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    Clinical Trial Results:
    An exploratory, double-blind, double-dummy, randomised, 2-period, crossover, Phase IIa study to assess the influence of oxycodone/naloxone prolonged-release tablets (OXN PR) and oxycodone prolonged-release tablets (OxyPR) on intestinal microbiota and other gastrointestinal parameters in subjects suffering from non-malignant pain requiring an equivalent of 20 – 50 mg oxycodone prolonged-release per day

    Summary
    EudraCT number
    2012-001772-11
    Trial protocol
    CZ  
    Global end of trial date
    09 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jul 2016
    First version publication date
    24 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OXN2505
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Mundipharma Research GmbH
    Sponsor organisation address
    Höhenstraße 10, Limburg, United Kingdom, D-65549
    Public contact
    Clinical Trial Contact , Mundipharma Research GmbH & Co. KG, +44 1223424900, info@contact-clinical-trial.com
    Scientific contact
    Clinical Trial Contact , Mundipharma Research GmbH & Co. KG, +44 1223424900, 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
    09 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Quantitative analysis of intestinal microbiota as determined in stool samples of subjects treated with OXN PR compared to those treated with OxyPR. • To assess orocaecal transit time on the basis of intestinal absorption and intermediary bacterial metabolism as determined by breath tests (H2 breath test, CH4 breath test) in subjects treated with OXN PR compared to those treated with OxyPR.
    Protection of trial subjects
    1) Inclusion criteria: - Females less than one year post-menopausal had to have a negative 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 is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly e.g. sterilisation, implants, injectables, combined oral contraceptives, some intrauterine devices ((IUDs), 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 visits at pain and GE centres, 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 may have stopped study treatment at any time for safety or personal reasons. Subjects with serious diarrhoea, withdrawal syndrome, vital sign or laboratory abnormalities were also to be discontinued. 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 and abuse. In addition, safety was assessed by monitoring haematology, biochemistry, and urine values, periodic measurement of vital signs and ECGs and the performance of physical examinations.
    Background therapy
    Non-Investigational Medicinal Products (NIMPs) included rescue mediation as well as substances used in the breath tests. - OxyIR use (Run-in Period and Double-Blind Phase, Opioid-treated subjects (OTS) only): OxyIR was the only allowed rescue pain medication. It was to be dosed no sooner than every 4 hours as needed. For subjects receiving 20, 30 or 40 mg/day of oxycodone PR, the single rescue dose of OxyIR was 5 mg. For subjects receiving 50 mg/day of oxycodone PR, the single rescue dose of OxyIR was 10 mg. - Bisacodyl (Run-in Period and Double-Blind Phase, OTS only): As rescue medication for constipation, only bisacodyl suppository were to be used no sooner than 72 hours after a subject’s most recent bowel movement. - Mouthwash (Vademecum med® concentrate or equivalent product) (breath tests at Gastroenterological (GE) centres): Five splatters in a half glass of tap water (appr. 0.1 Liter) were given to subjects prior to the first breath test assessment. - Lactulose (breath tests at GE centres): A test solution was prepared ahead of each breath test assessment, containing 10 g lactulose (15 mL solution of Bifiteral®) plus 200 mL tap water. - Glucose and Insulin: Both NIMPs were administered at GE centres on an “as required” basis and at the discretion of the Investigator in subjects diagnosed with diabetes mellitus.
    Evidence for comparator
    Oxycodone/naloxone prolonged release (OXN), the investigational drug in this study, has comparable analgesic effficacy as oxycodone prolonged release (OxyPR), but causes less opioid-induced bowel dysfunction. This study is aimed to generate data about different gastrointestinal parameters in response to treatment of constipated subjects with OXN PR and OxyPR.
    Actual start date of recruitment
    22 Jul 2013
    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
    Czech Republic: 30
    Country: Number of subjects enrolled
    Germany: 122
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    121
    From 65 to 84 years
    29
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 2 countries at 27 pain centres (23 sites in Germany, 4 sites in the Czech Republic) and 6 Gastrointestinal (GE) centres (5 sites in Germany, 1 site in the Czech Republic). In addition, 10 pain centres in Germany were initiated but did not recruit any subjects.

    Pre-assignment
    Screening details
    OTS were screened for up to 14 days, followed by a Run-in period of 7-28 days. During the Run-In Period subjects had their opioid therapy converted to open-label OxyPR, which was titrated to an effective analgesic dose between 20-50 mg of Oxy PR per day (20, 30, 40 or 50 mg per day).

    Pre-assignment period milestones
    Number of subjects started
    152
    Number of subjects completed
    108 [1]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 6
    Reason: Number of subjects
    Consent withdrawn by subject: 2
    Reason: Number of subjects
    Run-in failure: 11
    Reason: Number of subjects
    Screening failure: 25
    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: As this is a cross-over study, 54 subjects started in each Treatment Group at the beginning of the double-blind Phase. Subjects who discontinued in cross-over period 1 were not included in subject numbers for cross-over period 2.
    Period 1
    Period 1 title
    Double-blind period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    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. Medication codes were not available until the completion of the study and until clinical data base lock, except in the case of emergency. Unblinding of treatment in single subject for regulatory reporting of SUSARs was done by designated drug safety personnel only

    Arms
    Are arms mutually exclusive
    No

    Arm title
    OXN PR
    Arm description
    All subjects taking OXN PR in cross-over period 1 or cross-over period 2
    Arm type
    Experimental

    Investigational medicinal product name
    Oxycodone/naloxone
    Investigational medicinal product code
    OXN PR
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OXN PR and matching placebos in the DB-Phase were blinded and administered orally, prescribed q12h. Dosing was fixed and symmetrical (20, 30, 40 or 50 mg/day of oxycodone PR).

    Arm title
    OxyPR
    Arm description
    All subjects taking OxyPR in cross-over period 1 or cross-over period 2
    Arm type
    Active comparator

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    OxyPR
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OxyPR and matching placebos in the DB-Phase were blinded and administered orally, prescribed q12h. Dosing was fixed and symmetrical (20, 30, 40 or 50 mg/day of oxycodone PR).

    Number of subjects in period 1
    OXN PR OxyPR
    Started
    104
    104
    Completed
    100
    98
    Not completed
    4
    6
         Adverse event, non-fatal
    -
    3
         Consent withdrawn by subject
    3
    1
         Administrative
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Double-blind period
    Reporting group description
    -

    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: As this is a cross-over study, 54 subjects started in each Treatment Group at the beginning of the double-blind Phase. Subjects who discontinued in cross-over period 1 were not included in subject numbers for cross-over period 2.
    Reporting group values
    Double-blind period Total
    Number of subjects
    108 108
    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 years and older)
    108 108
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.5 ± 10.75 -
    Gender categorical
    Units: Subjects
        Female
    76 76
        Male
    32 32
    Subject analysis sets

    Subject analysis set title
    Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis population is defined as all randomised subjects who receive at least one dose of IMPs and have at least one post-baseline assessments of the primary efficacy variables in each of the two treatment periods. All subjects which are part of the FAP are regarded as evaluable. In case that many subjects have only data from one treatment period a sensitivity analysis based on the reduced population will be considered

    Subject analysis set title
    Double Blind Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Double-blind safety population is defined as all enrolled subjects who were randomised and received at least one dose of IMP and have at least one safety assessment in the Double-Blind Phase.

    Subject analysis sets values
    Full Analysis Population Double Blind Safety Population
    Number of subjects
    98
    108
    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 years and older)
    98
    108
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.8 ± 10.32
    57.5 ± 10.75
    Gender categorical
    Units: Subjects
        Female
    68
    76
        Male
    30
    32

    End points

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    End points reporting groups
    Reporting group title
    OXN PR
    Reporting group description
    All subjects taking OXN PR in cross-over period 1 or cross-over period 2

    Reporting group title
    OxyPR
    Reporting group description
    All subjects taking OxyPR in cross-over period 1 or cross-over period 2

    Subject analysis set title
    Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis population is defined as all randomised subjects who receive at least one dose of IMPs and have at least one post-baseline assessments of the primary efficacy variables in each of the two treatment periods. All subjects which are part of the FAP are regarded as evaluable. In case that many subjects have only data from one treatment period a sensitivity analysis based on the reduced population will be considered

    Subject analysis set title
    Double Blind Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Double-blind safety population is defined as all enrolled subjects who were randomised and received at least one dose of IMP and have at least one safety assessment in the Double-Blind Phase.

    Primary: Orocaecal transit time

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    End point title
    Orocaecal transit time
    End point description
    To assess orocaecal transit time on the basis of intestinal absorption and intermediary bacterial metabolism as determined by breath tests (H2 breath test, CH4 breath test) in subjects treated with OXN PR compared to those treated with OxyPR. Orocaecal time was measured by H2/CH4/ analysis of expired air of subjects (breath tests).
    End point type
    Primary
    End point timeframe
    Breath test assessments at 5 minute intervals for H2/CH4: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 + Extension by 1 hour if needed.
    End point values
    OXN PR OxyPR
    Number of subjects analysed
    65
    62
    Units: Minutes
        least squares mean (confidence interval 95%)
    124.58 (112.47 to 136.69)
    131 (118.59 to 143.41)
    Statistical analysis title
    Difference in LS Means
    Statistical analysis description
    ANOVA with fixed terms for treatment, period and sequence and a random subject effect
    Comparison groups
    OXN PR v OxyPR
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.446
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.21
         upper limit
    10.37
    Notes
    [1] - The H2-CH4-breath test provides the exhalation results of H2 and CH4 in the ppm unit, while the 1-13C-sodium acetate breath test measures the ratio between 12C and 13C in breath samples (given as delta‰) and calculates the DOB value (delta over basal, given as delta‰) and the percentage of the 13C-dose exhaled per hour as %13C dose/h. Gastric emptying time is defined as the time of maximum 13C-CO2 [%13C dose/h] exhalation. Orocaecal transit time is defined as the first timepoint where H2 [ppm]

    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 is signed until 7 days after the subject left the study. This included new AEs that were reported in the 7 days following the subject’s completion/discontinuation visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    OXN PR
    Reporting group description
    All subjects taking OXN PR in cross-over period 1 or cross-over period 2

    Reporting group title
    OxyPR
    Reporting group description
    All subjects taking OxyPR in cross-over period 1 or cross-over period 2

    Serious adverse events
    OXN PR OxyPR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 104 (0.96%)
    1 / 104 (0.96%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Gastroenteritis
    Additional description: assessed as not related to IMP caused hospitalisation subject recovered
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroneteritis salmonella
    Additional description: assessed as not related to IMP caused hospitalisation subject recovered
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 104 (0.96%)
         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: 4.8%
    Non-serious adverse events
    OXN PR OxyPR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 104 (9.62%)
    15 / 104 (14.42%)
    Investigations
    Blood uric acid increased
    Additional description: All AEs of uric acid increased were not causally related to IMP.
         subjects affected / exposed
    4 / 104 (3.85%)
    5 / 104 (4.81%)
         occurrences all number
    4
    5
    Gastrointestinal disorders
    Diarrhoea
    Additional description: 3 AEs of diarrhoea in OXN PR Group and 2 in OxyPR Group were causally unrelated to IMP
         subjects affected / exposed
    5 / 104 (4.81%)
    3 / 104 (2.88%)
         occurrences all number
    5
    3
    Infections and infestations
    Nasopharyngitis
    Additional description: all AEs of nasopharyngitis were causally unrelated to IMP.
         subjects affected / exposed
    2 / 104 (1.92%)
    8 / 104 (7.69%)
         occurrences all number
    2
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2013
    Protocol Amendment No. 1 was a result of the German central Ethic Committee’s (cEC) response to the submission of the protocol 15-NOV-2012. The cEC responded on the 30 January 2013. The amendment is considered a “substantial amendment” as sections of it affect in- and exclusion criteria. In addition, minor text corrections and inconsistencies have been corrected.
    16 May 2013
    Protocol Amendment No. 2 was a result of the response letter by the German competent authority (BfArM) dated 02 April 2013. The Sponsor had obtained a conditional approval for the study. The condition was to submit a manufacturing license for the weighing and filling of 13C-Sodium Acetate. Since the process to get the manufacturing license for this product would have been very complex, involving release by a qualified person and additional documentation, the Sponsor decided to remove the 13C-Sodium Acetate breath test from the study. The amendment was considered a “substantial amendment” because of changes to study procedures.

    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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