A Study to Evaluate the Efficacy and Safety of NexoBrid in Children With Thermal Burns Compared the Standard of Care

Phase 3

• Conditions: Thermal Burns
• Interventions: Drug: NexoBrid; Procedure: Standard of Care

• Registration Number: NCT02278718
• Lead Sponsor: MediWound Ltd

Brief Summary

This study will be a two-arms study intending to demonstrate superiority of NexoBrid treatment over SOC in children with thermal burns. The study objective is to evaluate the safety and clinical benefit of NexoBrid in hospitalized children (0-17 years) with deep partial and/or full thickness thermal burns of 1-30% TBSA and to compare NexoBrid to standard of care (SOC).

Detailed Description

A total of 160 patients will be randomized into NexoBrid and SOC treatment (80 patients per arm).

Age distribution will be managed as follows:

* 45 patients 0-23 months old

* 45 patients 24 months-3 years old

* 30 patients 4-11 years old

* 20 patients 12-17 years old The remaining 20 patients will be enrolled to any of the above groups, per their age during enrollment.

The study will be conducted in three stages. In Stage I, at least 24 children age 4-18 years, hospitalized in burn units, with deep partial thickness burns ranging from 1%-30% TBSA, and who meet the entrance criteria, will be enrolled. Upon completion of stage I, a safety analysis will be performed on safety parameters and the results will be evaluated by a Data Safety Monitoring Board (DSMB) as defined in the agreed charter. If the DSMB does not have any safety concerns, Stage II will commence, this time enrolling at least 26 additional children aged of 1-18 years according to the study procedures. A DSMB will be convened to assess the safety data of the first 50 patients enrolled at stages 1 \& 2. If the DSMB has not found any safety concerns, stage III will commence in which patients from the age of birth to 18 years will be included (stage III will include 110 remaining patients required to reach a total of 160 patients).

Following the enrollment of a subject to the study and prior to randomization, physicians will define one or more Target Wounds (TWs) per subject according to TWs definition. All subjects' DPT and FT burns that fit the specified criteria are intended to receive study treatment per randomized study arm and therefore, must be designated as TWs.

Prior to eschar removal treatment with NexoBrid or SOC 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 or SOC, following randomization). Subsequent to eschar removal, all wounds will be assessed and treated in the same manner, in accordance with post-eschar removal wound care strategy. Furthermore, subjects will undergo daily assessments (Vital signs (VS) and pain assessments) for one week and weekly assessments thereafter, until wound closure. Following wound closure, subjects will be followed up at 6 weeks, 12 weeks, and after that, at 6, 12, 18 and 24 months (for a blinded assessment of cosmesis, function and QoL evaluation).

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.

Study Timeline

• Study First Submitted: 2014-10-27
• Study First Submitted QC: 2014-10-28
• Study First Posted: 2014-10-30
• Study Start: 2015-05
• Primary Completion: 2021-04
• Status Verified: 2022-07
• Last Update Submitted: 2022-07-24
• Last Update Posted: 2022-07-27
• Study Completion: 2022-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 145

Inclusion Criteria

Not provided

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,
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
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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NexoBrid Gel	NexoBrid	NexoBrid Gel is applied to the burn wound at a dose of 2g or 5g NexoBrid sterile powder mixed with 20g or 50g sterile Gel Vehicle per 180cm\^2 of TBSA for four hours.
Standard of Care	Standard of Care	Non surgical and Surgical Debridement

Primary Outcome Measures

Name	Time	Method
Time to Complete Eschar Removal (in Days)	From randomization date 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.	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, assessed until complete eschar removal is achieved (in days)

Secondary Outcome Measures

Name	Time	Method
Incidence of Surgical Excision Performed for Eschar Removal	Until complete eschar removal has been achieved. Complete eschar removal was achieved within 0.99 days (95% CI: 0.88 to 1.04) for the NexoBrid treatment arm and 5.99 days (95% CI: 2.71 to9.84) for the SOC treatment arm.	Number of patients who needed surgical excision for eschar removal
Blood Loss Related to Eschar Removal	Hematocrit - immediately before each procedure and 4 hrs after its completion. The amount of blood transfused will be summed over all transfusions carried out during the debridement procedure and up to 24 hrs from the end time of the debridement procedure	Measured by actual blood loss \[ABL\]. Actual blood loss was the calculated blood loss summed over all procedures carried out to remove eschar, using hematocrit values measured immediately before each procedure and 4 hours after its completion and the amount of blood transfused was summed over all transfusions carried out during the debridement procedure and up to 24 hours from the end time of the debridement procedure.
Percent Area of Autograft Performed in DPT Wounds - Main Analysis, Patient Level.	Assessment will be performed by the investigator immediately after each autograft procedure was performed, before application of coverage.	Percent area of deep partial thickness wounds autografted
Incidence of Autograft Performed in Deep Partial Thickness Wounds	Patient's wounds were assessed until complete healing of all wounds, during the period from complete eschar removal was achieved until complete wound closure. Median time in the population was approx. 4.5 weeks and longest follow up period was of 12 weeks	Number of autografts performed in deep partial thickness wounds

Trial Locations

Locations (36)

Uniwersytecki Szpital Dzieciecy w Krakowie; 🇵🇱 Kraków, Poland

Shriners Hospital for Children; 🇺🇸 Boston, Massachusetts, United States

Drexel University; 🇺🇸 Philadelphia, Pennsylvania, United States

Harborview Medical Center; 🇺🇸 Seattle, Washington, United States

Maricopa Special Health Care District; 🇺🇸 Phoenix, Arizona, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

The University of South Florida Board of Trustees; 🇺🇸 Tampa, Florida, United States

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Marg; 🇮🇳 New Delhi, Delhi, India

University of Miami; 🇺🇸 Miami, Florida, United States

Krishna Rajendra Hospital; 🇮🇳 Mysuru, India

Vardhman Mahavir Medical College (VLCC) and Safdarjung Hospital; 🇮🇳 New Delhi, India

University Of Florida; 🇺🇸 Gainesville, Florida, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

University of Kansas Medical Center Research Institute, Inc.; 🇺🇸 Kansas City, Kansas, United States

University Hospital, Department of Plastic Surgery; 🇧🇪 Gent, Belgium

Unfallkrankenhaus Berlin Zentrum für Schwerbrandverletzte mit Plastischer Chirurgie; 🇩🇪 Berlin, Germany

S. Khechinashvili University Hospital; 🇬🇪 Tbilisi, Georgia

Klinikum Stuttgart - Olgahospital; 🇩🇪 Stuttgart, Germany

MRE Bethesda Gyermekkórháza; 🇭🇺 Budapest, Hungary

Acute Burn Care &Trauma Surgery, Dept Surgery/Burn Center, Rode Kruis Ziekenhuis, LUMC University Leiden; 🇳🇱 Beverwijk, Netherlands

Universitary Integrated Hospital Verona (AOUI Verona),; 🇮🇹 Verona, Italy

Spitalul Clinic de Urgenta pentru Copii "Sfanta Maria"; 🇷🇴 Iasi, Romania

Univerzitná nemocnica Bratislava, Klinika popálenin a rekonštrukčnej chirurgie; 🇸🇰 Bratislava, Slovakia

Spitalul Clinic de Urgenta Tg- Mures; 🇷🇴 Târgu-Mureş, Romania

Boulevar Sur s/n; 🇪🇸 Valencia, Spain

La Paz University Hospital; 🇪🇸 Madrid, Spain

Birmingham Children´s Hospital NHS Foundation Trust; 🇬🇧 Birmingham, United Kingdom

B.A.Z Megyei Kórház és Egyetemi Oktatókórház; 🇭🇺 Miskolc, Hungary

Shawn Jekins Children's Hospital; 🇺🇸 Charleston, South Carolina, United States

Klinikai Kozpont Gyermekgyogyaszati Klinika; 🇭🇺 Pécs, Hungary

Royal Manchester Children's Hospital; 🇬🇧 Manchester, United Kingdom

Szpital Dzieciecy im.prof.dr.med Jana Bogdanowicza, Oddzial Chirurgii i Urologii Dzieciecej z Pododdzialem Leczenia Oparzen; 🇵🇱 Warszawa, Poland

CNPE "City clinical hospital of immediate and urgent medical aid n.a.Meshchaninov" of Kharkiv CC and State institution 'Zaitsev V.T. Institute of general and urgent surgery of the National academy of medical sciences of Ukraine'; 🇺🇦 Kharkiv, Ukraine

Communal institution "Odessa Regional Clinical Medical Center"; 🇺🇦 Odesa, Ukraine

Legacy Emanuel Hospital & Health Center dba Legacy Research Institute; 🇺🇸 Portland, Oregon, United States