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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Assess the Efficacy and Safety of Intercostal Nerve Block with Liposome Bupivacaine in Subjects Undergoing Posterolateral Thoracotomy

    Summary
    EudraCT number
    		 2012-003275-19
    Trial protocol
    		 CZ   PL   BG  
    Global end of trial date
    20 Jun 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jul 2021
    First version publication date
    26 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    402-C-322
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01802411
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pacira Pharmaceuticals
    Sponsor organisation address
    5 Sylvan Way, Parsippany, United States, 07054
    Public contact
    Clinical Operations, Pacira Pharmaceuticals, Inc., +1 858-625-2424, medinfo@pacira.com
    Scientific contact
    Clinical Operations, Pacira Pharmaceuticals, Inc., +1 858-625-2424, jennifer.gordon@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
    19 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of intercostal nerve block using liposome bupivacaine compared with placebo in subjects undergoing posterolateral thoracotomy.
    Protection of trial subjects
    Post surgical recue pain medication was provided as necessary.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 70
    Country: Number of subjects enrolled
    Bulgaria: 48
    Country: Number of subjects enrolled
    Czechia: 35
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Georgia: 27
    Worldwide total number of subjects
    185
    EEA total number of subjects
    153
    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)
    126
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Before a subject underwent any study-specific screening procedures, the Investigator/designee explained the study purpose, procedures, expected effects and potential adverse reactions. A copy of the IRB- or IEC-approved ICF was provided to the subject, who was given sufficient time to ask questions and decide whether or not to participate.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EXPAREL 266 mg
    Arm description
    		 Intercostal nerve block using single total administration of 20 mL EXPAREL (bupivacaine liposome injectable suspension) 266 mg (approximately 88 mg [6.6 mL] to each of three nerve segments)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    EXPAREL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Intercostal nerve block using single total administration of 20 mL EXPAREL (bupivacaine liposome injectable suspension) 266 mg (approximately 88 mg [6.6 mL] to each of three nerve segments)

    Arm title
    		 Placebo
    Arm description
    		 Intercostal nerve block using single total administration of 20 mL normal saline (6.6 mL to each of three nerve segments)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Intercostal nerve block using single total administration of 20 mL normal saline (6.6 mL to each of three nerve segments)

    Number of subjects in period 1
    		EXPAREL 266 mg Placebo
    Started
    94
    91
    Completed
    82
    74
    Not completed
    12
    17
         Adverse event, serious fatal
    2
    1
         Adverse event, non-fatal
    2
    6
         Lack of efficacy
    8
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EXPAREL 266 mg
    Reporting group description
    		 Intercostal nerve block using single total administration of 20 mL EXPAREL (bupivacaine liposome injectable suspension) 266 mg (approximately 88 mg [6.6 mL] to each of three nerve segments)

    Reporting group title
    Placebo
    Reporting group description
    		 Intercostal nerve block using single total administration of 20 mL normal saline (6.6 mL to each of three nerve segments)

    Reporting group values
    		 EXPAREL 266 mg Placebo Total
    Number of subjects
    		 94 91 185
    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)
    		 57.9 ± 12.71 58.5 ± 13.03 -
    Gender categorical
    Units: Subjects
        Female
    		 30 31 61
        Male
    		 64 60 124
    Race
    Units: Subjects
        White
    		 94 91 185
        Not Recorded
    		 0 0 0
    Ethnic Group
    Units: Subjects
        Hispanic or Latino
    		 4 3 7
        Not Hispanic or Latino
    		 90 88 178
        Not Recorded
    		 0 0 0
    ASA Class
    American Society of Anesthesiologists
    Units: Subjects
        ASA 1
    		 32 24 56
        ASA 2
    		 48 50 98
        ASA 3
    		 14 17 31
    height (cm)
    Units: cm
        arithmetic mean (standard deviation)
    		 170.7 ± 8.87 169.8 ± 8.22 -
    weight (kg)
    Units: kg
        arithmetic mean (standard deviation)
    		 77.0 ± 15.0 75.8 ± 12.96 -

    End points

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    End points reporting groups
    Reporting group title
    EXPAREL 266 mg
    Reporting group description
    		 Intercostal nerve block using single total administration of 20 mL EXPAREL (bupivacaine liposome injectable suspension) 266 mg (approximately 88 mg [6.6 mL] to each of three nerve segments)

    Reporting group title
    Placebo
    Reporting group description
    		 Intercostal nerve block using single total administration of 20 mL normal saline (6.6 mL to each of three nerve segments)

    Primary: Area Under the Curve (AUC) of Pain Intensity at Rest Through 72 Hours

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    End point title
    		 Area Under the Curve (AUC) of Pain Intensity at Rest Through 72 Hours
    End point description
    AUC of pain intensity scores at rest through 72 hours postsurgery. Participants assumed a resting position that did not exacerbate his or her postsurgical pain. Pain intensity scores were measured at baseline and 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours postsurgery, at first request for rescue pain medication, and on day 12 using the numeric rating scale at rest (NRS-R; 0=no pain and 10=worst possible pain).
    End point type
    Primary
    End point timeframe
    0, 1, 2, 4, 8, 12, 36, 48, 60, and 72 hours post surgery
    End point values
    		 EXPAREL 266 mg Placebo
    Number of subjects analysed
    94
    91
    Units: score on a scale * hr
        least squares mean (standard error)
    472.1 ± 37.19
    459.0 ± 36.57
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    EXPAREL 266 mg v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5598
    Method
    		 ANCOVA
    Parameter type
    		 LSMD
    Point estimate
    13.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31
         upper limit
    		 57

    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 (morphine equivalent) through 72 hours postsurgery
    End point type
    Secondary
    End point timeframe
    0-72 hours post surgery
    End point values
    		 EXPAREL 266 mg Placebo
    Number of subjects analysed
    94
    91
    Units: mg morphine equivalent dose
        arithmetic mean (standard deviation)
    70.88 ± 37.537
    71.38 ± 39.418
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of randomization through the day 30 follow-up contact
    Adverse event reporting additional description
    The safety population included all participants who received study drug, with analysis based on actual treatment received. Treatment-emergent adverse events that were solicited from the neurological assessment or from the opioid-related AE questionnaire were included in this table.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    EXPAREL 266 mg
    Reporting group description
    		 Intercostal nerve block using single total administration of 20 mL EXPAREL (bupivacaine liposome injectable suspension) 266 mg (approximately 88 mg [6.6 mL] to each of three nerve segments)

    Reporting group title
    Placebo
    Reporting group description
    		 Intercostal nerve block using single total administration of 20 mL normal saline (6.6 mL to each of three nerve segments)

    Serious adverse events
    		 EXPAREL 266 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 94 (12.77%)
    9 / 91 (9.89%)
         number of deaths (all causes)
    2
    4
         number of deaths resulting from adverse events
    2
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (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)
    Brain neoplasm
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         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
    postprocedural hemorrhage
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart injury
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma uraemic
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (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
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    acute renal failure
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lobar pneumonia
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection Pseudomonal
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 91 (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: 0.05%
    Non-serious adverse events
    		 EXPAREL 266 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 94 (67.02%)
    54 / 91 (59.34%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 94 (8.51%)
    5 / 91 (5.49%)
         occurrences all number
    9
    5
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 94 (2.13%)
    7 / 91 (7.69%)
         occurrences all number
    2
    7
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    7 / 94 (7.45%)
    2 / 91 (2.20%)
         occurrences all number
    9
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 94 (15.96%)
    12 / 91 (13.19%)
         occurrences all number
    17
    12
    Fatigue
         subjects affected / exposed
    9 / 94 (9.57%)
    4 / 91 (4.40%)
         occurrences all number
    9
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 94 (9.57%)
    7 / 91 (7.69%)
         occurrences all number
    9
    7
    Vomiting
         subjects affected / exposed
    9 / 94 (9.57%)
    8 / 91 (8.79%)
         occurrences all number
    9
    9
    Skin and subcutaneous tissue disorders
    pruritus generalized
         subjects affected / exposed
    2 / 94 (2.13%)
    5 / 91 (5.49%)
         occurrences all number
    2
    5
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    7 / 94 (7.45%)
    4 / 91 (4.40%)
         occurrences all number
    7
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Study drug delivery to intercostal nerve via instillation, not US-guided injection, likely prevented optimal placement/retention, as supported by pharmacokinetic data. Efficacy of study drug as regional nerve block could not be meaningfully evaluated
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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