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    Clinical Trial Results:
    Naloxegol and assessments of opioid induced bowel dysfunction

    Summary
    EudraCT number
    		 2015-000419-42
    Trial protocol
    		 DK  
    Global end of trial date
    18 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2021
    First version publication date
    07 May 2021
    Other versions
    Summary report(s)
    		 Final study report_Naloxegol

    Trial information

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    Trial identification
    Sponsor protocol code
    Nalogexol-2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mech-Sense, Aalborg University Hospital
    Sponsor organisation address
    Mølleparkvej 4, Aalborg, Denmark, 9000
    Public contact
    Mech-Sense, Mech-Sense, Aalborg University Hospital, 45 97663523, amd@rn.dk
    Scientific contact
    Mech-Sense, Mech-Sense, Aalborg University Hospital, 45 97663523, amd@rn.dk
    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
    21 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect on naloxegol on opioid induced bowel dysfunction (OIBD) using a compressive, objective design to explore motility, secretion and sphincter function
    Protection of trial subjects
    MR-scans rely on magnetism and are therefore harmless, as no radiation is involved. Subjects will fill out a form regarding metal implants/pacemaker/etc. with a medical doctor prior to the scanning. The FLIP procedure is previously approved (N-20090008) and does not constitute an actual risk but may be associated with some discomfort. The MTS-2 is not considered harmful, and its small size permits unhindered passage through the GI tract. However, it is not completely certain whether MR scanning of the healthy volunteers with the MTS-2 capsule remaining in the GI tract, will affect the magnetic capsule, the MR scanner or most importantly, the healthy volunteer in any way. Therefore, emphasis on precautions has been made to ensure that this does not happen. Prolonged release opioids within therapeutic doses are considered safe to use experimentally, but administration is associated with adverse effects. In the event that the adverse effects are too cumbrous for a subject, administering an antidote intravenously such as naloxone can effectively reverse the adverse effects. The potential risk of developing psychological dependence (substance dependence) manifested, as a morbid desire to consume opioids in order to achieve a specific psychological experience is highly improbable in therapeutic doses of prolonged release formulations. Therefore, healthy volunteers will be thoroughly screened and these factors are accounted for in exclusion criteria. All subjects are required to fill out a Subjective Opiate Withdrawal Scale (SOWS) questionnaire three days after receiving the last dose in all study periods to monitor whether any degree of dependence is developing.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2015
    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
    Denmark: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 25
    Intermediate milestone: Number of subjects
    Fulfilled in- and exclusion criteria: 25
    Intermediate milestone: Number of subjects
    Introduction to QST and FLIP: 25
    Number of subjects completed
    		 25

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oxycodone+Naloxegol
    Arm description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and active treatment (naloxegol)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oxycodone was administered as an orally ingested tablet with prolonged release. Oxycodone treatment commenced of 10 mg twice on day 1 (daily dose 20 mg). The following days (day 2-4) they received 15 mg oxycodone twice (daily dose 30 mg) to maintain a steady plasma concentration and to induce effects from prolonged opioid treatment (e.g. constipation). On day 6 they were treated with oxycodone 15 mg once (daily dose 15 mg).

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol was administered orally as film-coated tablets. Subjects were treated with naloxegol 25 mg once a day orally (day 2-6).

    Arm title
    		 Oxycodone+Placebo
    Arm description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and placebo matching naloxegol
    Arm type
    		 Placebo

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oxycodone was administered as an orally ingested tablet with prolonged release. Oxycodone treatment commenced of 10 mg twice on day 1 (daily dose 20 mg). The following days (day 2-4) they received 15 mg oxycodone twice (daily dose 30 mg) to maintain a steady plasma concentration and to induce effects from prolonged opioid treatment (e.g. constipation). On day 6 they were treated with oxycodone 15 mg once (daily dose 15 mg).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered orally as film-coated tablets. Subjects were treated with a placebo tablet once a day orally (day 2-6). Placebo tablets were similar to naloxegol tablets only excluding the active ingredient.

    Number of subjects in period 1
    		Oxycodone+Naloxegol Oxycodone+Placebo
    Started
    13
    12
    Colonic transit time (MTS-2)
    13
    12
    Completed
    13
    12
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oxycodone+Naloxegol
    Arm description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and active treatment (naloxegol)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oxycodone was administered as an orally ingested tablet with prolonged release. Oxycodone treatment commenced of 10 mg twice on day 1 (daily dose 20 mg). The following days (day 2-4) they received 15 mg oxycodone twice (daily dose 30 mg) to maintain a steady plasma concentration and to induce effects from prolonged opioid treatment (e.g. constipation). On day 6 they were treated with oxycodone 15 mg once (daily dose 15 mg).

    Investigational medicinal product name
    Naloxegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naloxegol was administered orally as film-coated tablets. Subjects were treated with naloxegol 25 mg once a day orally (day 2-6).

    Arm title
    		 Oxycodone+Placebo
    Arm description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and placebo matching naloxegol
    Arm type
    		 Placebo

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oxycodone was administered as an orally ingested tablet with prolonged release. Oxycodone treatment commenced of 10 mg twice on day 1 (daily dose 20 mg). The following days (day 2-4) they received 15 mg oxycodone twice (daily dose 30 mg) to maintain a steady plasma concentration and to induce effects from prolonged opioid treatment (e.g. constipation). On day 6 they were treated with oxycodone 15 mg once (daily dose 15 mg).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered orally as film-coated tablets. Subjects were treated with a placebo tablet once a day orally (day 2-6). Placebo tablets were similar to naloxegol tablets only excluding the active ingredient.

    Number of subjects in period 2
    		Oxycodone+Naloxegol Oxycodone+Placebo
    Started
    13
    12
    Colonic transit time (MTS-2)
    12
    12
    Completed
    12
    12
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 25 25
    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 (standard deviation)
    		 25.3 ( 6.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    Oxycodone+Naloxegol
    Reporting group description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and active treatment (naloxegol)

    Reporting group title
    Oxycodone+Placebo
    Reporting group description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and placebo matching naloxegol
    Reporting group title
    Oxycodone+Naloxegol
    Reporting group description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and active treatment (naloxegol)

    Reporting group title
    Oxycodone+Placebo
    Reporting group description
    		 Experimental model of opioid-induced bowel disorder (oxycodone) and placebo matching naloxegol

    Primary: Colorectal transit time in Naloxegol group vs. placebo

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    End point title
    		 Colorectal transit time in Naloxegol group vs. placebo
    End point description
    End point type
    Primary
    End point timeframe
    day 2
    End point values
    		 Oxycodone+Naloxegol Oxycodone+Placebo Oxycodone+Naloxegol Oxycodone+Placebo
    Number of subjects analysed
    12
    12
    12
    12
    Units: hours
        median (full range (min-max))
    45 (35.5 to 53)
    59.7 (52 to 68.3)
    45 (35.5 to 53)
    59.7 (52 to 68.3)
    Attachments
    		 Transit time Naloxegol vs. Placebo
    Statistical analysis title
    		 Wilcoxon signed rank sum test
    Statistical analysis description
    For transit time data, Wilcoxon signed rank sum test was used to compare total and segmental transit times during the two treatments.
    Comparison groups
    Oxycodone+Naloxegol v Oxycodone+Placebo v Oxycodone+Naloxegol v Oxycodone+Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - P-values less than 0.05 were considered statistically significant

    Primary: Total gastrointestinal transit time

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    End point title
    		 Total gastrointestinal transit time
    End point description
    End point type
    Primary
    End point timeframe
    day 2
    End point values
    		 Oxycodone+Naloxegol Oxycodone+Placebo Oxycodone+Naloxegol Oxycodone+Placebo
    Number of subjects analysed
    12
    12
    12
    12
    Units: hours
        median (full range (min-max))
    56.8 (48 to 65.7)
    71.3 (63 to 79.5)
    56.8 (48 to 65.7)
    71.3 (63 to 79.5)
    Attachments
    		 Transit time Naloxegol vs. Placebo
    Statistical analysis title
    		 Wilcoxon signed rank sum test
    Statistical analysis description
    For transit time data, Wilcoxon signed rank sum test was used to compare total and segmental transit times during the two treatments.
    Comparison groups
    Oxycodone+Naloxegol v Oxycodone+Placebo v Oxycodone+Naloxegol v Oxycodone+Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - P-values less than 0.05 were considered statistically significant

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of informed consent until three days after period 2 has been concluded.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Oxycodone+Naloxegol
    Reporting group description
    		 -

    Reporting group title
    Oxycodone + placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Oxycodone+Naloxegol Oxycodone + placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oxycodone+Naloxegol Oxycodone + placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 25 (96.00%)
    23 / 24 (95.83%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 25 (36.00%)
    14 / 24 (58.33%)
         occurrences all number
    9
    14
    Headache
         subjects affected / exposed
    10 / 25 (40.00%)
    10 / 24 (41.67%)
         occurrences all number
    10
    10
    Fatigue
         subjects affected / exposed
    16 / 25 (64.00%)
    17 / 24 (70.83%)
         occurrences all number
    16
    17
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    13 / 25 (52.00%)
    14 / 24 (58.33%)
         occurrences all number
    13
    14
    Nausea
         subjects affected / exposed
    10 / 25 (40.00%)
    15 / 24 (62.50%)
         occurrences all number
    10
    15
    Vomiting
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 24 (16.67%)
         occurrences all number
    3
    4
    Abdominal pain
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    Skin irritation
    Additional description: Skin itch
         subjects affected / exposed
    11 / 25 (44.00%)
    12 / 24 (50.00%)
         occurrences all number
    11
    12
    Metabolism and nutrition disorders
    Dry mouth
         subjects affected / exposed
    10 / 25 (40.00%)
    9 / 24 (37.50%)
         occurrences all number
    10
    9

    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.
    None reported
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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
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