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    Clinical Trial Results:
    A multicenter, multinational, randomized, controlled, assessor blinded study, performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid compared to Gel Vehicle and compared to Standard of Care

    Summary
    EudraCT number
    2014-001672-55
    Trial protocol
    DE   CZ   RO   LV   IT  
    Global end of trial date
    20 Aug 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Nov 2021
    First version publication date
    13 Nov 2021
    Other versions
    Summary report(s)
    CSR 12 month
    CSR 24 month

    Trial information

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    Trial identification
    Sponsor protocol code
    MW2010-03-02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02148705
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MediWound Ltd
    Sponsor organisation address
    42 Hayarkon Street, Yavne, Israel, 8122745
    Public contact
    Lior Rosenberg, MediWound Ltd, 972 779714100, liorr@mediwound.com
    Scientific contact
    Lior Rosenberg, MediWound Ltd, 972 779714100, liorr@mediwound.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
    23 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstration of safety and efficacy of NexoBrid® in removing burn eschar in hospitalized patients with deep partial thickness and full thickness thermal burn wounds.
    Protection of trial subjects
    The study will be carried out in accordance with accepted international standards, which meet regulations relating to Good Clinical Practice (GCP). These standards are drawn from the following guidelines: ICH Guideline for Good Clinical Practice, 1 May 1996 amended September 1997 and Declaration of Helsinki (as amended in Seoul, October 2008), concerning medical research in humans. The investigator(s) will ensure that this study is conducted in full conformity with the principles of the "Declaration of Helsinki" and with the laws and regulations of the participating countries, whichever affords the greater protection to the individual. It is the responsibility of the investigator to obtain informed consent in written form (according to local legal requirements) from each subject participating in this study. All patients will be informed of the aims, methods, anticipated benefits, potential hazards and confidentiality of data. Candidates will also be told that they are free to refuse participation at any time.
    Background therapy
    Patients will be treated in the same way in all study arms (NexoBrid, SOC or Gel vehicle) except for the eschar removal stage which will be performed as per the randomization study arm. Prior to initiation of eschar removal treatment subjects will be medicated with appropriate analgesia and undergo wound cleansing and dressing of all wounds with antibacterial solutions. Following wound cleansing and antibacterial treatments, subjects will undergo the eschar removal process as per treatment assignment (NexoBrid, SOC or Gel Vehicle, following randomization). Subsequent to complete eschar removal, all wounds will be assessed and treated in the same manner, in accordance with post-eschar removal wound care strategy. Post eschar removal, subjects will undergo daily vital signs and pain assessments, until hospital discharge (HD) and weekly assessments of wound progress, until wound closure.
    Evidence for comparator
    Comparators: Standard of Card (SOC) and Gel Vehicle (Collagenase Santyl®): Eschar removal is considered a critical initial stage of the comprehensive wound care process. Early (ie, within 1 to 2 days/before the onset of inflammation) and rapid debridement of eschar is essential to initiate body’s own wound healing process, to allow clinical visual evaluation of burn severity and depth, preserve viable tissue, and prevent further complications. The SOC for burn eschar removal relies primarily on surgical tangential excision to mechanically remove the eschar. According to 1 estimate, these nonselective methods are estimated to excise tissue that consists of 30% to 50% viable dermal tissue, thereby increasing the surface area needed for autografting along with increased risk of scar formation and functional compromise. Alternatively, physicians can use a nonsurgical debridement, which includes collagenase ointment (Collagenase Santyl®), antimicrobial agents such as silver sulfadiazine (SSD), or various hydrogels which result in a lengthy sloughing period. Collagenase Santyl ointment is a licensed, nonsurgical debridement product that currently exists on the US market.
    Actual start date of recruitment
    01 Jan 2015
    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: 98
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Georgia: 11
    Worldwide total number of subjects
    175
    EEA total number of subjects
    64
    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)
    159
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The patients included in this study were hospitalized burn victims with DPT (deep partial thickness) and FT (full thickness) thermal burns

    Pre-assignment
    Screening details
    Signing of Informed Consent, demographics, medical history, concomitant medication, physical examination, vital signs, pain assessment, burn etiology, clinical assessment of the burn, randomization

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]
    Blinding implementation details
    For patients who were randomized to one of the topical treatment arms, NexoBrid or Gel Vehicle, eschar removal assessment was performed by an assessor blinded to the treatment arm. The eschar removal assessment was performed by an individual who was not involved in the treatment of the patient or wound, as the treating physician could distinguish between treatments administered to each patient. For the purpose of standardization, if feasible, the same blinded assessor was assigned at each center

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    NexoBrid
    Arm description
    NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the active component. Following mixing of the powder with the gel vehicle, each gram of the prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).
    Arm type
    Experimental

    Investigational medicinal product name
    NexoBrid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and gel for gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    2 or 5 g of NexoBrid sterile powder was mixed in 20 or 50 g of sterile Gel Vehicle (ratio of 1:10), NexoBrid was applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20 g sterile Gel Vehicle per 1% of TBSA (~ surface of an adult palm) for 4 hours (or 5 g NexoBrid sterile powder mixed with 50 g sterile Gel Vehicle per 2.5% of TBSA). The NexoBrid powder and the Gel Vehicle were mixed at the patient’s bedside ≤15 minutes prior to use.

    Arm title
    SOC (Standard of Care)
    Arm description
    Standard of care. Includes surgical and/or non surgical eschar remomal procedures.
    Arm type
    Standard of care

    Investigational medicinal product name
    Standard of care procedures
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream, Cutaneous solution, Ointment
    Routes of administration
    Cutaneous use, Topical use
    Dosage and administration details
    SOC arm will include surgical and/or non-surgical eschar removal procedures. Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excisions. Non-surgical procedures will include the application of (collagenase ointment (e.g. Santyl), antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. Bacitracin, Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, Acticoat). The need of either non-surgical or surgical procedures will be determined by the burn specialists and can be repeated as needed until complete debridement.

    Arm title
    Gel Vehicle
    Arm description
    Gel Vehicle will be applied on the burn skin.
    Arm type
    Placebo

    Investigational medicinal product name
    Gel Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn skin. Gel Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel per 1% of TBSA (~ surface of an adult palm) or 50 grams per 2.5% TBSA for four hours. Gel Vehicle may be applied for a second time to the same burn area, if eschar removal from the target wound after the first application is not complete but at least 50% of the eschar was removed during the first application. The Gel Vehicle may only be applied twice to the same burn wound area. Gel Vehicle should not be applied to more than 15% TBSA (±3% TBSA) in one session.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: For patients who were randomized to 1 of the topical treatment arms, NexoBrid or Gel Vehicle, escharremoval assessment was performed by an assessor blinded to the treatment arm. The eschar removal assessment was performed by an individual who was not involved in the treatment of the patient orwound, as the treating physician could distinguish between treatments administered to each patient.
    Number of subjects in period 1
    NexoBrid SOC (Standard of Care) Gel Vehicle
    Started
    75
    75
    25
    First stage
    67
    63
    23
    Second stage
    56
    58
    20
    Third stage
    43
    36
    10
    Completed
    43
    36
    10
    Not completed
    32
    39
    15
         Adverse event, serious fatal
    2
    -
    -
         Consent withdrawn by subject
    4
    8
    -
         Subject received no study drug treatment
    -
    1
    -
         Patient withdrew due to relocation
    -
    1
    -
         Pregnancy
    -
    1
    -
         Lost to follow-up
    24
    27
    13
         Patient in incarcerated
    -
    1
    -
         Jail
    1
    -
    -
         Left country
    1
    -
    -
         Site closure
    -
    -
    1
         Not treated
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NexoBrid
    Reporting group description
    NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the active component. Following mixing of the powder with the gel vehicle, each gram of the prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).

    Reporting group title
    SOC (Standard of Care)
    Reporting group description
    Standard of care. Includes surgical and/or non surgical eschar remomal procedures.

    Reporting group title
    Gel Vehicle
    Reporting group description
    Gel Vehicle will be applied on the burn skin.

    Reporting group values
    NexoBrid SOC (Standard of Care) Gel Vehicle Total
    Number of subjects
    75 75 25 175
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    69 69 21 159
        From 65-84 years
    6 6 4 16
        85 years and over
    0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    26 16 10 52
        Male
    49 59 15 123

    End points

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    End points reporting groups
    Reporting group title
    NexoBrid
    Reporting group description
    NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the active component. Following mixing of the powder with the gel vehicle, each gram of the prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).

    Reporting group title
    SOC (Standard of Care)
    Reporting group description
    Standard of care. Includes surgical and/or non surgical eschar remomal procedures.

    Reporting group title
    Gel Vehicle
    Reporting group description
    Gel Vehicle will be applied on the burn skin.

    Subject analysis set title
    Full analysis set including only NexoBrid and Gel Vehicle trea
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subset of the FAS including only NexoBrid and Gel Vehicle treatment arms

    Primary: Incidence of Complete Eschar Removal

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    End point title
    Incidence of Complete Eschar Removal [1]
    End point description
    The primary efficacy endpoint was analyzed using a subset of the FAS including only NexoBrid and Gel Vehicle treatment arms. The main analysis was based on the binary variable (yes/no): “has complete eschar removal been achieved in all TWs” and compared NexoBrid with the Gel Vehicle.
    End point type
    Primary
    End point timeframe
    Stage 1: Acute Phase – baseline to 3 months after wound closure
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Following the goal to seek an indication for NexoBrid that focuses on non surgical eschar removal, this primary endpoint will assess whether non-surgical eschar removal by NexoBrid allows effective removal of the offending eschar compared with its comparator.
    End point values
    NexoBrid Gel Vehicle Full analysis set including only NexoBrid and Gel Vehicle trea
    Number of subjects analysed
    75
    25
    100
    Units: Patients
    75
    25
    100
    Statistical analysis title
    Primary Endpoint
    Statistical analysis description
    The primary efficacy endpoint was analyzed using a subset of the FAS including only NexoBrid and Gel Vehicle treatment arms. The main analysis was based on the binary variable (yes/no): “has complete eschar removal been achieved in all TWs” and compared NexoBrid with the Gel Vehicle.
    Comparison groups
    NexoBrid v Gel Vehicle
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    288.281
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.549
         upper limit
    13984.356
    Notes
    [2] - Demonstrate the superiority of NexoBrid treatment over Gel Vehicle

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All stages: from study start to study termination
    Adverse event reporting additional description
    Adverse event data is based on CRF data entry
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    SOC AE
    Reporting group description
    The analysis of AEs was based on the Safety Analysis Set consisting of 68 patients treated with SOC

    Reporting group title
    Gel Vehicle AE
    Reporting group description
    The analysis of AEs was based on the Safety Analysis Set consisting of 24 patients treated with Gel Vehicle

    Reporting group title
    NexoBrid AE
    Reporting group description
    The analysis of AEs was based on the Safety Analysis Set consisting of 77 patients treated with NexoBrid.

    Serious adverse events
    SOC AE Gel Vehicle AE NexoBrid AE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 68 (13.24%)
    3 / 24 (12.50%)
    10 / 77 (12.99%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Squamous cell carcinoma of the oral cavity
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Vascular disorders
    Phlebitis superficial
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (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
    Deep vein thrombosis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Surgical and medical procedures
    Cholecystectomy
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Eventration repair
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Internal fixation of fracture
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Therapeutic procedure
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Failure to thrive
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chest pain
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Infusion site thrombosis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (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
    Acute respiratory distress syndrome
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Acute respiratory failure
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Neonatal respiratory failure
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient tachypnoea of the newborn
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Suicide attempt
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         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
    Graft loss
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Thermal burn
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital tricuspid valve incompetence
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngomalacia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patent ductus arteriosus
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Persistent foetal circulation
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular septal defect
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trisomy 21
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
    Additional description: Prefererred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Bifascicular block
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Nervous system disorders
    Cerebral ventricle dilatation
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (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
    Gastrointestinal disorders
    Appendicitis noninfective
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         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
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Diverticulitis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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
    Sepsis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection bacterial
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (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%
    Non-serious adverse events
    SOC AE Gel Vehicle AE NexoBrid AE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 68 (60.29%)
    15 / 24 (62.50%)
    49 / 77 (63.64%)
    Vascular disorders
    Arterial thrombosis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Extremity necrosis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Haemorrhage
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    0
    1
    2
    Hypotension
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    2
    Phlebitis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Phlebitis superficial
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Varicose vein
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Surgical and medical procedures
    Colon operation
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Wound drainage
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Cyst
    Additional description: Prferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Hyperthermia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Pain
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 24 (0.00%)
    6 / 77 (7.79%)
         occurrences all number
    2
    0
    11
    Hypothermia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    2
    Pyrexia
    Additional description: Preferred Term
         subjects affected / exposed
    6 / 68 (8.82%)
    2 / 24 (8.33%)
    6 / 77 (7.79%)
         occurrences all number
    8
    3
    7
    Peripheral swelling
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Allergy to arthropod sting
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Drug hypersensitivity
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspnoea
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Increased viscosity of bronchial secretion
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Laryngospasm
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    Pulmonary oedema
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Adjustment disorder
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Agitation
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Alcoholism
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Drug dependence
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Anxiety
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Depression
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Insomnia
    Additional description: Preferred Term
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 24 (4.17%)
    4 / 77 (5.19%)
         occurrences all number
    4
    1
    4
    Emotional distress
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Major depression
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Panic disorder
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Mental status changes
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Substance use disorder
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Post-traumatic stress disorder
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Sleep disorder
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Suicide attempt
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Investigations
    Bacterial test
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Blood pressure increased
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    Bacterial test positive
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Body temperature increased
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    C-reactive protein increased
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    2
    Haemoglobin decreased
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic enzyme increased
    Additional description: Prferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Lymphocyte count decreased
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 24 (8.33%)
    1 / 77 (1.30%)
         occurrences all number
    0
    2
    1
    Inflammatory marker increased
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    White blood cell count increased
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Accidental overdose
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Contusion
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Craniocerebral injury
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Graft loss
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 24 (4.17%)
    3 / 77 (3.90%)
         occurrences all number
    2
    1
    4
    Hand fracture
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Incisional hernia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Intentional overdose
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Limb injury
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    Muscle strain
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Paravenous drug administration
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Post procedural haemorrhage
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Post-traumatic pain
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Skin abrasion
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Skin graft failure
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Skin laceration
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    Subcutaneous haematoma
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    2
    Sunburn
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Wound complication
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    3
    0
    3
    Thermal burn
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Cardiac disorders
    Sinus tachycardia
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    Tachycardia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    5 / 77 (6.49%)
         occurrences all number
    0
    0
    5
    Nervous system disorders
    Dizziness
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Cervical radiculopathy
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
    Additional description: Preferred Term
         subjects affected / exposed
    3 / 68 (4.41%)
    3 / 24 (12.50%)
    3 / 77 (3.90%)
         occurrences all number
    3
    3
    7
    Seizure
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Leukocytosis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    0
    0
    4
    Thrombocytosis
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    2
    0
    1
    Haemorrhagic anaemia
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    Ear and labyrinth disorders
    Tinnitus
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Ascites
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
    Additional description: Preferred Term
         subjects affected / exposed
    7 / 68 (10.29%)
    2 / 24 (8.33%)
    4 / 77 (5.19%)
         occurrences all number
    7
    2
    4
    Diarrhoea
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Melaena
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
    Additional description: Preferred Term
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 24 (16.67%)
    5 / 77 (6.49%)
         occurrences all number
    6
    4
    5
    Tooth loss
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
    Additional description: Preferred Term
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 24 (4.17%)
    5 / 77 (6.49%)
         occurrences all number
    4
    1
    5
    Skin and subcutaneous tissue disorders
    Dermatitis contact
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    1
    0
    2
    Hypertrophic scar
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    2
    1
    0
    Milia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    0
    0
    4
    Skin lesion
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Skin warm
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Urinary retention
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Renal failure
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: Preferred Term
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    4
    0
    2
    Arthritis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Arthralgia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Extremity contracture
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    Joint contracture
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Costochondritis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Muscle spasms
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Joint range of motion decreased
    Additional description: Preferred Term
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 24 (16.67%)
    3 / 77 (3.90%)
         occurrences all number
    30
    21
    8
    Neck pain
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Myalgia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    0
    Pain in extremity
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    3 / 77 (3.90%)
         occurrences all number
    0
    1
    3
    Osteoarthritis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    0
    Spinal pain
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Temporomandibular joint syndrome
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Periarthritis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bacterial infection
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Abscess jaw
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Candida infection
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Cellulitis
    Additional description: Preferred Term
         subjects affected / exposed
    4 / 68 (5.88%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    4
    0
    1
    Ear infection
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Folliculitis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    1
    1
    4
    Fungal skin infection
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Gastrointestinal viral infection
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Herpes zoster
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Hordeolum
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Influenza
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 24 (4.17%)
    2 / 77 (2.60%)
         occurrences all number
    4
    1
    2
    Otitis media
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    2
    Pneumonia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Rhinitis
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 24 (4.17%)
    0 / 77 (0.00%)
         occurrences all number
    1
    1
    0
    Sepsis
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Septic arthritis staphylococcal
    Additional description: Prferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
    Additional description: Preferred Term
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    4
    1
    1
    Subcutaneous abscess
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Staphylococcal skin infection
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    1
    0
    1
    Tooth abscess
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Wound infection
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    3 / 77 (3.90%)
         occurrences all number
    1
    0
    3
    Urinary tract infection
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    1
    0
    5
    Wound infection bacterial
    Additional description: Preferred Term
         subjects affected / exposed
    4 / 68 (5.88%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    4
    0
    3
    Wound infection staphylococcal
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Wound infection fungal
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Bacterial disease carrier
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Dehydration
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    2 / 77 (2.60%)
         occurrences all number
    0
    0
    2
    Hyperkalaemia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Hypocalcaemia
    Additional description: Preferred Term
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 24 (0.00%)
    0 / 77 (0.00%)
         occurrences all number
    1
    0
    0
    Hypokalaemia
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 24 (4.17%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    1
    Malnutrition
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1
    Vitamin D deficiency
    Additional description: Preferred Term
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 24 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2014
    Protocol Version 7
    22 Feb 2015
    Protocol Version 8
    12 Aug 2015
    Protocol Version 9
    23 Jun 2016
    Protocol Version 11

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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