    -
    -
    1
    1
         Lack of efficacy
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 standard care of topical clobetasol propionate 0.05% plus a short course of oral prednisolone. N.B Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon. This is in conjunction with an initial reducing course of oral prednisolone (20mg per day to reduce by 5mg per week over 4 weeks until stop (i.e. 20mg/day for 1 week, then 15mg/day for 1 week, then 10mg/day for 1 week, then 5mg/day for 1 week then stop)

    Reporting group title
    Research arm 1
    Reporting group description
    		 Oral hydroxychloroquine (up to 200mg twice daily) PLUS topical clobetasol propionate 0.05%% in the same regimen as in the control group. The exact dose will be decided by the treating physician according to clinical requirement. Oral hydroxychloroquine shoRuld be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group title
    Research arm 2
    Reporting group description
    		 Oral methotrexate (starting at 5mg weekly titrated upwards over 3-4 months to a ceiling dose of 25mg weekly) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral methotrexate should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group title
    Research arm 3
    Reporting group description
    		 Oral mycophenolate mofetil (starting at 500mg OD titrated upwards over 3-4 months to a ceiling dose of 3g/day) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral mycophenolate mofetil should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group values
    		 Control group Research arm 1 Research arm 2 Research arm 3 Total
    Number of subjects
    		 5 6 4 5 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 5 6 4 5 20
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 5 6 4 5 20
        Male
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 standard care of topical clobetasol propionate 0.05% plus a short course of oral prednisolone. N.B Topical clobetasol propionate 0.05% will be used once daily for one month, alternate days for 1 month then twice weekly thereon. This is in conjunction with an initial reducing course of oral prednisolone (20mg per day to reduce by 5mg per week over 4 weeks until stop (i.e. 20mg/day for 1 week, then 15mg/day for 1 week, then 10mg/day for 1 week, then 5mg/day for 1 week then stop)

    Reporting group title
    Research arm 1
    Reporting group description
    		 Oral hydroxychloroquine (up to 200mg twice daily) PLUS topical clobetasol propionate 0.05%% in the same regimen as in the control group. The exact dose will be decided by the treating physician according to clinical requirement. Oral hydroxychloroquine shoRuld be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group title
    Research arm 2
    Reporting group description
    		 Oral methotrexate (starting at 5mg weekly titrated upwards over 3-4 months to a ceiling dose of 25mg weekly) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral methotrexate should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group title
    Research arm 3
    Reporting group description
    		 Oral mycophenolate mofetil (starting at 500mg OD titrated upwards over 3-4 months to a ceiling dose of 3g/day) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral mycophenolate mofetil should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Primary: treatment success

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    End point title
    		 treatment success [1]
    End point description
    • Patient Global Assessment of disease severity of 0 or 1 on a 4-point scale
    End point type
    Primary
    End point timeframe
    6 months treatment period
    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: Number of recruits too low to warrant statistical analyses
    End point values
    		 Control group Research arm 1 Research arm 2 Research arm 3
    Number of subjects analysed
    5
    6
    4
    4
    Units: percent
        number (not applicable)
    5
    6
    3
    4
    No statistical analyses for this end point

    Secondary: Reduction in soreness

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    End point title
    		 Reduction in soreness
    End point description
    Numbers of participants who reported a reduction in skin soreness
    End point type
    Secondary
    End point timeframe
    Assessed at 6 months treatment
    End point values
    		 Control group Research arm 1 Research arm 2 Research arm 3
    Number of subjects analysed
    5
    6
    3
    4
    Units: whole numbers
    0
    1
    0
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants will be asked to contact the study site immediately in the event of any serious adverse event. All adverse events will be recorded and closely monitored until resolution, stabilisation, or until it has been shown that the study medication or
    Adverse event reporting additional description
    All serious adverse events will be recorded and reported to the MHRA and REC as part of the annual reports. SUSARs will be reported within the statutory timeframes to the MHRA and REC as stated below. The Chief Investigator shall be responsible for all adverse event reporting.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    		 All participants

    Reporting group title
    Research arm 2
    Reporting group description
    		 Oral methotrexate (starting at 5mg weekly titrated upwards over 3-4 months to a ceiling dose of 25mg weekly) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral methotrexate should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group title
    Research arm 1
    Reporting group description
    		 Oral hydroxychloroquine (up to 200mg twice daily) PLUS topical clobetasol propionate 0.05%% in the same regimen as in the control group. The exact dose will be decided by the treating physician according to clinical requirement. Oral hydroxychloroquine should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Reporting group title
    Research arm 3
    Reporting group description
    		 Oral mycophenolate mofetil (starting at 500mg OD titrated upwards over 3-4 months to a ceiling dose of 3g/day) PLUS topical clobetasol propionate 0.05% in the same regimen as in the control group. Oral mycophenolate mofetil should be used as per usual practice following national guidelines including appropriate safety monitoring.

    Serious adverse events
    		 Control Research arm 2 Research arm 1 Research arm 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Control Research arm 2 Research arm 1 Research arm 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
    Skin and subcutaneous tissue disorders
    Inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 4 (50.00%)
         occurrences all number
    4
    0
    6
    4

    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.
    Due to the small number of participants, clinical results are reported descriptively.
    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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