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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
    2013-002948-91
    Trial protocol
    DE   CZ   AT   ES   PL  
    Global end of trial date
    09 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jun 2016
    First version publication date
    25 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1315V9232
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01993940
    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
    16 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 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 rational 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 sever 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
    04 Nov 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
    United States: 480
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Czech Republic: 29
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    550
    EEA total number of subjects
    70
    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)
    468
    From 65 to 84 years
    82
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The screening period consisted 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 0.2mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    naldemedine 0.2mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet containing 0.2mg 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 was administered once daily (QD) for the 12 weeks of treatment

    Number of subjects in period 1
    naldemedine 0.2mg Placebo
    Started
    276
    274
    Completed
    237
    231
    Not completed
    39
    43
         Protocol deviation
    4
    7
         Other
    1
    1
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    16
    11
         Consent withdrawn by subject
    15
    19
         Lost to follow-up
    2
    5

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    naldemedine 0.2mg Placebo Total
    Number of subjects
    276 274 550
    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)
    232 236 468
        From 65-84 years
    44 38 82
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.1 ± 10.48 52.9 ± 11.4 -
    Gender categorical
    Units: Subjects
        Female
    165 168 333
        Male
    111 106 217

    End points

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    End points reporting groups
    Reporting group title
    naldemedine 0.2mg
    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 0.2mg Placebo
    Number of subjects analysed
    276
    274
    Units: Proportion of responders
    number (confidence interval 95%)
        Proportion of responders
    52.5 (46.5 to 58.6)
    33.6 (28 to 39.5)
    Statistical analysis title
    Proportion of Responders
    Comparison groups
    naldemedine 0.2mg v Placebo
    Number of subjects included in analysis
    550
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion difference
    Point estimate
    18.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.8
         upper limit
    27
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.12

    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 0.2mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    naldemedine 0.2mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 271 (3.32%)
    13 / 274 (4.74%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy mediastinal
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (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%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 271 (0.00%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (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
    Renal failure acute
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 271 (0.00%)
    2 / 274 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (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 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    naldemedine 0.2mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    134 / 271 (49.45%)
    127 / 274 (46.35%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 271 (2.21%)
    0 / 274 (0.00%)
         occurrences all number
    6
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 271 (2.21%)
    3 / 274 (1.09%)
         occurrences all number
    21
    9
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 271 (2.21%)
    0 / 274 (0.00%)
         occurrences all number
    7
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 271 (5.17%)
    3 / 274 (1.09%)
         occurrences all number
    19
    4
    Diarrhoea
         subjects affected / exposed
    24 / 271 (8.86%)
    5 / 274 (1.82%)
         occurrences all number
    26
    5
    Flatulence
         subjects affected / exposed
    6 / 271 (2.21%)
    9 / 274 (3.28%)
         occurrences all number
    7
    9
    Nausea
         subjects affected / exposed
    13 / 271 (4.80%)
    9 / 274 (3.28%)
         occurrences all number
    15
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 271 (2.21%)
    2 / 274 (0.73%)
         occurrences all number
    6
    2
    Back pain
         subjects affected / exposed
    10 / 271 (3.69%)
    6 / 274 (2.19%)
         occurrences all number
    10
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 271 (2.21%)
    7 / 274 (2.55%)
         occurrences all number
    7
    7
    Sinusitis
         subjects affected / exposed
    4 / 271 (1.48%)
    7 / 274 (2.55%)
         occurrences all number
    4
    7
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 271 (2.58%)
    5 / 274 (1.82%)
         occurrences all number
    9
    5
    Urinary tract infection
         subjects affected / exposed
    5 / 271 (1.85%)
    14 / 274 (5.11%)
         occurrences all number
    5
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2014
    The key changes that Amendment 1 (11 June 2014) made to the protocol included the following: added clarification of discontinuing regular use of laxatives at start of screening and through the 12-week Treatment Period, clarification of stratification based on morphine-equivalent dosing as well as redefined allowable use of tramadol and tapentadol, clarification of exclusion criteria related to severe constipation prior to and during the Screening Period, and clarification of primary efficacy endpoint related to last observation carried forward (LOCF).
    16 Oct 2014
    The key changes that Amendment 2 (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 mITT Population to produce a population that more accurately accounted for the challenges encountered by subjects required to use an EDC 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 “nonresponse” 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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