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    Clinical Trial Results:
    Reducing painful colonoscopies in women participating in a colorectal cancer screening program: A randomized controlled trial

    Summary
    EudraCT number
    		 2016-005090-13
    Trial protocol
    		 NO  
    Global end of trial date
    15 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Mar 2022
    First version publication date
    12 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    "Painstudy"1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01538550
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cancer Registry of Norway
    Sponsor organisation address
    P.O. box 5313 Majorstuen, Oslo, Norway, 0304
    Public contact
    Tarmkreftscreening, Cancer Registry of Norway, anna.schult@kreftregisteret.no
    Scientific contact
    Tarmkreftscreening, Cancer Registry of Norway, anna.schult@kreftregisteret.no
    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
    09 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the present trial is firstly to evaluate whether Fentanyl administrated prior to colonoscopy is associated with a lower risk of moderate or severe pain as compared to Fentanyl given on demand, to women undergoing colonoscopy; secondly to evaluate whether Rapifen on demand is associated with a lower risk of moderate or severe pain compared to Fentanyl given on demand, to women undergoing colonoscopy.
    Protection of trial subjects
    Adverse events occuring during colonoscopy or within 30 days after colonoscopy were registered and documented and reported to the Norwegian Medicines Agency and the regional ethical committee if appropriate. Events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). An endoscopy nurse were continously monitoring the patient and kept verbal contact with the patient. Oxygen saturation and heart rate were continously monitored and blood pressure was measured every 10th minute.
    Background therapy
    		 NA
    Evidence for comparator
    		 Strategies to prevent painful colonoscopies include amongst others improved medication strategy. A recent review of current sedation recommendations concluded that there is a lack of harmonisation regarding the recommended level of sedation and type of drugs. Sedation is associated with adverse events and may also influence the effect of screening because it hampers dynamic position change and thus may reduce the adenoma detection rate. Furthermore, sedation has been identified as a barrier to CRC screening, probably because healthy screenees do not accept potential risks and inconveniences of medication. If sedation-free colonoscopies are the standard, on-demand medication is commonly offered if pain occurs. Unsedated colonoscopy minimizes complications and costs and enables patients to return to normal daily activities immediately after the procedure. Studies comparing sedation on-demand medication to medication before colonoscopy are inconsistent. Targeted preemptive medication in individuals at high risk for pain like women might be more appropriate than medication prior to colonoscopy to everyone. Both fentanyl and alfentanil are well tolerated and commonly used during colonoscopies but Alfentanil has a superior pharmacodynamical profile for on-demand administration as it is more potent and has an extremely rapid onset of action. The present trial aimed to investigate whether fentanyl administered before colonoscopy in women is more effective in reducing the proportion of painful colonoscopies than fentanyl administered on-demand. Further, in an exploratory setting, we also investigated the effectiveness of a third strategy of analgesia, alfentanil on-demand. Fentanyl on-demand was the standard medication at the two participating units.
    Actual start date of recruitment
    12 Jun 2017
    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
    Norway: 539
    Worldwide total number of subjects
    539
    EEA total number of subjects
    539
    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)
    217
    From 65 to 84 years
    322
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 06/2017 to 05/2020, all women aged 55–79 years who were referred to colonoscopy in a Norwegian CRC screening trial after a positive screeningtest were eligible. To reach the required sample size, women of the same age scheduled for a clinical non-screening outpatient colonoscopy at the two centres were recruited from 05/2018.

    Pre-assignment
    Screening details
    		 1819 women were invited to participate. 568 consented and were randomised. After randomisation, 29 individuals were excluded (exclusion criteria were detected, consent was withdrawn, colonoscopy could not be carried out due to insufficient bowel cleaning). 539 participants were included in ITT analysis and 477 in per-protocol analysis.

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

    Arms
    Arm title
    		 all over
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 + 50 mcg initially, step-up with 50 mcg. Lower dose for those < 50 kg

    Investigational medicinal product name
    Alfentanil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.5 mg initially, step up with o.25 or 0.5 mg

    Number of subjects in period 1
    		all over
    Started
    539
    Completed
    539

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    all over
    Reporting group description
    		 -

    Reporting group values
    		 all over Total
    Number of subjects
    		 539 539
    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
    		 0 0
        85 years and over
    		 0 0
        55-79
    		 539 539
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.8 ± 6.0 -
    Gender categorical
    Units: Subjects
        Female
    		 539 539
        Male
    		 0 0
    Adequate bowel cleansing
    Units: Subjects
        Bowel cleansing
    		 539 539
    Expectation painful colonoscopy
    Units: Subjects
        Expect pain
    		 539 539
    Previous painful colonoscopy
    Units: Subjects
        Previous pain
    		 539 539
    Abdominal surgery
    Units: Subjects
        Surgery
    		 539 539
    Previous diverticulitis
    Units: Subjects
        Diverticulitis
    		 539 539
    IBS with pain
    Units: Subjects
        IBS
    		 539 539
    Heart rate
    Units: per minute
        arithmetic mean (standard deviation)
    		 ± -
    VAS before examination
    Pain score before
    Units: mm
        arithmetic mean (standard deviation)
    		 ± -
    BMI
    Bodymass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 ± -
    Oxygen saturation (pre-procedure)
    Units: percent
        arithmetic mean (standard deviation)
    		 ± -
    Subject analysis sets

    Subject analysis set title
    Fentanyl on-demand
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those randomised to Fentanyl on-demand

    Subject analysis set title
    Fentanyl prior
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those randomised to Fentanyl prior to colonoscopy

    Subject analysis set title
    Alfentanil on-demand
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    those randomised to Alfentanul on-demand

    Subject analysis sets values
    		 Fentanyl on-demand Fentanyl prior Alfentanil on-demand
    Number of subjects
    183
    177
    179
    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
        55-79
    183
    177
    179
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.8 ± 6.1
    66.7 ± 5.9
    67.1 ± 5.8
    Gender categorical
    Units: Subjects
        Female
    183
    177
    179
        Male
    Adequate bowel cleansing
    Units: Subjects
        Bowel cleansing
    165
    161
    162
    Expectation painful colonoscopy
    Units: Subjects
        Expect pain
    89
    88
    96
    Previous painful colonoscopy
    Units: Subjects
        Previous pain
    34
    44
    49
    Abdominal surgery
    Units: Subjects
        Surgery
    96
    91
    86
    Previous diverticulitis
    Units: Subjects
        Diverticulitis
    9
    12
    7
    IBS with pain
    Units: Subjects
        IBS
    12
    9
    14
    Heart rate
    Units: per minute
        arithmetic mean (standard deviation)
    75.8 ± 12.5
    74.9 ± 12.4
    75.0 ± 12.5
    VAS before examination
    Pain score before
    Units: mm
        arithmetic mean (standard deviation)
    0.5 ± 1.1
    0.3 ± 0.9
    0.3 ± 0.8
    BMI
    Bodymass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    26.0 ± 4.9
    26.5 ± 5.2
    26.4 ± 5.2
    Oxygen saturation (pre-procedure)
    Units: percent
        arithmetic mean (standard deviation)
    97.1 ± 1.8
    97.0 ± 1.7
    96.8 ± 2.0

    End points

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    End points reporting groups
    Reporting group title
    all over
    Reporting group description
    		 -

    Subject analysis set title
    Fentanyl on-demand
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those randomised to Fentanyl on-demand

    Subject analysis set title
    Fentanyl prior
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Those randomised to Fentanyl prior to colonoscopy

    Subject analysis set title
    Alfentanil on-demand
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    those randomised to Alfentanul on-demand

    Primary: Pain

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    End point title
    		 Pain
    End point description
    The primary endpoint was the proportion of women who experienced moderate or severe pain during colonoscopy, defined as painful colonoscopy, recorded within the Gastronet questionnaire the first post-colonoscopy day.
    End point type
    Primary
    End point timeframe
    Pain during colonoscopy
    End point values
    		 Fentanyl on-demand Fentanyl prior Alfentanil on-demand
    Number of subjects analysed
    161
    151
    162
    Units: number
        Painful colonoscopy
    71
    38
    64
    Attachments
    		 Untitled (Filename: Figure2_colour.tif)
    Statistical analysis title
    		 Pain comparison Fentanyl arms
    Comparison groups
    Fentanyl on-demand v Fentanyl prior
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Pain comparison on-demand
    Comparison groups
    Fentanyl on-demand v Alfentanil on-demand
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Willingness to repeat

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    End point title
    		 Willingness to repeat
    End point description
    Secondary endpoints were willingness to repeat the colonoscopy with identical procedural process
    End point type
    Secondary
    End point timeframe
    Asked the day after colonoscopy
    End point values
    		 Fentanyl on-demand Fentanyl prior Alfentanil on-demand
    Number of subjects analysed
    151
    157
    163
    Units: Number
        Willingness to repeat
    142
    151
    145
    Statistical analysis title
    		 Willingness to repeat Fentanyl arms
    Comparison groups
    Fentanyl on-demand v Fentanyl prior
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Willingness to repeat on demand arms
    Comparison groups
    Fentanyl on-demand v Alfentanil on-demand
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Serious adverse events

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    End point title
    		 Serious adverse events
    End point description
    Adverse events with impairment of vital parameters (i.e., systolic blood pressure <100 mmHg, heart rate <50 beats/minute, oxygen saturation <90% without oxygen supplement) were defined as serious adverse events.
    End point type
    Secondary
    End point timeframe
    During colonoscopy and within 30 days after
    End point values
    		 Fentanyl on-demand Fentanyl prior Alfentanil on-demand
    Number of subjects analysed
    183
    177
    179
    Units: Number
        Serious adverse events
    5
    6
    5
    Statistical analysis title
    		 SAE comparison Fentanyl arms
    Comparison groups
    Fentanyl on-demand v Fentanyl prior
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 SAE comparison on-demand groups
    Comparison groups
    Fentanyl on-demand v Alfentanil on-demand
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Cecum intubation rate

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    End point title
    		 Cecum intubation rate
    End point description
    Cecum intubation was defined as reaching the cecum with a CF colonoscope and without administration of benzodiazepine (midazolam) during the examination.
    End point type
    Secondary
    End point timeframe
    during colonoscopy
    End point values
    		 Fentanyl on-demand Fentanyl prior Alfentanil on-demand
    Number of subjects analysed
    179
    175
    176
    Units: Number
        Cecum intiubation rate
    159
    160
    166
    Statistical analysis title
    		 CIR comparison Fentanyl arms
    Comparison groups
    Fentanyl on-demand v Fentanyl prior
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 CIR comparison on-demand arms
    Comparison groups
    Fentanyl on-demand v Alfentanil on-demand
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.06
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Need for recovery

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    End point title
    		 Need for recovery
    End point description
    The proportion of participants who were not able to leave the endoscopy unit immediately after a colonoscopy.
    End point type
    Secondary
    End point timeframe
    At the day of colonoscopy
    End point values
    		 Fentanyl on-demand Fentanyl prior Alfentanil on-demand
    Number of subjects analysed
    155
    158
    164
    Units: Number
        Need for recovery
    52
    60
    46
    Attachments
    		 Untitled (Filename: Supplementary.docx)
    Statistical analysis title
    		 Comparison on-demand groups-need for recovery
    Comparison groups
    Alfentanil on-demand v Fentanyl on-demand
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Comparison Fentanyl groups-need for recovery
    Comparison groups
    Fentanyl on-demand v Fentanyl prior
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse event occured during colonoscopy or within 30 days after examination
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Adverse Evens- Fentanyl prior
    Reporting group description
    		 all adverse events, both defined as non-serious and serious

    Reporting group title
    Adverse events-Fentanyl on demand
    Reporting group description
    		 -

    Reporting group title
    Adverse events - Alfentanil on demand
    Reporting group description
    		 -

    Serious adverse events
    		 Adverse Evens- Fentanyl prior Adverse events-Fentanyl on demand Adverse events - Alfentanil on demand
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 183 (2.73%)
    6 / 177 (3.39%)
    5 / 179 (2.79%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Product issues
    SAEs related to analgesia
    Additional description: Systolic blood pressure < 100 mmHg and/or heart rate < 50 bpm and/or oxygen saturation < 90 % without supplemental oxygen
         subjects affected / exposed
    5 / 183 (2.73%)
    6 / 177 (3.39%)
    5 / 179 (2.79%)
         occurrences causally related to treatment / all
    5 / 5
    6 / 6
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adverse Evens- Fentanyl prior Adverse events-Fentanyl on demand Adverse events - Alfentanil on demand
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 183 (4.37%)
    15 / 177 (8.47%)
    11 / 179 (6.15%)
    Product issues
    AEs related to analgesia
    Additional description: Events requiring intravenous antiemetics, intravenous fluids, intravenous spasmolytics, elevating lower extremities.
         subjects affected / exposed
    8 / 183 (4.37%)
    15 / 177 (8.47%)
    11 / 179 (6.15%)
         occurrences all number
    8
    15
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2017
    Sample size increased to 480, admission from the reginal ethical committee and Norwegian Medicines Agency

    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/34534048
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