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    Clinical Trial Results:
    Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac Trial).

    Summary
    EudraCT number
    2013-002951-14
    Trial protocol
    GB  
    Global end of trial date
    17 Jan 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    12/0357
    Additional study identifiers
    ISRCTN number
    ISRCTN32729817
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    NIHR project number: 11/129/187, NIHR UKCRN identifier: 16857, IRAS identifier: 134697
    Sponsors
    Sponsor organisation name
    Comprehensive Clinical Trials Unit at UCL
    Sponsor organisation address
    Institute of Clinical Trials and Methodology, 90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.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
    19 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effectiveness of imiquimod 5% cream versus podophyllotoxin 0.15% cream in the treatment of external anogenital warts. The primary objective was to compare the proportions of participants receiving each treatment who have complete resolution of warts by 16 weeks and remain free of warts up to 48 weeks after starting treatment. To compare the effectiveness of a course of quadrivalent HPV (qHPV) vaccine started at the same time as topical wart treatment with the placebo, in improving wart clearance at 16 weeks and preventing recurrence up to 48 weeks.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, the Declaration of Helsinki (2008), the principles of Good Clinical Practice as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, and the National Health Service Research Governance Framework for Health and Social Care. Dose and frequency modifications of topical treatment in the event of an adverse event were permitted. Podophyllotoxin (PDX): deferred for one week (three days of treatment), then restarted with twice-daily dosing (three days consecutively and four days off treatment, in weekly cycles); deferred for one week, then restarted with once-daily dosing; if PDX was not tolerated at any dose, then PDX stopped and either cryotherapy (4 weeks’ post-randomisation) or imiquimod (after 16 weeks) given. Imiquimod (IMIQ): frequency of dosing reduced to twice a week; frequency of dosing reduced to once a week; if IMIQ was not tolerated at any dose, then IMIQ stopped and either cryotherapy (after 4 weeks) or PDX (after 16 weeks) given. Protocol pre-defined reasons for discontinuation of trial medication were in place in the event of participants experiencing: unacceptable treatment toxicity or adverse event; inter-current illness that prevents further treatment; withdrawal of consent for the treatment by the participant; pregnancy; suspected unexpected serious adverse reaction (SUSAR); any change in the participant’s condition that in the clinician’s opinion justifies the discontinuation of treatment; protocol violations; cure; administrative reasons or other reasons. All participants could choose to discontinue trial treatment at any time, without giving a reason, without penalty or loss of benefits to which they would otherwise be entitled. Investigation and treatment of adverse events were as per NHS standard of care.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 503
    Worldwide total number of subjects
    503
    EEA total number of subjects
    503
    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)
    503
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were recruited from 22 sexual health clinics in England and Wales with randomisations between 17 November 2014 and 06 January 2017. Participants were randomised (1:1) to IMIQ cream for up to 16 weeks or PDX cream for 4 weeks (up to 16 weeks), with simultaneous randomisation (1:1) to qHPV vaccine or saline control at 0, 8, 24 weeks.

    Pre-assignment
    Screening details
    Adult patients presenting to genitourinary medicine clinics with first or repeat episode of external anogenital warts diagnosed clinically, untreated in the last 3 months, and no prior qHPV vaccine, who are suitable for self-administered topical wart treatment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Topical treatments were unblinded due to differences in posology, dispensed in original packs. The qHPV vaccine and saline placebo were dispensed as prefilled syringes in blinded packaging (opaque plastic sleeve inside a labelled carton). It was not possible to source matching syringes for a fully blinded placebo so the injection was administered by a member of staff who was not part of the trial team involved in the assessment of the participant.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    IMIQ + qHPV
    Arm description
    Application of 5% imiquimod (IMIQ) cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours + quadrivalent human papillomavirus vaccine (qHPV) administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).
    Arm type
    Active comparator

    Investigational medicinal product name
    Imiquimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Application of 5% cream to wart area for three days of the week (every other day). The cream should be applied at bed time and left on overnight, then washed off after 6-10 hours.

    Investigational medicinal product name
    Quadrivalent human papillomavirus vaccine [types 6, 11, 16, 18]
    Investigational medicinal product code
    Other name
    Gardasil
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks); vaccine volume 0.5ml contains alum adjuvant.

    Arm title
    PDX + qHPV
    Arm description
    Podophyllotoxin (PDX) 0.15% cream applied to the lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles + quadrivalent human papillomavirus vaccine (qHPV) administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).
    Arm type
    Active comparator

    Investigational medicinal product name
    Podophyllotoxin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Application of 0.15% Podophyllotoxin (PDX) cream to lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles. The licensed duration is 4 weeks, but it is common practice to extend this period if there is a partial response to therapy.

    Investigational medicinal product name
    Quadrivalent human papillomavirus vaccine [types 6, 11, 16, 18]
    Investigational medicinal product code
    Other name
    Gardasil
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks); vaccine volume 0.5ml, contains alum adjuvant.

    Arm title
    IMIQ + placebo
    Arm description
    Application of 5% Imiquimod (IMIQ) cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours + saline placebo administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).
    Arm type
    Active comparator

    Investigational medicinal product name
    Imiquimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Application of 5% cream to wart area for three days of the week (every other day). The cream should be applied at bed time and left on overnight, then washed off after 6-10 hours.

    Investigational medicinal product name
    Sodium chloride 0.9%
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks); volume 0.5ml.

    Arm title
    PDX + placebo
    Arm description
    Application of 0.15% Podophyllotoxin (PDX) cream to lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles + saline placebo administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).
    Arm type
    Active comparator

    Investigational medicinal product name
    Podophyllotoxin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Application of 0.15% Podophyllotoxin (PDX) cream to lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles. The licensed duration is 4 weeks, but it is common practice to extend this period if there is a partial response to therapy.

    Investigational medicinal product name
    Sodium chloride 0.9%
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks); volume 0.5ml.

    Number of subjects in period 1
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo
    Started
    125
    126
    126
    126
    Week 16
    105
    106
    103
    103
    Week 48
    89
    88
    88
    87
    Completed
    89
    88
    88
    87
    Not completed
    36
    38
    38
    39
         Lost to follow-up
    36
    38
    38
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IMIQ + qHPV
    Reporting group description
    Application of 5% imiquimod (IMIQ) cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours + quadrivalent human papillomavirus vaccine (qHPV) administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group title
    PDX + qHPV
    Reporting group description
    Podophyllotoxin (PDX) 0.15% cream applied to the lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles + quadrivalent human papillomavirus vaccine (qHPV) administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group title
    IMIQ + placebo
    Reporting group description
    Application of 5% Imiquimod (IMIQ) cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours + saline placebo administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group title
    PDX + placebo
    Reporting group description
    Application of 0.15% Podophyllotoxin (PDX) cream to lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles + saline placebo administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo Total
    Number of subjects
    125 126 126 126 503
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31 ± 10 31 ± 10 32 ± 10 30 ± 10 -
    Gender categorical
    Units: Subjects
        Female
    42 42 43 43 170
        Male
    83 84 83 83 333
    Previous occurrence of warts
    Units: Subjects
        None
    63 63 63 63 252
        1 or more
    62 63 63 63 251
    HIV positive
    Units: Subjects
        Yes
    2 4 3 3 12
        No
    123 122 123 123 491
    Total number of warts
    Units: Subjects
        1-5 warts
    63 80 66 57 266
        6-10 warts
    26 23 38 32 119
        11-20 warts
    24 15 17 21 77
        >20 warts
    11 8 5 16 40
        Missing
    1 0 0 0 1
    Sexual orientation
    Units: Subjects
        Heterosexual
    104 102 102 102 410
        Homosexual
    15 20 16 16 67
        Bisexual
    5 4 8 8 25
        Other
    1 0 0 0 1
    Previous episode(s) of warts
    Units: Subjects
        Yes
    65 68 63 64 260
        No
    60 58 63 62 243
    Previous treatment for warts (in those with a previous episode)
    Units: Subjects
        Yes
    64 67 63 62 256
        No
    1 1 0 2 4
        Not applicable
    60 58 63 62 243
    Previous bivalent HPV vaccine
    Units: Subjects
        Yes
    10 12 8 13 43
        No
    115 114 118 110 457
        Not recorded
    0 0 0 3 3
    Smoking
    Units: Subjects
        Daily
    42 33 36 40 151
        Less than daily
    13 15 10 21 59
        Ex-smoker
    32 27 34 25 118
        Never smoked
    37 50 46 40 173
        Missing
    1 1 0 0 2
    Quality of Life reported
    Units: Subjects
        Yes
    110 116 119 110 455
        No
    15 10 7 16 48
    Attended at least one follow-up visit
    Units: Subjects
        Yes
    118 117 109 116 460
        No
    7 9 17 10 43
    Switched topical treatment at any time
    Units: Subjects
        Yes
    15 15 19 26 75
        No
    110 111 107 100 428
    Timing of first topical treatment switch
    Units: Subjects
        Before 4 weeks
    2 0 0 2 4
        4-16 weeks
    1 3 4 4 12
        After 16 weeks
    12 12 15 20 59
        Not applicable
    110 111 107 100 428
    Completed less than maximum licensed duration of topical treatment
    Units: Subjects
        Yes
    71 13 68 16 168
        No
    54 113 58 110 335
    Extended PDX beyond 4 weeks (PDX arms only)
    Units: Subjects
        Yes
    0 87 0 80 167
        No
    0 39 0 46 85
        Not applicable
    125 0 126 0 251
    Any cryotherapy received
    Units: Subjects
        Yes
    56 62 61 68 247
        No
    69 64 65 58 256
    Timing of first cryotherapy
    Units: Subjects
        Before 4 weeks
    0 1 1 2 4
        4-16 weeks
    17 24 9 22 72
        After 16 weeks
    39 37 51 44 171
        Not applicable
    69 64 65 58 256
    Received any other treatment at their treatment centre other than cryotherapy at any time
    Units: Subjects
        Yes
    5 4 4 9 22
        No
    120 122 122 117 481
    Received any treatment from a source outside their treatment centre
    Units: Subjects
        Yes
    5 5 5 6 21
        No
    120 121 121 120 482
    Number of vaccines given
    Units: Subjects
        None
    1 0 0 0 1
        1 dose
    11 13 7 15 46
        2 doses
    17 15 11 13 56
        3 doses
    89 89 91 88 357
        Not recorded
    7 9 17 10 43
    Reasons for withdrawal from topical treatment
    Units: Subjects
        Non-compliance
    0 0 0 1 1
        Pregnancy
    0 0 0 1 1
        Adverse reactions
    6 1 2 5 14
        Lost to follow-up
    19 19 21 19 78
        Other
    1 4 1 10 16
        Not applicable
    99 102 102 90 393
    Reasons for withdrawal from vaccine/placebo treatment
    Units: Subjects
        Pregnancy
    0 0 0 1 1
        Adverse reactions
    0 0 0 2 2
        Lost to follow-up
    19 19 22 19 79
        Other
    0 1 0 2 3
        Not applicable
    106 106 104 102 418
    Diameter of largest wart
    Units: mm
        median (inter-quartile range (Q1-Q3))
    3 (2 to 5) 3 (2 to 5) 3 (2 to 5) 3 (2 to 5) -
    Partners in the last 3 months
    Units: Number of partners
        median (inter-quartile range (Q1-Q3))
    1 (1 to 1) 1 (1 to 2) 1 (1 to 1) 1 (1 to 1) -
    Number of qHPV doses administered
    Units: Dose
        median (inter-quartile range (Q1-Q3))
    3 (3 to 3) 3 (2 to 3) 3 (3 to 3) 3 (3 to 3) -
    Number of STI episodes
    Units: episode
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1) 0 (0 to 1) 0 (0 to 1) 0 (0 to 1) -
    Quality of Life - EQ-5D-5L: Health Utility
    Units: health utility
        arithmetic mean (standard deviation)
    0.94 ± 0.11 0.92 ± 0.13 0.94 ± 0.10 0.92 ± 0.10 -
    Quality of Life - EQ-5D-5L: Visual analogue scale (VAS)
    Units: score out of 100
        arithmetic mean (standard deviation)
    83 ± 12 82 ± 13 82 ± 14 82 ± 15 -

    End points

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    End points reporting groups
    Reporting group title
    IMIQ + qHPV
    Reporting group description
    Application of 5% imiquimod (IMIQ) cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours + quadrivalent human papillomavirus vaccine (qHPV) administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group title
    PDX + qHPV
    Reporting group description
    Podophyllotoxin (PDX) 0.15% cream applied to the lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles + quadrivalent human papillomavirus vaccine (qHPV) administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group title
    IMIQ + placebo
    Reporting group description
    Application of 5% Imiquimod (IMIQ) cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours + saline placebo administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Reporting group title
    PDX + placebo
    Reporting group description
    Application of 0.15% Podophyllotoxin (PDX) cream to lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles + saline placebo administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks).

    Subject analysis set title
    IMIQ
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    This reporting group were randomised to receive Imiquimod, whether in combination with qHPV vaccine or placebo. Therefore, the included arms are IMIQ + qHPV and IMIQ + placebo.

    Subject analysis set title
    PDX
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    This reporting group were randomised to receive PDX, whether in combination with qHPV or placebo. Therefore, the included arms are PDX + qHPV and PDX + placebo.

    Subject analysis set title
    qHPV
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    This reporting group were randomised to receive qHPV vaccine, whether in combination with IMIQ or PDX topical treatment. Therefore, the included arms are IMIQ + qHPV and PDX + qHPV.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    This reporting group were randomised to receive placebo vaccine, whether in combination with IMIQ or PDX. Therefore, the included arms are IMIQ + placebo and PDX + placebo.

    Primary: Wart free at 16 weeks and remaining wart free between 16 and 48 weeks - Topical effect

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    End point title
    Wart free at 16 weeks and remaining wart free between 16 and 48 weeks - Topical effect
    End point description
    Proportion of participants who were wart free by 16 weeks, and who remained wart free to 48 weeks (no recurrences)
    End point type
    Primary
    End point timeframe
    Assessed from 16 to 48 weeks post-randomisation.
    End point values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo IMIQ PDX
    Number of subjects analysed
    101
    99
    98
    99
    199
    198
    Units: participants
        Achieved
    35
    38
    25
    30
    60
    68
        Not achieved
    66
    61
    73
    69
    139
    130
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Analysis carried out on multiply imputed data. The analysis for the trial treatment factors (vaccine and topical) are based on comparisons at the margins of the 2 x 2 table, meaning all participants randomised to PDX will be compared with all participants randomised to IMIQ, and all participants randomised to qHPV vaccine will be compared with all participants randomised to saline placebo.
    Comparison groups
    IMIQ v PDX
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.23
    Notes
    [1] - Reference group - PDX
    Statistical analysis title
    Complete case analysis
    Comparison groups
    IMIQ v PDX
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.27

    Primary: Wart free at 16 weeks and remaining wart free between 16 and 48 weeks - Vaccine effect

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    End point title
    Wart free at 16 weeks and remaining wart free between 16 and 48 weeks - Vaccine effect
    End point description
    Proportion of participants who were wart free by 16 weeks, and who remained wart free to 48 weeks.
    End point type
    Primary
    End point timeframe
    Assessed from 16 to 48 weeks post-randomisation
    End point values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo qHPV Placebo
    Number of subjects analysed
    101
    99
    98
    99
    200
    197
    Units: Subjects
        Achieved
    35
    38
    25
    30
    73
    55
        Not achieved
    66
    61
    73
    69
    127
    142
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Analysis carried out on multiply imputed data. The analysis for the trial treatment factors (vaccine and topical) are based on comparisons at the margins of the 2 x 2 table, meaning all participants randomised to PDX will be compared with all participants randomised to IMIQ, and all participants randomised to qHPV vaccine will be compared with all participants randomised to saline placebo.
    Comparison groups
    qHPV v Placebo
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    2.2
    Notes
    [2] - Reference group - Placebo
    Statistical analysis title
    Complete case analysis
    Comparison groups
    qHPV v Placebo
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    ≥ 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    2.41

    Secondary: Remaining wart free at 48 weeks after clearance at 16 weeks - Vaccine effect

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    End point title
    Remaining wart free at 48 weeks after clearance at 16 weeks - Vaccine effect
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed up to Week 48
    End point values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo qHPV Placebo
    Number of subjects analysed
    43
    53
    39
    42
    96
    81
    Units: Subjects
        Achieved
    35
    38
    25
    30
    73
    55
        Not achieved
    9
    15
    14
    12
    23
    26
    Statistical analysis title
    Primary analysis
    Comparison groups
    qHPV v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    2.63
    Notes
    [3] - Analysis carried out on multiply imputed data. The analysis for the trial treatment factors (vaccine and topical) are based on comparisons at the margins of the 2 x 2 table, meaning all participants randomised to PDX will be compared with all participants randomised to IMIQ, and all participants randomised to qHPV vaccine will be compared with all participants randomised to saline placebo.
    Statistical analysis title
    Complete case analysis
    Comparison groups
    qHPV v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    3.63

    Secondary: Remaining wart free at 48 weeks after clearance at 16 weeks - Topical effect

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    End point title
    Remaining wart free at 48 weeks after clearance at 16 weeks - Topical effect
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 48 weeks
    End point values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo IMIQ PDX
    Number of subjects analysed
    43
    53
    39
    42
    82
    95
    Units: Subjects
        Achieved
    35
    38
    25
    30
    60
    68
        Not achieved
    9
    15
    14
    12
    22
    27
    Statistical analysis title
    Primary analysis
    Comparison groups
    IMIQ v PDX
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.78
    Notes
    [4] - Reference group - PDX
    Statistical analysis title
    Complete case analysis
    Comparison groups
    IMIQ v PDX
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.95

    Secondary: Wart free at 16 weeks - Topical effect

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    End point title
    Wart free at 16 weeks - Topical effect
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 16 weeks
    End point values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo IMIQ PDX
    Number of subjects analysed
    104
    105
    103
    102
    207
    207
    Units: Subjects
        Achieved
    58
    70
    56
    57
    114
    127
        Not achieved
    46
    35
    47
    45
    93
    80
    Statistical analysis title
    Primary analysis
    Comparison groups
    IMIQ v PDX
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.14
    Notes
    [5] - Reference group - PDX
    Statistical analysis title
    Complete case analysis
    Comparison groups
    IMIQ v PDX
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.13

    Secondary: Wart free at 16 weeks - Vaccine effect

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    End point title
    Wart free at 16 weeks - Vaccine effect
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 16 weeks
    End point values
    IMIQ + qHPV PDX + qHPV IMIQ + placebo PDX + placebo qHPV Placebo
    Number of subjects analysed
    104
    105
    103
    102
    209
    205
    Units: Subjects
        Achieved
    58
    70
    56
    57
    128
    113
        Not acheived
    46
    35
    47
    45
    81
    92
    Statistical analysis title
    Primary analysis
    Comparison groups
    qHPV v Placebo
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.91
    Notes
    [6] - Reference group - Placebo
    Statistical analysis title
    Complete case analysis
    Comparison groups
    qHPV v Placebo
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Mixed models analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.95

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious adverse events (AEs) and adverse reactions (ARs) within 5 working days to the Sponsor (UCL CCTU). Serious AEs and serious ARs should be reported immediately to the Sponsor.
    Adverse event reporting additional description
    Do not include: -Local reactions to topical treatment/vaccinations -Medical or surgical procedures -Pre-existing disease/condition present before treatment that does not worsen -Hospitalisation where no untoward/unintended response has occurred -Medication overdose without signs/symptoms -Complications of standard therapy -Elective abortions
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Podophyllotoxin (PDX)
    Reporting group description
    Podophyllotoxin 0.15% cream applied to the lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles. The licensed treatment duration is 4 weeks, but it is common practice to extend this period if there is a partial response to therapy.

    Reporting group title
    Imiquimod (IMIQ)
    Reporting group description
    Application of 5% cream to wart area for three days of the week (every other day), for up to 16 weeks. Applied at bed time and left on overnight, then washed off after 6-10 hours.

    Reporting group title
    Quadrivalent human papillomavirus vaccine (qHPV)
    Reporting group description
    Administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks); vaccine volume 0.5ml; contains alum adjuvant.

    Reporting group title
    Saline (placebo)
    Reporting group description
    Administered at 0, 2, and 6 months (baseline, 8 weeks, 24 weeks); vaccine volume 0.5ml.

    Serious adverse events
    Podophyllotoxin (PDX) Imiquimod (IMIQ) Quadrivalent human papillomavirus vaccine (qHPV) Saline (placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 252 (3.97%)
    7 / 251 (2.79%)
    9 / 251 (3.59%)
    8 / 252 (3.17%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Surgical and medical procedures
    Myomectomy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal death
    Additional description: Miscarriage at 20 weeks (fetal death), grade 3.
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine infection
    Additional description: Grade 3.
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rupture of infected uterine fibroid
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Motorcycle accident
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Occipital neuralgia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulceration
    Additional description: Grade 3.
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Psychosis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyrotoxicosis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         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
    Podophyllotoxin (PDX) Imiquimod (IMIQ) Quadrivalent human papillomavirus vaccine (qHPV) Saline (placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 252 (40.48%)
    131 / 251 (52.19%)
    112 / 251 (44.62%)
    121 / 252 (48.02%)
    Vascular disorders
    Various vascular
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    1
    0
    General disorders and administration site conditions
    Various general
         subjects affected / exposed
    6 / 252 (2.38%)
    16 / 251 (6.37%)
    10 / 251 (3.98%)
    12 / 252 (4.76%)
         occurrences all number
    6
    16
    10
    12
    Psychiatric disorders
    Various psychiatric
         subjects affected / exposed
    6 / 252 (2.38%)
    0 / 251 (0.00%)
    5 / 251 (1.99%)
    1 / 252 (0.40%)
         occurrences all number
    6
    0
    5
    1
    Reproductive system and breast disorders
    Various reproductive & breast
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 251 (0.80%)
    2 / 251 (0.80%)
    2 / 252 (0.79%)
         occurrences all number
    2
    2
    2
    2
    Injury, poisoning and procedural complications
    Various injury
         subjects affected / exposed
    5 / 252 (1.98%)
    7 / 251 (2.79%)
    3 / 251 (1.20%)
    9 / 252 (3.57%)
         occurrences all number
    5
    7
    3
    9
    Investigations
    Various investigations
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 251 (0.40%)
    1 / 251 (0.40%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    1
    1
    Cardiac disorders
    Various cardiac
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Various respiratory, thoracic
         subjects affected / exposed
    6 / 252 (2.38%)
    5 / 251 (1.99%)
    4 / 251 (1.59%)
    7 / 252 (2.78%)
         occurrences all number
    6
    5
    4
    7
    Blood and lymphatic system disorders
    Various blood and lymphatic
         subjects affected / exposed
    3 / 252 (1.19%)
    1 / 251 (0.40%)
    3 / 251 (1.20%)
    1 / 252 (0.40%)
         occurrences all number
    3
    1
    3
    1
    Nervous system disorders
    Various nervous system
         subjects affected / exposed
    7 / 252 (2.78%)
    5 / 251 (1.99%)
    6 / 251 (2.39%)
    6 / 252 (2.38%)
         occurrences all number
    7
    5
    6
    6
    Eye disorders
    Various eye
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 251 (0.00%)
    2 / 251 (0.80%)
    1 / 252 (0.40%)
         occurrences all number
    3
    0
    2
    1
    Ear and labyrinth disorders
    Various ear and labyrinth
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    1 / 252 (0.40%)
         occurrences all number
    2
    0
    1
    1
    Gastrointestinal disorders
    Various GI
         subjects affected / exposed
    8 / 252 (3.17%)
    10 / 251 (3.98%)
    5 / 251 (1.99%)
    13 / 252 (5.16%)
         occurrences all number
    8
    10
    5
    13
    Renal and urinary disorders
    Various renal & urinary
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Various skin
         subjects affected / exposed
    23 / 252 (9.13%)
    45 / 251 (17.93%)
    29 / 251 (11.55%)
    39 / 252 (15.48%)
         occurrences all number
    23
    45
    29
    39
    Musculoskeletal and connective tissue disorders
    Various MSK
         subjects affected / exposed
    3 / 252 (1.19%)
    7 / 251 (2.79%)
    6 / 251 (2.39%)
    4 / 252 (1.59%)
         occurrences all number
    3
    7
    6
    4
    Metabolism and nutrition disorders
    Various metabolism & nutrition
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 251 (0.80%)
    2 / 251 (0.80%)
    1 / 252 (0.40%)
         occurrences all number
    1
    2
    2
    1
    Infections and infestations
    Various infections
         subjects affected / exposed
    23 / 252 (9.13%)
    28 / 251 (11.16%)
    29 / 251 (11.55%)
    22 / 252 (8.73%)
         occurrences all number
    23
    28
    29
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2014
    Substantial amendment 1 - Protocol version 3.0 dated 06 Mar 2014: 1) Removal of active placebo arm, trial design amended to 2x2 factorial design. 2) Vaccines will be supplied in single units. The use of a replenishment added. 3) Accountability of creams and vaccines has been revised to reflect ‘Risk-adapted approaches to the management of clinical trials of investigational medicinal products’ set out by the MHRA. 4) The labelling of creams has been updated in line with exemption of Regulation 46 of The Medicines for Human Use (Clinical Trials) Regulations 2004 SI 1031, subject to MHRA approval.
    23 May 2014
    Substantial amendment 2 - Protocol version 4.0 dated 13 May 2014: 1) Modified to reflect the use of a non-matching placebo injection syringe for approximately the first 250 vaccine/placebo injection doses and the change of UCL CTU to UCL CCTU. 2) The UCL Clinical Trials Unit has been re-named the UCL Comprehensive Clinical Trials Unit. The change of name has been amended throughout the protocol. 3) Removal of reference to ‘double blind’. 4) Clarification of labelling of topical treatments.
    30 Sep 2014
    Substantial amendment 4: Addition of a site.
    16 Oct 2014
    Substantial amendment 3: Updated SmPC for Gardasil.
    10 Nov 2014
    Substantial amendment 5: Addition of two sites.
    01 Dec 2014
    Substantial amendment 6: Addition of two sites.
    03 Feb 2015
    Substantial amendment 8: Addition of a site.
    06 Feb 2015
    Substantial amendment 7: Updated SmPC for Gardasil.
    25 Feb 2015
    Substantial amendment 9: Poster for use in sexual health clinics.
    03 Mar 2015
    Substantial amendment 10: Addition of two new sites; removal of one site.
    13 Apr 2015
    Substantial amendment 11: Updated SmPC for imiquimod.
    21 May 2015
    Substantial amendment 13: Addition of two new sites.
    09 Jun 2015
    Substantial amendment 12: Updated sIMPD to include glass syringes.
    16 Jun 2015
    Substantial amendment 14: Addition of a new site.
    04 Aug 2015
    Substantial amendment 16: Addition of a new site.
    10 Aug 2015
    Substantial amendment 17: Addition of a new site.
    14 Aug 2015
    Substantial amendment 15: Updated SmPC for Gardasil.
    29 Oct 2015
    Substantial amendment 19: 1) Use of poster (advertisement materials for research participants) in general practices. 2) Addition of Welsh sites and Welsh language provision. 3) Addition of three new sites.
    17 Nov 2015
    Substantial amendment 18: Updated SmPC for Warticon.
    24 Dec 2015
    Substantial amendment 20: Addition of three new sites.
    02 Mar 2016
    Substantial amendment 21 - Protocol version 5.0 dated 21 Dec 2015: 1. Inclusion of HIV-positive patients who are either on effective anti-retroviral therapy (ART) or have deferred ART, with a CD4 count of more than 500 2. The provision of more details of blood sampling (timing, volume of blood) for the peripheral blood mononuclear cells sub-study. Changes to protocol and patient information sheet. 3. Specification in the protocol of the timeframe of scheduled visits. 4. Clarification in the protocol of when cryotherapy can be used. 5. Consent form changes to request permission from HIV-positive patients to use HIV blood test results, and reformatting of the sections requiring only one answer (yes or no). 6. Inclusion of a text box on the poster for local site details. The poster without the text box will be made into flyers for distribution within recruiting clinics.
    21 Mar 2016
    Substantial amendment 22: Addition of three new sites.
    26 Apr 2016
    Substantial amendment 23: Addition of two new sites; change of PI at one site.
    24 Jun 2016
    Substantial amendment 24: Updated SmPC for Gardasil.
    26 Jun 2017
    Substantial amendment 25 - Protocol version 6.0 dated 04 May 2017: 1) the reduction of the sample size from 1000 to 500 participants and the addition of revised sample size calculations for the two components of the composite primary outcome as important secondary outcomes for each factor. 2) Clarification of the secondary outcomes. 3) Removal of reference to Stage 2 placebo syringe blinding, which will no longer be performed due to manufacturing issues.
    05 Jul 2017
    Substantial amendment 26: Letter for participants who miss scheduled trial visits to request follow-up information.
    06 Dec 2017
    Substantial amendment 27: 1) Pregnancy monitoring follow-up consent form and information sheet. 2) Six sites to be removed. 3) Change of principal investigator at two sites.

    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.
    Some baseline characteristics (sexual practices, current contraception, previous STIs, wart treatment for last episode, and position of warts were not included in the summary of results as the categories were not mutually exclusive.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30400777
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