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    Clinical Trial Results:
    A randomised double blind, placebo controlled study of the efficacy of topical menthol for pain relief during topical photodynamic therapy.

    Summary
    EudraCT number
    		 2015-002849-59
    Trial protocol
    		 GB  
    Global end of trial date
    13 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Dec 2020
    First version publication date
    17 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2015PQ01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee
    Sponsor organisation address
    Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
    Public contact
    Professor Sally Ibbotson, University of Dundee, 1382383297 01382383297, s.h.ibbotson@dundee.ac.uk
    Scientific contact
    Professor Sally Ibbotson, University of Dundee, 1382383297 01382383297, s.h.ibbotson@dundee.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
    06 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Is the pain of topical photodynamic therapy (PDT) significantly different when using menthol in aqueous cream applied before PDT compared with PDT using only placebo (aqueous cream).
    Protection of trial subjects
    The objective of the study was to assess potential pain relief during standard PDT treatment. Potential participants received a participant information sheet, which detailed the requirements of the study before they attended clinic for screening. All participants had >24h to read the Participant information sheet and to discuss the study with family, friends, staff involved in the study. Written informed consent was obtained prior to any study specific procedures,
    Background therapy
    		 The background therapy was ALA photodynamic therapy used as standard routine practice for actinic keratoses of the face and scalp according to licensed practice.
    Evidence for comparator
    		 Cell and animal model data derived during our own pre-clinical studies indicated that menthol was likely to be effective for pain relief during PDT alone. The rationale for including the placebo was that we could not be sure that menthol would be effective for pain relief when used in humans. Wright et al., Pain. 2018 Feb;159(2):284-297. doi: 10.1097/j.pain.0000000000001096.
    Actual start date of recruitment
    29 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    0
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients referred to the photodynamic therapy clinic at Ninewells Hospital, UK with actinic keratoses on both sides of the face and scalp. First patient recruited 23.10.18 and last patient recruited 12.6.19

    Pre-assignment
    Screening details
    		 Patients >18 years with actinic keratoses on both sides of face and scalp and able to provide informed consent. 40 patients screened and 10 recruited. Patients not recruited declined because of extra time needed for study (4), requested alternative AK treatment (8), not meeting study criteria (5), unknown reasons (3).

    Pre-assignment period milestones
    Number of subjects started
    		 10
    Number of subjects completed
    		 10

    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, Data analyst, Assessor
    Blinding implementation details
    Assessors (Dermatologist, technologist, nurse, data analyst) were not aware of which side received which intervention. It is possible that patients (from sensation [cooling] of menthol) might not remain fully blinded. Patients were instructed not to tell those assessors if they suspected they knew which intervention was applied to each side. After treatment, patients were asked to provide an opinion as to which treatment was applied to each side. Menthol vapour in the room helped with blinding

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 5% menthol in aqueous cream
    Arm description
    		 5% menthol in aqueous cream (active IMP) applied to one half of face/scalp
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5% menthol in aqueous cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    5% W/W MENTHOL IN AQUEOUS CREAM applied to active site

    Arm title
    		 AQUEOUS CREAM
    Arm description
    		 Aqueous cream applied to other half of face/scalp
    Arm type
    		 Placebo

    Investigational medicinal product name
    aqueous cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    aqueous cream applied to placebo treated area

    Number of subjects in period 1
    		5% menthol in aqueous cream AQUEOUS CREAM
    Started
    10
    10
    Completed
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 10 patients recruited for this paired within subject comparison study and completed study - so 20 units of randomisation as 2 sites compared against each other within each suject

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 10 10
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 80 (69 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Pain of PDT - menthol treated side
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All 10 subjects with analysis of the within-subject comparison of the primary endpoint of pain immediately after PDT, comparing sides of face/scalp exposed to IMP or placebo - reporting on menthol exposed side

    Subject analysis set title
    Pain of PDT - placebo treated side
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo treated side reported on

    Subject analysis sets values
    		 Pain of PDT - menthol treated side Pain of PDT - placebo treated side
    Number of subjects
    10
    10
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    0
        From 65-84 years
    10
    10
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    1
    1
        Male
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    5% menthol in aqueous cream
    Reporting group description
    		 5% menthol in aqueous cream (active IMP) applied to one half of face/scalp

    Reporting group title
    AQUEOUS CREAM
    Reporting group description
    		 Aqueous cream applied to other half of face/scalp

    Subject analysis set title
    Pain of PDT - menthol treated side
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All 10 subjects with analysis of the within-subject comparison of the primary endpoint of pain immediately after PDT, comparing sides of face/scalp exposed to IMP or placebo - reporting on menthol exposed side

    Subject analysis set title
    Pain of PDT - placebo treated side
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo treated side reported on

    Primary: Pain immediately after PDT comparing IMP and placebo treated sides within subject

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    End point title
    		 Pain immediately after PDT comparing IMP and placebo treated sides within subject
    End point description
    Pain measured by VAS 0-10cm scale immediately after PDT comparing IMP and placebo treated sides
    End point type
    Primary
    End point timeframe
    Pain immediately after PDT
    End point values
    		 5% menthol in aqueous cream AQUEOUS CREAM
    Number of subjects analysed
    10
    10
    Units: VAS 0-10cm
        arithmetic mean (full range (min-max))
    6.58 (2 to 10)
    6.31 (2 to 10)
    Statistical analysis title
    		 paired T-test comparing IMP and placebo
    Statistical analysis description
    Paired T-test and associated methods to calculate confidence interval to compare VAS pain scores between IMP and placebo treated sides immediately after PDT
    Comparison groups
    AQUEOUS CREAM v 5% menthol in aqueous cream
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.82
    Variability estimate
    Standard deviation
    Dispersion value
    0.77
    Notes
    [1] - two-sided

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During IMP and placebo application
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2.1
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 Adverse events that may have related to IMP/placebo were documented. Other than minor headache in two patients, no other adverse events were observed. The inflammatory phototoxic insult of PDT is expected and was due to the expected effect of PDT itself.

    Serious adverse events
    		 All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    Nervous system disorders
    headache
    Additional description: mild headache in two patients, one reported over 6 days and one reported over 7 days. unlikely related to IMP/placebo.
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2019
    protocol amended dated 27th March 2019 version 6 - in order to include interim analysis of data in light of new information available regarding alternative less painful PDT treatments available for the condition under study. The approval dates for the interim analysis (AM03) are: 29/5/19 (REC) and 8/7/19 (MHRA)

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Sep 2019
    protocol amended dated 27th March 2019 version 6 - in order to include interim analysis of data in light of new information available regarding alternative less painful PDT treatments available for the condition under study - leading to interruption and premature discontinuation of study Dr Dawe, study statistician undertook interim analysis and recommended not continuing the study based on interim analysis, dated 6/9/19.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination of study meant small number of recruits and data for analysis. However, during the time of the study an alternative less painful daylight PDT became routinely and widely available

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29194091
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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