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    Summary
    EudraCT Number:2014-003066-24
    Sponsor's Protocol Code Number:MW2012-01-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-10-27
    Trial 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 number2014-003066-24
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.4.1Sponsor's protocol code numberMW2012-01-01
    A.5.4Other Identifiers
    Name:INDNumber:065448
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/006/2017
    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 pointSergej Graf
    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 35
    B.5.5Fax number004942143 48 659
    B.5.6E-mailsgraf@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 IMPCutaneous use
    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 g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 stem
    D.IMP: 2
    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 IMPCutaneous use
    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 g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 stem
    D.8 Information on Placebo
    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 safety and clinical benefit of NexoBrid in hospitalized children (0-18 years) with deep partial and/or full thickness thermal burns of 1-30% TBSA and to compare NexoBrid to standard of care (SOC).
    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 20.0
    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
    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.
    E.2.2Secondary objectives of the trial
    The following secondary objectives are assessed compared between SOC and NexoBrid:
    1.Reduction in surgical need- Incidence of surgical excision performed for eschar removal. This Endpoint (EP) supplements the primary EP by further assessing NexoBrid’s impact on the reduction in surgical needs.
    2. Blood loss related to eschar removal- Demonstrate superiority of NexoBrid over SOC with regard to the blood loss occurred during the eschar removal procedures.
    3.Incidence of autograft performed in deep partial thickness wounds only
    4. % area of deep partial thickness wounds autografted
    5. Cosmesis assessment using MVSS at 24 months following the confirmatory wound closure visit
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    8.1.1 8.1.1 Inclusion Criteria- Patient level
    1. Stage 1: Males and females between 4 years to 18 years of age,
    Stage 2 (upon DSMB review): Males and females between 1 year to 18 years of age,
    Stage 3 (upon DSMB review): Males and females between 0 years to 18 years of age.
    2. Thermal burns caused by fire/flame, scalds or contact.
    3. Patient total burns area ≥ 1% DPT and / or FT,
    4. Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or FT in depth,
    5. Signed written informed consent by a legal guardian can be obtained within 84 hours of the burn injury.
    8.1.2 8.1.2 Inclusion Criteria - Wound level
    At least one wound (a continuous burn area which can be treated in one session; might include several anatomical areas) in a patient should meet all following criteria:
    1. Wound that is ≥ 1% TBSA (DPT and/or FT) (not including face, perineal or genital),
    2. Wound is composed of DPT and/or FT in depth. Superficial partial thickness areas may be included in the wound area only if cannot be separated from deeper areas (e.g. surrounded by or mixed with DPT areas) and might interfere with the treatment of the deeper areas,
    3. Wound that is potentially intended for surgical eschar removal,
    4. Wound’s blisters can be unroofed, as judged by the investigator.
    E.4Principal exclusion criteria
    1. Patients weighing less than 3kg,
    2. Patients who are unable to follow study procedures and follow up period,
    3. Patients with electrical or chemical burns,
    4. Patient with a continuous burn area above 15% TBSA,
    5. Patients with no DPT and/or FT burn area (only SPT wounds),
    6. Patient with circumferential anterior/posterior trunk fire/flame burns, >15% TBSA (Circumferential is defined as encircling ≥ 80% of the trunk circumference),
    7. The following pre-enrolment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3),
    8. Patients with diagnosed infections as described in Section ‎13.2.6 of study protocol,
    9. Diagnosis of smoke inhalation injury,
    10. Patients with pre-enrolment wounds which are covered by eschar saturated with iodine or by SSD pseudoeschar (e.g. pseudoeschar as a result of >12h SSD treatment),
    11. Patients with pre-enrolment escharotomy,
    12. Pregnant women (positive pregnancy test) or nursing mothers,
    13. Poorly controlled diabetes mellitus (HbA1c>9%),
    14. Known Cardio-pulmonary disease, oxygen-dependent pulmonary diseases, broncho-pneumonia, uncontrolled asthma,
    15. Known conditions which interfere with circulation (peripheral vascular disease, edema, lymphedema, surgery to the regional lymph nodes, obesity),
    16. Any known conditions that would preclude safe participation in the study or adding further risk to the basic acute burn trauma (such as immuno-compromising diseases, life threatening trauma, severe pre-existing coagulation disorder, pulmono-cardiovascular, liver or neoplastic disease),
    17. ASA greater than 2 (see Appendix 13- ASA classification system in study protocol)
    18. Chronic systemic steroid intake,
    19. History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or papain,
    20. Current (within 12 months prior to screening) suicide attempt,
    21. Enrollment in any investigational drug trial within 4 weeks prior to screening,
    22. Current (within 12 months prior to screening) alcohol (daily consumption > 3 units for males and >2 units for females) or drug abuse ,
    23. Prisoners and incarcerated
    24. Patients who might depend on the clinical study site or investigator.
    25. Patient expresses objection to participate in the study.
    26. Patients with other severe cutaneous trauma at the same sites as the burns (i.e. blunt, avulsion or deep abrasion) or previous burn(s) at the same treatment site(s)
    27. General condition of patient would contraindicate surgery
    E.5 End points
    E.5.1Primary end point(s)
    1. Earlier eschar removal (in days): Demonstrate superiority over SOC for eschar removal as measured by a survival analysis of incidence of complete eschar removal as a function of time. Eschar removal will be measured at the end of the debridement starting from randomization date.
    2. Reduction in surgical needs: Demonstrate superiority over SOC in reduction in surgical need for excisional eschar removal as measured by an analysis of % wound area surgically excised for eschar removal (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision).
    3. Cosmesis and Function: Demonstrate non-inferiority to SOC in quality of scars of burns (using POSAS) treated with NexoBrid, measured at 24 months from wound closure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Start of randomization
    2. End of eschar removal
    3. 24 months from wound closure.
    4. Interim analysis when all patients reach 12 months FU
    E.5.2Secondary end point(s)
    1. Reduction in surgical need- Incidence of surgical excision performed for eschar removal. This endpoint supplements the primary EP by further assessing NexoBrid’s impact on the reduction in surgical needs.
    2. Incidence of autograft performed in deep partial thickness wounds only
    3. % area of deep partial thickness wounds autografted
    4. Incidence of wound closure
    5. Time to reach complete wound closure assessed in days, starting from Randomization date
    6. Cosmesis assessment using MVSS at 12 weeks and months, 6, 12, 18 and 24 following the confirmatory wound closure visit.
    7. Long term Quality of Life will be measured using EQ5D at 12 weeks and months 6, 12, 18 and 24 following to the confirmatory wound closure visit.
    8. Long term functionality evaluation of the extremities (using the ‘Lower Extremity Functional Scale’ and 'QuickDASH' questionnaires and 'Range Of Motion' measurements) will be evaluated at 12 weeks and months 6, 12, 18 and 24 months following to the confirmatory wound closure visit.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -time until complete eschar removal has been achieved.
    -end of the topical agent soaking period.
    -Time to reach complete wound closure assessed in days, starting from Randomization date.
    -3, 6, 9, 12, 18 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    scar evaluation is blinded
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Comparator arm is Standard of care
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Georgia
    Israel
    Ukraine
    United States
    Belgium
    Bulgaria
    France
    Germany
    Hungary
    Italy
    Latvia
    Netherlands
    Poland
    Romania
    Slovakia
    Spain
    United Kingdom
    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 Yes
    F.1.1Number of subjects for this age range: 160
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 1
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 4
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 45
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 85
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Both parents/legal guardians are asked to consent on child participation. Children the age of 7-18 get their own additional ICF. If minor goes to site with one parent the other parents signature can be obtained later asap.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 160
    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 Decision2014-12-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-17
    P. End of Trial
    P.End of Trial StatusOngoing
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