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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Femoral Nerve Block with EXPAREL for Postsurgical Analgesia in Subjects Undergoing Total Knee Arthroplasty

    Summary
    EudraCT number
    		 2015-005179-25
    Trial protocol
    		 BE   DK  
    Global end of trial date
    30 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2021
    First version publication date
    10 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    402-C-326
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02713178
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pacira Pharmaceuticals
    Sponsor organisation address
    5 Sylvan Way, Parsippany, United States, 07054
    Public contact
    Pacira Medical Information, Pacira Pharmaceuticals, Inc., +1 855-793-9727 , medinfo@pacira.com
    Scientific contact
    Pacira Medical Information, Pacira Pharmaceuticals, Inc., +1 855-793-9727 , medinfo@pacira.com
    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
    30 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the magnitude and duration of the analgesic effect achieved following single-dose injection femoral nerve block with EXPAREL in subjects undergoing primary unilateral total knee arthroplasty (TKA).
    Protection of trial subjects
    Initially, unblinded review of the data and a relative risk analysis were to be conducted if any of the following, based on the incidence rate, were identified during blinded data review: -Severe or serious AE of special interest (AESI), including cardiac AESI and neurologic AESI exceeding 5% and in at least 5 subjects -Severe dizziness exceeding 10% or in at least 5 subjects -Severe AEs or serious AEs (SAEs), regardless of relationship to study drug, exceeding 20% or in at least 10 subjects If the risk relative to placebo was greater than 2, the study was to be either permanently stopped or the study eligibility criteria were to be revised to exclude subjects who were at a higher risk for a particular AE. After review of the Study Stopping Rules with the FDA (05 January 2017), these were changed as follows: -Incidence rate of severe or serious AESIs as defined by the protocol including cardiac AESIs and neurologic AESIs exceeding 5% or in at least 5 subjects -Incidence rate of severe dizziness exceeding 10% or in at least 5 subjects Incidence rate of severe or SAEs regardless of relationship to study drug exceeding 20% or in at least 10 subjects
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2016
    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
    United States: 116
    Country: Number of subjects enrolled
    Belgium: 109
    Country: Number of subjects enrolled
    Denmark: 5
    Worldwide total number of subjects
    230
    EEA total number of subjects
    114
    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)
    100
    From 65 to 84 years
    128
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between June 3, 2016 and June 30, 2017 at 13 sites in the US and Europe

    Pre-assignment
    Screening details
    		 Participants were recruited between June 3, 2016 and June 30, 2017 at 13 sites in the US and Europe

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Only pharmacist and administrator were unblinded onsite. These personnel were not involved with study assessments. An unblinded CRA monitored the site data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EXPAREL 133 mg
    Arm description
    		 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
    Arm type
    		 Experimental

    Investigational medicinal product name
    EXPAREL
    Investigational medicinal product code
    Other name
    bupivacaine liposome injectable suspension
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Not mentioned
    Dosage and administration details
    10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Arm title
    		 EXPAREL 266 mg
    Arm description
    		 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively
    Arm type
    		 Experimental

    Investigational medicinal product name
    EXPAREL
    Investigational medicinal product code
    Other name
    bupivacaine liposome injectable suspension
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Other use
    Dosage and administration details
    20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively

    Arm title
    		 Placebo
    Arm description
    		 20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Other use
    Dosage and administration details
    20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Number of subjects in period 1
    		EXPAREL 133 mg EXPAREL 266 mg Placebo
    Started
    75
    76
    79
    Completed
    75
    73
    74
    Not completed
    0
    3
    5
         Consent withdrawn by subject
    -
    2
    4
         Adverse event, non-fatal
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EXPAREL 133 mg
    Reporting group description
    		 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group title
    EXPAREL 266 mg
    Reporting group description
    		 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group title
    Placebo
    Reporting group description
    		 20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group values
    		 EXPAREL 133 mg EXPAREL 266 mg Placebo Total
    Number of subjects
    		 75 76 79 230
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ( 6.94 ) 66.0 ( 9.01 ) 65.4 ( 8.69 ) -
    Gender categorical
    Units: Subjects
        Female
    		 36 43 53 132
        Male
    		 39 33 26 98
    Race
    NIH/OMB
    Units: Subjects
        Black or African American
    		 8 5 12 25
        Asian
    		 0 1 0 1
        White
    		 66 69 67 202
        Other
    		 1 0 0 1
        Unknown/not reported
    		 0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic of Latino
    		 2 2 2 6
        Not Hispanic or Latino
    		 73 74 75 222
        Unknown or not reported
    		 0 0 2 2
    American Society of Anesthesiologists classification (ASA)
    American Society of Anesthesiologists (ASA) classification was determined by physicians using the ASA Physical Status Classification System which assesses the patient's pre-anesthesia medical co-morbidities. ASA 1 patients would be considered a normal, healthy patient. ASA 2 is a patient with mild systemic disease (eg, smoker, well controlled diabetes or high blood pressure (HBP)). ASA 3 is a patient with severe systemic disease (eg poorly controlled diabetes or HBP). ASA 4 is a patient with severe systemic disease that is a constant threat to life (eg, recent myocardial infarction, stroke).
    Units: Subjects
        ASA 1
    		 11 9 10 30
        ASA 2
    		 41 41 46 128
        ASA 3
    		 23 26 23 72
        ASA >/= 4
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    EXPAREL 133 mg
    Reporting group description
    		 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group title
    EXPAREL 266 mg
    Reporting group description
    		 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group title
    Placebo
    Reporting group description
    		 20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Primary: Measure title AUC of VAS pain intensity scores through 72 hours

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    End point title
    		 Measure title AUC of VAS pain intensity scores through 72 hours
    End point description
    AUC of VAS pain intensity scores through 72 hours. PAin intensity scores were measured on a 10-cm VAS (0=no pain and 10=worst possible pain).
    End point type
    Primary
    End point timeframe
    0-72 hours
    End point values
    		 EXPAREL 133 mg EXPAREL 266 mg Placebo
    Number of subjects analysed
    75
    76
    79
    Units: AUC of pain scores on VAS scales
        least squares mean (standard error)
    259.545 ( 19.011 )
    250.998 ( 18.849 )
    279.794 ( 18.493 )
    Statistical analysis title
    		 AUC VAS EXPAREL 133mg
    Comparison groups
    EXPAREL 133 mg v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4463
    Method
    		 ANOVA
    Parameter type
    		 LSMD
    Point estimate
    -20.249
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -72.361
         upper limit
    		 31.864
    Statistical analysis title
    		 AUC VAS EXPAREL 266 mg
    Comparison groups
    EXPAREL 266 mg v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2749
    Method
    		 ANOVA
    Parameter type
    		 LSMD
    Point estimate
    -28.796
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -80.483
         upper limit
    		 22.892

    Secondary: Total postsurgical opioid consumption through 72 hours

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    End point title
    		 Total postsurgical opioid consumption through 72 hours
    End point description
    Total postsurgical opioid consumption (converted to IV morphine equivalents) through 72 hours.
    End point type
    Secondary
    End point timeframe
    0-72 hours
    End point values
    		 EXPAREL 133 mg EXPAREL 266 mg Placebo
    Number of subjects analysed
    75
    76
    79
    Units: mg
        least squares mean (standard error)
    69.466 ( 4.403 )
    74.393 ( 4.669 )
    81.469 ( 5.006 )
    Statistical analysis title
    		 Total postsurgical opioid consumption EXPAREL 133m
    Comparison groups
    EXPAREL 133 mg v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.314
    Method
    		 ANOVA
    Parameter type
    		 LSM treatment ratio
    Point estimate
    0.906
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.748
         upper limit
    		 1.098
    Statistical analysis title
    		 Total postsurgical opioid consumption EXPAREL 266m
    Comparison groups
    EXPAREL 266 mg v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9369
    Method
    		 ANOVA
    Parameter type
    		 LSM treatment ratio
    Point estimate
    1.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.833
         upper limit
    		 1.218

    Secondary: Percentage of opioid free participants EXPAREL 133mg

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    End point title
    		 Percentage of opioid free participants EXPAREL 133mg
    End point description
    Percentage of participants who did not receive opioid medication through 72 hours
    End point type
    Secondary
    End point timeframe
    0-72 hours
    End point values
    		 EXPAREL 133 mg EXPAREL 266 mg Placebo
    Number of subjects analysed
    75
    76
    79
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening to day 29 postsurgery
    Adverse event reporting additional description
    adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg, abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without judgment about causality
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    EXPAREL 133 mg
    Reporting group description
    		 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group title
    EXPAREL 266 mg
    Reporting group description
    		 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection femoral nerve block ≥1 h preoperatively

    Reporting group title
    Placebo
    Reporting group description
    		 20 mL normal saline as single-injection femoral nerve block ≥1 h preoperatively

    Serious adverse events
    		 EXPAREL 133 mg EXPAREL 266 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 75 (6.67%)
    8 / 76 (10.53%)
    6 / 79 (7.59%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Investigations
    oxygen saturation decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    postprocedural hematoma
         subjects affected / exposed
    3 / 75 (4.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    postprocedural swelling
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 76 (1.32%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Motor dysfunction
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 76 (2.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    transient ischemic attack
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 76 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 EXPAREL 133 mg EXPAREL 266 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 75 (97.33%)
    74 / 76 (97.37%)
    76 / 79 (96.20%)
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    7 / 75 (9.33%)
    1 / 76 (1.32%)
    3 / 79 (3.80%)
         occurrences all number
    7
    1
    3
    Haemoglobin decreased
         subjects affected / exposed
    1 / 75 (1.33%)
    3 / 76 (3.95%)
    5 / 79 (6.33%)
         occurrences all number
    1
    3
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 76 (6.58%)
    0 / 79 (0.00%)
         occurrences all number
    4
    6
    0
    Post procedural haematoma
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 76 (1.32%)
    0 / 79 (0.00%)
         occurrences all number
    4
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    8 / 75 (10.67%)
    4 / 76 (5.26%)
    5 / 79 (6.33%)
         occurrences all number
    9
    4
    5
    Nervous system disorders
    Motor dysfunction
         subjects affected / exposed
    34 / 75 (45.33%)
    35 / 76 (46.05%)
    34 / 79 (43.04%)
         occurrences all number
    35
    37
    34
    Dysgeusia
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 76 (2.63%)
    6 / 79 (7.59%)
         occurrences all number
    3
    2
    6
    Sensory loss
         subjects affected / exposed
    2 / 75 (2.67%)
    6 / 76 (7.89%)
    1 / 79 (1.27%)
         occurrences all number
    2
    6
    1
    Headache
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 76 (2.63%)
    0 / 79 (0.00%)
         occurrences all number
    5
    2
    0
    Presyncope
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 76 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    0
    5
    Dizziness
         subjects affected / exposed
    3 / 75 (4.00%)
    7 / 76 (9.21%)
    5 / 79 (6.33%)
         occurrences all number
    5
    7
    7
    Confusional state
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 76 (2.63%)
    4 / 79 (5.06%)
         occurrences all number
    1
    2
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 75 (1.33%)
    6 / 76 (7.89%)
    5 / 79 (6.33%)
         occurrences all number
    1
    6
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    23 / 75 (30.67%)
    18 / 76 (23.68%)
    22 / 79 (27.85%)
         occurrences all number
    23
    18
    22
    Peripheral swelling
         subjects affected / exposed
    0 / 75 (0.00%)
    7 / 76 (9.21%)
    3 / 79 (3.80%)
         occurrences all number
    0
    7
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    27 / 75 (36.00%)
    34 / 76 (44.74%)
    24 / 79 (30.38%)
         occurrences all number
    28
    35
    26
    Constipation
         subjects affected / exposed
    12 / 75 (16.00%)
    16 / 76 (21.05%)
    15 / 79 (18.99%)
         occurrences all number
    12
    16
    15
    Vomiting
         subjects affected / exposed
    4 / 75 (5.33%)
    10 / 76 (13.16%)
    9 / 79 (11.39%)
         occurrences all number
    4
    10
    9
    Dyspepsia
         subjects affected / exposed
    2 / 75 (2.67%)
    5 / 76 (6.58%)
    2 / 79 (2.53%)
         occurrences all number
    2
    5
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 75 (5.33%)
    8 / 76 (10.53%)
    10 / 79 (12.66%)
         occurrences all number
    4
    8
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 76 (1.32%)
    4 / 79 (5.06%)
         occurrences all number
    1
    1
    4
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    3 / 75 (4.00%)
    10 / 76 (13.16%)
    8 / 79 (10.13%)
         occurrences all number
    3
    10
    8
    Musculoskeletal and connective tissue disorders
    Muscle twitching
         subjects affected / exposed
    5 / 75 (6.67%)
    7 / 76 (9.21%)
    4 / 79 (5.06%)
         occurrences all number
    6
    12
    5
    Joint swelling
         subjects affected / exposed
    2 / 75 (2.67%)
    2 / 76 (2.63%)
    5 / 79 (6.33%)
         occurrences all number
    2
    2
    5
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    5 / 75 (6.67%)
    5 / 76 (6.58%)
    5 / 79 (6.33%)
         occurrences all number
    5
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Feb 2016
    Amendment 1
    28 Sep 2016
    Amendment 2
    14 Nov 2016
    Amendment 3

    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
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