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    Clinical Trial Results:
    A randomised, double-blind, parallel group study comparing patient controlled analgesia with Penthrox® (methoxyflurane) versus placebo during colonoscopy

    Summary
    EudraCT number
    		 2017-003767-35
    Trial protocol
    		 BG   FI   SE  
    Global end of trial date
    02 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2019
    First version publication date
    28 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MR311-3501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mundipharma Research Limited
    Sponsor organisation address
    Unit 194 Cambridge Science Park, Milton Road, Cambridge, United Kingdom, CB4 0AB
    Public contact
    Clinical Operations, Mundipharma Research Limited, +44 1223424900, clinicaltrials@mundipharma-rd.eu
    Scientific contact
    Clinical Operations, Mundipharma Research Limited, +44 1223424900, clinicaltrials@mundipharma-rd.eu
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate superiority in the efficacy of Penthrox (methoxyflurane) versus placebo based on mean pain profile during colonoscopy; a difference of 1.5 on the numerical rating scale (NRS) between the 2 groups was regarded as clinically meaningful.
    Protection of trial subjects
    This study was performed in full compliance with applicable Good Clinical Practice as required by Declaration of Helsinki, International Council for Harmonisation and local and national regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 May 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
    Sweden: 8
    Country: Number of subjects enrolled
    Bulgaria: 64
    Country: Number of subjects enrolled
    Finland: 14
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    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)
    63
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 5 centres across 3 countries between 21 May 2018 and 02 Jul 2018. Subjects who had been referred to colonoscopy for clinical indications or cancer screening were recruited.

    Pre-assignment
    Screening details
    		 A total of 86 subjects were randomised to 1 of 2 treatment groups in a 1:1 ratio. Randomisation was stratified according to indication for colonoscopy (clinical indication/cancer screening).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Penthrox
    Arm description
    		 Subjects received maximum of 6 millilitre (mL) Penthrox inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the Penthrox for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of Penthrox if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication [intravenous (IV) opioids] could also be administered if required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Penthrox
    Investigational medicinal product code
    Other name
    Methoxyflurane
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 3 mL Penthrox inhaler device was provided immediately prior to the start of the colonoscopy procedure on Day 1. A second loaded inhaler could be provided on the subject’s request when the first device was deemed to be empty.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received a maximum of 10 mL of placebo (matching with Penthrox) inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the placebo for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of placebo if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication (IV opioids) could also be administered if required.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Inhalation vapour, liquid
    Routes of administration
    Inhalation use
    Dosage and administration details
    A 5 mL saline placebo in a Penthrox inhaler device was provided immediately prior to the start of the colonoscopy procedure on Day 1. A second loaded inhaler could be provided on the subject’s request when the first device was deemed to be empty.

    Number of subjects in period 1
    		Penthrox Placebo
    Started
    42
    44
    Received treatment
    42
    44
    Intent-to-treat (ITT) population
    41 [1]
    44
    Completed
    42
    44
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The ITT population included all subjects in the enrolled set who were randomised to IMP.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Penthrox
    Reporting group description
    		 Subjects received maximum of 6 millilitre (mL) Penthrox inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the Penthrox for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of Penthrox if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication [intravenous (IV) opioids] could also be administered if required.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a maximum of 10 mL of placebo (matching with Penthrox) inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the placebo for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of placebo if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication (IV opioids) could also be administered if required.

    Reporting group values
    		 Penthrox Placebo Total
    Number of subjects
    		 42 44 86
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 34 29 63
        From 65-84 years
    		 8 15 23
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 23 26 49
        Male
    		 19 18 37

    End points

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    End points reporting groups
    Reporting group title
    Penthrox
    Reporting group description
    		 Subjects received maximum of 6 millilitre (mL) Penthrox inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the Penthrox for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of Penthrox if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication [intravenous (IV) opioids] could also be administered if required.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a maximum of 10 mL of placebo (matching with Penthrox) inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the placebo for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of placebo if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication (IV opioids) could also be administered if required.

    Primary: Mean Worst Pain Measured on NRS During Colonoscopy

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    End point title
    		 Mean Worst Pain Measured on NRS During Colonoscopy
    End point description
    Pain was assessed on the NRS from start of the colonoscopy to the time the endoscope reaches the caecum (way in), every 5 min after reaching the caecum (way out) and immediately after colonoscopy. The NRS is a 11 point scale, where subjects rated their worst pain from 0 (no pain) to 10 (pain as bad as you can imagine). The mean of the worst pain was calculated for the ITT population [ITT which included all subjects in the enrolled set who were randomised to investigational medicinal product (IMP)] and had data available for analysis.
    End point type
    Primary
    End point timeframe
    Every 2 minutes from start of colonoscopy procedure until the start of way-out, every 5 minutes after the start of way-out, and immediately after colonoscopy on Day 1.
    End point values
    		 Penthrox Placebo
    Number of subjects analysed
    41
    44
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.49 ± 1.635
    3.61 ± 1.134
    Statistical analysis title
    		 Treatment difference: Penthrox Vs Placebo
    Statistical analysis description
    The least square mean, 95% confidence interval (CI) and p-value from an analysis of covariance (ANCOVA) model with randomised treatment group and baseline NRS as fixed effects, centre and stratification factor as random effects.
    Comparison groups
    Penthrox v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 -0.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first inhalation of IMP until end of the study, approximately 15 to 18 days.
    Adverse event reporting additional description
    The safety population included all subjects in the ITT population who received at least one inhalation of IMP (whether before or during the colonoscopy procedure).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Penthrox
    Reporting group description
    		 Subjects received maximum of 6 mL Penthrox inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the Penthrox for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of Penthrox if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication (IV opioids) could also be administered if required.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received a maximum of 10 mL of placebo (matching with Penthrox) inhalation for the duration of the colonoscopy procedure. Subjects were instructed to inhale the placebo for approximately 2 minutes as a premedication in a stepwise fashion from shallow to deep breaths. During the colonoscopy the subject was instructed to inhale the lowest possible dose to provide adequate analgesia. In addition, they were instructed to inhale further doses of placebo if the colonoscopist anticipated a potential for discomfort during the procedure. Rescue medication (IV opioids) could also be administered if required.

    Serious adverse events
    		 Penthrox Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Penthrox Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 42 (26.19%)
    11 / 44 (25.00%)
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Tension headache
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 44 (4.55%)
         occurrences all number
    3
    2
    Diverticulum intestinal
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 44 (2.27%)
         occurrences all number
    3
    1
    Haemorrhoids
         subjects affected / exposed
    5 / 42 (11.90%)
    5 / 44 (11.36%)
         occurrences all number
    5
    5
    Diverticulum
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 44 (4.55%)
         occurrences all number
    2
    2
    Large intestine polyp
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    One randomised subject was not included in the ITT population due to significant potential bias on statistical reporting due to knowledge of the study.
    For support, Contact us.
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    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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