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    Clinical Trial Results:
    Randomised, double-blind, placebo-controlled, parallel-group design, multi-centre, dose-escalation phase III trial to investigate the efficacy, safety, and tolerability of Naloxone HCl PR tablets administered in a dose range of 6 mg to 48 mg once daily in patients with opioid induced constipation

    Summary
    EudraCT number
    		 2012-004311-31
    Trial protocol
    		 HU   AT   CZ   DE   GB   SK   ES   IT   PL  
    Global end of trial date
    01 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 May 2020
    First version publication date
    15 May 2020
    Other versions
    Summary report(s)
    		 0177/DEV

    Trial information

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    Trial identification
    Sponsor protocol code
    0177/DEV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Develco Pharma Schweiz AG
    Sponsor organisation address
    Hohenrainstr. 12 D, Pratteln, Switzerland, 4133
    Public contact
    Head Clinical Development, Develco Pharma Schweiz AG, 0041 614255026, info@develco.ch
    Scientific contact
    Head Clinical Development, Develco Pharma Schweiz AG, 0041 614255026, info@develco.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that administration of Naloxone HCl PR (prolonged-release) tablets once daily is superior to Naloxone HCl PR Placebo in the improvement / reversal of opioid-induced constipation (OIC) as determined by the Bowel Function Index (BFI).
    Protection of trial subjects
    The trial will be conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996), as well as with the valid national law(s) of the participating country/ies, with the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) (E6) issued in June 1996, and with the Commission Directives 2001/20/EC and 2005/28/EC.
    Background therapy
    		 Trial opioids: Oxycodone (Oxy) hydrochloride prolonged-release tablets XL (20 mg, 40 mg, 80 mg), oral administration, once daily, total daily dose: 20 mg, 40 mg, 60 mg or 80 mg Hydromorphone (HyMo) hydrochloride prolonged-release tablets XL, (8 mg, 16 mg, 32 mg), oral administration, once daily, total daily dose: 8 mg, 16 mg, 24 mg or 32 mg Opioid rescue medication: Morphine sulphate 10 mg immediate-release tablets, oral administration, as needed, single dose: 5-20 mg, depending on trial opioid dose Laxative rescue medications: Bisacodyl 5 mg gastro-resistant tablets, oral administration, single dose: 5-20 mg (1-4 tablets) Bisacodyl 10 mg suppositories, rectal administration, single dose: 10 mg, 1 suppository
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Hungary: 65
    Country: Number of subjects enrolled
    Slovakia: 22
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Austria: 1
    Worldwide total number of subjects
    183
    EEA total number of subjects
    183
    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)
    119
    From 65 to 84 years
    63
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects of ≥ 18 years of age with had a documented history of constipation induced or worsened by their oral, transdermal or sublingual World Health Organization (WHO) step-II or step-III opioid medication were recruited.

    Pre-assignment
    Screening details
    		 A total of 267 subjects were screened, out of these, 183 subjects were randomized. 39 subjects were screening failures. Further 45 screened subjects prematurely discontinued from the trial before randomisation.

    Pre-assignment period milestones
    Number of subjects started
    		 267 [1]
    Number of subjects completed
    		 183

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 19
    Reason: Number of subjects
    		 Adverse event, serious non-fatal: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 5
    Reason: Number of subjects
    		 Noneligibility: 48
    Reason: Number of subjects
    		 Other: 11
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled subjects in the trial is the number of randomized subjects.
    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Overall - NLX
    Arm description
    		 Subjects received Naloxone HCl PR tablets (NLX 6 mg, 12 mg, 24 mg, 48 mg), oral administration, once daily, TDD: 6-48 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Naloxone hydrochloride
    Investigational medicinal product code
    NLX
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects started with the lowest total daily dose of 6 mg IMP and were treated on this dose level for 2 weeks. After 2 weeks, the dose was escalated to 12 mg IMP per day for a further 2 weeks. Each further escalation step (dose level of 24 mg and 48 mg IMP per day) lasted for at least 2 weeks.

    Arm title
    		 Overall - Placebo
    Arm description
    		 Subjects receive corresponding placebo tablets (NLX PLA 3 mg [placebo run-in only], 6 mg, 12 mg, 24 mg, 48 mg), oral administration, once daily, TDD: 3-48 mg
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All subjects received Naloxone HCl 3 mg PR Placebo once daily for 2 weeks during run-in phase. In Treatment phase Subjects started with the lowest total daily dose of 6 mg IMP and were treated on this dose level for 2 weeks. After 2 weeks, the dose was escalated to 12 mg IMP per day for a further 2 weeks. Each further escalation step (dose level of 24 mg and 48 mg IMP per day) lasted for at least 2 weeks.

    Number of subjects in period 1
    		Overall - NLX Overall - Placebo
    Started
    121
    62
    Completed
    102
    56
    Not completed
    19
    6
         Consent withdrawn by subject
    1
    -
         Treatment failure
    4
    2
         Adverse event, non-fatal
    4
    2
         Other
    9
    2
         Noneligibility
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall - NLX
    Reporting group description
    		 Subjects received Naloxone HCl PR tablets (NLX 6 mg, 12 mg, 24 mg, 48 mg), oral administration, once daily, TDD: 6-48 mg

    Reporting group title
    Overall - Placebo
    Reporting group description
    		 Subjects receive corresponding placebo tablets (NLX PLA 3 mg [placebo run-in only], 6 mg, 12 mg, 24 mg, 48 mg), oral administration, once daily, TDD: 3-48 mg

    Reporting group values
    		 Overall - NLX Overall - Placebo Total
    Number of subjects
    		 121 62 183
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0 0
        Newborns (0-27days)
    		 0 0 0
        Infants and toddlers (28days – 23months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 year)
    		 0 0 0
        From 18 - 64 years
    		 82 37 119
        From 65 – 84 years
    		 39 24 63
        Over 85 years
    		 0 1 1
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 59 ± 10.42 60.6 ± 12.67 -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 80 41 121
        Male
    		 41 21 62

    End points

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    End points reporting groups
    Reporting group title
    Overall - NLX
    Reporting group description
    		 Subjects received Naloxone HCl PR tablets (NLX 6 mg, 12 mg, 24 mg, 48 mg), oral administration, once daily, TDD: 6-48 mg

    Reporting group title
    Overall - Placebo
    Reporting group description
    		 Subjects receive corresponding placebo tablets (NLX PLA 3 mg [placebo run-in only], 6 mg, 12 mg, 24 mg, 48 mg), oral administration, once daily, TDD: 3-48 mg

    Subject analysis set title
    Overall - NLX x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of the double-blind IMP.

    Subject analysis set title
    Overall - Placebo x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of the double-blind IMP.

    Subject analysis set title
    Overall - NLX x FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised subjects, who receive at least one dose of the double-blind IMP, and with at least one post-baseline (i.e. after Visit 4) assessment of BFI during the double-blind dose-escalation / treatment phase and have at least 7 days duration of the double-blind dose-escalation / treatment phase

    Subject analysis set title
    Overall - Placebo x FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised subjects, who receive at least one dose of the double-blind IMP, and with at least one post-baseline (i.e. after Visit 4) assessment of BFI during the double-blind dose-escalation / treatment phase and have at least 7 days duration of the double-blind dose-escalation / treatment phase

    Primary: BFI absolute change

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    End point title
    		 BFI absolute change
    End point description
    BFI absolute change between baseline (Visit 4) and the end of Week 12 of the double-blind dose-escalation / treatment phase
    End point type
    Primary
    End point timeframe
    Baseline up to Week 12 in Treatment Phase
    End point values
    		 Overall - NLX x FAS Overall - Placebo x FAS
    Number of subjects analysed
    121
    62
    Units: BFI score
    number (standard deviation)
        BFI score
    102
    57
    Statistical analysis title
    		 Statistical Analysis of BFI Score by Week
    Statistical analysis description
    BFI scores are analysed via a mixed model for repeated measures analysis, with treatment, week, pooled centre, gender, opioid and opioid TDD (low-dose, high-dose) as fixed factors, baseline BFI and standardised laxative rescue medication use per week during run-in phase as covariates
    Comparison groups
    Overall - NLX x FAS v Overall - Placebo x FAS
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1534
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -4.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.82
         upper limit
    		 1.87

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first intake of IMP and not more than 14 days after last administration of IMP
    Adverse event reporting additional description
    Only numbers of TEAEs are reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Overall - NLX x Safety
    Reporting group description
    		 Subjects in the Safety set treated with NLX

    Reporting group title
    Overall - Placebo x Safety
    Reporting group description
    		 Subjects in the Safety set treated with Placebo

    Serious adverse events
    		 Overall - NLX x Safety Overall - Placebo x Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 121 (4.13%)
    0 / 62 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Cardiac disorders
    Cardiac failure acute
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (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
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall - NLX x Safety Overall - Placebo x Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 121 (59.50%)
    37 / 62 (59.68%)
    Vascular disorders
    Haematoma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Nerve block
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chills
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Asthenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Drug withdrawal syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Oedema peripheral
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 121 (3.31%)
    2 / 62 (3.23%)
         occurrences all number
    5
    2
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    Sarcoidosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Oropharyngeal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Mood altered
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Nightmare
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Restlessness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Sleep disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Investigations
    Arthroscopy
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    General physical condition abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Liver function test abnormal
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Weight increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hand fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Patella fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Arrhythmia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure acute
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    2 / 62 (3.23%)
         occurrences all number
    3
    2
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    14 / 121 (11.57%)
    9 / 62 (14.52%)
         occurrences all number
    20
    12
    Hypoaesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Paraesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Normochromic normocytic anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Thrombocytosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Lacrimation increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 121 (9.09%)
    5 / 62 (8.06%)
         occurrences all number
    11
    5
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 121 (8.26%)
    4 / 62 (6.45%)
         occurrences all number
    11
    6
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 121 (3.31%)
    2 / 62 (3.23%)
         occurrences all number
    4
    2
    Anal fissure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 121 (2.48%)
    2 / 62 (3.23%)
         occurrences all number
    4
    3
    Dry mouth
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Dyspepsia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Flatulence
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Gastrooesophageal reflux disease
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 121 (5.79%)
    5 / 62 (8.06%)
         occurrences all number
    8
    6
    Toothache
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Psoriasis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Micturition disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Arthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Bursitis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Intervertebral disc protrusion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Joint swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Rotator cuff syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Spinal deformity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Tendonitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Acute sinusitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Cystitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    2
    Gastroenteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Gastrointestinal infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal viral infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Influenza
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    Laryngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 121 (5.79%)
    4 / 62 (6.45%)
         occurrences all number
    9
    5
    Parotitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    2 / 62 (3.23%)
         occurrences all number
    2
    2
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Viral infection
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    Hypercholesterolaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Hyperkalaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Increased appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2013
    Global Protocol Amendment No. 1 It broadens exclusion criterion no. 9 due to revised safety considerations justified by existing literature and SmPCs of drugs containing naloxone hydrochloride PR. In addition, the procedure for re-testing of laboratory tests of Visit 1 is stated more clearly. An error in Section 10.3.1 regarding trial opioid assignment is corrected.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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