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    Clinical Trial Results:
    Efficacy, safety and tolerability of multiple doses of oral cebranopadol in subjects with moderate to severe chronic pain due to diabetic peripheral neuropathy

    Summary
    EudraCT number
    		 2013-000473-68
    Trial protocol
    		 AT   IT   NL   BE   ES   DE   DK  
    Global end of trial date
    28 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    27 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF6005/08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01939366
    WHO universal trial number (UTN)
    		 U1111-1151-4331
    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
    28 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the analgesic efficacy, safety, and tolerability of once daily orally administered cebranopadol in a total of 3 fixed doses (100 µg, 300 µg, and 600 µg cebranopadol) compared to placebo in subjects with moderate to severe chronic pain due to DPN.
    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 authorities were notified of the trial and amendments as required by national regulations, and where necessary relevant authorization was obtained. Furthermore, the competent authorities were notified of this trial in accordance with national requirements.
    Background therapy
    		 Allowed concomitant treatments were: • Anti-diabetic medication (kept stable for the duration of the trial, unless changes were medically warranted). • Acetylsalicylic acid at oral doses equal or lower than 325 mg per day for cardiovascular prophylaxis. • Anti-emetics and laxatives for the treatment but not for prophylaxis. • Selective serotonin reuptake inhibitors and hypnotics including benzodiazepines and non-benzodiazepines if previously used regularly, on a stable dose, according to the Summary of Product Characteristics for at least 4 weeks prior to Enrollment Visit and planned to continue on the same dose regimen throughout the trial. • Triptans for the treatment of migraine. • Vitamin B12 injections. • Inhaled steroids and topical (skin) steroids. • Non-pharmacological pain therapies, provided that the subjects have been on that therapy for at least 4 weeks prior to the Enrollment Visit and continue to undergo therapy for the duration of the trial at the same frequency and intensity as before. − Transcutaneous electrical nerve simulation (TENS). − Acupuncture. − Biofeedback. − Chiropractic manipulation. Paracetamol (500 mg tablets) was provided as rescue medication for unacceptable pain due to DPN, with the following exception: no rescue medication was allowed during the last 3 days before Baseline Visit. The maximum total daily dose of paracetamol was 2 g. Paracetamol should not have been taken for more than 3 consecutive days at the maximum allowed total daily dose. In addition, the use of rescue medication at the maximum allowed total daily dose was not to be exceeded for 20 days in total during the Maintenance Phase and the Follow-up Period.
    Evidence for comparator
    		 Neuropathic pain Efficacy has been shown in trials in diabetic neuropathy, post herpetic neuralgia and spinal cord injury. Efficacy has not been studied in other models of neuropathic pain. Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks with twice a day dosing (BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar. In clinical trials up to 12 weeks for both peripheral and central neuropathic pain, a reduction in pain was seen by week 1 and was maintained throughout the treatment period. In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and 18% of the patients on placebo had a 50% improvement in pain score.
    Actual start date of recruitment
    27 Sep 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
    Netherlands: 16
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Austria: 27
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 154
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    United States: 55
    Worldwide total number of subjects
    314
    EEA total number of subjects
    259
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    181
    From 65 to 84 years
    133
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject signed informed consent on the 27 September 2013 and the last subject completed the trial on the 28 January 2015.

    Pre-assignment
    Screening details
    		 699 subjects signed informed consent in 82 active sites. The main reason for a subject not being allocated to treatment was a failure to meet the inclusion/exclusion criteria (322 subjects). 13 allocated subjects from 2 sites were excluded from the SAF and FAS analyses due to CGP non-compliance; 2 more subjects were allocated but not treated.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Matching placebo and double dummy technique.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Matching Placebo
    Arm description
    		 Placebo was matched to pregabalin and cebranopadol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching cebranopadol film-coated tablets were taken once daily in the morning, placebo capsules matching over-encapsulated pregabalin were taken BID (morning and evening).

    Arm title
    		 Cebranopadol 100 µg
    Arm description
    		 Participants randomized to 100 μg cebranopadol started with 100 μg per day and remained on 100 μg per day.
    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
    Cebranopadol film-coated tablets were taken once daily in the morning.

    Arm title
    		 Cebranopadol 300 µg
    Arm description
    		 Participants randomized to 300 μg cebranopadol started with 100 μg per day. On day 4 participants increased their dose to 300 μg per day and then remained on 300 μg per day.
    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
    Cebranopadol film-coated tablets were taken once daily in the morning.

    Arm title
    		 Cebranopadol 600 µg
    Arm description
    		 Participants randomized to 600 μg cebranopadol started with 200 μg per day and increased to 400 μg per day on day 4 and to 600 μg on day 7, thereafter they remained on 600 μg per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cebranopadol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cebranopadol film-coated tablets were taken once daily in the morning.

    Arm title
    		 Pregabalin 600 mg
    Arm description
    		 Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pregabalin over-encapsulated capsules were taken in the morning and in the evening. In the 2-week Titration Phase, the pregabalin starting dose was 75 mg twice daily (BID) on Day 1 with an increase to 150 mg BID on Day 4, to 225 mg BID on Day 8, and to 300 mg BID on Day 12. In the Maintenance Phase, pregabalin was to be taken at the target dose of 300 mg BID but with the option to permanently reduce to 225 mg BID if not tolerated. At the end of the Maintenance Phase, the pregabalin dose was to be gradually tapered off over 1 week (150 mg BID for 4 days and 75 mg BID for 3 days).

    Number of subjects in period 1
    		Matching Placebo Cebranopadol 100 µg Cebranopadol 300 µg Cebranopadol 600 µg Pregabalin 600 mg
    Started
    62
    64
    61
    62
    65
    Completed
    48
    52
    41
    27
    51
    Not completed
    14
    12
    20
    35
    14
         Consent withdrawn by subject
    3
    1
    -
    2
    2
         Adverse event, non-fatal
    5
    8
    17
    30
    8
         Not specified
    1
    -
    -
    2
    2
         Sponsor decision
    2
    -
    -
    -
    -
         Lost to follow-up
    -
    1
    1
    -
    -
         Inclusion criteria not met
    -
    -
    1
    -
    -
         Lack of efficacy
    3
    2
    1
    1
    1
         Protocol deviation
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Matching Placebo
    Reporting group description
    		 Placebo was matched to pregabalin and cebranopadol.

    Reporting group title
    Cebranopadol 100 µg
    Reporting group description
    		 Participants randomized to 100 μg cebranopadol started with 100 μg per day and remained on 100 μg per day.

    Reporting group title
    Cebranopadol 300 µg
    Reporting group description
    		 Participants randomized to 300 μg cebranopadol started with 100 μg per day. On day 4 participants increased their dose to 300 μg per day and then remained on 300 μg per day.

    Reporting group title
    Cebranopadol 600 µg
    Reporting group description
    		 Participants randomized to 600 μg cebranopadol started with 200 μg per day and increased to 400 μg per day on day 4 and to 600 μg on day 7, thereafter they remained on 600 μg per day.

    Reporting group title
    Pregabalin 600 mg
    Reporting group description
    		 Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.

    Reporting group values
    		 Matching Placebo Cebranopadol 100 µg Cebranopadol 300 µg Cebranopadol 600 µg Pregabalin 600 mg Total
    Number of subjects
    		 62 64 61 62 65 314
    Age categorical
    Safety Set
    Units: Subjects
        Adults (18-64 years)
    		 32 37 38 39 35 181
        From 65-84 years
    		 30 27 23 23 30 133
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Safety Set
    Units: years
        arithmetic mean (standard deviation)
    		 63.3 ( 10.3 ) 62.2 ( 8.6 ) 61.6 ( 8.7 ) 62.2 ( 8.1 ) 61.7 ( 9.9 ) -
    Gender categorical
    Safety Set
    Units: Subjects
        Female
    		 13 20 23 22 16 94
        Male
    		 49 44 38 40 49 220
    Height
    Safety Set
    Units: meter
        arithmetic mean (standard deviation)
    		 1.736 ( 0.076 ) 1.721 ( 0.098 ) 1.736 ( 0.092 ) 1.717 ( 0.104 ) 1.736 ( 0.11 ) -
    Weight
    Safety Set
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 99 ( 15.99 ) 95.77 ( 15.62 ) 96.51 ( 18.12 ) 93.72 ( 16.05 ) 92.25 ( 17.28 ) -
    Body Mass Index (BMI)
    Safety Set
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 32.8 ( 4.53 ) 32.3 ( 4.41 ) 31.87 ( 4.39 ) 31.7 ( 4.29 ) 30.66 ( 5.26 ) -
    Pain Assessment - Average 24-hour pain
    The pain was assessed in the evening before IMP intake. The subject was asked to answer the following question: “Please rate your pain by selecting the one number that best describes your pain on average during the last 24 hours.” Subject’s pain assessments on an 11-point NRS (0 = no pain, 10 = pain as bad as you can imagine) using an e-diary: average pain during the last 24 hours. Safety Set.
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 6.84 ( 1.15 ) 6.92 ( 1.34 ) 6.8 ( 1.37 ) 6.8 ( 1.25 ) 6.78 ( 1.22 ) -
    Pain Assessment - Worst 24-hour pain
    The pain was assessed in the evening before IMP intake. The subject was asked to answer the following question: “Please rate your pain by selecting the one number that best describes your pain at its worst during the last 24 hours”. Subject’s pain assessments on an 11-point NRS (0 = no pain, 10 = pain as bad as you can imagine) using an e-diary: worst pain during the last 24 hours. Safety Set.
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 7.33 ( 1.14 ) 7.41 ( 1.36 ) 7.32 ( 1.28 ) 7.38 ( 1.21 ) 7.32 ( 1.16 ) -
    Pain Assessment - Current Morning Pain
    The pain was assessed in the morning before IMP intake. The subject was asked to answer the following question: “Please rate your pain by selecting the one number that best describes how much pain you have right now”. Subject’s pain assessments on an 11-point NRS (0 = no pain, 10 = pain as bad as you can imagine) using an e-diary: current pain in the morning. Safety Set.
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 6.58 ( 1.48 ) 6.6 ( 1.58 ) 6.58 ( 1.53 ) 6.44 ( 1.46 ) 6.61 ( 1.44 ) -
    Pain Assessment - Current Evening Pain
    The pain was assessed in the evening before IMP intake. The subject was asked to answer the following question: “Please rate your pain by selecting the one number that best describes how much pain you have right now”. Subject’s pain assessments on an 11-point NRS (0 = no pain, 10 = pain as bad as you can imagine) using an e-diary: current pain in the evening. Safety Set.
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 6.55 ( 1.34 ) 6.98 ( 1.5 ) 6.87 ( 1.46 ) 6.68 ( 1.33 ) 6.75 ( 1.36 ) -
    Diabetic Peripheral Neuropathic Pain Impact Measure (DPNPI)
    The DPNPI measure was developed at Forest Research Institute to assess the key impacts of living with painful DPN on daily and physical functioning. Three domains in the DPNPI: Physical/Mobility (8 items), Sleep (5 items), and Daily Activity (5 items) are reported as a total score (0 to 100). A lower score indicates a better health state. Full Analysis Set.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 57.4 ( 18.1 ) 59.7 ( 18 ) 56.8 ( 22.1 ) 57.7 ( 21 ) 56.6 ( 18.9 ) -
    Neuropathic Pain Symptom Inventory (NPSI)
    The NPSI is a self-administered questionnaire specifically designed for the evaluation of different neuropathic pain qualities/intensity of neuropathic pain components. The questionnaire includes a list of 10 descriptors resulting in a total score from 0 to 1. A score of 0 indicates that there are no neuropathic symptoms. A score of 1 indicates that all neuropathic symptoms are present and at their worst possible intensity. Full Analysis Set.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 0.48 ( 0.208 ) 0.505 ( 0.203 ) 0.523 ( 0.202 ) 0.49 ( 0.206 ) 0.491 ( 0.178 ) -
    Sleep Problems Index
    The Sleep Problems Index measures 3 items of the Chronic Pain Sleep Inventory (CPSI), i.e. trouble falling asleep (CPSI1), awakened by pain during the night (CPSI3) and awakened by pain in the morning (CPSI4). Each item of the CPSI is scaled separately using 100 mm visual analog scales. Higher scores indicate greater Sleep Problems. Full Analysis Set.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 153.9 ( 85.9 ) 173.5 ( 78.1 ) 158.1 ( 94.9 ) 155.9 ( 88.9 ) 171.6 ( 83.1 ) -
    EuroQol-5 Dimension quality of life questionnaire
    The EQ-5D Health Questionnaire will be completed by the subjects and has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each of the 5 dimensions has 5 possible levels: no, slight, moderate, severe and extreme. The index uses general population weighted estimates for various health states. In general, the range of the single weighted average index and tends to vary between 0 = death and 1 = perfect health. Full Analysis Set.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 0.51 ( 0.21 ) 0.515 ( 0.207 ) 0.506 ( 0.248 ) 0.504 ( 0.21 ) 0.5 ( 0.217 ) -

    End points

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    End points reporting groups
    Reporting group title
    Matching Placebo
    Reporting group description
    		 Placebo was matched to pregabalin and cebranopadol.

    Reporting group title
    Cebranopadol 100 µg
    Reporting group description
    		 Participants randomized to 100 μg cebranopadol started with 100 μg per day and remained on 100 μg per day.

    Reporting group title
    Cebranopadol 300 µg
    Reporting group description
    		 Participants randomized to 300 μg cebranopadol started with 100 μg per day. On day 4 participants increased their dose to 300 μg per day and then remained on 300 μg per day.

    Reporting group title
    Cebranopadol 600 µg
    Reporting group description
    		 Participants randomized to 600 μg cebranopadol started with 200 μg per day and increased to 400 μg per day on day 4 and to 600 μg on day 7, thereafter they remained on 600 μg per day.

    Reporting group title
    Pregabalin 600 mg
    Reporting group description
    		 Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.

    Primary: Change in Average Pain Intensity

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    End point title
    		 Change in Average Pain Intensity
    End point description
    Subjects will be asked to record their pain intensity in the evening. Subjects were asked to rate how much pain they had on average in the past 24 hours. The subject scored their pain intensity 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". Baseline average pain scores were calculated from the averages of all scores recorded during the 3 days prior to randomization. The average pain at week 6 will be the average pain scores calculated from all pain scores measured during week 6.
    End point type
    Primary
    End point timeframe
    Baseline to End of Week 6 of the Maintenance Phase
    End point values
    		 Matching Placebo Cebranopadol 100 µg Cebranopadol 300 µg Cebranopadol 600 µg Pregabalin 600 mg
    Number of subjects analysed
    61
    64
    60
    58
    64
    Units: unit(s)
    number (confidence interval 95%)
        Change in Average Pain Intensity
    -1.55 (-2.1 to -1)
    -2.24 (-2.78 to -1.7)
    -2.28 (-2.86 to -1.71)
    -2.56 (-3.2 to -1.91)
    -2.79 (-3.33 to -2.26)
    Statistical analysis title
    		 Cebranopadol 100 µg versus Matching Placebo
    Statistical analysis description
    The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.
    Comparison groups
    Matching Placebo v Cebranopadol 100 µg
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0621 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mixed Model Analysis
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Notes
    [1] - The analysis consisted of the contrasts (mixed model Wald tests) of individual cebranopadol doses versus placebo during Week 6 of Maintenance Phase.
    [2] - Due to the exploratory character of this trial, no multiple testing adjustment for control of the false positive rate was applied.
    Statistical analysis title
    		 Cebranopadol 300 µg versus Matching Placebo
    Statistical analysis description
    The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.
    Comparison groups
    Matching Placebo v Cebranopadol 300 µg
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0564 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mixed Model Analysis
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Notes
    [3] - The analysis consisted of the contrasts (mixed model Wald tests) of individual cebranopadol doses versus placebo during Week 6 of Maintenance Phase.
    [4] - Due to the exploratory character of this trial, no multiple testing adjustment for control of the false positive rate was applied.
    Statistical analysis title
    		 Cebranopadol 600 µg versus Matching Placebo
    Statistical analysis description
    The mixed model repeated measurement (MMRM) model included fixed effects of pooled sites, treatment, week, treatment-by-week interaction, baseline pain, and a subject-specific random effect. The model was based on the weekly average 24-hour pain intensity of the 2 weeks in the Titration Phase and 6 weeks in the Maintenance Phase. An unstructured covariance matrix was used to model the covariance structure, denominator degrees of freedom were estimated using the Kenward-Roger approximation.
    Comparison groups
    Matching Placebo v Cebranopadol 600 µg
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0153 [6]
    Method
    		 Mixed Model Analysis
    Parameter type
    		 Mixed Model Analysis
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.83
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41
    Notes
    [5] - The analysis consisted of the contrasts (mixed model Wald tests) of individual cebranopadol doses versus placebo during Week 6 of Maintenance Phase.
    [6] - Due to the exploratory character of this trial, no multiple testing adjustment for control of the false positive rate was applied.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline Visit first IMP dose (Day 1) to Visit 9 (Day 71).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Matching Placebo
    Reporting group description
    		 Placebo was matched to pregabalin and cebranopadol.

    Reporting group title
    Cebranopadol 100 µg
    Reporting group description
    		 Participants randomized to 100 μg cebranopadol started with 100 μg per day and remained on 100 μg per day.

    Reporting group title
    Cebranopadol 300 µg
    Reporting group description
    		 Participants randomized to 300 μg cebranopadol started with 100 μg per day. On day 4 participants increased their dose to 300 μg per day and then remained on 300 μg per day.

    Reporting group title
    Cebranopadol 600 µg
    Reporting group description
    		 Participants randomized to 600 μg cebranopadol started with 200 μg per day and increased to 400 μg per day on day 4 and to 600 μg on day 7, thereafter they remained on 600 μg per day.

    Reporting group title
    Pregabalin
    Reporting group description
    		 Stepwise titration from 75 mg twice a day to 300 mg twice a day over 2 weeks.

    Serious adverse events
    		 Matching Placebo Cebranopadol 100 µg Cebranopadol 300 µg Cebranopadol 600 µg Pregabalin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 64 (1.56%)
    2 / 61 (3.28%)
    4 / 62 (6.45%)
    1 / 65 (1.54%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    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
    Vomiting
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    2 / 62 (3.23%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    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
    Diabetes mellitus
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Matching Placebo Cebranopadol 100 µg Cebranopadol 300 µg Cebranopadol 600 µg Pregabalin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 62 (69.35%)
    47 / 64 (73.44%)
    50 / 61 (81.97%)
    52 / 62 (83.87%)
    49 / 65 (75.38%)
    Investigations
    Weight increase
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 64 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
    5 / 65 (7.69%)
         occurrences all number
    1
    0
    0
    0
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 62 (9.68%)
    8 / 64 (12.50%)
    10 / 61 (16.39%)
    21 / 62 (33.87%)
    12 / 65 (18.46%)
         occurrences all number
    7
    9
    11
    21
    18
    Headache
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 64 (4.69%)
    6 / 61 (9.84%)
    3 / 62 (4.84%)
    4 / 65 (6.15%)
         occurrences all number
    2
    3
    6
    3
    4
    Somnolence
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 64 (4.69%)
    8 / 61 (13.11%)
    8 / 62 (12.90%)
    3 / 65 (4.62%)
         occurrences all number
    1
    4
    8
    9
    4
    Tremor
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 64 (1.56%)
    1 / 61 (1.64%)
    1 / 62 (1.61%)
    4 / 65 (6.15%)
         occurrences all number
    0
    1
    1
    1
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 62 (3.23%)
    8 / 64 (12.50%)
    11 / 61 (18.03%)
    10 / 62 (16.13%)
    5 / 65 (7.69%)
         occurrences all number
    2
    8
    11
    11
    5
    Oedema peripheral
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 64 (4.69%)
    3 / 61 (4.92%)
    1 / 62 (1.61%)
    6 / 65 (9.23%)
         occurrences all number
    1
    3
    3
    1
    8
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 64 (0.00%)
    6 / 61 (9.84%)
    0 / 62 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    6
    0
    0
    Constipation
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 64 (4.69%)
    6 / 61 (9.84%)
    7 / 62 (11.29%)
    6 / 65 (9.23%)
         occurrences all number
    4
    3
    7
    8
    6
    Diarrhoea
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 64 (6.25%)
    2 / 61 (3.28%)
    3 / 62 (4.84%)
    2 / 65 (3.08%)
         occurrences all number
    5
    4
    2
    3
    2
    Dry mouth
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 64 (1.56%)
    1 / 61 (1.64%)
    8 / 62 (12.90%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    1
    9
    1
    Nausea
         subjects affected / exposed
    6 / 62 (9.68%)
    6 / 64 (9.38%)
    22 / 61 (36.07%)
    16 / 62 (25.81%)
    6 / 65 (9.23%)
         occurrences all number
    6
    6
    28
    16
    6
    Vomiting
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 64 (3.13%)
    10 / 61 (16.39%)
    17 / 62 (27.42%)
    1 / 65 (1.54%)
         occurrences all number
    2
    2
    20
    20
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 64 (4.69%)
    8 / 61 (13.11%)
    6 / 62 (9.68%)
    1 / 65 (1.54%)
         occurrences all number
    2
    3
    8
    7
    1
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 64 (1.56%)
    1 / 61 (1.64%)
    2 / 62 (3.23%)
    0 / 65 (0.00%)
         occurrences all number
    5
    1
    1
    2
    0
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    6 / 62 (9.68%)
    5 / 64 (7.81%)
    3 / 61 (4.92%)
    3 / 62 (4.84%)
    6 / 65 (9.23%)
         occurrences all number
    6
    5
    3
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    6 / 62 (9.68%)
    3 / 64 (4.69%)
    1 / 61 (1.64%)
    1 / 62 (1.61%)
    5 / 65 (7.69%)
         occurrences all number
    7
    3
    1
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2013
    - Introduction of an additional mandatory criterion for discontinuation in case of lack of efficacy. - Exchange of the English example of the COWS questionnaire in the appendix. - Minor corrections regarding the description of the handling of prematurely discontinued subjects, physical examination, medical history, concomitant medication, and the microscopic examination of the urine dipstick test. - Correction of the description regarding the process for generation of subject numbers.
    12 Dec 2013
    Additional mandatory criterion for the compulsory discontinuation of subjects in the UK in case of an increase in the QTcF interval of >60 ms compared to baseline.
    16 Jan 2014
    Modification of inclusion and exclusion criteria to better reflect daily clinical practice and broaden the target population.
    28 Jul 2014
    Prolongation of the subject recruitment period by 6 months which became necessary due to the slower than anticipated recruitment.

    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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