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    Summary
    EudraCT Number:2014-001672-55
    Sponsor's Protocol Code Number:MW2010-03-02
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2014-001672-55
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.4.1Sponsor's protocol code numberMW2010-03-02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02148705
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMediWound Ltd.
    B.1.3.4CountryIsrael
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMediWound Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGCP-Service International Ltd. & Co.KG
    B.5.2Functional name of contact pointTatjana Stoever
    B.5.3 Address:
    B.5.3.1Street AddressAnne-Conway-Str. 2
    B.5.3.2Town/ cityBremen
    B.5.3.3Post code28359
    B.5.3.4CountryGermany
    B.5.4Telephone number004942189 67 66 38
    B.5.5Fax number004942143 48 659
    B.5.6E-mailtstoever@gcp-service.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NexoBrid
    D.2.1.1.2Name of the Marketing Authorisation holderMediWound Germany GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/02/107
    D.3 Description of the IMP
    D.3.1Product nameNexoBrid
    D.3.4Pharmaceutical form Powder and gel for gel
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNconcentrate of proteolytic enzymes enriched in bromelain
    D.3.9.3Other descriptive nameCONCENTRATE OF PROTEOLYTIC ENZYMES ENRICHED IN BROMELAIN
    D.3.9.4EV Substance CodeSUB91744
    D.3.10 Strength
    D.3.10.1Concentration unit gm/m2 gram(s)/square meter
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number220 to 3300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product Yes
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typemixture of enzymes (Bromelain) extracted from pineapple
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGel
    D.8.4Route of administration of the placeboTopical use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The study objective is to evaluate the efficacy and safety of NexoBrid in removing burn eschar in hospitalized subjects with thermal burns.
    E.1.1.1Medical condition in easily understood language
    Dead tissue of a burn wound has to be removed to promote healing of the wound.
    E.1.1.2Therapeutic area Diseases [C] - Injuries, poisonings, and occupational diseases [C21]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level HLT
    E.1.2Classification code 10043418
    E.1.2Term Thermal burns
    E.1.2System Organ Class 100000004863
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing complete eschar removal as compared with Gel Vehicle.
    E.2.2Secondary objectives of the trial
    To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing earlier complete eschar removal, reduction in patients’ surgical burden and its related blood loss as compared to SOC,
    and to assess the safety of NexoBrid compared to SOC, including demonstration that treatment with NexoBrid does not cause an unacceptable level of harm on wound closure outcome and long term outcomes of cosmesis and function.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria- Patient level
    1. Males and females; ≥ 18 years of age,
    2. Thermal burns caused by fire/flame, scalds or contact,
    3. Patient total burns area ≥ 3% DPT and / or FT,
    4. Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or FT in depth,
    5. Informed consent can be obtained within 84 hours of the burn injury,
    6. Patients who are willing and able to sign a written consent form.

    Inclusion Criteria – Wound level
    1. At least one wound (a continuous burn area) that is ≥0.5% TBSA (DPT and/or FT) (this
    minimal wound size should not include face, perineal or genital),13
    All planned target wounds (TWs) should meet the following criteria:
    2. SPT areas that cannot be demarcated from DPT and FT areas should be less than 50% of the %
    TBSA of the TW
    3. Wound’s blisters can be removed/unroofed, as judged by the investigator.
    E.4Principal exclusion criteria
    Exclusion Criteria- Patient level
    1. Patients who are unable to follow study procedures and follow up period,
    2. Modified Baux index14 ≥ 80,
    3. Patients with burned charred fingers, 3rd degree in depth and possibly devoid of circulation,
    4. Patients with abraded wound/s that cannot be treated by an enzymatic debrider application
    (NexoBrid) will be excluded from the study,
    5. Patients with electrical or chemical burns,
    6. Patients with circumferential (≥ 80% of the limb circumference) DPT and/or FT burns defined
    as Extremities at Risk (EAR) as described in section 11.8,
    7. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3),
    8. Patients with pre-enrolment wounds which are covered by eschar heavily saturated with iodine
    or by SSD pseudoeschar (e.g. pseudoeschar as a result of >12 h SSD treatment),
    9. Patients with pre-enrollment escharotomy,
    10. Patients with diagnosed infections as described in Section 11.9 of study protocol,
    11. Diagnosis of smoke inhalation injury,
    12. Pregnant women (positive pregnancy test) or nursing mothers,
    13. Poorly controlled diabetes mellitus (HbA1c>11%) in patients with known diabetes as captured in
    the medical history,
    14. BMI greater than 39.0 kg/m2 in patients with burns area of up to 15% TBSA or BMI greater than
    34.0 kg/m2 in patients with burns area of more than 15% %TBSA,
    15. ASA greater than 2 (Appendix 13- ASA classification system),
    16. Cardio-pulmonary disease (MI within 6 months prior to injury, severe pulmonary hypertension,
    severe COPD or pre-existing oxygen-dependent pulmonary diseases, severe broncho-pneumonia
    within 1 month prior to injury, steroid dependent asthma or uncontrolled asthma),
    17. Pre-existing diseases which interfere with circulation (severe peripheral vascular disease, severe
    edema and/or lymphedema, regional lymph nodes dissection, significant varicose veins),
    18. Any conditions that would preclude safe participation in the study or adding further risk to the
    basic acute burn trauma (such as severe immuno-compromising diseases, life threatening
    trauma, severe pre-existing coagulation disorder, severe cardiovascular disorder, significant
    pulmonary disorder, significant liver disorder including post alcoholic abuse impaired function
    or neoplastic disease, blast injury),
    19. Chronic systemic steroid intake,
    20. History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or papain,
    21. Current (within 12 months prior to screening) suicide attempt,
    22. Mentally incapacitated adults who are incapable of giving legal consent Enrollment in any
    investigational drug trial within 4 weeks prior to screening,
    23. Current (within 12 months prior to screening) severe alcohol or drug use disorder (see definition
    in section 1.1),
    24. Prisoners and incarcerated,
    25. Patients who might depend on the clinical study site or investigator.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be investigated at a "per patient" level:
    Incidence of complete eschar removal: Demonstrate superiority over Gel Vehicle for eschar removal as measured by incidence of complete eschar removal assessed by the blinded assessor at the end of the topical agent soaking period (6 hours after start of the 1st topical application).
    Or, in cases where 2 applications are performed, complete ER is assessed 6 hours after start of the 2nd Treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of the topical agent soaking period.
    E.5.2Secondary end point(s)
    The following secondary endpoints will be evaluated in this study and compared between NexoBrid and SOC.
    1. Reduction in surgical need- Demonstrate superiority of NexoBrid over SOC in reduction of surgical need for excisional eschar removal as measured by an analysis of incidence of surgical eschar removal (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision).
    2. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC in reduction of the time to achieve complete eschar removal.
    3. Blood loss- Demonstrate superiority of NexoBrid over SOC with regard to the blood loss incurred during the eschar removal procedures

    Safety Endpoints
    The following group of safety endpoints will be evaluated in this study and compared between NexoBrid and SOC. These endpoints are used to ensure that NexoBrid does not cause an unacceptable level of harm.
    1. Time to reach complete wound closure assessed in days, starting from randomization date. Demonstrate that NexoBrid does not cause any clinically meaningful harm to the patients with respect to the wound healing process by comparing NexoBrid mean time to wound closure with SOC mean time to wound closure, where a difference of not more than 7 days difference will be interpreted as clinically not relevant.
    2. Cosmesis and function at 12 months from wound closure - A measure of cosmesis, using MVSS, will be used to demonstrate - that treatment with NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as compared to scars quality of burns treated with SOC, measured at 12 months from wound closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean MVSS score.
    3. Cosmesis and function at 24 months from wound closure - A measure of cosmesis, using MVSS, will be used to demonstrate that Treatment with NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as compared to scars quality of burns treated with SOC, measured at 24 months from wound closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean MVSS score.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -time when complete eschar removal has been achieved.
    - time when complete wound closure has been achieved
    -12 and 24 months following to the confirmatory wound closure visit
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard of Care
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Czech Republic
    Germany
    Israel
    Italy
    Romania
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2014-06-23. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 175
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients are treated according to standard of care after end of participation in the trial.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-09-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-06
    P. End of Trial
    P.End of Trial StatusCompleted
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