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    Clinical Trial Results:
    Squamous cell carcinoma prevention in organ transplant recipients using topical treatments: a feasibility study (SPOT)

    Summary
    EudraCT number
    		 2013-000893-32
    Trial protocol
    		 GB  
    Global end of trial date
    03 Jul 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Dec 2020
    First version publication date
    04 Sep 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    This update is to now include new data from the clinical photography sub study which contributes to exploratory outcome data, and some minor corrections to existing data after abnormalities were detected during publication writing. No changes impact critical data items or the primary outcome of the trial.
    Summary report(s)
    		 SPOT Public Summary for lay readers

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    008171BLT
    Additional study identifiers
    ISRCTN number
    		 ISRCTN26398197
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CRCTU Number: SK2007
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    Lower Ground Floor, 5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Mrs Yolande Jefferson-Hulme, Cancer Research UK Clinical Trials Unit (CRCTU), 44 0121 4143792, SPOT@trials.bham.ac.uk
    Scientific contact
    Mrs Yolande Jefferson-Hulme, Cancer Research UK Clinical Trials Unit (CRCTU), 44 0121 4143792, SPOT@trials.bham.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
    15 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cutaneous squamous cell carcinoma (cSCC) is economically a major burden to the NHS. The incidence is approximately 30,000 new cases per year in the UK. Immunosuppressed organ transplant recipients (OTR) have a more than 100-fold increased risk and an accelerated carcinogenic process, making them an ideal population in which to test interventions aimed at preventing cSCC. Premalignant lesions, termed actinic keratoses (AK), are present on sun-damaged skin and effective topical agents are available to treat them. The close relationship between AK and cSCC means that such topical treatment of a field bearing multiple AK should significantly reduce subsequent risk of developing cSCC, but this assumption has never been proven. The main objective of the trial is to determine the feasibility of performing a phase III RCT for either of the two interventions, whilst also assessing their activity.
    Protection of trial subjects
    The trial has been performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects, adopted by the 18th World Medical Association General Assembly, Helsinki, Finland, June 1964, amended at the 48th World Medical Association General Assembly, Somerset West, Republic of South Africa, October 1996 (see Appendix 5). The trial was conducted in accordance with the Research Governance Framework for Health and Social Care, the applicable UK Statutory Instruments, (which include the Medicines for Human Use Clinical Trials 2004 and subsequent amendments, the Data Protection Act 1998 and Human Tissue Act 2008) and the International Conference on Harmonisation Guidelines for GCP (ICH GCP). This trial was carried out under a Clinical Trial Authorisation in accordance with the Medicines for Human Use Clinical Trials regulations. The protocol was submitted to, and approved by, the REC prior to circulation. Before any patients were enrolled into the trial, the Principal Investigator at each site was required to obtain local R&D approval. Sites were not permitted to enrol patients until written confirmation of R&D approval was received by the SPOT Trial Office. It was the responsibility of the Principal Investigator to ensure that all subsequent amendments gained the necessary local approval. This was all done to protect the health and interest of individual patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first site was activated in December 2014 and the first patient was recruited on 10-Dec-2014. The last patient was recruited on 07-Sep-2016. The trial was closed to recruitment later that day. Recruitment to the ICP Arm closed in September 2015, with a total of 61 patients. Recruitment to the OTR arm reached 40 patients.

    Pre-assignment
    Screening details
    		 Screening procedures were undertaken for OTR who would potentially participate in the randomised trial and were performed 4-5 weeks before the treatment phase commenced.These included: Medical history Skin Exam Details of immunosuppressive treatment and previous treatment for AK Clinical assessment Punch Biopsy Vitamin D hCG Renal Function

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OTR : 5-Fluorouracil (with discretionary sunscreen)
    Arm description
    		 Treatment Cycle 1 5-fluorouracil 1-2x/day for 4 wks Four Weeks Rest Treatment Cycle 2 5-fluorouracil 1-2x/day for 4 wks Sunscreen as required throughout
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Marketing Authorisation: PL 46302/0128
    Other name
    Efudix 5% cream.
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Treatment Cycle 1 5-fluorouracil 1-2x/day for 4 weeks (elf-administered) Four Weeks Rest Treatment Cycle 2 5-fluorouracil 1-2x/day for 4 weeks (elf-administered) Sunscreen as required throughout

    Arm title
    		 OTR: 5% Imiquimod (with discretionary sunscreen)
    Arm description
    		 Treatment Cycle 1 Imiquimod 3-5x/wk for 4 wks Four Weeks Rest Treatment Cycle 2 Imiquimod 3-5x/wk for 4 wks Sunscreen as required throughout
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5% Imiquimod
    Investigational medicinal product code
    Marketing Authorisation: EU/1/98/080/001-002
    Other name
    ALDARA 5% cream
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Treatment Cycle 1 Imiquimod 3-5x/wk for 4 wks Four Weeks Rest Treatment Cycle 2 Imiquimod 3-5x/wk for 4 wks Sunscreen as required throughout

    Arm title
    		 OTR: Standard Care (discretionary sunscreen only)
    Arm description
    		 Sunscreen as required throughout
    Arm type
    		 Experimental

    Investigational medicinal product name
    Discretionary Sunscreen (Mixed Brands)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Sunscreen as required throughout

    Number of subjects in period 1
    		OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only)
    Started
    13
    14
    13
    Completed
    13
    14
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OTR : 5-Fluorouracil (with discretionary sunscreen)
    Reporting group description
    		 Treatment Cycle 1 5-fluorouracil 1-2x/day for 4 wks Four Weeks Rest Treatment Cycle 2 5-fluorouracil 1-2x/day for 4 wks Sunscreen as required throughout

    Reporting group title
    OTR: 5% Imiquimod (with discretionary sunscreen)
    Reporting group description
    		 Treatment Cycle 1 Imiquimod 3-5x/wk for 4 wks Four Weeks Rest Treatment Cycle 2 Imiquimod 3-5x/wk for 4 wks Sunscreen as required throughout

    Reporting group title
    OTR: Standard Care (discretionary sunscreen only)
    Reporting group description
    		 Sunscreen as required throughout

    Reporting group values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Total
    Number of subjects
    		 13 14 13 40
    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))
    		 64.82 (61.85 to 68.76) 66.36 (57.27 to 68.92) 65.59 (62.1 to 69.13) -
    Gender categorical
    Units: Subjects
        Female
    		 2 4 3 9
        Male
    		 11 10 10 31
    Gender
    Units: Subjects
        Male
    		 11 10 10 31
        Female
    		 2 4 3 9
    Stratification factor: Treatment zone
    Units: Subjects
        Head and neck
    		 7 7 6 20
        Acral
    		 6 7 7 20
    Patient currently taking Acitretin?
    Units: Subjects
        No
    		 7 12 12 31
        Yes
    		 6 2 1 9
    Previously diagnosed with skin cancer?
    Units: Subjects
        No
    		 2 4 3 9
        Yes
    		 11 9 10 30
        Not Supplied
    		 0 1 0 1
    Age (years)
    Units: --
        median (inter-quartile range (Q1-Q3))
    		 64.82 (61.85 to 68.76) 66.36 (57.27 to 68.92) 65.59 (62.10 to 69.13) -
    Vitamin D (nmol/L)
    Units: --
        median (inter-quartile range (Q1-Q3))
    		 48.00 (35.10 to 65.00) 60.50 (55.00 to 75.60) 49.00 (36.00 to 80.20) -
    Subject analysis sets

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total number of patients randomised in the trial

    Subject analysis sets values
    		 Full analysis
    Number of subjects
    40
    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))
    65.39 (58.52 to 69.02)
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    31
    Gender
    Units: Subjects
        Male
    31
        Female
    9
    Stratification factor: Treatment zone
    Units: Subjects
        Head and neck
    20
        Acral
    20
    Patient currently taking Acitretin?
    Units: Subjects
        No
    31
        Yes
    9
    Previously diagnosed with skin cancer?
    Units: Subjects
        No
    9
        Yes
    30
        Not Supplied
    1
    Age (years)
    Units: --
        median (inter-quartile range (Q1-Q3))
    65.39 (58.52 to 69.02)
    Vitamin D (nmol/L)
    Units: --
        median (inter-quartile range (Q1-Q3))
    55.00 (39.00 to 75.60)

    End points

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    End points reporting groups
    Reporting group title
    OTR : 5-Fluorouracil (with discretionary sunscreen)
    Reporting group description
    		 Treatment Cycle 1 5-fluorouracil 1-2x/day for 4 wks Four Weeks Rest Treatment Cycle 2 5-fluorouracil 1-2x/day for 4 wks Sunscreen as required throughout

    Reporting group title
    OTR: 5% Imiquimod (with discretionary sunscreen)
    Reporting group description
    		 Treatment Cycle 1 Imiquimod 3-5x/wk for 4 wks Four Weeks Rest Treatment Cycle 2 Imiquimod 3-5x/wk for 4 wks Sunscreen as required throughout

    Reporting group title
    OTR: Standard Care (discretionary sunscreen only)
    Reporting group description
    		 Sunscreen as required throughout

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total number of patients randomised in the trial

    Primary: The proportion of eligible patients willing to be randomised into the trial

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    End point title
    		 The proportion of eligible patients willing to be randomised into the trial [1]
    End point description
    End point type
    Primary
    End point timeframe
    Screening
    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: Analysis has already been provided, the proportion and 95% confidence intervals have been specified already
    End point values
    		 Full analysis
    Number of subjects analysed
    Units: percent
        number (confidence interval 95%)
    67 (55 to 77)
    No statistical analyses for this end point

    Primary: The proportion of patients who complete treatment Cycle 1, for each active treatment arm

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    End point title
    		 The proportion of patients who complete treatment Cycle 1, for each active treatment arm [2]
    End point description
    End point type
    Primary
    End point timeframe
    Cycle 1
    Notes
    [2] - 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: Analysis has already been provided, the proportion and 95% confidence intervals have been specified already
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only)
    Number of subjects analysed
    13
    14
    0 [3]
    Units: percent
        number (confidence interval 95%)
    85 (55 to 98)
    93 (66 to 100)
    ( to )
    Notes
    [3] - This arm did not have treatment cycles and therefore cannot be included in this analysis
    No statistical analyses for this end point

    Primary: The proportion of patients who require treatment Cycle 2 and complete it, for each active treatment arm

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    End point title
    		 The proportion of patients who require treatment Cycle 2 and complete it, for each active treatment arm [4]
    End point description
    End point type
    Primary
    End point timeframe
    Cycle 2
    Notes
    [4] - 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: Analysis has already been provided, the proportion and 95% confidence intervals have been specified already
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only)
    Number of subjects analysed
    12
    14
    0 [5]
    Units: percent
        number (confidence interval 95%)
    83 (52 to 98)
    93 (66 to 100)
    ( to )
    Notes
    [5] - This arm did not have treatment cycles and therefore cannot be included in this analysis
    No statistical analyses for this end point

    Primary: The proportion of patients who would be willing to use the treatment again

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    End point title
    		 The proportion of patients who would be willing to use the treatment again [6]
    End point description
    End point type
    Primary
    End point timeframe
    End of trial
    Notes
    [6] - 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: Analysis has already been provided, the proportion and 95% confidence intervals have been specified already
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Full analysis
    Number of subjects analysed
    11
    11
    9
    31
    Units: percent
        number (confidence interval 95%)
    73 (39 to 94)
    82 (48 to 98)
    89 (52 to 100)
    81 (63 to 93)
    No statistical analyses for this end point

    Secondary: Clearance of AK trial treatment field(s): defined as the proportion of patients which have had AKs identified at baseline that are no longer detectable at 4 weeks post treatment

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    End point title
    		 Clearance of AK trial treatment field(s): defined as the proportion of patients which have had AKs identified at baseline that are no longer detectable at 4 weeks post treatment
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks post treatment
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Full analysis
    Number of subjects analysed
    13
    14
    11
    38
    Units: percent
        number (confidence interval 95%)
    23 (5 to 54)
    14 (2 to 43)
    9 (0 to 41)
    16 (6 to 31)
    Statistical analysis title
    		 5-Fluorouracil vs. Standard Care Risk Difference
    Comparison groups
    OTR : 5-Fluorouracil (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.596
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.43
    Statistical analysis title
    		 5% Imiquimod vs. Standard Care Risk Difference
    Comparison groups
    OTR: Standard Care (discretionary sunscreen only) v OTR: 5% Imiquimod (with discretionary sunscreen)
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.3

    Secondary: Clearance of AK trial treatment field(s): defined as the proportion of patients which have had AKs identified at baseline that are no longer detectable at 8 weeks post treatment

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    End point title
    		 Clearance of AK trial treatment field(s): defined as the proportion of patients which have had AKs identified at baseline that are no longer detectable at 8 weeks post treatment
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks post treatment
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Full analysis
    Number of subjects analysed
    12
    14
    13
    39
    Units: percent
        number (confidence interval 95%)
    42 (15 to 72)
    14 (2 to 43)
    0 (0 to 25)
    18 (8 to 34)
    Statistical analysis title
    		 5-Fluorouracil vs. Standard Care Risk Difference
    Comparison groups
    OTR : 5-Fluorouracil (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.015
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.7
    Statistical analysis title
    		 5% Imiquimod vs. Standard Care Risk Difference
    Comparison groups
    OTR: Standard Care (discretionary sunscreen only) v OTR: 5% Imiquimod (with discretionary sunscreen)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.481
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.33

    Secondary: Persistence of AK clearance trial treatment field: defined as the proportion of patients (with 100% AK clearance) with AKs which were cleared at 4 weeks post treatment which remain undetectable at the completion of the 12 month follow-up period

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    End point title
    		 Persistence of AK clearance trial treatment field: defined as the proportion of patients (with 100% AK clearance) with AKs which were cleared at 4 weeks post treatment which remain undetectable at the completion of the 12 month follow-up period
    End point description
    It is not possible to present 5% Imiquimod (with discretionary sunscreen) (0/2) vs. Standard Care (discretionary sunscreen only) (0/3) due to both groups have 0 as the numerator.
    End point type
    Secondary
    End point timeframe
    12 month follow-up period
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Full analysis
    Number of subjects analysed
    3
    2
    1
    6
    Units: percent
        number (confidence interval 95%)
    0 (0 to 71)
    0 (0 to 84)
    0 (0 to 98)
    0 (0 to 46)
    No statistical analyses for this end point

    Secondary: Persistence of AK clearance trial treatment field: defined as the proportion of patients (with 100% AK clearance) with AKs which were cleared at 8 weeks post treatment which remain undetectable at the completion of the 12 month follow-up period

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    End point title
    		 Persistence of AK clearance trial treatment field: defined as the proportion of patients (with 100% AK clearance) with AKs which were cleared at 8 weeks post treatment which remain undetectable at the completion of the 12 month follow-up period
    End point description
    Risk difference was not calculable due to Standard Care (discretionary sunscreen only) having 0 patients who cleared at week 8, thus the proportion was 0/0.
    End point type
    Secondary
    End point timeframe
    12 months follow-up
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Full analysis
    Number of subjects analysed
    6
    2
    0 [7]
    8
    Units: percent
        number (confidence interval 95%)
    25 (1 to 81)
    50 (1 to 99)
    ( to )
    33 (4 to 78)
    Notes
    [7] - The proportion for this arm is 0/0
    No statistical analyses for this end point

    Secondary: Development of cSCC at 12 months post treatment

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    End point title
    		 Development of cSCC at 12 months post treatment
    End point description
    The 1 year event rates are presented here
    End point type
    Secondary
    End point timeframe
    Trial entry until 12 months follow-up
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) Full analysis
    Number of subjects analysed
    13
    14
    13
    40
    Units: percent
        number (confidence interval 95%)
    47 (25 to 77)
    50 (28 to 77)
    31 (13 to 63)
    37 (25 to 54)
    Statistical analysis title
    		 5-Fluorouracil vs.Standard Care
    Comparison groups
    OTR: Standard Care (discretionary sunscreen only) v OTR : 5-Fluorouracil (with discretionary sunscreen)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.52
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 5.39
    Statistical analysis title
    		 5% Imiquimod vs. Standard Care
    Comparison groups
    OTR: 5% Imiquimod (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.32
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 6.58

    Secondary: EQ5D Quality of Life

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    End point title
    		 EQ5D Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of trial follow-up
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only)
    Number of subjects analysed
    11
    13
    13
    Units: mean
    11
    13
    13
    Statistical analysis title
    		 5-Fluorouracil vs. Standard Care
    Statistical analysis description
    This is the model output for treatment from a multilevel mixed-effects model for EQ5D
    Comparison groups
    OTR : 5-Fluorouracil (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.675
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.077
         upper limit
    		 0.119
    Statistical analysis title
    		 5% Imiquimod vs. Standard Care
    Statistical analysis description
    This is the model output for treatment from a multilevel mixed-effects model for EQ5D
    Comparison groups
    OTR: Standard Care (discretionary sunscreen only) v OTR: 5% Imiquimod (with discretionary sunscreen)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.475
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.063
         upper limit
    		 0.134

    Secondary: DLQI Quality of Life

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    End point title
    		 DLQI Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of trial follow-up
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only)
    Number of subjects analysed
    11
    13
    13
    Units: Mean
    11
    13
    13
    Statistical analysis title
    		 5-Fluorouracil vs. Standard Care
    Comparison groups
    OTR : 5-Fluorouracil (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.778
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.787
         upper limit
    		 2.087
    Statistical analysis title
    		 5% Imiquimod vs. Standard Care
    Comparison groups
    OTR: 5% Imiquimod (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.282
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.302
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.071
         upper limit
    		 3.674

    Secondary: AK Index Quality of Life

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    End point title
    		 AK Index Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of trial follow-up
    End point values
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: 5% Imiquimod (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only)
    Number of subjects analysed
    10
    13
    11
    Units: Mean
    10
    13
    11
    Statistical analysis title
    		 5-Fluorouracil vs. Standard Care
    Comparison groups
    OTR : 5-Fluorouracil (with discretionary sunscreen) v OTR: Standard Care (discretionary sunscreen only)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.65
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.347
         upper limit
    		 8.326
    Statistical analysis title
    		 5% Imiquimod vs. Standard Care
    Comparison groups
    OTR: Standard Care (discretionary sunscreen only) v OTR: 5% Imiquimod (with discretionary sunscreen)
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.812
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.281
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.287
         upper limit
    		 11.849

    Other pre-specified: Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments : Cohen's kappa (k)

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    End point title
    		 Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments : Cohen's kappa (k)
    End point description
    Two sets of 10 photographs have been used in this analysis for a total of 20. The first set of 10 photographs were independently analysed by 2 observers (Charlotte Proby and Rubeta Matin) and each observer identified AKs on their photographs. This data was then collated by Zeeshaan Hasan for each observer, resulting in 2 separate tables with all of the AKs identified by each. Then the clinical data was matched with the AK data obtained from the photographic assessments, resulting in a matched table which illustrates the AK in the clinical data and its matched counterparts for both observers. This analysis was repeated for a second set of photographs. Concordance of clinical AK assessments with assessment obtained from the paired photographic evaluation was analysed using Cohen's kappa (k) for identification of individual AKs. Comparisons are between observer 1 = Charlotte Proby, observer 2 = Rubeta Matin and the clinical data.
    End point type
    Other pre-specified
    End point timeframe
    Two sets of 10 photographs have been used in this analysis
    End point values
    		 Full analysis
    Number of subjects analysed
    Units: concordance
    number (not applicable)
        First set: observer 1 vs. observer 2
    0.34
        Second set: observer 1 vs. observer 2
    0.57
        First set: observer 1 vs. clinical data
    0.00
        Second set: observer 1 vs. clinical data
    0.00
        First set: observer 2 vs. clinical data
    0.00
        Second set: observer 2 vs. clinical data
    0.00
    No statistical analyses for this end point

    Other pre-specified: Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments : ICC

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    End point title
    		 Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments : ICC
    End point description
    Two sets of 10 photographs have been used in this analysis for a total of 20. The first set of 10 photographs were independently analysed by 2 observers (Charlotte Proby and Rubeta Matin) and each observer identified AKs on their photographs. This data was then collated by Zeeshaan Hasan for each observer, resulting in 2 separate tables with all of the AKs identified by each. Then the clinical data was matched with the AK data obtained from the photographic assessments, resulting in a matched table which illustrates the AK in the clinical data and its matched counterparts for both observers. This analysis was repeated for a second set of photographs. Concordance of clinical AK assessments with assessment obtained from the paired photographic evaluation was analysed using intra-class correlation coefficient (ICC) for identification of total number of AKs. Comparisons are between observer 1 = Charlotte Proby, observer 2 = Rubeta Matin and the clinical data.
    End point type
    Other pre-specified
    End point timeframe
    Two sets of 10 photographs have been used in this analysis
    End point values
    		 Full analysis
    Number of subjects analysed
    8
    Units: concordance
    number (not applicable)
        First set: observer 1 vs. observer 2
    0.72
        Second set: observer 1 vs. observer 2
    0.79
        First set: observer 1 vs. clinical data
    0.02
        Second set: observer 1 vs. clinical data
    0.76
        First set: observer 2 vs. clinical data
    0.08
        Second set: observer 2 vs. clinical data
    0.66
        First set: all data
    0.36
        Second set: all data
    0.73
    No statistical analyses for this end point

    Other pre-specified: Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments : Kendall's

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    End point title
    		 Measure concordance of AK diagnosis by clinicians: defined as assessing the concordance of clinicians scores vs the scores from the paired photographic assessments : Kendall's
    End point description
    Two sets of 10 photographs have been used in this analysis for a total of 20. The first set of 10 photographs were independently analysed by 2 observers (Charlotte Proby and Rubeta Matin) and each observer identified AKs on their photographs. This data was then collated by Zeeshaan Hasan for each observer, resulting in 2 separate tables with all of the AKs identified by each. Then the clinical data was matched with the AK data obtained from the photographic assessments, resulting in a matched table which illustrates the AK in the clinical data and its matched counterparts for both observers. This analysis was repeated for a second set of photographs. Concordance of clinical AK assessments with assessment obtained from the paired photographic evaluation was analysed using Kendall's concordance correlation coefficient for comparing keratosis score. Comparisons are between observer 1 = Charlotte Proby, observer 2 = Rubeta Matin and the clinical data.
    End point type
    Other pre-specified
    End point timeframe
    Two sets of 10 photographs have been used in this analysis
    End point values
    		 Full analysis
    Number of subjects analysed
    8
    Units: Concordance
    number (not applicable)
        First set: observer 1 vs. observer 2
    0.53
        Second set: observer 1 vs. observer 2
    0.56
        First set: observer 1 vs. clinical data
    0.45
        Second set: observer 1 vs. clinical data
    0.39
        First set: observer 2 vs. clinical data
    0.44
        Second set: observer 2 vs. clinical data
    0.35
        First set: all data
    0.37
        Second set: all data
    0.33
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting was from commencement of treatment to 30 days after completion of trial treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    OTR : 5-Fluorouracil (with discretionary sunscreen)
    Reporting group description
    		 Treatment Cycle 1 5-fluorouracil 1-2x/day for 4 wks Four Weeks Rest Treatment Cycle 2 5-fluorouracil 1-2x/day for 4 wks Sunscreen as required throughout

    Reporting group title
    OTR: Standard Care (discretionary sunscreen only)
    Reporting group description
    		 Sunscreen as required throughout

    Reporting group title
    OTR: 5% Imiquimod (with discretionary sunscreen)
    Reporting group description
    		 Treatment Cycle 1 Imiquimod 3-5x/wk for 4 wks Four Weeks Rest Treatment Cycle 2 Imiquimod 3-5x/wk for 4 wks Sunscreen as required throughout

    Serious adverse events
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) OTR: 5% Imiquimod (with discretionary sunscreen)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Neuropathic pain (R foot)
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 OTR : 5-Fluorouracil (with discretionary sunscreen) OTR: Standard Care (discretionary sunscreen only) OTR: 5% Imiquimod (with discretionary sunscreen)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 13 (61.54%)
    3 / 13 (23.08%)
    11 / 14 (78.57%)
    Vascular disorders
    Bruising
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Chest pain - cardiac
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 13 (7.69%)
    4 / 14 (28.57%)
         occurrences all number
    5
    2
    7
    Flu like symptoms
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    1
    0
    4
    Malaise
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 13 (7.69%)
    2 / 14 (14.29%)
         occurrences all number
    2
    1
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    External ear inflammation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    2 / 14 (14.29%)
         occurrences all number
    0
    1
    2
    Nausea
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 13 (15.38%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    2
    Vomiting
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Photosensitivity
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    7 / 13 (53.85%)
    1 / 13 (7.69%)
    3 / 14 (21.43%)
         occurrences all number
    11
    1
    4
    Skin hypopigmentation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 13 (7.69%)
    2 / 14 (14.29%)
         occurrences all number
    2
    2
    2
    Bone pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    1
    Soft tissue injury
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    Crystal arthropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    R foot pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2013
    Substantial amendment: Protocol Update -Addition of “or intolerance” to exclusion criteria regarding trial medication - Change to recruitment and follow up duration - Other minor amendments & corrections
    09 Dec 2016
    Substantial amendment: Protocol Update -Updated Section 6.1 randomisation method -Updated section 5.1.1: clarify that biopsies can be taken from inside or outside the treatment area -Updated section 7.6 to remove reference to Reference Safety Information (RSI) and replace with Summary of Product Characteristics (SPC). -Updated Section 7.3.4 to incorporate guidance from SPC relating to avoidance of exposure to UV radiation -Updated section 6.2, Section 7.5.2 to clarify that photocopies of the transparencies form part of the CRF -Updated Sponsor and Trial Staff contact details -Other minor amendments & corrections

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29782648
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