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    Clinical Trial Results:
    A multi-center, randomized study on oral 8-methoxypsoralen plus UVA with or without maintenance therapy in mycosis fungoides EORTC/ISCL stage Ia to IIb.

    Summary
    EudraCT number
    		 2012-000212-28
    Trial protocol
    		 AT  
    Global end of trial date
    02 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M-PUVA2012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Graz
    Sponsor organisation address
    Auenbruggerplatz 8, Graz, Austria,
    Public contact
    Information Klinische Studie, Medical University of Graz, 43 316385 12538, dermatologie@medunigraz.at
    Scientific contact
    Information Klinische Studie, Medical University of Graz, 43 316385 12538, dermatologie@medunigraz.at
    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
    02 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether PUVA maintenance therapy does prolong disease free survival after initial complete response.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2012
    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
    Austria: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    18
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in April 2012. The last patient was enrolled in March 2016. Enrollment was closed in August 2016.

    Pre-assignment
    Screening details
    		 28 patients were assessed for eligibility. 1 patient was excluded due to an unconfirmed histologic diagnosis. 27 patients received induction treatment. Of these, 19....... patients reached complete remission and were randomised.

    Period 1
    Period 1 title
    Enrolment to randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Initial treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxsoralen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Initial treatment with a maximum duration of 24 weeks, depending on whether complete remission occurred

    Number of subjects in period 1
    		Initial treatment
    Started
    28
    Randomisation
    19
    Completed
    19
    Not completed
    9
         Screening failure
    1
         Adverse event, non-fatal
    1
         Non achievement of complete remission
    7
    Period 2
    Period 2 title
    Randomisation to complete follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance group
    Arm description
    		 Maintenance treatment was given once a week for one month (4 weeks), every 2 weeks for 2 months (8 weeks) and after three months once a month over 6 months. After 9 (10, 11, or 12) months of maintenance therapy (14 treatments) patients discontinued therapy. If PUVA treatment did lead to erythema during maintenance therapy, the dose for the next treatment was reduced by up to 30%.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxsoralen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Maintenance treatment was given once a week for one month (4 weeks), every 2 weeks for 2 months (8 weeks) and after three months once a month over 6 months. After 9 (10, 11, or 12) months of maintenance therapy (14 treatments) patients discontinued therapy. If PUVA treatment didlead to erythema during maintenance therapy, the dose for the next treatment was reduced by up to 30%.

    Arm title
    		 Control
    Arm description
    		 Patients received no therapy. Patients were followed up at the same intervals like patients in study arm A (maintenance).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Maintenance group Control
    Started
    11
    8
    Completed
    11
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enrolment to randomisation
    Reporting group description
    		 -

    Reporting group values
    		 Enrolment to randomisation Total
    Number of subjects
    		 28 28
    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)
    		 18 18
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        65-85 years
    		 10 10
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 22 22

    End points

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    End points reporting groups
    Reporting group title
    Initial treatment
    Reporting group description
    		 -
    Reporting group title
    Maintenance group
    Reporting group description
    		 Maintenance treatment was given once a week for one month (4 weeks), every 2 weeks for 2 months (8 weeks) and after three months once a month over 6 months. After 9 (10, 11, or 12) months of maintenance therapy (14 treatments) patients discontinued therapy. If PUVA treatment did lead to erythema during maintenance therapy, the dose for the next treatment was reduced by up to 30%.

    Reporting group title
    Control
    Reporting group description
    		 Patients received no therapy. Patients were followed up at the same intervals like patients in study arm A (maintenance).

    Subject analysis set title
    Mainentance group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Maintenance treatment was given once a week for one month (4 weeks), every 2 weeks for 2 months (8 weeks) and after three months once a month over 6 months. After 9 (10, 11, or 12) months of maintenance therapy (14 treatments) patients discontinued therapy.

    Subject analysis set title
    Control group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients received no therapy

    Primary: median time to recurrence after complete remission

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    End point title
    		 median time to recurrence after complete remission
    End point description
    The median duration of disease-free rremission was 15 months in patients with maintenance therapy compared with 4 months in those without it (p: 0.02)
    End point type
    Primary
    End point timeframe
    max. 12 months
    End point values
    		 Mainentance group Control group
    Number of subjects analysed
    10
    8
    Units: days
    10
    8
    Statistical analysis title
    		 Median duration of disease-free remission
    Comparison groups
    Mainentance group v Control group
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: Expression of Treg-related molecules in lesional tissue

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    End point title
    		 Expression of Treg-related molecules in lesional tissue
    End point description
    Expression of CD3 and CD4 mRNA was significantly lower than at baseline. The expression of CTLA-4, Foxp3, GITR and TGF-ß was quantified to characterize Tregs in skin and their change throughout treatment. In general, the expression of each of these markers was higher in lesional skin at baseline than in normal skin from donors. After 12 to 24 weeks, PUVA treatment significantly reduced the expression of these markers.
    End point type
    Secondary
    End point timeframe
    after 12 to 24 weeks of PUVA treatment
    End point values
    		 Initial treatment
    Number of subjects analysed
    28
    Units: Relative units
    28
    No statistical analyses for this end point

    Secondary: T-cell proliferative capacity

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    End point title
    		 T-cell proliferative capacity
    End point description
    Analysis of T-cell proliferative capacity in cells from blood at baseline and throughout treatment showed that PUVA therapy reduced the response to CD3/CD28 stimulation, reaching statistical significance after 12 to 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Start of induction phase until end of induction phase (12 to 24 weeks)
    End point values
    		 Initial treatment
    Number of subjects analysed
    28
    Units: Treg index
    28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of informed consent to end of follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Enrolled patients
    Reporting group description
    		 -

    Serious adverse events
    		 Enrolled patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 28 (7.14%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Melanoma
    Additional description: Melanoma in situ
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enrolled patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 28 (82.14%)
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    7 / 28 (25.00%)
         occurrences all number
    7
    Vertigo
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cephalalgia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Burning sensation skin
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Application site itching
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Urticaria
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Administration site erythema
         subjects affected / exposed
    12 / 28 (42.86%)
         occurrences all number
    13
    Skin lesion
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Increased serum creatinine
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 28 (3.57%)
         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
    30 Jan 2013
    Addition of two study sites
    03 May 2013
    Change of one principal investigator
    05 Aug 2013
    Change of one principal investigator
    10 Mar 2014
    Change of one principal investigator
    05 Jun 2014
    Possible prolongation of initial treatment phase from 3 to max. 6 months Change of one exclusion criterion Addition of the observatory arm for patients who did not response completely after initial therapy after the maximum treatment period Change of time period for taking of biopsies Additional amount of blood taken

    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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