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    Clinical Trial Results:
    Primary Imiquimod Treatment versus Surgery for Vulvar Intraepithelial Neoplasia: A Prospective Randomized Controlled Trial

    Summary
    EudraCT number
    		 2012-002052-17
    Trial protocol
    		 AT  
    Global end of trial date
    11 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2022
    First version publication date
    02 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PITVIN
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medizinische Universität Graz
    Sponsor organisation address
    Auenbruggerplatz 14, Graz, Austria, 8036
    Public contact
    Univ.- Frauenklinik Graz, Medizinische Universität Graz, 43 316385 12150, kks@medunigraz.at
    Scientific contact
    Univ.- Frauenklinik Graz, Medizinische Universität Graz, 43 316385 12150, kks@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
    04 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The present study aims to compare primary imiquimod treatment with the standard treatment (surgery) for treatment of VIN (complete clinical response).
    Protection of trial subjects
    Trial subjects will be invited for a clinical follow-up (medical history and clinical examination) Subjects will be identified with Study IDs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 110
    Worldwide total number of subjects
    110
    EEA total number of subjects
    110
    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)
    88
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 146 patients assessed for eligibility 36 excluded (16 did not meet inclusion criteria, 20 declined to participüate) 110 enrolled and randomly assigned

    Pre-assignment
    Screening details
    		 Patients with histologically confirmed vulvar HSIL

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imiquimod
    Arm description
    		 Topical treatment with Imiquimod
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imiquimod
    Investigational medicinal product code
    Other name
    Aldara
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Treatment with imiquimod was self-administered for a period of 4 months with possible extension to 6 months. Patients were handed a package of 5% imiquimod cream (Aldara®, Mylan) and received comprehensive oral and written instructions for usage. They were instructed to apply a thin layer of cream on the affected area remaining overnight without a cover in a slowly escalating dosage scheme: once a week for two weeks, twice a week the following two weeks, and if tolerated, 3 times a week for the last weeks

    Arm title
    		 Surgery
    Arm description
    		 Patients allocated to surgical treatment were informed about the surgical procedure at the study center, and written informed consent was obtained. The type of surgery, i.e. excision or ablation, was based on clinical findings and the surgeon`s judgement and was performed according to the standard procedures of the clinical trial site.
    Arm type
    		 Surgery

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Imiquimod Surgery
    Started
    56
    54
    Completed
    54
    53
    Not completed
    2
    1
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imiquimod
    Reporting group description
    		 Topical treatment with Imiquimod

    Reporting group title
    Surgery
    Reporting group description
    		 Patients allocated to surgical treatment were informed about the surgical procedure at the study center, and written informed consent was obtained. The type of surgery, i.e. excision or ablation, was based on clinical findings and the surgeon`s judgement and was performed according to the standard procedures of the clinical trial site.

    Reporting group values
    		 Imiquimod Surgery Total
    Number of subjects
    		 56 54 110
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 54.0 (44.0 to 67.0) 49.0 (43.0 to 60.0) -
    Gender categorical
    only female patients were included
    Units: Subjects
        Female
    		 56 54 110
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT analysis was performed in 107 patients (54 imiquimod, 53 surgery)

    Subject analysis set title
    Per-protocoll population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    98 patients completed the study per-protocol (46 imiquimod and 52 surgery)

    Subject analysis sets values
    		 Intention-to-treat population Per-protocoll population
    Number of subjects
    107
    98
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    51.0 (43.0 to 62.0)
    51.5 (44.0 to 62.0)
    Gender categorical
    only female patients were included
    Units: Subjects
        Female
    107
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Imiquimod
    Reporting group description
    		 Topical treatment with Imiquimod

    Reporting group title
    Surgery
    Reporting group description
    		 Patients allocated to surgical treatment were informed about the surgical procedure at the study center, and written informed consent was obtained. The type of surgery, i.e. excision or ablation, was based on clinical findings and the surgeon`s judgement and was performed according to the standard procedures of the clinical trial site.

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT analysis was performed in 107 patients (54 imiquimod, 53 surgery)

    Subject analysis set title
    Per-protocoll population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    98 patients completed the study per-protocol (46 imiquimod and 52 surgery)

    Primary: Complete clinical response

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    End point title
    		 Complete clinical response
    End point description
    Complete clinical response (CCR) was defined as no clinical evidence of vulvar lesion, meaning 100% reduction of primary lesion size after primary allocated study treatment (one surgical intervention or local imiquimod treatment up to 6 months). Clinical response was determined by clinical assessment and confirmed by control biopsy. In case of discrepancy between clinical evaluation and histology, the endpoint was adjusted according to the histological result.
    End point type
    Primary
    End point timeframe
    The primary endpoint was clinical response at 6 months.
    End point values
    		 Imiquimod Surgery Per-protocoll population
    Number of subjects analysed
    46
    52
    98
    Units: Number of patients
    37
    41
    98
    Statistical analysis title
    		 Primary outcome
    Statistical analysis description
    To evaluate the non-inferiority of imiquimod to surgical treatment, the difference in CCR proportions (surgical vs imiquimod) at 6 months and the corresponding 95% CIs were estimated with the Farrington-Manning method. Imiquimod was regarded as non-inferior if the upper bound of the CI did not exceed 20%. As a sensitivity analysis of the primary endpoint, we used the Cochran-Mantel-Haenszel method to adjust the proportion difference regarding the stratum used for randomisation.
    Comparison groups
    Imiquimod v Surgery
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0056
    Method
    		 Farrington-Manning Test
    Parameter type
    		 difference in proportion
    Point estimate
    0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.015
         upper limit
    		 0.018
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Imiquimod
    Reporting group description
    		 -

    Reporting group title
    Surgery
    Reporting group description
    		 -

    Serious adverse events
    		 Imiquimod Surgery
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 56 (7.14%)
    9 / 52 (17.31%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    3 / 56 (5.36%)
    9 / 52 (17.31%)
         occurrences causally related to treatment / all
    1 / 6
    4 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Imiquimod Surgery
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 56 (100.00%)
    52 / 52 (100.00%)
    Surgical and medical procedures
    Headache
         subjects affected / exposed
    28 / 56 (50.00%)
    12 / 52 (23.08%)
         occurrences all number
    28
    12
    Fatigue
         subjects affected / exposed
    30 / 56 (53.57%)
    15 / 52 (28.85%)
         occurrences all number
    30
    15
    Muscle discomfort
         subjects affected / exposed
    16 / 56 (28.57%)
    8 / 52 (15.38%)
         occurrences all number
    16
    8
    Vulvar erosion
         subjects affected / exposed
    17 / 56 (30.36%)
    14 / 52 (26.92%)
         occurrences all number
    17
    14
    Genital erythema
         subjects affected / exposed
    30 / 56 (53.57%)
    24 / 52 (46.15%)
         occurrences all number
    30
    24

    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.
    selection bias: only patients compliant with the study medication were included in the per-protocol analysis. Measurement bias: patients receiving imiquimod had on average more assessments

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35483400
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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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