A Study to Evaluate the Efficacy and Safety of NexoBrid in Subjects With Thermal Burns

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

This study will be a three-arms study intending to demonstrate superiority of NexoBrid treatment over the Gel Vehicle placebo control treatment and over SOC in thermal burn subjects.

The study objectives are:

1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing complete eschar removal as compared with Gel vehicle,
2. 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,
3. 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.

Study Overview

• Status: Completed
• Conditions: Thermal Burns
• Intervention / Treatment: Drug: NexoBrid; Drug: Gel Vehicle; Procedure: Standard of Care (SOC)

Detailed Description

This is a multi-center, multi-national, randomized, controlled, assessor blinded, three-arm study aiming to demonstrate superiority of NexoBrid treatment over Gel Vehicle control and over SOC treatment in thermal burn subjects with burns. Following the enrollment of a patient to the study and prior to randomization Physicians will define one or more Target Wounds (TWs) per subject according to TWs definition. All subjects' deep (DPT and FT) burns that comply with the specified entrance criteria are intended to receive study treatment per the randomized study arm.

The randomization procedure will be initiated only after all Target wounds of a subject have been defined. Patients will be assigned to the treatment arm in a 3:3:1 ratio (NexoBrid: SOC : Gel Vehicle).

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. Following wound closure confirmation visit, subjects will be followed up at 1, 3, 6, 12, 18 and 24 months post wound closure for long term outcomes evaluation.

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, B 9000
    • University Hospital, Department of Plastic Surgery
• Czechia
  • Brno, Czechia, 62500
    • Klinika popálenin a rekonstrukční chirurgie, Fakultní nemocnice Brno
• Georgia
  • Tbilisi, Georgia, 0179
    • Khechinashvili University Hospital - Thermal Injuries
• Germany
  • Berlin, Germany
    • Unfallkrankenhaus Berlin Zentrum für Schwerbrandverletzte mit Plastischer Chirurgie
  • Bochum, Germany, 44789
    • BG Universitätsklinikum Bergmannsheil GmbH
• Israel
  • Haifa, Israel
    • Rambam Medical Center
• Italy
  • Napoli, Italy
    • Hospital A. Cardarelli of Napoli
  • Pisa, Italy, 56125
    • Ospedale di Cisanello
• Romania
  • Bucharest, Romania, 010713
    • Spitalul Clinic de Urgenta de Chirurgie Plastica, Reparatorie si Arsuri
  • Bucharest, Romania, 042122
    • Spitalul Clinic de Urgenta "Sf. Ioan"
  • Bucharest, Romania, 41915
    • Spitalul Clinic de Urgenta "Bagdasar-Arseni"
• United States
  • Alabama
    • Mobile, Alabama, United States, 36617
      • University of South Alabama Department of Surgery
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Maricopa Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado at Denver, Teaching
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Washington Hospital Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida- Dept. of Surgery
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Joseph M. Still Research Foundation, Inc.
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • The University of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Burnett Burn Center at The University of Kansas Hospital
  • Maryland
    • Baltimore, Maryland, United States, 8163
      • Johns Hopkins Bayview Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • The General Hospital Corporation d/b/a Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10065
      • New-York Presbyterian Hospital
    • Stony Brook, New York, United States, 11794
      • Emergency Medicine Stony Brook University Hospital
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital and Health Network
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • Regional Medical Center ,Regional One Health
  • Texas
    • Galveston, Texas, United States, 77550
      • University of Texas Medical Branch
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53211
      • Columbia St. Mary's, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 77 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria- Patient level

1. Males and females; ≥ 18
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 including face, perineal or genital area.

   All planned target wounds (TWs) should meet the following criteria:

2. SPT area 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.

Exclusion Criteria- Patient level

1. Patients who are unable to follow study procedures and follow up period.
2. Modified Baux index ≥ 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) 2 as described in the protocol.
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 hours 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 burn area up to 15% TBSA or BMI greater than 34.0 kg/m2 in patients with burn area 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, edema, lymphedema, regional lymph nodes, 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
23. Enrollment in any investigational drug trial within 4 weeks prior to screening,
24. Current (within 12 months prior to screening) alcohol or drug abuse (see definition in section 1.1)
25. Prisoners and incarcerated,
26. Patients who might depend on the clinical study site or investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NexoBrid Gel; NexoBrid Gel is applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile Gel Vehicle per 1% of TBSA (~ surface of an adult palm) for four hours.	Drug: NexoBrid
Placebo Comparator: Gel Vehicle; Gel Vehicle is applied to the burn wound at a dose of 20 g sterile Gel per 1% of TBSA (~ surface of an adult palm) for four hours.	Drug: Gel Vehicle
Active Comparator: Standard of Care (SOC); Subjects in the SOC group may be treated with a combination of surgical and non-surgical eschar removal procedures, according to the investigator's judgment.	Procedure: Standard of Care (SOC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Endpoint: Number of Participants With Complete Eschar Removal.	Comparison of NexoBrid over Gel Vehicle for eschar removal as measured by Number of Participants with complete eschar removal at the end of the topical agent soaking period by a blinded assessor.	post application (post 2 h soaking)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Endpoint: Number of Participants With Surgical Excision Performed or Eschar Removal for NexoBrid vs SOC (FAS)	Comparison of NexoBrid over SOC in number of Participants with 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).	Post application (post 2 h soaking) for NexoBrid arm and immediately post surgical excision for SOC arm.
Secondary Endpoint: Comparison of Time (Days) to Complete Eschar Removal	Comparison of NexoBrid over SOC with regard to the time (in days) when complete eschar removal has been achieved. Results of the Generalized Wilcoxon-Gehan Test Adjusted for Overall TW Depths, TBSA Group, Center Group, and Number of TWs (FAS)	From randomization until complete eschar removal. For NexoBrid, assessed post application (post 2 h soaking) and for SOC assessed immediately post last dressing change for non-surgical SOC arm and immediately post excision for surgical SOC arm.
Secondary Endpoint: Patient-Level Comparison of Actual Blood Loss (Volume in mL) Related to Eschar Removal for NexoBrid vs SOC (FAS)	Comparison of NexoBrid over SOC with regard to the blood loss (volume in mL) occurred during the eschar removal procedures.	For NexoBrid arm, blood loss during NexoBrid application until post soaking. For SOC arm, blood loss during SOC procedures, through last dressing change for non-surgical SOC arm and through excision surgery for surgical SOC arm.

Collaborators and Investigators

• Sponsor: MediWound Ltd

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2015
• Primary Completion (Actual): June 12, 2018
• Study Completion (Actual): August 20, 2020

Study Registration Dates

• First Submitted: May 22, 2014
• First Submitted That Met QC Criteria: May 27, 2014
• First Posted (Estimated): May 28, 2014

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: June 11, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: fire/flame; scalds; contact
• Additional Relevant MeSH Terms: Wounds and Injuries; Burns
• Other Study ID Numbers: MW 2010-03-02