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    Clinical Trial Results:
    A multicenter, multinational, randomized, controlled, open label study, performed in children with thermal burns, to evaluate the efficacy and safety of NexoBrid as compared to standard of care (SOC) treatment

    Summary
    EudraCT number
    		 2014-003066-24
    Trial protocol
    		 CZ   ES   SK   DE   BE   AT   BG   NL   FR   SE   GB   HU   PL   IT  
    Global end of trial date
    19 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Sep 2024
    First version publication date
    25 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MW2012-01-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02278718
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 US (FDA): IND065448
    Sponsors
    Sponsor organisation name
    MediWound, Ltd.
    Sponsor organisation address
    42 Hayarkon Street, North Industrial Area, Yavne, Israel, 8122745
    Public contact
    Asi Haviv, DMD, Medical Director, MediWound, Ltd., 972 7797141000,
    Scientific contact
    Asi Haviv, DMD, Medical Director, MediWound, Ltd., 972 7797141000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000142-PIP02-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is: -To demonstrate enzymatic eschar removal efficacy of NexoBrid by providing earlier, complete eschar removal. -To demonstrate enzymatic eschar removal efficacy of NexoBrid by reducing patients’ surgical burden and resulting in non inferior final outcomes of cosmesis and function as compared to SOC. -To assess the safety of NexoBrid compared to SOC.
    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 1.5.96, amended September 1997 (Post step errata July 2002) and Declaration of Helsinki (as amended in Fortaleza, Brazil, October 2013), concerning medical research in humans. In the Netherlands, the NVK (The Netherlands Association for Paediatric Medicine) code of conduct for dealing with subjects’ expressions of objection in the course of the research will be adhered to as well. 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 or SOC) except for the Eschar Removal stage which will be performed as per the randomization study arm. 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 Vital Signs and pain assessments, daily, until HD (Hospital Discharge) and weekly assessments of wound progress thereafter, until wound closure. Following wound closure confirmation, subjects will be followed up for 3 months (at week 6 and 12) and after that at 6, 12, 18 and 24 months post wound closure for long term outcomes evaluation. In addition, all subjects will be invited to one additional extended follow up visit that will occur at least 30 months after wound closure confirmation for a blinded assessment of cosmesis, function and QoL evaluation.
    Evidence for comparator
    		 Comparators: Standard of Card (SOC) Conservative, non-surgical treatment by the antimicrobial SSD (Silver Sulphadiazine) dressing followed by daily dressing change and bathing is designed basically to slowly slough and debride the eschar-covered- wound by autolysis without excessive infection. SSD should not be used on a clean bed as it decreases epithelialization.
    Actual start date of recruitment
    01 Dec 2014
    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: 28
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Georgia: 4
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    India: 30
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    145
    EEA total number of subjects
    59
    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)
    45
    Children (2-11 years)
    80
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    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
    12-Week Follow-up
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Assessor was blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NexoBrid
    Arm description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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
    Two grams or 5 grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of sterile Gel Vehicle to obtain NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g NexoBrid/20g Gel per 180cm² for four hours. In most cases, NexoBrid is effective after a single application; however it may be applied for a second time to the same burn area based on the investigator's judgment of debridement efficacy. NexoBrid should not be applied more than twice to the same burn wound area. NexoBrid should not be applied to more than 15% TBSA in one session. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Arm title
    		 SOC (Standard of Care)
    Arm description
    		 Standard of care. Includes surgical and/or non surgical eschar removal 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
    Conjunctival use , Topical use
    Dosage and administration details
    Surgical procedures intended for eschar removal are pre-specified in the protocol for standardization and will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excision. Non-surgical procedures intended for eschar removal are pre-specified below for standardization and will include the application of 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). Non-Surgical procedure is considered as one procedure for the whole period of any continuous dressing changes of more than 24h until either complete eschar removal is achieved or until surgical eschar removal is conducted. 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. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Number of subjects in period 1
    		NexoBrid SOC (Standard of Care)
    Started
    72
    73
    Completed
    66
    66
    Not completed
    6
    7
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    1
    -
         Randomized Patient but did not receive Study IMP
    -
    1
         Lost to follow-up
    2
    3
         The Patient was randomized but did not receive Stu
    2
    -
    Period 2
    Period 2 title
    12-Month Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Assessor was blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NexoBrid
    Arm description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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
    Two grams or 5 grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of sterile Gel Vehicle to obtain NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g NexoBrid/20g Gel per 180cm² for four hours. In most cases, NexoBrid is effective after a single application; however it may be applied for a second time to the same burn area based on the investigator's judgment of debridement efficacy. NexoBrid should not be applied more than twice to the same burn wound area. NexoBrid should not be applied to more than 15% TBSA in one session. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Arm title
    		 SOC (Standard of Care)
    Arm description
    		 Standard of care. Includes surgical and/or non surgical eschar removal 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
    Conjunctival use , Topical use
    Dosage and administration details
    Surgical procedures intended for eschar removal are pre-specified in the protocol for standardization and will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excision. Non-surgical procedures intended for eschar removal are pre-specified below for standardization and will include the application of 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). Non-Surgical procedure is considered as one procedure for the whole period of any continuous dressing changes of more than 24h until either complete eschar removal is achieved or until surgical eschar removal is conducted. 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. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Number of subjects in period 2
    		NexoBrid SOC (Standard of Care)
    Started
    66
    66
    Completed
    64
    61
    Not completed
    2
    5
         Consent withdrawn by subject
    2
    1
         Lost to follow-up
    -
    4
    Period 3
    Period 3 title
    24-Month Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Assessor was blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NexoBrid
    Arm description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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
    Two grams or 5 grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of sterile Gel Vehicle to obtain NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g NexoBrid/20g Gel per 180cm² for four hours. In most cases, NexoBrid is effective after a single application; however it may be applied for a second time to the same burn area based on the investigator's judgment of debridement efficacy. NexoBrid should not be applied more than twice to the same burn wound area. NexoBrid should not be applied to more than 15% TBSA in one session. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Arm title
    		 SOC (Standard of Care)
    Arm description
    		 Standard of care. Includes surgical and/or non surgical eschar removal 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
    Conjunctival use , Topical use
    Dosage and administration details
    Surgical procedures intended for eschar removal are pre-specified in the protocol for standardization and will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excision. Non-surgical procedures intended for eschar removal are pre-specified below for standardization and will include the application of 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). Non-Surgical procedure is considered as one procedure for the whole period of any continuous dressing changes of more than 24h until either complete eschar removal is achieved or until surgical eschar removal is conducted. 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. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Number of subjects in period 3
    		NexoBrid SOC (Standard of Care)
    Started
    64
    61
    Completed
    58
    53
    Not completed
    6
    8
         Consent withdrawn by subject
    1
    2
         Not arrived to the final visit
    1
    -
         Lost to follow-up
    4
    6
    Period 4
    Period 4 title
    30-Month Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Assessor was blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NexoBrid
    Arm description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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
    Two grams or 5 grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of sterile Gel Vehicle to obtain NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g NexoBrid/20g Gel per 180cm² for four hours. In most cases, NexoBrid is effective after a single application; however it may be applied for a second time to the same burn area based on the investigator's judgment of debridement efficacy. NexoBrid should not be applied more than twice to the same burn wound area. NexoBrid should not be applied to more than 15% TBSA in one session. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Arm title
    		 SOC (Standard of Care)
    Arm description
    		 Standard of care. Includes surgical and/or non surgical eschar removal 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
    Conjunctival use , Topical use
    Dosage and administration details
    Surgical procedures intended for eschar removal are pre-specified in the protocol for standardization and will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excision. Non-surgical procedures intended for eschar removal are pre-specified below for standardization and will include the application of 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). Non-Surgical procedure is considered as one procedure for the whole period of any continuous dressing changes of more than 24h until either complete eschar removal is achieved or until surgical eschar removal is conducted. 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. Treatment was only applied at the beginning of the Study, no application at the Follow-Up Visits.

    Number of subjects in period 4
    		NexoBrid SOC (Standard of Care)
    Started
    58
    53
    Completed
    45
    36
    Not completed
    13
    17
         Consent withdrawn by subject
    4
    4
         N/A
    2
    -
         The patient did not arrive to the final visit
    1
    -
         Lost to follow-up
    6
    13

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    12-Week Follow-up
    Reporting group description
    		 -

    Reporting group values
    		 12-Week Follow-up Total
    Number of subjects
    		 145 145
    Age categorical
    0 Months - 18 Years
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 45 45
        Children (2-11 years)
    		 80 80
        Adolescents (12-17 years)
    		 20 20
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 55 55
        Male
    		 90 90

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    NexoBrid
    Reporting group description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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 removal procedures.
    Reporting group title
    NexoBrid
    Reporting group description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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 removal procedures.
    Reporting group title
    NexoBrid
    Reporting group description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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 removal procedures.
    Reporting group title
    NexoBrid
    Reporting group description
    		 NexoBrid is presented as partially purified Bromelain powder and gel vehicle for preparation of a gel for cutaneous use. 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 removal procedures.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes all patients who were randomized into the trial.

    Primary: Time to complete eschar removal

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    End point title
    		 Time to complete eschar removal
    End point description
    Eschar removal was measured at the end of debridement starting from randomisation date. Eschar removal (days) can demonstrate superiority of NexoBrid over SoC as measured by a survival analysis of incidence of complete eschar removal when complete eschar removal was achieved for each patient, from the time of randomization.
    End point type
    Primary
    End point timeframe
    From the time of randomization - baseline until 12-Month Follow-Up.
    End point values
    		 NexoBrid SOC (Standard of Care)
    Number of subjects analysed
    72
    73
    Units: Days
    1
    6
    Statistical analysis title
    		 Efficacy
    Statistical analysis description
    Time until complete eschar removal was defined as the time until complete echar removal has been achieved.
    Comparison groups
    NexoBrid v SOC (Standard of Care)
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Wilcoxon-Gehan
    Confidence interval

    Primary: Percent Wound Area Surgically Excised for Eschar Removal

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    End point title
    		 Percent Wound Area Surgically Excised for Eschar Removal
    End point description
    Demonstrate superiority over SOC in reduction in surgical need for excisional eschar removal as measured by an analysis of percent wound area surgically excised for eschar removal (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision).
    End point type
    Primary
    End point timeframe
    From the time of randomization - baseline until 12-Month Follow-up.
    End point values
    		 NexoBrid SOC (Standard of Care)
    Number of subjects analysed
    72
    73
    Units: percent wound area
    2
    48
    Statistical analysis title
    		 % wound area surgically excised for eschar removal
    Comparison groups
    NexoBrid v SOC (Standard of Care)
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    45.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.6
         upper limit
    		 58.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.83

    Primary: Cosmesis and Function

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    End point title
    		 Cosmesis and Function
    End point description
    To demonstrate non-inferiority to SoC in quality of scars of burns (using MVSS) treated with NexoBrid, measured at 12 and 24 month from wound closure
    End point type
    Primary
    End point timeframe
    Cosmesis assessment at 12-Month and 24-Month Follow-Up.
    End point values
    		 NexoBrid SOC (Standard of Care) NexoBrid SOC (Standard of Care)
    Number of subjects analysed
    72
    73
    66
    66
    Units: MVSS score
    4
    5
    3
    4
    Statistical analysis title
    		 MVSS Regression Results 12-Month Follow-Up
    Comparison groups
    NexoBrid v SOC (Standard of Care)
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.85
         upper limit
    		 3.67
    Variability estimate
    Standard deviation
    Dispersion value
    0.91
    Statistical analysis title
    		 MVSS Regression Results 24- Month Follow-Up
    Comparison groups
    NexoBrid v SOC (Standard of Care)
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 3.25
    Variability estimate
    Standard deviation
    Dispersion value
    0.86

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Per protocol amendment, the extended long-term FU visit at ≥ 30M did not include documentation of AEs and SAEs that occurred after the 24M FU visit.
    Adverse event reporting additional description
    For 24M FU Period, TEAEs (Treatment-Emergent Adverse Events) were analysed separately for 2 different periods: 1. Between the 12 months FU and the 24 months FU (12M-24M FU Period) 2. In the cumulative period (0-24M FU Period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    NexoBrid AE
    Reporting group description
    		 Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Intensity – 12M-24M FU Period (SAS)

    Reporting group title
    SOC AE
    Reporting group description
    		 -

    Serious adverse events
    		 NexoBrid AE SOC AE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 69 (7.25%)
    1 / 70 (1.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Withdrawal syndrome
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngospasm
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint contracture
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         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
    		 NexoBrid AE SOC AE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 69 (39.13%)
    30 / 70 (42.86%)
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    4 / 69 (5.80%)
    6 / 70 (8.57%)
         occurrences all number
    4
    6
    Pyrexia
         subjects affected / exposed
    7 / 69 (10.14%)
    4 / 70 (5.71%)
         occurrences all number
    7
    4
    Chills
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 70 (1.43%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    Asthma
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 70 (2.86%)
         occurrences all number
    1
    2
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 70 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 70 (0.00%)
         occurrences all number
    2
    0
    Accidental overdose
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences all number
    1
    0
    Wound complication
         subjects affected / exposed
    6 / 69 (8.70%)
    5 / 70 (7.14%)
         occurrences all number
    6
    5
    Injury
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 69 (1.45%)
    3 / 70 (4.29%)
         occurrences all number
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 70 (2.86%)
         occurrences all number
    1
    2
    Neuralgia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 69 (4.35%)
    1 / 70 (1.43%)
         occurrences all number
    3
    1
    Nausea
         subjects affected / exposed
    3 / 69 (4.35%)
    3 / 70 (4.29%)
         occurrences all number
    3
    3
    Vomiting
         subjects affected / exposed
    5 / 69 (7.25%)
    4 / 70 (5.71%)
         occurrences all number
    5
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 70 (0.00%)
         occurrences all number
    4
    0
    Pruritus
         subjects affected / exposed
    9 / 69 (13.04%)
    7 / 70 (10.00%)
         occurrences all number
    9
    7
    Blister
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    Bromhidrosis
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Joint contracture
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 69 (5.80%)
    3 / 70 (4.29%)
         occurrences all number
    4
    3
    Folliculitis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2
    Rhinovirus infection
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 70 (0.00%)
         occurrences all number
    2
    0
    Ear infection
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 70 (0.00%)
         occurrences all number
    2
    0
    Wound infection
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2014
    Protocol Version 4
    08 Sep 2014
    Protocol Version 5
    02 Dec 2014
    Protocol Version 6
    28 Dec 2014
    Protocol Version 6.01
    31 Dec 2014
    Protocol Version 6.02
    02 Jan 2017
    Protocol Version 7
    28 Mar 2017
    Protocol Version 7.01
    01 Jun 2017
    Protocol Version 7.02
    26 Dec 2017
    Protocol Version 8
    29 Jul 2019
    Protocol Version 9.01
    26 Aug 2019
    Protocol Version 9
    16 Nov 2020
    Protocol Version 10
    16 Nov 2020
    Protocol Version 10.01
    16 Jun 2021
    Protocol Version 11
    16 Jun 2021
    Protocol Version 11.01

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Sep 2020
    Study was re-submitted in Belguim due to already closed Study. A new Eudra-CT.-No needed to be used: 2022-001909-53 The site was closed on 17-Sep-2020 when all patients completed the study at site (however, in other countries the study was ongoing). Because also the authorities were informed about the site/study closure in Belgium (only 1 site participated) a new trial must be submitted and this was done on 29-Jun-2022. Site was re-initiated again on 09-Nov-2022.
    09 Nov 2022

    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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