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    Clinical Trial Results:
    Efficacy, safety, and tolerability of oral Cebranopadol versus morphine sulphate PR in subjects with chronic moderate to severe pain related to cancer.

    Summary
    EudraCT number
    		 2012-001316-35
    Trial protocol
    		 BE   GB   DE   HU   SE   ES   SK   PL   NL   AT   DK   BG   HR  
    Global end of trial date
    16 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2016
    First version publication date
    30 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF6005/07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01964378
    WHO universal trial number (UTN)
    		 U1111-1143-1808
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52099
    Public contact
    GRT Trial Information Desk, Grünenthal GmbH, +49 2415693223, clinical-trials@grunenthal.com
    Scientific contact
    GRT Trial Information Desk, Grünenthal GmbH, +49 2415693223, clinical-trials@grunenthal.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
    29 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of orally administered Cebranopadol in comparison with morphine sulfate PR in subjects suffering from chronic moderate to severe pain related to cancer.
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory and competent authorities were notified of the trial as required by national regulations, and, where necessary, relevant authorization was obtained. Subjects were informed and monitored by the investigator not to take prohibited medications. The last intake of Investigational Medicinal Product (IMP) took place in the evening of the day of the End of Treatment Visit. The use of rescue medication was allowed until the next day. From that day onwards (Follow-up Period), subjects were allowed to use any analgesic concomitant medication (unless specified otherwise under concomitant medications/therapies) or could start their participation in the extension trial (KF6005/09). For subjects not participating in the extension trial, a Follow-up Visit was planned 4 – 7 days after last IMP intake. At least 14 days (up to 18 days) after the End of Treatment Visit, investigators were to call the subjects for a final update on adverse events.
    Background therapy
    		 Allowed concomitant treatments with certain limitations were: - Hypnotics. - Anti-emetics for treatment of adverse events or as part of a chemotherapy and/or radiotherapy regimen. - Non-steroidal anti-inflammatory & antirheumatic drugs & non-opioid analgesics. - Chemotherapy & hormonal anti-cancer therapy. - Radiotherapy (pain-relieving radiotherapy was not allowed). - Laxatives. - Serotonin & noradrenaline reuptake inhibitors, anticonvulsants, neuroleptics and antiparkinsonian drugs - Physiotherapy and other non-pharmacological pain therapy. - Corticosteroids and bisphosphonates. - Strong inducers or inhibitors of cytochrome P450 3A4, if stable for at least 2 weeks before enrollment.
    Evidence for comparator
    		 Morphine sulfate PR was selected as comparator because its mechanism of action is primarily based on MOP agonism, whereas cebranopadol combines MOP agonism with NOP agonism, and represents the most commonly used gold standard opioid with the longest history of use in patients suffering from cancer-related pain. It is broadly acknowledged that morphine is highly effective in the treatment of cancer-related pain.
    Actual start date of recruitment
    29 Oct 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
    Poland: 58
    Country: Number of subjects enrolled
    Slovakia: 40
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Serbia: 8
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    200
    EEA total number of subjects
    190
    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)
    103
    From 65 to 84 years
    94
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial started on 29 Oct 2013 with the enrollment of the first subject and was completed on 16 Oct 2015 when the last subject completed the last follow-up examination.

    Pre-assignment
    Screening details
    		 A total of 200 subjects were enrolled.

    Pre-assignment period milestones
    Number of subjects started
    		 200
    Intermediate milestone: Number of subjects
    Allocated to treatment: 132
    Intermediate milestone: Number of subjects
    Treated with IMP: 126
    Number of subjects completed
    		 126

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 4
    Reason: Number of subjects
    		 inclusion/exclusion criteria not met: 65
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 Adverse event, serious fatal: 2
    Reason: Number of subjects
    		 not specified: 2
    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
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    A double-dummy technique was used to ensure blinding of the IMP.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cebranopadol
    Arm description
    		 Subjects took one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cebranopadol
    Investigational medicinal product code
    GRT6005
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The minimum daily dose of cebranopadol was 200 µg. The incremental/decremental dose of cebranopadol was 200 µg per day. The maximum daily dose was 1000 µg/day. The aim of the titration was to reach the subject’s individual optimal dose defined as a balance between self-reported analgesia and side effects. The first decision on uptitration was taken on Day 3 (after 1 day of IMP intake). From Day 4 on, decisions for uptitration to the next higher dose step were taken after at least 4 days on a dose level. During the Titration Phase, downward titration by 1 step was allowed. In the Maintenance Phase, subjects continued at the same dose that provided optimal therapeutic benefit during the Titration Phase. No dose adjustments were allowed during the Maintenance Phase.

    Arm title
    		 Morphine Prolonged Release
    Arm description
    		 Subjects took morphine capsule(s) in the morning and in the evening and placebo double-dummy cebranopadol-like tablet(s) in the morning.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine Prolonged Release
    Investigational medicinal product code
    Other name
    Morphine sulfate pentahydrate
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The minimum daily dose of morphine prolonged release was 30 mg. The incremental/decremental dose of morphine was 30 mg per day. The maximum daily dose was 150 mg. The aim of the titration was to reach the subject’s individual optimal dose defined as a balance between self-reported analgesia and side effects. The first decision on uptitration was taken on Day 3 (after 1 day of IMP intake). From Day 4 on, decisions for uptitration to the next higher dose step were taken after at least 4 days on a dose level. During the Titration Phase, downward titration by 1 step was allowed. In the Maintenance Phase, subjects continued at the same dose that provided optimal therapeutic benefit during the Titration Phase. No dose adjustments were allowed during the Maintenance Phase.

    Number of subjects in period 1 [1]
    		Cebranopadol Morphine Prolonged Release
    Started
    65
    61
    Completed
    41
    45
    Not completed
    24
    16
         Adverse event, serious fatal
    3
    2
         Consent withdrawn by subject
    7
    5
         Adverse event, non-fatal
    12
    5
         inclusion/exclusion criteria not met
    1
    -
         Lost to follow-up
    -
    1
         not specified
    1
    1
         Lack of efficacy
    -
    1
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 200 subjects were enrolled. The baseline period reports the number of subjects that were exposed to at least one dose of Investigational Medicinal Product (IMP), i.e. Safety Analysis Set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cebranopadol
    Reporting group description
    		 Subjects took one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.

    Reporting group title
    Morphine Prolonged Release
    Reporting group description
    		 Subjects took morphine capsule(s) in the morning and in the evening and placebo double-dummy cebranopadol-like tablet(s) in the morning.

    Reporting group values
    		 Cebranopadol Morphine Prolonged Release Total
    Number of subjects
    		 65 61 126
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 36 35 71
        From 65-84 years
    		 29 26 55
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ( 9.18 ) 61 ( 10.64 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 22 49
        Male
    		 38 39 77
    Race
    Units: Subjects
        White
    		 65 61 126
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 58 60 118
        Not Reported
    		 5 1 6
    Prior opioid treatment
    Units: Subjects
        WHO Step II analgesic
    		 27 28 55
        WHO Step III analgesic excluding morphine
    		 22 21 43
        Morphine
    		 16 12 28
    ECOG Status
    Eastern Cooperative Oncology Group (ECOG) performance status: 0 = Fully active. 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. 3 = Capable of only limited self-care. 4 = Completely disabled. 5 = Dead.
    Units: Subjects
        Status 0
    		 17 13 30
        Status 1
    		 30 30 60
        Status 2
    		 18 18 36
        Status 3
    		 0 0 0
        Status 4
    		 0 0 0
        Status 5
    		 0 0 0
    Cancer history - Stage IV
    There were 10 subjects (N=3 cebranopadol and N=7 morphine with an unknown stage at enrolmment) Multiple entries were possible for cancer history stage thus only the details for Stage IV, the most frequent staging, is reflected.
    Units: Subjects
        Stage IV
    		 52 45 97
        Other
    		 12 16 28
        Missing
    		 1 0 1
    Subjects with neuropathic pain component
    Based on medical history.
    Units: Subjects
        Neuropathic component present
    		 28 24 52
        No neuropathic component present
    		 37 37 74
    Subjects with a visceral pain component
    Units: Subjects
        Visceral pain present
    		 31 28 59
        No viseral pain present
    		 34 33 67
    Subjects with a somatic pain component
    Units: Subjects
        Somatic pain component present
    		 39 34 73
        No somatic pain component present
    		 26 27 53
    Height
    Units: meter
        arithmetic mean (standard deviation)
    		 1.6889 ( 0.09097 ) 1.692 ( 0.07952 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 73.52 ( 14.126 ) 71.23 ( 12.807 ) -
    Body Mass Index (BMI)
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 25.74 ( 4.39 ) 24.84 ( 4.022 ) -
    Baseline pain intensity
    For this assessment, each subject was asked "Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours" on an 11-point Numerical Rating Scale, where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The value was calculated from the mean of the 3 assessments of average pain intensity in the last 24 hours recorded during the last 3 days prior to the dosing visit, calculated when at least one assessment in this three-day window was available.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 6.23 ( 1 ) 6.3 ( 1.23 ) -
    Worst daily pain intensity
    For this assessment, each subject was asked "Please rate your pain by selecting the one number that best describes your pain at its worst during the last 24 hours" on an 11-point Numerical Rating Scale, where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The value reported is the mean of the 3 assessments of worst pain intensity in the last 24 hours recorded during the last 3 days prior to the first dosing visit, calculated when at least one assessment in this three-day window was available.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 7.27 ( 1.222 ) 7.29 ( 1.117 ) -
    Time since cancer pain onset
    Time since cancer pain onset (in weeks) before informed consent signature.
    Units: weeks
        arithmetic mean (standard deviation)
    		 62.25 ( 111.915 ) 60.22 ( 79.792 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cebranopadol
    Reporting group description
    		 Subjects took one or two tablet(s) of cebranopadol in the morning and one or two placebo double-dummy morphine-like capsule(s) in the morning and the evening.

    Reporting group title
    Morphine Prolonged Release
    Reporting group description
    		 Subjects took morphine capsule(s) in the morning and in the evening and placebo double-dummy cebranopadol-like tablet(s) in the morning.

    Subject analysis set title
    Cebranopadol Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS describes a subset of subjects in the FAS. The PPS included all allocated subjects who completed at least 2 weeks of treatment in the maintenance phase and had no major protocol deviations relevant for efficacy evaluations.

    Subject analysis set title
    Morphine Prolonged Release Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS describes a subset of subjects in the FAS. The PPS included all allocated subjects who completed at least 2 weeks of treatment in the maintenance phase and had no major protocol deviations relevant for efficacy evaluations.

    Subject analysis set title
    Cebranopadol Full Analysis Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all allocated subjects who took at least 1 dose of the IMP and had at least 1 day with information for the amount of rescue medication intake after the first intake of double-blind IMP.

    Subject analysis set title
    Morphine Prolonged Release Full Analysis Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all allocated subjects who took at least 1 dose of the IMP and had at least 1 day with information for the amount of rescue medication intake after the first intake of double-blind IMP.

    Primary: Average amount of daily rescue medication (morphine IR) intake over the last 2 weeks of the Maintenance Phase

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    End point title
    		 Average amount of daily rescue medication (morphine IR) intake over the last 2 weeks of the Maintenance Phase
    End point description
    Morphine sulfate immediate release (IR) 10 mg tablets were supplied as rescue medication to trial participants. The daily use of morphine sulfate 10 mg immediate release tablets was documented by each participant in the trial. The total daily amount of morphine IR was subject to an upper limit recommendation. The primary endpoint was the average amount of daily rescue medication intake over the last 2 weeks of the maintenance period. No dose adjustments of the morphine prolonged release or cebranopadol was allowed during the maintenance period.
    End point type
    Primary
    End point timeframe
    Maintenance Period (Week 3 and Week 4 )
    End point values
    		 Cebranopadol Per Protocol Population Morphine Prolonged Release Per Protocol Population Cebranopadol Full Analysis Population Morphine Prolonged Release Full Analysis Population
    Number of subjects analysed
    43
    45
    64
    61
    Units: milligram(s)/24 hours
        least squares mean (standard error)
    4.25 ( 1.7 )
    8.92 ( 1.72 )
    3.46 ( 1.71 )
    10.94 ( 1.75 )
    Statistical analysis title
    		 Rescue Intake Cebranopadol vs Morphine PR - FAS
    Statistical analysis description
    The MMRM (mixed model repeated measurement) model includes fixed effects of pooled country, treatment, week, treatment-by-week interaction, history of opioid intake, baseline pain intensity as covariate & subject-specific random effects. Dependent variable being the weekly average rescue medication intake. For subjects in the FAS having no data in the Maintenance Phase the average amount of rescue medication over the last 3 days of titration was imputed to the 1st week of the Maintenance Phase.
    Comparison groups
    Cebranopadol Full Analysis Population v Morphine Prolonged Release Full Analysis Population
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 MMRM
    Point estimate
    -7.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.05
         upper limit
    		 -2.918
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3
    Notes
    [1] - A non-inferiority margin of 8 mg.
    Statistical analysis title
    		 Rescue Intake Cebranopadol vs Morphine PR – PPS
    Statistical analysis description
    The MMRM (mixed model repeated measurement) model includes fixed effects of pooled country, treatment, week, treatment-by-week interaction, history of opioid intake, baseline pain intensity as covariate & subject-specific random effects. Dependent variable being the weekly average rescue medication intake. For subjects in the FAS having no data in the Maintenance Phase the average amount of rescue medication over the last 3 days of titration was imputed to the 1st week of the Maintenance Phase.
    Comparison groups
    Cebranopadol Per Protocol Population v Morphine Prolonged Release Per Protocol Population
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 MMRM
    Point estimate
    -4.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.245
         upper limit
    		 -0.099
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3
    Notes
    [2] - A non-inferiority margin of 8 mg.

    Secondary: Proportion of subjects with clinically relevant pain reductions

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    End point title
    		 Proportion of subjects with clinically relevant pain reductions
    End point description
    The secondary efficacy endpoint was the proportion of subjects with clinically relevant pain reduction (Responder / Non-responder) over the last 2 weeks of the Maintenance Phase. Definition of clinically relevant pain reduction: • Average pain intensity of less than 4 points on the 11-point NRS. Or • Reduction in average pain intensity by at least 30% (compared to the baseline assessment). Or • Reduction in average pain intensity by greater than or equal to 2 points (compared to the baseline assessment). (The average pain intensity is the average of the 24-hour pain intensities over the last 2 weeks of the Maintenance Phase.)
    End point type
    Secondary
    End point timeframe
    Maintenance week 3 and 4.
    End point values
    		 Cebranopadol Per Protocol Population Morphine Prolonged Release Per Protocol Population Cebranopadol Full Analysis Population Morphine Prolonged Release Full Analysis Population
    Number of subjects analysed
    43
    45
    64
    61
    Units: Subjects
        Responder
    35
    40
    48
    51
        Non-responder
    8
    5
    16
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first IMP intake up to day of last IMP (6 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Cebranopadol
    Reporting group description
    		 -

    Reporting group title
    Morphine Prolonged Release
    Reporting group description
    		 -

    Serious adverse events
    		 Cebranopadol Morphine Prolonged Release
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 65 (21.54%)
    11 / 61 (18.03%)
         number of deaths (all causes)
    3
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    5 / 65 (7.69%)
    7 / 61 (11.48%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Metastases to central nervous system
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (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
    Fungal infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cebranopadol Morphine Prolonged Release
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 65 (80.00%)
    48 / 61 (78.69%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    6 / 65 (9.23%)
    5 / 61 (8.20%)
         occurrences all number
    7
    5
    Paraesthesia
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 61 (1.64%)
         occurrences all number
    4
    1
    Dizziness
         subjects affected / exposed
    2 / 65 (3.08%)
    6 / 61 (9.84%)
         occurrences all number
    2
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 65 (10.77%)
    10 / 61 (16.39%)
         occurrences all number
    7
    10
    Oedema peripheral
         subjects affected / exposed
    7 / 65 (10.77%)
    0 / 61 (0.00%)
         occurrences all number
    8
    0
    Asthenia
         subjects affected / exposed
    6 / 65 (9.23%)
    8 / 61 (13.11%)
         occurrences all number
    6
    9
    Pyrexia
         subjects affected / exposed
    4 / 65 (6.15%)
    4 / 61 (6.56%)
         occurrences all number
    6
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 65 (4.62%)
    5 / 61 (8.20%)
         occurrences all number
    3
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 65 (3.08%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 65 (12.31%)
    15 / 61 (24.59%)
         occurrences all number
    11
    15
    Nausea
         subjects affected / exposed
    8 / 65 (12.31%)
    10 / 61 (16.39%)
         occurrences all number
    11
    12
    Vomiting
         subjects affected / exposed
    8 / 65 (12.31%)
    5 / 61 (8.20%)
         occurrences all number
    13
    6
    Diarrhoea
         subjects affected / exposed
    4 / 65 (6.15%)
    5 / 61 (8.20%)
         occurrences all number
    4
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 61 (1.64%)
         occurrences all number
    4
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 65 (3.08%)
    6 / 61 (9.84%)
         occurrences all number
    2
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 65 (7.69%)
    9 / 61 (14.75%)
         occurrences all number
    5
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2013
    This amendment was in place before First Subject Enrolled. The selection criteria were adapted to exclude opioid-naive subjects. The primary endpoint was changed to assess the amount of rescue medication taken. The primary endpoint was analyzed on the Full Analysis Set and on the Per Protocol Set. The number of planned interim analyses was reduced to 1. The sample size was adapted to include 524 allocated subjects due to the change of the primary endpoint. Morphine sulfate PR as a once daily formulation was replaced by a twice daily formulation. Administration strategy (double-dummy), selection criteria, rules for concomitant medication and times for pain assessments were adapted accordingly to cover the change of comparator formulation and improved scientific knowledge on cebranopadol. It was planned to offer an extension trial to subjects who completed the treatment of this trial (separate trial protocol).
    16 Dec 2014
    Protocol exclusion and discontinuation criteria on creatinine clearance were adapted based on new scientific data. Exclusion criteria were adapted to allow re-enrollment of subjects who would be eligible for the trial due to the changes made as part of this amendment or if a subject was an enrollment failure due to technical failure of equipment. The enrollment period was extended. For allowed concomitant medication and therapies, clarifications were made for chemotherapy, medications effecting the QT interval, corticosteroids and anti-emetic treatment. Further clarifications concerned history/presence of cerebral tumor, check of previous opioid medication and assessment of Child-Pugh score and DN4 questionnaire. The tests to be performed when a subject prematurely discontinues the trial were extended. The statistical sections of the protocol were aligned with the descriptions given in the statistical analysis plan. Sensitivity analyses were changed to allow for a direct comparison of the primary and sensitivity results of the primary endpoint assuming missing mechanisms. Reference to Forest Research Institute was removed as they were no longer involved in the development of cebranopadol.

    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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