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    Clinical Trial Results:
    A randomised, double-blind, double-dummy, parallel-group multicenter study to demonstrate improvement in symptoms of constipation and non-inferiority in analgesic efficacy in subjects with non-malignant or malignant pain that requires around-the-clock opioid therapy taking 50/25-80/40 mg twice daily as oxycodone/naloxone prolonged release (OXN PR) tablets compared to subjects taking 50-80 mg twice daily oxycodone prolonged release (OxyPR) tablets alone.

    Summary
    EudraCT number
    		 2010-021995-27
    Trial protocol
    		 GB   CZ   DE   FI   DK   RO  
    Global end of trial date
    10 Feb 2014

    Results information
    Results version number
    		 v1
    This version publication date
    09 Feb 2016
    First version publication date
    12 Aug 2015
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    OXN3506
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01438567
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mundipharma Research GmbH & Co. KG
    Sponsor organisation address
    Höhenstrasse 10, Limburg, Germany, D-65549
    Public contact
    Clinical Trial Contact, Mundipharma Research GmbH & Co. KG, 0049 6431701453, info@contact-clinical-trial.com
    Scientific contact
    Clinical Trial Contact, Mundipharma Research GmbH & Co. KG, 0049 6431701453, info@contact-clinical-trial.com
    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
    10 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To demonstrate that subjects taking OXN PR have improvement in symptoms of constipation as measured by the Bowel Function Index (BFI) compared to subjects taking OxyPR. 2. To demonstrate non-inferiority of OXN PR compared to OxyPR with respect to the analgesic efficacy based on the subjects' "Average Pain over last 24 Hours" assessed at each Double-blind Phase visit as measured by the Pain Intensity Scale.
    Protection of trial subjects
    The approved dose range of OXN PR is up to OXN80/40 mg PR per day, which is sufficient to manage a significant segment of the population of patients with severe pain. However, it is evident that there is a need of OXN PR daily doses higher than 80/40 mg. Currently, in the OXN PR SmPC allowance for this situation is made by the compromise that “for patients requiring higher doses of OXN PR, administration of supplemental oxycodone at the same time interval should be considered taking into account the maximum daily dose of 400 mg oxycodone PR”. However it is to be considered that in the case of supplemental oxycodone dosing the beneficial effect of naloxone on the bowel function may be impaired as also outlined in the current SmPC. Consequently, patients in need of higher doses would clearly benefit from the maintenance of the 2:1 ratio in doses beyond OXN80/40 mg PR per day. Based on the available data, there is accumulating evidence that OXN PR is efficacious and generally well tolerated in doses up to OXN160/80 mg PR per day. Therefore it can be assumed that OXN PR can be used safely in patients requiring daily doses above OXN 80/40 mg PR per day and the administration of daily dose up to OXN180/90 mg PR in study OXN3506 does not add any risk to the subjects. OxyIR was the only allowed analgesic rescue medication. It was to be dosed no sooner than every 4 hours as needed. Six rescue doses of OxyIR was the total maximum amount of analgesic rescue medication per day. For a subject stabilised on 50 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 15 mg; for a subject stabilised on 60 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 20 mg; for a subject stabilised on 70 or 80 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 25 mg.
    Background therapy
    		 Oxycodone immediate-release (IR) capsules (5, 10, 20 mg) was the only allowed analgesic rescue medication. It was to be dosed no sooner than every 4 hours as needed. Six rescue doses of OxyIR was the total maximum amount of analgesic rescue medication per day. For a subject stabilised on 50 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 15 mg; for a subject stabilised on 60 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 20 mg; for a subject stabilised on 70 or 80 mg of OXN PR or OxyPR twice daily, the rescue dose of OxyIR would have been 25 mg.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Aug 2011
    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
    Australia: 4
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Poland: 55
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Czech Republic: 62
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 69
    Worldwide total number of subjects
    243
    EEA total number of subjects
    238
    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)
    181
    From 65 to 84 years
    60
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 363 subjects were enrolled, of whom 44 (12.1%) subjects were screening failures. The most frequently named reason for screening failure was failing of screening procedures in 25 subjects (6.9%). Adverse events led to the screening failure of 8 subjects (2.2%) and serious adverse events caused 3 screening failures (0.8%).

    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, Carer, Assessor
    Blinding implementation details
    During the Double-blind Phase, the subject and all personnel involved with the conduct and the interpretation of the study, including the investigators, site personnel, and the Sponsor’s staff, were blinded to the medication codes. The randomisation schedule was filed securely by the Sponsor/IRT provider, in a manner such that blinding was properly maintained throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oxycodone-naloxone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone-naloxone
    Investigational medicinal product code
    OXN
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10/5, 20/10, and 40/20 mg OXN PR tablets administered 12 -hourly to give the following dose levels: OXN 50/25 mg PR, OXN 60/30 mg PR, OXN 70/35 mg PR and OXN 80/40 mg PR twice daily

    Arm title
    		 Oxycodone
    Arm description
    		 Oxycodone prolonged-release
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    OXY
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10, 20, and 40 mg OxyPR tablets plus matching placebos for 10/5, 20/10 and 40/20 mg OXN PR tablets to give dose levels of: OxyPR 50 mg, OxyPR 60 mg, OxyPR 70 mg and OxyPR 80 mg twice daily.

    Number of subjects in period 1
    		Oxycodone-naloxone Oxycodone
    Started
    123
    120
    Completed
    105
    104
    Not completed
    18
    16
         Adverse event, serious fatal
    1
    3
         Consent withdrawn by subject
    6
    8
         Administrative
    -
    2
         Adverse event, non-fatal
    8
    2
         Not specified
    1
    -
         Lack of efficacy
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 This study was composed of three phases: a Pre-randomisation Phase, a Double-blind Phase and an Extension Phase. The Pre-randomisation Phase contained two periods: the Screening Period and the Run-in Period. The Screening Period involved prospective assessments and was designed to qualify subjects for participation in the Run-in Period. The Run-in Period was designed to titrate OxyPR to analgesic effect, qualify subjects for participation in the Double-blind Phase, e.g. confirm their constipation, and enable identification of a starting dose equivalent for the study medication to be used after randomisation. The Double-blind Phase was designed to demonstrate improvement in symptoms of constipation and non-inferiority in analgesic efficacy from OXN PR compared to subjects taking OxyPR tablets alone. This is the analysis of the core study, which summarises the results of the Pre-randomisation Phase and the Double-blind Phase.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 243 243
    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)
    		 181 181
        From 65-84 years
    		 60 60
        85 years and over
    		 2 2
    Gender categorical
    Units: Subjects
        Female
    		 143 143
        Male
    		 100 100
    Subject analysis sets

    Subject analysis set title
    Full analysis population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomised and received at least one dose of study medication during the Double-blind Phase and who had at least a one week Double-blind assessment of the primary efficacy variable, the BFI.

    Subject analysis set title
    Double-blind safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least one dose of Double-blind study medication and had at least one safety assessment after that dose.

    Subject analysis set title
    Per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who received at least 4 weeks study medication during the Double-blind Phase and who sufficiently complied with the study protocol.

    Subject analysis sets values
    		 Full analysis population Double-blind safety population Per-protocol population
    Number of subjects
    237
    243
    192
    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)
    178
    181
        From 65-84 years
    57
    60
        85 years and over
    2
    2
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    143
        Male
    100

    End points

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    End points reporting groups
    Reporting group title
    Oxycodone-naloxone
    Reporting group description
    		 -

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone prolonged-release

    Subject analysis set title
    Full analysis population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomised and received at least one dose of study medication during the Double-blind Phase and who had at least a one week Double-blind assessment of the primary efficacy variable, the BFI.

    Subject analysis set title
    Double-blind safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least one dose of Double-blind study medication and had at least one safety assessment after that dose.

    Subject analysis set title
    Per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who received at least 4 weeks study medication during the Double-blind Phase and who sufficiently complied with the study protocol.

    Primary: Improvement in Bowel Function Index

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    End point title
    		 Improvement in Bowel Function Index
    End point description
    The BFI is a 3-term questionnaire to measure constipation from the patient’s perspective. Study personnel asked the subject to rate ease of defecation, feeling of incomplete bowel evacuation and personal judgment of constipation in the last 7 days on a scale of 0 to 100, with lower numbers representing good and higher numbers representing poor bowel function. The BFI was assessed on Visit 1, 2 and 3 in the pre-randomisation Phase and on Visit 7,-10 in the Double-blind Phase.
    End point type
    Primary
    End point timeframe
    From baseline at start of double-blind phase (Visit 3) to 5 weeks.
    End point values
    		 Oxycodone-naloxone Oxycodone Full analysis population
    Number of subjects analysed
    104
    101
    205
    Units: Units
        arithmetic mean (standard deviation)
    -32.5 ± 26.96
    -14.2 ± 22.65
    -23.5 ± 26.52
    Statistical analysis title
    		 Superiority of OXN vs oxycodone (BFI improvement)
    Statistical analysis description
    The objective of the analysis of BFI was to show that OXN PR is superior to OxyPR, using a one-tailed test at a 2.5% significance level. The null hypothesis was that there is no difference between the treatment groups. The alternative hypothesis was that there is a difference between the treatment groups. A mixed model epeated measures analysis of covariance of the BFI was carried out for Weeks 1, 2, 4 and 5 as repeated measures.
    Comparison groups
    Oxycodone-naloxone v Oxycodone
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 Repeated measures analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.23
         upper limit
    		 -9.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.14
    Notes
    [1] - Full analysis population was used for this analysis.

    Primary: Non-inferiority of OXN vs oxycodone (Average 24 hour pain)

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    End point title
    		 Non-inferiority of OXN vs oxycodone (Average 24 hour pain)
    End point description
    The subjects’ average pain over the last 24 hours as measured by the Pain Intensity Scale (NRS 0-10), with 0 meaning no pain and 10 meaning worst imaginable pain.
    End point type
    Primary
    End point timeframe
    Average pain over the last 24 hours at Week 5.
    End point values
    		 Oxycodone-naloxone Oxycodone
    Number of subjects analysed
    93
    94
    Units: Units
        arithmetic mean (standard deviation)
    3.6 ± 1.17
    3.4 ± 1.32
    Statistical analysis title
    		 Non-inferiority of OXN vs oxycodone (Average pain)
    Statistical analysis description
    The objective of the analysis of average pain over 24 hours was to show that OXN PR is non-inferior to OxyPR, using a one-tailed test at a 2.5% significance level. The null hypothesis was that the ratio between OXN PR and OxyPR in the ‘Average Pain over the last 24 hours’ is greater than or equal to 120%. The alternative hypothesis was that the ratio between OXN PR and OxyPR is lower than 120%. The change from baseline was analysed using a mixed model repeated measures analysis.
    Comparison groups
    Oxycodone-naloxone v Oxycodone
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Repeated measures analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs that occurred during the Double-blind Phase were those with an onset date on or after the first dose of Double-blind study medication up to and including 7 days after the last dose of study medication.
    Adverse event reporting additional description
    Only treatment emergent AEs were included in the summary tables. A treatment emergent AE was defined as any AE (or worsening of an AE) with an onset date on or after the first dose of study medication . This also included AEs with an onset date up to and including 7 days after the last dose of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Oxycodone-naloxone
    Reporting group description
    		 -

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone prolonged-release

    Serious adverse events
    		 Oxycodone-naloxone Oxycodone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 123 (2.44%)
    4 / 120 (3.33%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
         subjects affected / exposed
    2 / 123 (1.63%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bone abscess
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oxycodone-naloxone Oxycodone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 123 (16.26%)
    9 / 120 (7.50%)
    Nervous system disorders
    Hyperhidrosis
         subjects affected / exposed
    8 / 123 (6.50%)
    3 / 120 (2.50%)
         occurrences all number
    8
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    12 / 123 (9.76%)
    6 / 120 (5.00%)
         occurrences all number
    12
    6

    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
    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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