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    Clinical Trial Results:
    A Randomized Double-blind, Placebo-controlled, Parallel-group, Multicenter, Phase 3 Study to Evaluate the Long-term Safety of Naldemedine for the Treatment of Opioid-induced Constipation in Subjects with Non-malignant Chronic Pain Receiving Opioid Therapy

    Summary
    EudraCT number
    2013-002949-11
    Trial protocol
    GB   DE   SE   BE   EE   PT   HU   AT   DK   ES   PL  
    Global end of trial date
    12 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Apr 2017
    First version publication date
    09 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1326V9235
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01965652
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shionogi Inc.
    Sponsor organisation address
    300 Campus Drive , Florham Park, United States, NJ 07932
    Public contact
    Juan Camilo Arjona Ferreira, Shionogi Inc., +1 8008499407, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Juan Camilo Arjona Ferreira, Shionogi Inc., +1 8008499407, shionogiclintrials-admin@shionogi.co.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the overall safety and tolerability of naldemedine in subjects with non-malignant chronic pain receiving a stable opioid therapy regimen for ≥1 month and having opioid-induced constipation (OIC)
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. The rationale of the study, procedural details, and investigational goals were explained to each subject, along with potential risks and benefits. Each subject was assured of his/her right to withdraw from the study at any time. In order to minimize the risk for severe constipation, particularly in subjects potentially receiving placebo, the study design allowed for use of rescue laxatives (provided by the sponsor) in subjects who did not have a bowel movement for 72 hours or more, regardless of the subject being on a regular laxative regimen or not.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    United States: 1049
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 57
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 34
    Worldwide total number of subjects
    1246
    EEA total number of subjects
    161
    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)
    1068
    From 65 to 84 years
    178
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The screening period consists of a minimum of 14 days and maximum 28-day period.

    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, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    naldemedine 0.2 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    naldemedine 0.2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet containing 0.2 mg of the active compound was administered once daily (QD) for the 52 weeks of treatment.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo tablet was administered once daily (QD) for the 52 weeks of treatment.

    Number of subjects in period 1
    naldemedine 0.2 mg Placebo
    Started
    623
    623
    Completed
    413
    413
    Not completed
    210
    210
         Protocol deviation
    34
    38
         Other
    18
    21
         Pregnancy
    -
    1
         Adverse event, serious fatal
    3
    4
         Adverse event, non-fatal
    40
    37
         Consent withdrawn by subject
    62
    69
         Lost to follow-up
    53
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    naldemedine 0.2 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    naldemedine 0.2 mg Placebo Total
    Number of subjects
    623 623 1246
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    521 547 1068
        From 65-84 years
    102 76 178
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.4 ± 11.69 52.7 ± 10.53 -
    Gender categorical
    Units: Subjects
        Female
    385 404 789
        Male
    238 219 457

    End points

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    End points reporting groups
    Reporting group title
    naldemedine 0.2 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Assessments of summary measures of treatment-emergent adverse events (TEAEs)

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    End point title
    Assessments of summary measures of treatment-emergent adverse events (TEAEs)
    End point description
    End point type
    Primary
    End point timeframe
    From Baseline to week 52
    End point values
    naldemedine 0.2 mg Placebo
    Number of subjects analysed
    621
    619
    Units: Percentage of frequency of TEAEs
        number (not applicable)
    68.4
    72.1
    Statistical analysis title
    Assessments of summary measures of TEAEs
    Comparison groups
    Placebo v naldemedine 0.2 mg
    Number of subjects included in analysis
    1240
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference of proportion
    Point estimate
    -3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    1.5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between the first dose and 14 days after the last dose of study drug
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    naldemedine 0.2 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    naldemedine 0.2 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    60 / 621 (9.66%)
    73 / 619 (11.79%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 621 (0.16%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 621 (0.32%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery restenosis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 621 (0.32%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 621 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 621 (0.16%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 621 (0.32%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 621 (0.32%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    2 / 621 (0.32%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 621 (0.32%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flatulence
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric volvulus
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder prolapse
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin necrosis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (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
    Arthralgia
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 621 (0.32%)
    5 / 619 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 621 (0.00%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    2 / 621 (0.32%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 621 (0.32%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    5 / 621 (0.81%)
    3 / 619 (0.48%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 621 (0.32%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 621 (0.16%)
    2 / 619 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site infection
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 621 (0.16%)
    0 / 619 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 621 (1.13%)
    4 / 619 (0.65%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 621 (0.00%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 621 (0.16%)
    1 / 619 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    naldemedine 0.2 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    419 / 621 (67.47%)
    436 / 619 (70.44%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 621 (1.61%)
    14 / 619 (2.26%)
         occurrences all number
    10
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 621 (2.09%)
    10 / 619 (1.62%)
         occurrences all number
    13
    11
    Headache
         subjects affected / exposed
    28 / 621 (4.51%)
    33 / 619 (5.33%)
         occurrences all number
    31
    34
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    15 / 621 (2.42%)
    12 / 619 (1.94%)
         occurrences all number
    18
    12
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    14 / 621 (2.25%)
    12 / 619 (1.94%)
         occurrences all number
    15
    13
    Abdominal pain
         subjects affected / exposed
    50 / 621 (8.05%)
    18 / 619 (2.91%)
         occurrences all number
    55
    19
    Abdominal pain upper
         subjects affected / exposed
    30 / 621 (4.83%)
    18 / 619 (2.91%)
         occurrences all number
    34
    21
    Constipation
         subjects affected / exposed
    19 / 621 (3.06%)
    20 / 619 (3.23%)
         occurrences all number
    21
    22
    Diarrhoea
         subjects affected / exposed
    68 / 621 (10.95%)
    33 / 619 (5.33%)
         occurrences all number
    77
    42
    Flatulence
         subjects affected / exposed
    11 / 621 (1.77%)
    16 / 619 (2.58%)
         occurrences all number
    11
    16
    Nausea
         subjects affected / exposed
    49 / 621 (7.89%)
    35 / 619 (5.65%)
         occurrences all number
    52
    46
    Vomiting
         subjects affected / exposed
    36 / 621 (5.80%)
    18 / 619 (2.91%)
         occurrences all number
    40
    22
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 621 (2.09%)
    13 / 619 (2.10%)
         occurrences all number
    13
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    15 / 621 (2.42%)
    6 / 619 (0.97%)
         occurrences all number
    16
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    28 / 621 (4.51%)
    23 / 619 (3.72%)
         occurrences all number
    31
    26
    Back pain
         subjects affected / exposed
    34 / 621 (5.48%)
    27 / 619 (4.36%)
         occurrences all number
    40
    32
    Muscle spasms
         subjects affected / exposed
    10 / 621 (1.61%)
    16 / 619 (2.58%)
         occurrences all number
    11
    16
    Pain in extremity
         subjects affected / exposed
    13 / 621 (2.09%)
    17 / 619 (2.75%)
         occurrences all number
    18
    22
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    21 / 621 (3.38%)
    16 / 619 (2.58%)
         occurrences all number
    23
    20
    Gastroenteritis viral
         subjects affected / exposed
    14 / 621 (2.25%)
    12 / 619 (1.94%)
         occurrences all number
    16
    12
    Influenza
         subjects affected / exposed
    15 / 621 (2.42%)
    13 / 619 (2.10%)
         occurrences all number
    15
    14
    Nasopharyngitis
         subjects affected / exposed
    26 / 621 (4.19%)
    29 / 619 (4.68%)
         occurrences all number
    31
    33
    Sinusitis
         subjects affected / exposed
    23 / 621 (3.70%)
    24 / 619 (3.88%)
         occurrences all number
    26
    26
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 621 (5.80%)
    33 / 619 (5.33%)
         occurrences all number
    42
    42
    Urinary tract infection
         subjects affected / exposed
    38 / 621 (6.12%)
    51 / 619 (8.24%)
         occurrences all number
    44
    59

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2013
    • Added a serum pregnancy test at Visit 2 (Day 1) prior to dosing for all females of childbearing potential • Added directions for collecting data for laxative use during the Treatment Period at study site visits and recording the data on the CRF • Added directions for recording all opioid pain medication(s) dosing daily in the eDiary during the Screening Period and for the first 2 weeks of the Treatment Period • Added directions that opioid therapy was then to be captured on the CRF throughout the entire duration of the study • Added list of prohibited medications that were not to be taken by subjects at any time during the study; specified that the Visit 8 (Week 24) safety data would be analyzed by the DSMB
    16 Jun 2014
    • Added text to the synopsis and inclusion criteria stating that subjects must meet the following criteria based on an eDiary to be completed over a 14-consecutive-day qualifying period during the 28-day Screening Period: no more than 4 SBMs total over the 14-consecutive-day qualifying period. In addition, no more than 3 SBMs in a given week of the qualifying period. • Added text to specify that subjects might use laxatives during the Screening Period. • Added text to specify that tramadol and tapentadol would not be used in the calculations for either inclusion criterion No. 3, calculation of the stable opioid regimen at a total average daily dose of ≥ 30 mg equivalents of oral morphine sulfate, or for stratification by average daily dose of 30 to 100 mg equivalents of oral morphine sulfate versus > 100 mg equivalents of oral morphine sulfate. Specified that use of tramadol and tapentadol was allowed in the trial but only in conjunction with other opioid agonists • Added subheading stating that the change in frequency of BMs from baseline to selected timepoints in the Treatment Period was to be assessed as an efficacy endpoint. Subjects were to monitor BMs during the 52-week Treatment Period and were to be asked to complete the Bowel Habits paper diary. Also that during the Treatment Period, subjects were to record BM data on the paper diary during the week prior to each of the selected study visits (ie, Bowel Habits paper diary should have been filled out during Weeks 11, 23, 35, and 51, corresponding to the week prior to Study Visits 6, 8, 10 and 13, respectively).
    26 Feb 2015
    • Change wording primary objective to “Assess the overall safety and tolerability of naldemedine in subjects with non-malignant chronic pain receiving a stable opioid therapy regimen for ≥ 1 month and having OIC.” • Change sample size per alignment with ICHE1. • Modifications made to Overall Study Design and Plan: separation of Treatment Period into Core Period Data Set and Supplemental Period Data Set (Study visits and Schedule of Events remained as presented). • Precisions made regarding blinding and unblinding. • (Efficacy) Assessments changed to Secondary (Efficacy) Assessments. • Early Termination changed: subjects who terminated early should also have Follow-up Period Visit, 2 weeks after last dose of study drug. • Addition made to General Considerations: “The Core Period Data Set will consist of all subjects with at least 24 weeks of treatment (up to and including Visit 8 at minimum). The Core Period Data Set is considered a complete and “stand alone” data set that will be used for Global Registration purposes. The Supplemental Period Data Set will consist of all remaining data (study visits not completed at the time of the Core Period data lock). For Statistical purposes, a Combined data set will also be compiled that will consist of the Core Period and the Supplemental Period.” • Primary endpoint changed from number of MACEs during 52-week Treatment Period to “Safety: The incidence of TEAEs, serious TEAEs, and AEs leading to discontinuation”. TEAEs will be used for safety analyses. The definition of TEAE is an AE which occurs from first dose of study drug until 14 days after last study dose.” • Addition AEs of Special Interest: MACEs and Assessment of Opioid Withdrawal.

    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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