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    Clinical Trial Results:
    An open-label, multi-site trial to describe the safety and tolerability of oral cebranopadol administered for 26 weeks in subjects with cancer-related pain who have completed treatment in the KF6005/07 trial

    Summary
    EudraCT number
    2013-001877-26
    Trial protocol
    SE   GB   BE   HU   SK   AT   DE   DK   PL   ES   BG   NL   HR  
    Global end of trial date
    03 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jan 2017
    First version publication date
    29 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF6005/09
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1144-0778
    Other trial identifiers
    Grünenthal GmbH: 168935
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52099
    Public contact
    GRT Trial Information Desk, Grünenthal GmbH, 0049 2415693223, clinical-trials@grunenthal.com
    Scientific contact
    GRT Trial Information Desk, Grünenthal GmbH, 0049 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
    12 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to describe the safety and tolerability of prolonged exposure to cebranopadol in subjects suffering from cancer related pain
    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. Subjects were followed-up at a regular basis with a total of 15 planned visits over 28 weeks. A final follow-up visit was planned 2 weeks after the last intake of cebranopadol Investigational Medicinal Product (IMP).
    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 during treatment and until the follow-up visit (starting from the 2 weeks before enrollment into the KF6005/07 trial). - Investigators were free to prescribe on demand medication (within limits - if not listed as forbidden medication). This medication could be used in case of unbearable or breakthrough pain according to the respective summary of product characteristics.
    Evidence for comparator
    There was no comparator in this trial.
    Actual start date of recruitment
    18 Dec 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: 17
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Slovakia: 21
    Worldwide total number of subjects
    76
    EEA total number of subjects
    72
    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)
    43
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First subject was enrolled on the 18 Dec 2013 (first dose taken on the 19 Dec 2013) and the last subject completed the trial on the 03 May 2016. All subjects in this trial completed the maintenance period in the KF6005/07 trial.

    Pre-assignment
    Screening details
    Subjects who completed treatment in KF6005/07 and who were still in need of around-the-clock pain analgesia with strong opioids directly entered the KF6005/09 trial from the KF6005/07 trial. Seventy-six subjects (37 previously on cebranopadol and 39 subjects previously morphine treatment) were enrolled in this trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Subjects who completed the treatment in KF6005/07 were to start on a daily dose of 200 or 400 µg cebranopadol in the KF6005/09 trial. The treatment code from the KF6005/07 was not unblinded at the time when the subject started the cebranopadol treatment. All subjects were titrated to their optimal dose.

    Arms
    Arm title
    Cebranopadol
    Arm description
    Subjects who completed the treatment in KF6005/07 and were suitable and willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects.
    Arm type
    Experimental

    Investigational medicinal product name
    Cebranopadol film-coated tablets
    Investigational medicinal product code
    GRT6005
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects started on a cebranopadol treatment based on a predefined set of criteria. The decision on up-titration took place after 4 days of IMP use on certain dose level (exception: first dose level). Subjects were allowed to titrate up to a maximum daily dose of 1000 µg/day. Subjects were instructed to take cebranopadol orally once daily in the morning. The recommendation was to take cebranopadol between 06:00 h and 10:00 h, with a glass of water. The dose selected at the end of the Titration Phase was used during the Maintenance Phase. However, the dose could have been adjusted during the Maintenance Phase. Additionally, at any time during the trial, the dose may be discontinued for a certain period of time (e.g., because of adverse events). During the Titration Phase and the Maintenance Phase, all subjects were permitted to receive treatment for unbearable (breakthrough) pain.

    Number of subjects in period 1
    Cebranopadol
    Started
    76
    Subjects completed the titration phase
    67
    Subjects that completed treatment
    39
    Completed
    38
    Not completed
    38
         Protocol deviation
             1
         Lack of efficacy
             5
         cancer progression
             2
         withdrawn as forbidden meds required
             1
         Adverse event, serious fatal
             10
         pre-specified protocol discontinuation criterion
             5
         Adverse event, non-fatal
             8
         Consent withdrawn by subject
             5
         Lost to follow-up
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    76 76
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    43 43
        From 65-84 years
    33 33
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.7 ± 9.81 -
    Gender categorical
    Units: Subjects
        Female
    32 32
        Male
    44 44
    Race
    Units: Subjects
        Asian
    0 0
        Black
    0 0
        White
    76 76
    Height
    Units: meter
        arithmetic mean (standard deviation)
    1.684 ± 0.0844 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    72 ± 14.04 -
    Body Mass Index (BMI)
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    25.36 ± 4.5 -
    Average pain during the last week
    The electronic case report form (eCRF) pain intensity assessment, baseline average pain intensity is the value of average pain during the last week recorded at baseline. The subject scored their average pain intensity during the last week on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.9 ± 1.97 -

    End points

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    End points reporting groups
    Reporting group title
    Cebranopadol
    Reporting group description
    Subjects who completed the treatment in KF6005/07 and were suitable and willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects.

    Primary: Incidence of treatment emergent adverse events

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    End point title
    Incidence of treatment emergent adverse events [1]
    End point description
    The safety of cebranopadol was assessed by the number of subjects with treatment emergent adverse events (TEAEs). A TEAE was any adverse event that occurred after the first administration of IMP, i.e. cebranopadol in this trial. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs.
    End point type
    Primary
    End point timeframe
    up to 28 weeks (26 weeks of cebranopadol treatment and 2 weeks follow-up after the last dose was planned per subject).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary end point for this open-label, single-arm trial was the incidence of Treatment Emergent Adverse Events during the 26 week open-label treatment period and the 2 week follow-up period. This was collected to assess long term safety on cebranopadol. No statistical testing or inference was planned on this primary objective.
    End point values
    Cebranopadol
    Number of subjects analysed
    76
    Units: subjects
    64
    No statistical analyses for this end point

    Secondary: Intensity of Treatment Emergent Adverse Events

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    End point title
    Intensity of Treatment Emergent Adverse Events
    End point description
    A treatment emergent adverse event (TEAE) was any adverse event that occurred after the first administration of IMP, i.e. cebranopadol in this trial. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs. The “intensity” of adverse event were classified as: Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted. Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration. Severe: symptoms affected the usual daily activity.
    End point type
    Secondary
    End point timeframe
    up to 28 weeks (26 weeks of cebranopadol treatment)
    End point values
    Cebranopadol
    Number of subjects analysed
    76 [2]
    Units: Events
        Mild intensity
    242
        Moderate intensity
    300
        Severe intensity
    119
    Notes
    [2] - There were a total of 661 reported Treatment Emergent Adverse Events reported in 76 subjects.
    No statistical analyses for this end point

    Secondary: Changes from baseline in the average pain intensity

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    End point title
    Changes from baseline in the average pain intensity
    End point description
    The subject scored their average pain intensity during the last week on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". Absolute change from baseline for average pain intensity during the last week were summarized descriptively for all subjects that scored their pain intensities.
    End point type
    Secondary
    End point timeframe
    Baseline Visit to Visit 14 (End of Treatment Visit) , i.e. up to 26 weeks.
    End point values
    Cebranopadol
    Number of subjects analysed
    59 [3]
    Units: units of a scale
        arithmetic mean (standard deviation)
    0.8 ± 2.14
    Notes
    [3] - Subjects with data available.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A treatment emergent adverse event was any adverse event that occurred after the first administration of IMP, i.e. cebranopadol in this trial. In addition, pretreatment adverse events which worsened during the treatment period were also considered TEAEs.
    Adverse event reporting additional description
    One subject experienced a serious non-treatment emergent adverse event preferred term "malignant neoplasm progression" before starting cebranopadol in this trial.
    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
    Subjects who completed the treatment in KF6005/07 and were willing to participate in this trial went into a Titration Phase (approximately 2 weeks). During the Titration Phase, the subjects were titrated to their individual optimal daily dose of cebranopadol, defined as a balance between self-reported analgesia and side effects. The dose selected at the end of the Titration Phase was used during the Maintenance Phase. However, the dose could have been adjusted during the Maintenance Phase. During the Titration Phase and the Maintenance Phase, all subjects were permitted to receive treatment for unbearable (breakthrough) pain.

    Serious adverse events
    Cebranopadol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 76 (42.11%)
         number of deaths (all causes)
    10
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Aortic thrombosis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    19 / 76 (25.00%)
         occurrences causally related to treatment / all
    0 / 26
         deaths causally related to treatment / all
    0 / 7
    Metastases to liver
    Additional description: One of the subject's with the serious adverse event "metastases to liver" also had "malignant neoplasm progression" reported as a serious adverse event with outcome death. Thus the number of fatalities is 10.
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Epididymitis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cebranopadol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 76 (82.89%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    7
    Leukocytosis
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Leukopenia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    7
    Thrombocytopenia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    6
    Thrombocytosis
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    8
    Somnolence
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    9
    Dizziness
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 76 (25.00%)
         occurrences all number
    21
    Fatigue
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    10
    Feeling drunk
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Oedema peripheral
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    10
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Insomnia
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Anxiety
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    7
    Nervousness
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 76 (14.47%)
         occurrences all number
    13
    Diarrhoea
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    5
    Abdominal pain upper
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    15 / 76 (19.74%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    11
    Arthralgia
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    8
    Musculoskeletal pain
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    10
    Pain in extremity
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 76 (22.37%)
         occurrences all number
    21
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2015
    Protocol Amendment dated 06 Jan 2015. Protocol exclusion and discontinuation criteria on creatinine clearance were adapted based on new scientific data. Clarifications were made for allowed concomitant medication and therapies medications affecting the QT interval. Clarifications were made for when the Child-Pugh score has to be assessed. The time window for the Follow-up Visit was specified. Reference to Forest Research Institute was removed as they are 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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