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    Clinical Trial Results:
    A Prospective, Randomised, Controlled Study Evaluating EVARREST® Fibrin Sealant Patch in Controlling Mild or Moderate Hepatic Parenchyma or Soft Tissue Bleeding During Open Abdominal, Retroperitoneal, Pelvic and Thoracic (Non-Cardiac) Surgery in Paediatric Patients

    Summary
    EudraCT number
    		 2013-003557-24
    Trial protocol
    		 GB   BE  
    Global end of trial date
    12 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2022
    First version publication date
    27 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    400-12-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02227992
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ETHICON Inc
    Sponsor organisation address
    1000 US Highway 202 South, Raritan, United States, NJ08869
    Public contact
    Patricia Schleckser, ETHICON Inc, pschleck@its.jnj.com
    Scientific contact
    Dr. Richard Kocharian, MD, PhD, ETHICON Inc, 1 908 642 3787, rkochar1@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001149-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and haemostatic effectiveness of EVARREST® Fibrin Sealant Patch (EVARREST®) when used as an adjunct to control mild or moderate soft tissue and parenchymal bleeding during open hepatic, abdominal, pelvic, retroperitoneal, and thoracic (non-cardiac) surgery in paediatric patients.
    Protection of trial subjects
    Study information was presented to the patient (where applicable) and their legal guardian by a trained member of the research team. The final taking of the informed consent was completed by the Investigator or sub-investigator when the potential participant and their legal guardian were completely satisfied with the information presented. Venipuncture was required, however we minimised the number required and where possible results that were already available were used rather than repeating the test. Visits were conducted at times where the patient would routinely attend the hospital where possible. Physical examinations were undertaken by a trained member of the research team in a private area or room, or if this procedure was completed routinely upon admission to the hospital, it was not repeated. The study was reviewed and approved by the Ethics Committee in the country where the study was being conducted.
    Background therapy
    		 During surgery or in the surgical management of trauma, surgeons encounter bleeding from a variety of tissue types. The need to effectively manage haemostasis during surgery has had a strong influence on the development of modern surgical techniques. Bleeding during surgical procedures may manifest in many forms. It can be discrete or diffuse from a large surface area. It can be from large or small vessels; arterial (high pressure) or venous (low pressure) of high or low volume. It may be easily accessible, or it may originate from difficult to access sites. This bleeding may be of any intensity: mild, moderate, or severe. The selection of appropriate methods or products for the control of bleeding is dependent upon many factors, which include but are not limited to bleeding severity, anatomical location of the source and the proximity of adjacent critical structures, whether the bleeding is from a discrete source or from a broader surface area, visibility and precise identification of the source and access to the source. Tissue type and fragility/friability, coagulation system status and patient stability are also factors for consideration. Haemostasis is a prerequisite for wound healing, and, under normal physiologic conditions, it is achieved by means of the coagulation cascade. Conventional methods to achieve haemostasis includes use of surgical techniques, sutures, ligatures or clips, and energy-based coagulation or cauterisation. When these conventional measures are ineffective or impractical, adjunctive haemostasis techniques and products are typically utilised, including topical absorbable haemostats.
    Evidence for comparator
    		 With a clinical history spanning more than 60 years, SURGICEL® has been used as an adjunct to achieve and accelerate haemostasis when various types of bleeding were observed intra operatively. The product can be placed on the source of bleeding with manual compression to facilitate haemostasis and was therefore considered a suitable control product for use in this study.
    Actual start date of recruitment
    31 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    0
    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)
    11
    Children (2-11 years)
    22
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first subject was enrolled on 31st July 2014 and the last subject was recruited on 26th October 2021. The last subject's last visit took place on 12th November 2021.

    Pre-assignment
    Screening details
    		 Prospective subjects were screened within 21 days prior to surgery. Prior to any study related procedures, subjects were fully informed of all aspects of the study. Subjects or subject legal representative/parent were asked to sign a Consent Form. Assent process occurred when applicable.

    Period 1
    Period 1 title
    Full Analysis Set (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EVARREST
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    EVARREST Fibrin Sealant Patch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sealant matrix
    Routes of administration
    Topical use
    Dosage and administration details
    Per protocol, subjects assigned to EVARREST received up to 6.9 square cm per kilogram of body weight. Where subject's body weight allowed, additional pads could be placed up to a maximum of four (4) units of the 4 x 4 inches (10.2 x 10.2 centimeters) or a maximum of eight (8) units of the 2 x 4 inches (5.1 x 10.2 centimeters) of EVARREST was allowed to be implanted covering the entire TBS and overlapped the TBS with a margin of 1-2 cm. After placement of the study product, firm manual continual manual compression was applied over the entire bleeding area until 4 minutes had lapsed from the time of randomisation. Maximum amount of EVARREST used in this study was 1 patch per subject.

    Arm title
    		 SURGICEL
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SURGICEL Original
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sealant matrix
    Routes of administration
    Topical use
    Dosage and administration details
    The dosage and product administration were followed as per the product IFU. After placement of SURGICEL, firm manual continual manual compression was applied over the entire bleeding area until 4 minutes had lapsed from the time of randomisation. Maximum amount of SURGICEL used in this study was 2 kits per subject.

    Number of subjects in period 1
    		EVARREST SURGICEL
    Started
    20
    20
    Completed
    19
    19
    Not completed
    1
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EVARREST
    Reporting group description
    		 -

    Reporting group title
    SURGICEL
    Reporting group description
    		 -

    Reporting group values
    		 EVARREST SURGICEL Total
    Number of subjects
    		 20 20 40
    Age Categorical
    Units: Participants
        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)
    		 6 5 11
        Children (2-11 years)
    		 11 11 22
        Adolescents (12-17 years)
    		 3 4 7
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        median (full range (min-max))
    		 3.0 (0.8 to 13.0) 4.0 (0.3 to 14.0) -
    Gender Categorical
    Units: Participants
        Female
    		 9 7 16
        Male
    		 11 13 24
    Race, Customized
    Units: Subjects
        White/Caucasian
    		 18 17 35
        Asian
    		 0 1 1
        Black/African American
    		 1 0 1
        Other
    		 1 2 3
    Ethnicity
    Units: Subjects
        Hispanic
    		 1 2 3
        Non-Hispanic
    		 19 18 37
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised subjects

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the Full Analysis Set with no major protocol deviations affecting the primary effectiveness endpoint (agreed prior to database lock)

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received treatment

    Subject analysis sets values
    		 Full Analysis Set Per Protocol Safety Set
    Number of subjects
    40
    33
    40
    Age Categorical
    Units: Participants
        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)
    11
    8
    11
        Children (2-11 years)
    22
    20
    22
        Adolescents (12-17 years)
    7
    5
    7
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age Continuous
    Units: years
        median (full range (min-max))
    3.0 (0.3 to 14.0)
    3.0 (0.3 to 14.00)
    3.0 (0.3 to 14.0)
    Gender Categorical
    Units: Participants
        Female
    16
    12
    16
        Male
    24
    21
    24
    Race, Customized
    Units: Subjects
        White/Caucasian
    35
    28
    35
        Asian
    1
    1
    1
        Black/African American
    1
    1
    1
        Other
    3
    3
    3
    Ethnicity
    Units: Subjects
        Hispanic
    3
    2
    3
        Non-Hispanic
    37
    31
    37

    End points

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    End points reporting groups
    Reporting group title
    EVARREST
    Reporting group description
    		 -

    Reporting group title
    SURGICEL
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised subjects

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the Full Analysis Set with no major protocol deviations affecting the primary effectiveness endpoint (agreed prior to database lock)

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received treatment

    Primary: Absolute Time to Haemostasis

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    End point title
    		 Absolute Time to Haemostasis [1]
    End point description
    Absolute haemostasis is defined as time lapsed from randomisation to the last moment in time at which detectable bleeding at the Target Bleeding Site was observed.
    End point type
    Primary
    End point timeframe
    Intra-operatively from randomisation to last moment in time at which detectable bleeding at Target Bleeding Site was observed
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: 95% confidence intervals for the median absolute time to haemostasis was conducted for the overall analysis only and is presented in the table for Absolute Time to Haemostasis
    End point values
    		 EVARREST SURGICEL
    Number of subjects analysed
    20
    20
    Units: Minutes
        median (confidence interval 95%)
    4.0 (4.00 to 4.00)
    4.0 (4.00 to 7.62)
    No statistical analyses for this end point

    Primary: Absolute Time to Haemostasis (Subjects in Paediatric Group (1 month (>= 28 days from birth) to <1 year)

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    End point title
    		 Absolute Time to Haemostasis (Subjects in Paediatric Group (1 month (>= 28 days from birth) to <1 year) [2]
    End point description
    Absolute haemostasis is defined as time lapsed from randomisation to the last moment in time at which detectable bleeding at the Target Bleeding Site was observe
    End point type
    Primary
    End point timeframe
    Randomisation to last moment in time at which detectable bleeding at Target Bleeding Site was observed
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: 95% confidence intervals were conducted for the overall analysis only and is presented in the table for Absolute Time to Haemostasis
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    1
    3
    4
    Units: Minutes
        median (full range (min-max))
    4.0 (4.0 to 4.0)
    6.0 (4.0 to 6.9)
    5.0 (4.0 to 6.9)
    No statistical analyses for this end point

    Primary: Absolute Time to Haemostasis (Subject in Paediatric group [>/= 1 year to < 18 years])

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    End point title
    		 Absolute Time to Haemostasis (Subject in Paediatric group [>/= 1 year to < 18 years]) [3]
    End point description
    Absolute haemostasis is defined as time lapsed from randomisation to the last moment in time at which detectable bleeding at the Target Bleeding Site was observe
    End point type
    Primary
    End point timeframe
    Randomisation to last moment in time at which detectable bleeding at Target Bleeding Site was observed
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: 95% confidence intervals were conducted for the overall analysis only and is presented in the table for Absolute Time to Haemostasis
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    19
    17
    36
    Units: Minutes
        median (full range (min-max))
    4.0 (4.0 to 117.0)
    4.0 (4.0 to 39.0)
    4.0 (4.0 to 117.0)
    No statistical analyses for this end point

    Primary: Summary of Absolute Time to Haemostasis (Primary Effectiveness Endpoint) by Treatment and Age group

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    End point title
    		 Summary of Absolute Time to Haemostasis (Primary Effectiveness Endpoint) by Treatment and Age group [4]
    End point description
    Absolute haemostasis is defined as time lapsed from randomisation to the last moment in time at which detectable bleeding at the Target Bleeding Site was observed.
    End point type
    Primary
    End point timeframe
    Randomisation to last moment in time at which detectable bleeding at Target Bleeding Site was observed
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: 95% confidence intervals were conducted for the overall analysis only and is presented in the table for Absolute Time to Haemostasis
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    20 [5]
    20 [6]
    40 [7]
    Units: Minutes
    median (full range (min-max))
        Infants and Toddlers (28 days to <24 months)
    4.0 (4.0 to 4.0)
    4.0 (4.0 to 6.9)
    4.0 (4.0 to 6.9)
        Children (2 to 11 years)
    4.0 (4.0 to 117.0)
    4.0 (4.0 to 39.0)
    4.0 (4.0 to 117.0)
        Adolescent (12 to <18 years)
    4.0 (4.0 to 7.5)
    4.0 (4.0 to 10.0)
    4.0 (4.0 to 10.0)
        All subjects
    4.0 (4.0 to 117.0)
    4.0 (4.0 to 39.0)
    4.0 (4.0 to 117.0)
    Notes
    [5] - Infants/Toddlers: 6 subjects Children: 11 subjects Adolescent: 3 subjects All: 20 subjects
    [6] - Infants/Toddlers: 5 subjects Children: 11 subjects Adolescent: 4 subjects All: 20 subjects
    [7] - Infants and Toddlers: Children: Adolescent:
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Achieving Haemostatic Success at 4 minutes

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    End point title
    		 Proportion of Subjects Achieving Haemostatic Success at 4 minutes
    End point description
    Proportion of subjects achieving haemostatic success at 4 minutes following randomisation and no bleeding requiring treatment at the Target Bleeding Site occurs any time prior to final fascial closure
    End point type
    Secondary
    End point timeframe
    Intra-operatively from randomisation to 4 minutes following randomisation
    End point values
    		 EVARREST SURGICEL
    Number of subjects analysed
    20
    20
    Units: Percentage
    number (confidence interval 95%)
        Proportion of subjects
    80.0 (56.3 to 94.3)
    60.0 (36.1 to 80.9)
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Ahieving Haemostatic Success at 10 minutes

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    End point title
    		 Proportion of Subjects Ahieving Haemostatic Success at 10 minutes
    End point description
    Proportion of subjects achieving haemostatic success at 4 minutes following randomisation and no bleeding requiring treatment at the Target Bleeding Site occurs any time prior to final fascial closure
    End point type
    Secondary
    End point timeframe
    Intra-operatively from randomisation to 10 minutes following randomisation
    End point values
    		 EVARREST SURGICEL
    Number of subjects analysed
    20
    20
    Units: Percentage
    number (confidence interval 95%)
        Proportion of subjects
    95.0 (75.1 to 99.9)
    90.0 (68.3 to 98.8)
    No statistical analyses for this end point

    Secondary: Subjects With No Re-bleeding at Target Bleeding Site

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    End point title
    		 Subjects With No Re-bleeding at Target Bleeding Site
    End point description
    End point type
    Secondary
    End point timeframe
    Intra-operatively from randomisation up to the 30-day (+/- 14 days) follow-up visit
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    20
    20
    40
    Units: Percentage
        number (not applicable)
    95.0
    85.0
    90.0
    No statistical analyses for this end point

    Other pre-specified: Additional Treatment at Target Bleeding Site

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    End point title
    		 Additional Treatment at Target Bleeding Site
    End point description
    Any treatment applied to the Target Bleeding Site following randomised treatment
    End point type
    Other pre-specified
    End point timeframe
    Intra-operatively from application of randomised treatment to final fascial closure
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    20
    20
    40
    Units: Participants
    1
    5
    6
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with at Least 1 Adverse Event Related to Re-bleeding at Target Bleeding Site

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    End point title
    		 Number of Subjects with at Least 1 Adverse Event Related to Re-bleeding at Target Bleeding Site
    End point description
    Sponsor Assessment - Events assessed as possibly related or related to re-bleeding at Target Bleeding Site
    End point type
    Other pre-specified
    End point timeframe
    Product application to the 30 day (+/- 14 days) follow-up
    End point values
    		 EVARREST SURGICEL Safety Set
    Number of subjects analysed
    20
    20 [8]
    40
    Units: Participants
        number (not applicable)
    1
    3
    4
    Notes
    [8] - 1 SAE of bloody discharge was reported post-operatively & conservatively considered possibly related
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with at Least 1 Thrombotic Adverse Event

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    End point title
    		 Number of Subjects with at Least 1 Thrombotic Adverse Event
    End point description
    Sponsor assessment
    End point type
    Other pre-specified
    End point timeframe
    Intra-operatively from randomisation to 30 day (+/- 14 days) follow-up visit
    End point values
    		 EVARREST SURGICEL Safety Set
    Number of subjects analysed
    20
    20
    40
    Units: Participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Estimated Volume of Blood Loss

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    End point title
    		 Estimated Volume of Blood Loss
    End point description
    Estimated volume of intra-operative blood loss (including but not limited to the Target Bleeding Site)
    End point type
    Other pre-specified
    End point timeframe
    During surgery from first incision to final fascial closure
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    20
    20
    40
    Units: mL
        median (full range (min-max))
    100.0 (0.0 to 800.0)
    200.0 (15.0 to 2000.0)
    150.0 (0.0 to 2000.0)
    No statistical analyses for this end point

    Other pre-specified: Blood and Blood Product Transfusion

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    End point title
    		 Blood and Blood Product Transfusion
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Intra-operatively to 30-day (+/- 14 days) follow-up visit
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    20
    20
    40
    Units: Participants
        number (not applicable)
    12
    11
    23
    No statistical analyses for this end point

    Other pre-specified: Blood and Blood Products Transfused

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    End point title
    		 Blood and Blood Products Transfused
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Intra-operatively from first incision to the 30-day (+/- 14 days) follow-up visit
    End point values
    		 EVARREST SURGICEL Full Analysis Set
    Number of subjects analysed
    20
    20
    40
    Units: Participants
        Packed Red Blood Cells:0 Unit
    3
    2
    5
        Packed Red Blood Cells:1 Unit
    4
    4
    8
        Packed Red Blood Cells:2 Units
    4
    3
    7
        Packed Red Blood Cells:3 Units
    1
    1
    2
        Packed Red Blood Cells:4 Units
    0
    0
    0
        Packed Red Blood Cells:5 Units
    0
    0
    0
        Packed Red Blood Cells:6 Units
    0
    1
    1
        Whole Blood: 0 Unit
    9
    9
    18
        Whole Blood: 1 Unit
    2
    1
    3
        Whole Blood: 2 Units
    1
    1
    2
        Fresh Frozen Plasma: 0 Unit
    10
    11
    21
        Fresh Frozen Plasma: 1 Unit
    0
    0
    0
        Fresh Frozen Plasma: 2 Units
    1
    0
    1
        Fresh Frozen Plasma: 3 Units
    0
    0
    0
        Fresh Frozen Plasma: 4 Units
    0
    0
    0
        Fresh Frozen Plasma: 5 Units
    1
    0
    1
        Platelets: 0 Unit
    8
    9
    17
        Platelets: 1 Unit
    3
    1
    4
        Platelets: 2 Units
    1
    0
    1
        Platelets: 3 Units
    0
    1
    1
        Cryoprecipitates: 0 Unit
    12
    11
    23
        Other: 0 Unit
    11
    9
    20
        Other: 1 Unit
    0
    1
    1
        Other: 2 Units
    1
    1
    2
    No statistical analyses for this end point

    Other pre-specified: Laboratory Parameters - Haemoglobin, Haematocrit and Platelets

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    End point title
    		 Laboratory Parameters - Haemoglobin, Haematocrit and Platelets
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Between baseline (up to 21 days prior to surgery) and post-operative hospital discharge
    End point values
    		 EVARREST SURGICEL
    Number of subjects analysed
    20
    20
    Units: SI
    median (full range (min-max))
        Haemoglobin: g/L
    0.0 (-56.0 to 43.0)
    -10.0 (-150.0 to 44.0)
        Haematocrit: g/L
    0.0 (-0.2 to 0.1)
    -0.0 (-0.1 to 0.1)
        Platelet Count: (x10(9)/L)
    -89.0 (-531.0 to 112.0)
    -71.5 (-259.0 to 386.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Intra-operatively from randomisation up to and including the 30-day (+/- 14 days) follow-up visit
    Adverse event reporting additional description
    Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Only exacerbations of expected post operative pain based on the Investigator’s judgment was reported as an Adverse Event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    SURGICEL
    Reporting group description
    		 -

    Reporting group title
    EVARREST
    Reporting group description
    		 -

    Serious adverse events
    		 SURGICEL EVARREST
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 20 (25.00%)
    4 / 20 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Weight Decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         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)
    Neuroblastoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Bloody Discharge
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intussusception
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (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
    Hematuria
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (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
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         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: 0%
    Non-serious adverse events
    		 SURGICEL EVARREST
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 20 (85.00%)
    18 / 20 (90.00%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 20 (15.00%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Puncture site discharge
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    9 / 20 (45.00%)
    5 / 20 (25.00%)
         occurrences all number
    10
    5
    Device occlusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Vulval oedema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Tachypnoea
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Pleural effusion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Pneumothorax
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory distress
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood alkaline phosphate decreased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    International normalized ratio increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Urine output decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Blood pressure increased
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Procedural hypotention
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Procedural pain
         subjects affected / exposed
    7 / 20 (35.00%)
    3 / 20 (15.00%)
         occurrences all number
    7
    3
    Wound complication
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Wound secretion
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Anal injury
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Excoriation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Tachycardia
         subjects affected / exposed
    7 / 20 (35.00%)
    10 / 20 (50.00%)
         occurrences all number
    9
    10
    Nervous system disorders
    Horner’s syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Coagulopathy
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    4 / 20 (20.00%)
    2 / 20 (10.00%)
         occurrences all number
    4
    2
    Dry mouth
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    6 / 20 (30.00%)
    6 / 20 (30.00%)
         occurrences all number
    7
    7
    Constipation
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Haematemesis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Swelling face
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    Decubitus ulcer
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Joint instability
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Device related infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Escherichia infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypovolaemia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2014
    Protocol Amendment 1 was introduced to align the use of additional treatment at the TBS to previous adult studies. Additional clarification test was also added regarding eligible procedure types and information collected at the surgical visit. This amendment also introduced a new size of EVARREST patch (2 x 4 inch) and up-dated the number of mis-randomised subjects that would require summarisation in the FAS and Evaluable Analysis sets.
    17 Mar 2016
    Protocol Amendment 2 was introduced to change the sample size and age stratification as approved by the EMA under a PIP Modification. Reference to sample size was up-dated throughout, including statistical analysis section. Additional changes made at this included the definition of actively infected field which was added to exclusion criteria. A clarification to the assenting process was included. Pregnancy test at screening visit was removed and clarified that it should be with 24 hours of surgery for applicable patients and could be a serum or urine test. An up-date to the AE definition for post-operative pain was also added.
    13 Dec 2016
    Protocol Amendment 3 was introduced to update the TBS identification definition to align with adult studies. Height and weight were added to physical examination. The handling of EVARREST in the sterile field included additional information for clarity. Additional clarifications were made to when laboratory samples could be collected and the timepoint when concomitant medications were to be recorded from. Reference to subject initials was removed from the protocol as these were no longer being recorded. Up-dates to the description of EVARREST were included as well as previous clinical experience.
    05 Mar 2018
    Protocol Amendment 4 was introduced to remove fibrinogen from the coagulation sample as it was not required for the study. The period in which adverse events were to be entered into the EDC was also added in this amendment.

    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.
    This was a 40 subject enrolling only paediatric patients as part of a Paediatric Investigational Plan approved by the European Medicines Agency and UK Paediatric Investigation Plan approved by the MHRA.
    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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