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    Clinical Trial Results:
    A randomised, double-blind, double-dummy, cross-over multicenter study to demonstrate equivalence in analgesic efficacy and bowel function taking oxycodone equivalents of 120 and 160 mg per day as achieved with the higher OXN PR tablet strengths (OXN60/30 mg PR, OXN80/40 mg PR) twice daily compared to the identical daily dose taken as a combination of lower tablet strengths in subjects with non-malignant or malignant pain that requires around-the-clock opioid therapy.

    Summary
    EudraCT number
    		 2013-004888-31
    Trial protocol
    		 GB   CZ   IT   ES  
    Global end of trial date
    26 Jul 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Aug 2017
    First version publication date
    11 Mar 2017
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Extension Phase is completed

    Trial information

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    Trial identification
    Sponsor protocol code
    OXN3508
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02321397
    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
    European Medical Operations, Mundipharma Research GmbH & Co KG, +44 1223424900, info@contact-clinical-trials.com
    Scientific contact
    European Medical Operations, Mundipharma Research GmbH & Co KG, +44 1223424900, info@contact-clinical-trials.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
    22 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective: To demonstrate equivalence between multiple lower strength OXN PR tablets and a single higher strength OXN PR tablet taken at the same overall total daily dose as shown by: • Analgesic efficacy based on the mean of subjects’ ‘Average Pain over the last 24 hours’ at the last 2 visits of each Cross-over Period, as assessed by the Pain Intensity Scale. Co-primary objective: • Equivalent bowel function as assessed by the Bowel Function Index (BFI).
    Protection of trial subjects
    Protection of trial subjects: 1) Inclusion criteria: - Male or female subjects at least 18 years (females less than one year post-menopausal had to have a negative serum or urine pregnancy test prior to the first dose of study treatment, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control was defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner). - Subjects had to be willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent. 2) Exclusion criteria: - Several exclusion criteria excluded subjects who were at risk from the use of IMP (e.g. those with hypersensitivity) or the study methods (please refer to protocol) 3) Dose discontinuation: The Investigator(s) or subjects themselves were able to stop study treatment at any time for safety or personal reasons. Investigators were to discontinue a subject from study treatment if the subject demonstrated opioid withdrawal, had an SAE due to an opioid withdrawal syndrome, had Markedly Abnormal Laboratory values or abnormal vital signs or vigilance impairment fulfilling at least one SAE criterion, or required more than 160/80 mg OXN per day. 4) Safety assessments consisted of monitoring and recording all AEs and SAEs, observed or volunteered, regardless of suspected causal relationship to the IMP. This included reactions, interactions, accidents, illnesses, misuse, abuse, lab values, vital signs, ECG, vigilance and SOWS.
    Background therapy
    		 Rescue medication: Oxycodone immediate release capsules. Analgesic rescue medication may have been dosed no sooner than every 4 hours as needed. 6 analgesic rescue doses were the total maximum amount of analgesic rescue medication per day (on single occasions). The analgesic rescue medication dose was approximately 1/6th the total daily maintenance dose. For a subject stabilised on OXN60/30 mg PR twice daily (HST or LST), the rescue dose of OxyIR would have been 20 mg; for a subject stabilised on OXN80/40 mg PR twice daily (HST or LST), the rescue dose of OxyIR would have been 25 mg. Subjects, who consistently (i.e. ≥ 3 days per week) required more than 2 rescue doses per day of OxyIR were discontinued.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Nov 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Czech Republic: 70
    Country: Number of subjects enrolled
    Germany: 86
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    217
    EEA total number of subjects
    217
    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)
    149
    From 65 to 84 years
    65
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted a total of 40 sites in 6 countries (8 sites in the Czech Republic, 15 in Germany, 4 in Italy, 4 in Poland, 4 in Spain, 5 in the United Kingdom). In addition, 16 sites did not recruit subjects (1 in the Czech Republic, 2 in Germany, 5 in Spain, 5 in the UK, 1 in Italy and 2 in Poland).

    Pre-assignment
    Screening details
    		 Screening period: up to 2 weeks, Run-in Phase: 1-4 weeks. Subjects who did not comply with all screening inclusion and exclusion criteria or withdrew their consent prior to entering the Run-In Period were considered Screening Failures. The Run-In Period served to qualify the subject for entry into the Double-blind Phase.

    Pre-assignment period milestones
    Number of subjects started
    		 217
    Intermediate milestone: Number of subjects
    Run-in Period: 195
    Number of subjects completed
    		 155 [1]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 22
    Reason: Number of subjects
    		 Adverse event, non-fatal: 17
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Did not meet Double-blind Phase inclusion criteria: 16
    Reason: Number of subjects
    		 Lack of therapeutic effect: 4
    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: This study was done in a cross-over design. Subjects received both, low and high strength tablets within their respective dosing group.
    Period 1
    Period 1 title
    Double-blind Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 OXN80/40 PR LST
    Arm description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxycodone/naloxone 80/40 mg low strength tablets
    Investigational medicinal product code
    OXN80/40 LST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2x 40/20 mg oxycodone/naloxone combination twice daily. Total daily dose: 160mg/80mg oxycodone/naloxone

    Arm title
    		 OXN80/40 PR HST
    Arm description
    		 Subjects who received OXN High Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone/naloxone 80/40 mg high strength tablets
    Investigational medicinal product code
    OXN80/40 HST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80/40 mg oxycodone/naloxone combination twice daily. Total daily dose: 160mg/80mg oxycodone/naloxone

    Arm title
    		 OXN60/30 PR LST
    Arm description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxycodone/naloxone 60/30 mg low strength tablets
    Investigational medicinal product code
    OXN60/30 LST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20/10 and 40/20 mg oxycodone/naloxone combination twice daily. Total daily dose: 120mg/60mg oxycodone/naloxone

    Arm title
    		 OXN60/30 PR HST
    Arm description
    		 Subjects who received OXN High Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone/naloxone 60/30 mg high strength tablets
    Investigational medicinal product code
    OXN60/30 HST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60/30 mg oxycodone/naloxone combination twice daily. Total daily dose: 120mg/60mg oxycodone/naloxone

    Number of subjects in period 1
    		OXN80/40 PR LST OXN80/40 PR HST OXN60/30 PR LST OXN60/30 PR HST
    Started
    79
    76
    75
    73
    Interim analysis
    20 [2]
    20 [3]
    20 [4]
    20 [5]
    Completed
    75
    73
    72
    73
    Not completed
    4
    3
    3
    0
         Adverse event, serious fatal
    1
    -
    -
    -
         Consent withdrawn by subject
    -
    2
    1
    -
         Adverse event, non-fatal
    2
    -
    2
    -
         Lack of efficacy
    1
    1
    -
    -
    Notes
    [2] - 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 interim analysis was only done with a fraction of the subjects who took part in the study.
    [3] - 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 interim analysis was only done with a fraction of the subjects who took part in the study.
    [4] - 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 interim analysis was only done with a fraction of the subjects who took part in the study.
    [5] - 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 interim analysis was only done with a fraction of the subjects who took part in the study.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding. Subjects who had completed the Double-blind Phase had the option to receive open-label OXN PR HST for up to 24 additional weeks.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OXN160/80 mg PR HST
    Arm description
    		 Subjects who received OXN 80/40 mg tablets twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone/naloxone 80/40 mg high strength tablets
    Investigational medicinal product code
    OXN80/40 HST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80/40 mg oxycodone/naloxone combination twice daily. Total daily dose: 160mg/80mg oxycodone/naloxone

    Arm title
    		 OXN140/70 mg PR HST
    Arm description
    		 Subjects who received one OXN 80/40 mg tablet and one OXN 60/30 mg tablet per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone/naloxone 80/40 mg high strength tablets
    Investigational medicinal product code
    OXN80/40 HST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80/40 mg oxycodone/naloxone combination twice daily. Asymmetrical dosing of one OXN 80/40 mg tablet and one OXN 60/30 mg tablet per day. Total daily dose: 140mg/70mg oxycodone/naloxone

    Investigational medicinal product name
    Oxycodone/naloxone 60/30 mg high strength tablets
    Investigational medicinal product code
    OXN60/30 HST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80/40 mg oxycodone/naloxone combination twice daily. Asymmetrical dosing of one OXN 80/40 mg tablet and one OXN 60/30 mg tablet per day. Total daily dose: 140mg/70mg oxycodone/naloxone

    Arm title
    		 OXN120/60 mg PR HST
    Arm description
    		 Subjects who received OXN 60/30 mg tablets twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone/naloxone 60/30 mg high strength tablets
    Investigational medicinal product code
    OXN60/30 HST
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60/30 mg oxycodone/naloxone combination twice daily. Total daily dose: 120mg/60mg oxycodone/naloxone

    Number of subjects in period 2
    		OXN160/80 mg PR HST OXN140/70 mg PR HST OXN120/60 mg PR HST
    Started
    70
    2
    66
    Completed
    65
    2
    61
    Not completed
    5
    0
    5
         Adverse event, serious fatal
    1
    -
    -
         Consent withdrawn by subject
    1
    -
    2
         Administrative (unable to attend planned visits)
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    2
         Lost to follow-up
    1
    -
    -
         Lack of efficacy
    1
    -
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    OXN80/40 PR LST
    Reporting group description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.

    Reporting group title
    OXN80/40 PR HST
    Reporting group description
    		 Subjects who received OXN High Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.

    Reporting group title
    OXN60/30 PR LST
    Reporting group description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.

    Reporting group title
    OXN60/30 PR HST
    Reporting group description
    		 Subjects who received OXN High Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Basline period started after Screening and Run-In
    Reporting group values
    		 OXN80/40 PR LST OXN80/40 PR HST OXN60/30 PR LST OXN60/30 PR HST Total
    Number of subjects
    		 79 76 75 73
    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
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.7 ± 10.7 56.7 ± 10.78 56.9 ± 11.62 56.8 ± 11.76 -
    Gender categorical
    Units: Subjects
        Female
    		 38 38 44 44 83
        Male
    		 41 38 31 29 72

    End points

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    End points reporting groups
    Reporting group title
    OXN80/40 PR LST
    Reporting group description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.

    Reporting group title
    OXN80/40 PR HST
    Reporting group description
    		 Subjects who received OXN High Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.

    Reporting group title
    OXN60/30 PR LST
    Reporting group description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.

    Reporting group title
    OXN60/30 PR HST
    Reporting group description
    		 Subjects who received OXN High Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.
    Reporting group title
    OXN160/80 mg PR HST
    Reporting group description
    		 Subjects who received OXN 80/40 mg tablets twice daily

    Reporting group title
    OXN140/70 mg PR HST
    Reporting group description
    		 Subjects who received one OXN 80/40 mg tablet and one OXN 60/30 mg tablet per day.

    Reporting group title
    OXN120/60 mg PR HST
    Reporting group description
    		 Subjects who received OXN 60/30 mg tablets twice daily.

    Subject analysis set title
    OXN80/40 LST PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Population OXN80/40 LST treatment group

    Subject analysis set title
    OXN80/40 HST PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Population OXN80/40 HST treatment group

    Subject analysis set title
    OXN60/30 HST PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Population OXN60/30 HST treatment group

    Subject analysis set title
    OXN60/30 LST PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol Population OXN60/30 LST treatment group

    Subject analysis set title
    Total PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Total per protocol population

    Subject analysis set title
    OXN80/40 LST FAP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Population OXN80/40 LST treatment group

    Subject analysis set title
    OXN80/40 HST FAP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Population OXN80/40 HST treatment group

    Subject analysis set title
    OXN60/30 HST FAP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Population OXN60/30 HST treatment group

    Subject analysis set title
    OXN60/30 LST FAP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Population OXN60/30 LST treatment group

    Subject analysis set title
    Total FAP
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Population total

    Subject analysis set title
    OXN80/40 LST Interim
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving OXN80/40 LST in the interim analysis

    Subject analysis set title
    OXN80/40 HST Interim
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving OXN80/40 HST in the interim analysis

    Subject analysis set title
    OXN60/30 HST Interim
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving OXN60/30 HST in the interim analysis

    Subject analysis set title
    OXN60/30 LST Interim
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects receiving OXN60/30 LST in the interim analysis

    Subject analysis set title
    Interim total
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Total number of subjects in the interim analysis

    Subject analysis set title
    All LST PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects receiving LST tablets (OXN80/40mg and OXN60/30mg)

    Subject analysis set title
    All HST PPP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects receiving HST tablets (OXN80/40mg and OXN60/30mg)

    Subject analysis set title
    Total Exposure Safety Population (Extension Phase)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Total Exposure Safety Population was defined as subjects who received at least one dose of OXN PR HST in the Extension Phase and had at least one safety assessment after the first of such doses. Any patients who had a chance to report an AE (i.e., who attended a study visit) was considered to have had a safety assessment regardless of whether they have reported an AE or not. Subjects in the Total Exposure Safety Population were analysed ‘as treated’.

    Primary: Analgesic efficacy based on the mean of subjects’ ‘Average Pain over the last 24 hours’ at the last 2 visits of each Cross-over Period, as assessed by the Pain Intensity Scale

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    End point title
    		 Analgesic efficacy based on the mean of subjects’ ‘Average Pain over the last 24 hours’ at the last 2 visits of each Cross-over Period, as assessed by the Pain Intensity Scale
    End point description
    Pain Intensity Scale (Numeric Rating Scale (NRS) 0 – 10) – ‘Average Pain over the last 24 hours’, as assessed at Visits 5 and 6 and at Visits 8 and 9, respectively. The Primary analysis was done in the Interim Analysis. As the interim analysis already successfully proved equivalence in the average pain over the last 24 hours the analyses with the PPP and FAP were assumed to be descriptive.
    End point type
    Primary
    End point timeframe
    3 weeks, assessed after 2 and 3 weeks.
    End point values
    		 OXN80/40 LST PPP OXN80/40 HST PPP OXN60/30 HST PPP OXN60/30 LST PPP Total PPP OXN80/40 LST Interim OXN80/40 HST Interim OXN60/30 HST Interim OXN60/30 LST Interim Interim total
    Number of subjects analysed
    49 [1]
    49 [2]
    48 [3]
    48 [4]
    97 [5]
    20
    20
    20
    20
    40
    Units: Mean NRS over last 24 hours
    arithmetic mean (standard deviation)
        Week 2 (Visit 5 or 8)
    3.49 ± 1.043
    3.61 ± 1.397
    3.02 ± 1.082
    3.31 ± 1.24
    3.36 ± 1.115
    3.5 ± 1.32
    3.3 ± 1.3
    3.3 ± 0.73
    3.3 ± 1.21
    3.3 ± 1.06
        Week 3 (Visit 6 or 9)
    3.43 ± 1.118
    3.36 ± 1.253
    3.27 ± 1.106
    3.23 ± 1.077
    3.39 ± 1.073
    3.5 ± 1.23
    3.5 ± 1.15
    3.4 ± 1.1
    3.4 ± 1.18
    3.4 ± 1.02
    Notes
    [1] - Excluding subjects from the interim analysis
    [2] - Excluding subjects from the interim analysis
    [3] - Excluding subjects from the interim analysis
    [4] - Excluding subjects from the interim analysis
    [5] - Excluding subjects from the interim analysis
    Statistical analysis title
    		 Equivalence Ratio OXN60/30 Interim
    Statistical analysis description
    LST:HST ratio for OXN 60/30 dose interim analysis
    Comparison groups
    OXN60/30 LST Interim v OXN60/30 HST Interim
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    1.02
    Confidence interval
         level
    		 98.75%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.17
    Notes
    [6] - The average pain over the past 24 hours over the last 2 weeks of each period were analysed following the approach described in Hauschke et al., 1999 for proving equivalence based on the ratio of 2 mean values from a cross-over design. The analysis concluded on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the ratio of the mean treatment effects (HST/LST) over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.
    Statistical analysis title
    		 Equivalence Ratio OXN80/40 Interim
    Statistical analysis description
    LST:HST ratio for OXN 80/40 dose interim analysis (20 subjects)
    Comparison groups
    OXN80/40 LST Interim v OXN80/40 HST Interim
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    0.97
    Confidence interval
         level
    		 98.75%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.09
    Notes
    [7] - The average pain over the past 24 hours over the last 2 weeks of each period were analysed following the approach described in Hauschke et al., 1999 for proving equivalence based on the ratio of 2 mean values from a cross-over design. The analysis concluded on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the ratio of the mean treatment effects (HST/LST) over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.
    Statistical analysis title
    		 Equivalence Ratio OXN60/30 PPP
    Statistical analysis description
    LST:HST ratio for OXN 60/30 dose Per Protocol Population (48 subjects)
    Comparison groups
    OXN60/30 LST PPP v OXN60/30 HST PPP
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    0.96
    Confidence interval
         level
    		 98.75%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.03
    Notes
    [8] - The average pain over the past 24 hours over the last 2 weeks of each period were analysed following the approach described in Hauschke et al., 1999 for proving equivalence based on the ratio of 2 mean values from a cross-over design. The analysis concluded on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the ratio of the mean treatment effects (HST/LST) over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.
    Statistical analysis title
    		 Equivalence Ratio OXN80/40 PPP
    Statistical analysis description
    LST:HST ratio for OXN 80/40 dose Per Protocol Population (49 subjects)
    Comparison groups
    OXN80/40 HST PPP v OXN80/40 LST PPP
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    1.05
    Confidence interval
         level
    		 98.75%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.13
    Notes
    [9] - The average pain over the past 24 hours over the last 2 weeks of each period were analysed following the approach described in Hauschke et al., 1999 for proving equivalence based on the ratio of 2 mean values from a cross-over design. The analysis concluded on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the ratio of the mean treatment effects (HST/LST) over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.

    Primary: Equivalence of bowel function between LST an HST treatment

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    End point title
    		 Equivalence of bowel function between LST an HST treatment
    End point description
    BFI, as assessed at Visits 5 and 6 and at Visits 8 and 9, respectively. The BFI was the mean of the following items: Ease of defecation (NAS, 0=easy/no difficulty; 100=severe difficulty), Feeling of incomplete bowel evacuation (NAS, 0=not at all, 100=very strong), Personal judgement of constipation (NAS, 0=not at all, 100=very strong).
    End point type
    Primary
    End point timeframe
    3 weeks, assessed after 2 and 3 weeks.
    End point values
    		 OXN80/40 LST PPP OXN80/40 HST PPP OXN60/30 HST PPP OXN60/30 LST PPP Total PPP All LST PPP All HST PPP
    Number of subjects analysed
    68
    68
    68
    68
    136
    136
    136
    Units: Bowel Function Index (BFI)
    arithmetic mean (standard deviation)
        Week 2 (Visit 5 or 8)
    23.191 ± 23.2139
    23.039 ± 24.0914
    25.662 ± 23.6688
    23.971 ± 22.503
    23.966 ± 22.4976
    23.581 ± 22.7798
    24.35 ± 23.8288
        Week 3 (Visit 6 or 9)
    25.206 ± 26.0478
    23.73 ± 22.5886
    23.172 ± 19.6078
    20.466 ± 21.1836
    23.143 ± 21.4904
    22.836 ± 23.7718
    23.451 ± 21.0741
    Statistical analysis title
    		 BFI LST:HST ratio 60/30mg treatment
    Statistical analysis description
    LST:HST ratio of BFI for subjects in the OXN 60/30mg dose group (68 subjects)
    Comparison groups
    OXN60/30 LST PPP v OXN60/30 HST PPP
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.24
    Notes
    [10] - The co-primary efficacy analysis on the BFI applied the procedure described in Hauschke et al., 1999 for proving equivalence based on the ratio of two mean values from a cross-over design concluding on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the expected ratio of the mean treatment effects over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.
    Statistical analysis title
    		 BFI LST:HST ratio 80/40mg treatment
    Statistical analysis description
    LST:HST ratio of BFI for subjects in the OXN 80/40mg dose group (68 subjects)
    Comparison groups
    OXN80/40 LST PPP v OXN80/40 HST PPP
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [11]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.06
    Notes
    [11] - The co-primary efficacy analysis on the BFI applied the procedure described in Hauschke et al., 1999 for proving equivalence based on the ratio of two mean values from a cross-over design concluding on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the expected ratio of the mean treatment effects over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.
    Statistical analysis title
    		 BFI LST:HST ratio all subjects in the PPP
    Statistical analysis description
    LST:HST ratio of BFI for all subjects in the Per Protocol Population (136 subjects)
    Comparison groups
    All LST PPP v All HST PPP
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    Method
    Parameter type
    		 Ratio (LST:HST)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.11
    Notes
    [12] - The co-primary efficacy analysis on the BFI applied the procedure described in Hauschke et al., 1999 for proving equivalence based on the ratio of two mean values from a cross-over design concluding on equivalence of tested treatments if the two-sided (1-α)% Fieller confidence interval for the expected ratio of the mean treatment effects over the last 2 weeks of each period was fully contained in an equivalence range of 80% to 125%.

    Other pre-specified: Average Pain over the last 24 hours in the Extension Phase

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    End point title
    		 Average Pain over the last 24 hours in the Extension Phase
    End point description
    The 24 hours pain Numeric Rating Scale (NRS) is commonly used to evaluate pain in subjects with chronic non-malignant and malignant pain and its use is consistent with other studies in this development program. On the Pain Intensity Scale, the average pain over the last 24 hours before the visits was analysed. Pain values were assessed on a scale of 0 (meaning no pain) to 10 (meaning worst imaginable pain).
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 OXN160/80 mg PR HST OXN140/70 mg PR HST OXN120/60 mg PR HST Total Exposure Safety Population (Extension Phase)
    Number of subjects analysed
    70
    2
    66
    138
    Units: units on NRS
    arithmetic mean (standard deviation)
        Baseline of the core phase
    3.6 ± 0.88
    3.5 ± 0.71
    3.2 ± 1.1
    3.4 ± 1
        Baseline Extension Phase
    3.5 ± 1.26
    3 ± 0
    3.3 ± 1.04
    3.4 ± 1.16
        End of Extension Phase
    3.8 ± 1.43
    2.5 ± 0.71
    3.3 ± 1.2
    3.5 ± 1.34
    No statistical analyses for this end point

    Other pre-specified: Bowel Function Index in the Extension Phase

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    End point title
    		 Bowel Function Index in the Extension Phase
    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.
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 OXN160/80 mg PR HST OXN140/70 mg PR HST OXN120/60 mg PR HST Total Exposure Safety Population (Extension Phase)
    Number of subjects analysed
    70
    2
    66
    138
    Units: BFI units
    arithmetic mean (standard deviation)
        Baseline Core Study
    25.7 ± 23.65
    0.5 ± 0.71
    25.6 ± 24.81
    25.3 ± 24.14
        Baseline Extension Phase
    24.5 ± 25.96
    0.5 ± 0.71
    21.6 ± 18.97
    22.8 ± 22.79
        End of Extension Phase
    21.8 ± 23.66
    0 ± 0
    19.4 ± 16.86
    20.3 ± 20.63
    No statistical analyses for this end point

    Other pre-specified: Quality of Life Based on EuroQol EQ-5D Extension Phase

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    End point title
    		 Quality of Life Based on EuroQol EQ-5D Extension Phase
    End point description
    The EQ-5D is the most widely used generic preference-based measure of health-related quality of life which produces utility scores anchored at 0 for worst imaginable health state and 1 for best imaginable health state.
    End point type
    Other pre-specified
    End point timeframe
    6 weeks Core study plus 24 weeks extension Phase
    End point values
    		 OXN160/80 mg PR HST OXN140/70 mg PR HST OXN120/60 mg PR HST Total Exposure Safety Population (Extension Phase)
    Number of subjects analysed
    70
    2
    66
    138
    Units: EQ-5D Index score
    arithmetic mean (standard deviation)
        Baseline Core study
    0.4 ± 0.32
    0.5 ± 0.47
    0.6 ± 0.24
    0.5 ± 0.3
        Baseline Extension Phase
    0.6 ± 0.22
    0.6 ± 0.26
    0.7 ± 0.13
    0.7 ± 0.19
        End of Extension Phase
    0.5 ± 0.26
    1 ± 0
    0.7 ± 0.11
    0.6 ± 0.21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Events were recorded from the point at which the Informed Consent was signed until 7 days after the subject left the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    OXN80/40 PR LST
    Reporting group description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.

    Reporting group title
    OXN80/40 PR HST
    Reporting group description
    		 Subjects who received OXN High Strength Tablet on a dose level of 80 mg oxycodone and 40 mg naloxone.

    Reporting group title
    OXN60/30 PR LST
    Reporting group description
    		 Subjects who received OXN Low Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.

    Reporting group title
    OXN60/30 PR HST
    Reporting group description
    		 Subjects who received OXN High Strength Tablet on a dose level of 60 mg oxycodone and 30 mg naloxone.

    Reporting group title
    OXN160/80 PR HST Extension
    Reporting group description
    		 Subjects in the Extension Phase who received OXN160/80 mg PR HST (OXN 80/40 mg tablets twice daily).

    Reporting group title
    OXN120/60 PR HST Extension
    Reporting group description
    		 Subjects in the Extension Phase who received OXN120/60 mg PR HST (OXN 60/30 mg tablets twice daily).

    Reporting group title
    OXN140/70 PR HST Extension
    Reporting group description
    		 Subjects in the Extension Phase who received OXN140/70 mg PR HST (one OXN 80/40 mg tablet and one OXN 60/30 mg tablet per day).

    Serious adverse events
    		 OXN80/40 PR LST OXN80/40 PR HST OXN60/30 PR LST OXN60/30 PR HST OXN160/80 PR HST Extension OXN120/60 PR HST Extension OXN140/70 PR HST Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 76 (1.32%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    3 / 70 (4.29%)
    5 / 66 (7.58%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    2
    0
    0
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm
    Additional description: Not related to IMP
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
    Additional description: All occurrences unrelated to IMP. Fatal case under OXN80/40 PR HST treatment occurred in the extension phase
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Renal neoplasm
    Additional description: SAE occurred in the extension phase. Not related to IMP.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
    Additional description: SAE occurred in the extension phase. Not related to IMP.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery disease
    Additional description: SAE occurred in the extension phase. Not related to IMP.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
    Additional description: SAE occurred in the extension phase. Not related to IMP.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Petit mal epilepsy
    Additional description: Not related to IMP
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Not related to IMP
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    0 / 66 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: SAE occurred in the extension phase.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    1 / 70 (1.43%)
    0 / 66 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    Additional description: SAE occurred in the extension phase. Not related to IMP.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    Additional description: SAE occurred in the extension phase. Not related to IMP.
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    0 / 70 (0.00%)
    1 / 66 (1.52%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 OXN80/40 PR LST OXN80/40 PR HST OXN60/30 PR LST OXN60/30 PR HST OXN160/80 PR HST Extension OXN120/60 PR HST Extension OXN140/70 PR HST Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 76 (3.95%)
    5 / 75 (6.67%)
    3 / 73 (4.11%)
    6 / 70 (8.57%)
    11 / 66 (16.67%)
    1 / 2 (50.00%)
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 76 (1.32%)
    3 / 75 (4.00%)
    1 / 73 (1.37%)
    1 / 70 (1.43%)
    3 / 66 (4.55%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    3
    1
    1
    3
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 76 (1.32%)
    2 / 75 (2.67%)
    2 / 73 (2.74%)
    2 / 70 (2.86%)
    4 / 66 (6.06%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    2
    3
    4
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
    2 / 70 (2.86%)
    4 / 66 (6.06%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2014
    This Substantial Protocol Amendment added the Pain Intensity Scale – ‘Pain right now’ in the diaries of the Double-blind Phase, and as a further secondary objective of this study. The objective was phrased • To assess analgesic efficacy at intake of oxycodone/naloxone tablets during the last 2 weeks of each Cross-over Period. Table 1 and its footnotes were changed to include the ‘Pain right now’ documentation in the diary.
    11 Dec 2014
    This Non-Substantial Protocol Amendment recalculated the CV as requested by the Research Ethics Committee (UK) regarding pain based on clinical study OXN3506 and BFI based on clinical study OXN3401, and adjusted the sample size in accordance therewith. In the sample size estimation for the number of subjects to be analysed for ‘Average pain over the last 24 hours’ the CV between subjects changed from 0.29 to 0.27 and the CV within subjects from 0.29 to 0.15 for the arithmetic average of 2 visits. This changed the required number of evaluable subjects per OXN dose level from 24 subjects to 26 subjects, the total number of subjects from 48 to 52 and the number of subjects in the interim analysis from 36 to 40. For BFI, the CV was recalculated, resulting in a change of CV within subjects from 0.72 to 0.38 for the arithmetic average of 2 visits, and in number of evaluable subjects required to provide a power of ≥ 88% from 84 to 92. Overall the number of subjects to be randomised changed from 132 to 144.

    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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