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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 3 mg to 24 mg twice daily in patients with opioid induced constipation

    Summary
    EudraCT number
    		 2012-003218-14
    Trial protocol
    		 DE   HU   CZ   SK   ES   IT  
    Global end of trial date
    19 Aug 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)
    		 0176/DEV

    Trial information

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    Trial identification
    Sponsor protocol code
    0176/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
    02 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 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 twice 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 was conducted in compliance with the protocol, by trial personnel, who are qualified by education, training, and experience in their roles, with adherence to Good Clinical Practice (GCP), the applicable regulatory requirements and ethical principles based on the Declaration of Helsinki.
    Background therapy
    		 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
    12 Mar 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: 35
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Hungary: 72
    Country: Number of subjects enrolled
    Slovakia: 16
    Worldwide total number of subjects
    173
    EEA total number of subjects
    173
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    121
    From 65 to 84 years
    51
    85 years and over
    1

    Subject disposition

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

    Pre-assignment
    Screening details
    		 A total of 298 subjects were screened, out of these, 173 subjects were randomized. 64 subjects were screening failures. Further 61 screened subjects prematurely discontinued from the trial before randomisation.

    Pre-assignment period milestones
    Number of subjects started
    		 298 [1]
    Number of subjects completed
    		 173

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 18
    Reason: Number of subjects
    		 Adverse event, serious non-fatal: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 22
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Noneligibility: 61
    Reason: Number of subjects
    		 Other: 21
    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 (NLX) hydrochloride (HCl) prolonged-release (PR) tablets (3 mg, 6 mg, 12 mg, 24 mg), oral administration, twice daily, total daily dose: 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
    Total daily dose: 6-48 mg Subjects will start with the lowest total daily dose of 6 mg IMP and will be treated on this dose level for 2 weeks. After 2 weeks, the dose will be 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) will last for at least 2 weeks.

    Arm title
    		 Overall - Placebo
    Arm description
    		 Subjects receive corresponding placebo tablets (1.5 mg, 3 mg, 6 mg, 12 mg, 24 mg), oral administration, twice daily, total daily dose: 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
    Total daily dose: 6-48 mg All subjects will be treated with NLX PLA 1.5 mg during Run-in. In Treatment phase subjects will start with the lowest total daily dose of 6 mg IMP and will be treated on this dose level for 2 weeks. After 2 weeks, the dose will be 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) will last for at least 2 weeks.

    Number of subjects in period 1
    		Overall - NLX Overall - Placebo
    Started
    115
    58
    Completed
    97
    50
    Not completed
    18
    8
         Consent withdrawn by subject
    4
    -
         Treatment failure
    7
    3
         Adverse event, non-fatal
    4
    2
         Other
    1
    -
         Adverse event, serious non-fatal
    1
    1
         Noneligibility
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall - NLX
    Reporting group description
    		 Subjects received Naloxone (NLX) hydrochloride (HCl) prolonged-release (PR) tablets (3 mg, 6 mg, 12 mg, 24 mg), oral administration, twice daily, total daily dose: 6-48 mg

    Reporting group title
    Overall - Placebo
    Reporting group description
    		 Subjects receive corresponding placebo tablets (1.5 mg, 3 mg, 6 mg, 12 mg, 24 mg), oral administration, twice daily, total daily dose: 3-48 mg

    Reporting group values
    		 Overall - NLX Overall - Placebo Total
    Number of subjects
    		 115 58 173
    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
    		 74 47 121
        From 65 – 84 years
    		 40 11 51
        Over 85 years
    		 1 0 1
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 59 ( 12.19 ) 55.56 ( 9.92 ) -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 76 40 116
        Male
    		 39 18 57

    End points

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    End points reporting groups
    Reporting group title
    Overall - NLX
    Reporting group description
    		 Subjects received Naloxone (NLX) hydrochloride (HCl) prolonged-release (PR) tablets (3 mg, 6 mg, 12 mg, 24 mg), oral administration, twice daily, total daily dose: 6-48 mg

    Reporting group title
    Overall - Placebo
    Reporting group description
    		 Subjects receive corresponding placebo tablets (1.5 mg, 3 mg, 6 mg, 12 mg, 24 mg), oral administration, twice daily, total daily dose: 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 trial medication.

    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 trial medication.

    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 trial medication, and with at least one post-baseline (i.e. after Visit 4) assessment of BFI during 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 trial medication, and with at least one post-baseline (i.e. after Visit 4) assessment of BFI during 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
    114
    58
    Units: BFI score
    number (standard deviation)
        BFI score
    114
    58
    Statistical analysis title
    		 Statistical Analysis of BFI - LOCF
    Statistical analysis description
    ANCOVA is carried out using treatment, centre, age (≤65 years; >65 years), sex, opioid drug (oxycodone or hydromorphone) and opioid TDD (low-dose range; high-dose range) as categorical factors, and baseline BFI and number of days with laxative rescue medication use during the last 4 weeks as continuous covariates
    Comparison groups
    Overall - NLX x FAS v Overall - Placebo x FAS
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0478
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    -6.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.23
         upper limit
    		 -0.06

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

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

    Serious adverse events
    		 Overall - Placebo x Safety Overall - NLX x Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 115 (2.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular injury
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Post-traumatic stress disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall - Placebo x Safety Overall - NLX x Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 58 (46.55%)
    71 / 115 (61.74%)
    Vascular disorders
    Hot flush
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 115 (0.87%)
         occurrences all number
    1
    2
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 115 (2.61%)
         occurrences all number
    0
    3
    Hypertensive crisis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Hypotension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Lymphoedema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Phlebitis superficial
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Vascular calcification
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Tooth extraction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Drug withdrawal syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Spinal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    2
    Immune system disorders
    Hypersensitivity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Bronchopneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Cystitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    2
    0
    Fungal infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Gastritis viral
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Herpes zoster
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Infected bites
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Influenza
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 115 (1.74%)
         occurrences all number
    1
    2
    Laryngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 58 (8.62%)
    12 / 115 (10.43%)
         occurrences all number
    5
    15
    Oral herpes
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Otitis media
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Periodontitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Pharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 115 (1.74%)
         occurrences all number
    0
    2
    Pulpitis dental
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Rhinitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 115 (2.61%)
         occurrences all number
    0
    3
    Tonsillitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Viral diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Viral infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 115 (1.74%)
         occurrences all number
    1
    2
    Reproductive system and breast disorders
    Menopausal symptoms
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Metrorrhagia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Dysphonia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Oropharyngeal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 115 (2.61%)
         occurrences all number
    0
    3
    Rhinorrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 115 (0.87%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Anxiety disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Nervousness
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Psychotic disorder due to a general medical condition
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Restlessness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Tension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    2
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Blood glucose increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 115 (1.74%)
         occurrences all number
    0
    2
    Body temperature increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Weight decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Burn oesophageal
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Concussion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Face injury
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Hand fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Jaw fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Ligament rupture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Rib fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Wrist fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Dilatation ventricular
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 115 (1.74%)
         occurrences all number
    3
    2
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 58 (13.79%)
    15 / 115 (13.04%)
         occurrences all number
    10
    19
    Hypoaesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 115 (1.74%)
         occurrences all number
    0
    2
    Tinnitus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Vertigo
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 115 (1.74%)
         occurrences all number
    1
    2
    Eye disorders
    Lacrimation increased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 115 (0.87%)
         occurrences all number
    3
    1
    Photophobia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 115 (0.87%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 115 (1.74%)
         occurrences all number
    1
    2
    Abdominal distension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 115 (3.48%)
         occurrences all number
    1
    4
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 115 (3.48%)
         occurrences all number
    4
    4
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 115 (0.87%)
         occurrences all number
    1
    1
    Anorectal discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Defaecation urgency
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    9 / 115 (7.83%)
         occurrences all number
    0
    15
    Dyspepsia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 115 (1.74%)
         occurrences all number
    0
    2
    Frequent bowel movements
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Gastritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Gastrointestinal hypomotility
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    6 / 115 (5.22%)
         occurrences all number
    3
    6
    Salivary hypersecretion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Toothache
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 115 (0.87%)
         occurrences all number
    1
    1
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 115 (1.74%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Erythema multiforme
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Hyperhidrosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 115 (2.61%)
         occurrences all number
    1
    4
    Nail disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    6 / 115 (5.22%)
         occurrences all number
    2
    6
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 115 (4.35%)
         occurrences all number
    2
    5
    Flank pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Joint swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Limb deformity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Musculoskeletal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 115 (2.61%)
         occurrences all number
    0
    3
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 115 (2.61%)
         occurrences all number
    1
    3
    Spinal osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Tendinous contracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Hyperglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1
    Increased appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 115 (0.00%)
         occurrences all number
    1
    0
    Type 2 diabetes mellitus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 115 (0.87%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Aug 2013
    Global Protocol Amendment No. 2 It broadens exclusion criterion no. 9 due to revised safety considerations justified by existing literature and SmPCs of drugs containing naloxone hydrochloride PR.

    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
    For support, Contact us.
    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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