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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Naldemedine in the Treatment of Opioid-induced Constipation in Subjects with Non-malignant Chronic Pain Receiving Opioid Therapy

    Summary
    EudraCT number
    2013-002241-11
    Trial protocol
    DE   AT   CZ   GB   ES   PL  
    Global end of trial date
    22 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Jul 2016
    First version publication date
    21 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1314V9231
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01965158
    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
    10 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of naldemedine compared to placebo without concomitant laxative treatment in subjects with non-malignant chronic pain receiving a stable opioid 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 laxatives in subjects who did not have a bowel movement for 72 hours or more.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Aug 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    United States: 459
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Czech Republic: 31
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Poland: 4
    Worldwide total number of subjects
    545
    EEA total number of subjects
    86
    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)
    459
    From 65 to 84 years
    86
    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 2-week and maximum 4-week Period. Eligibility criteria were reviewed and qualified subjects providing informed consent entered the study.

    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 12 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 12 weeks of treatment.

    Number of subjects in period 1
    naldemedine 0.2 mg Placebo
    Started
    273
    272
    Completed
    233
    238
    Not completed
    40
    34
         Protocol deviation
    1
    1
         Other
    2
    -
         Adverse event
    14
    5
         Consent withdrawn by subject
    16
    23
         Lost to follow-up
    7
    5

    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
    273 272 545
    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)
    234 225 459
        From 65-84 years
    39 47 86
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.3 ± 10.44 53.4 ± 11.03 -
    Gender categorical
    Units: Subjects
        Female
    161 168 329
        Male
    112 104 216

    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: Proportion of responders, where a responder was defined as having ≥ 9 positive-response weeks out of the 12-week Treatment Period and 3 positive-response weeks out of the last 4 weeks of the 12-week Treatment Period

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    End point title
    Proportion of responders, where a responder was defined as having ≥ 9 positive-response weeks out of the 12-week Treatment Period and 3 positive-response weeks out of the last 4 weeks of the 12-week Treatment Period
    End point description
    End point type
    Primary
    End point timeframe
    From Baseline to week 12
    End point values
    naldemedine 0.2 mg Placebo
    Number of subjects analysed
    273
    272
    Units: Percentage
    number (confidence interval 95%)
        Proportion of Responders
    47.6 (41.6 to 53.7)
    34.6 (28.9 to 40.5)
    Statistical analysis title
    Proportion of Responders
    Comparison groups
    Placebo v naldemedine 0.2 mg
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion difference
    Point estimate
    13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.8
         upper limit
    21.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between the first dose and 28 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
    14 / 271 (5.17%)
    5 / 272 (1.84%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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
    Patent ductus arteriosus
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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 failure
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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
    Back pain
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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
    1 / 271 (0.37%)
    0 / 272 (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
    Appendicitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 272 (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
    0 / 271 (0.00%)
    1 / 272 (0.37%)
         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: 2%
    Non-serious adverse events
    naldemedine 0.2 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 271 (46.86%)
    122 / 272 (44.85%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 271 (1.48%)
    7 / 272 (2.57%)
         occurrences all number
    4
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 271 (2.21%)
    3 / 272 (1.10%)
         occurrences all number
    7
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 271 (5.90%)
    5 / 272 (1.84%)
         occurrences all number
    17
    6
    Abdominal pain upper
         subjects affected / exposed
    6 / 271 (2.21%)
    2 / 272 (0.74%)
         occurrences all number
    6
    2
    Diarrhoea
         subjects affected / exposed
    18 / 271 (6.64%)
    8 / 272 (2.94%)
         occurrences all number
    18
    8
    Nausea
         subjects affected / exposed
    13 / 271 (4.80%)
    7 / 272 (2.57%)
         occurrences all number
    13
    7
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    6 / 271 (2.21%)
    2 / 272 (0.74%)
         occurrences all number
    6
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 271 (1.85%)
    9 / 272 (3.31%)
         occurrences all number
    5
    9
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    4 / 271 (1.48%)
    6 / 272 (2.21%)
         occurrences all number
    4
    7
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 271 (2.21%)
    7 / 272 (2.57%)
         occurrences all number
    6
    7
    Urinary tract infection
         subjects affected / exposed
    7 / 271 (2.58%)
    8 / 272 (2.94%)
         occurrences all number
    7
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2013
    The key changes that Amendment 1 (4 October 2013) made to the protocol included the following: added clarification of BMCA inclusion criteria; added text to clarify eligibility criteria based on SBMs; changed text to clarify the steps taken for rescue laxative therapy; and added text to allow for Investigator discretion on medication that may have had a significant impact on the GI system or bowel habits.
    11 Jun 2014
    The key changes that Amendment 2 (11 June 2014) made to the protocol included the following: clarification of allowed laxatives during the Follow-up Period; redefined allowable use of tramadol and tapentadol for clarity; and revised time points for primary efficacy endpoint for more robust analysis.
    16 Oct 2014
    The key changes that Amendment 3 (16 October 2014) made to the protocol included the following: revised secondary efficacy endpoints to provide a more thorough clinical efficacy summary of naldemedine including effects from baseline to endpoint, baseline to the first week, straining, and CSBMs; added an exploratory endpoint to further assess the effect on SBMs without straining over time; removed PK assessment as an exploratory endpoint; changed the definition of the mITT Population to produce a population that more accurately accounted for challenges encountered by subjects required to use an electronic data capture tool; modified the Safety Population to be more inclusive in order to obtain a larger population; and further clarified the definition of insufficient primary endpoint data and a “non-response” week.

    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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