Clinical trial NCT02278718: A Study to Evaluate the Efficacy and Safety of NexoBrid in Children With Thermal Burns Compared the Standard of Care
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Thermal Burns
Lead sponsor: MediWound Ltd
Sponsor class: INDUSTRY
First posted: 2014-10-30
Enrollment: 145
Sex: ALL
Minimum age (years): 0
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria

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.

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.

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

Primary outcomes:
measure: Time to Complete Eschar Removal (in Days)
timeFrame: 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.
Secondary outcomes:
measure: Incidence of Surgical Excision Performed for Eschar Removal
timeFrame: 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.
measure: Blood Loss Related to Eschar Removal
timeFrame: 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
measure: Percent Area of Autograft Performed in DPT Wounds - Main Analysis, Patient Level.
timeFrame: Assessment will be performed by the investigator immediately after each autograft procedure was performed, before application of coverage.
measure: Incidence of Autograft Performed in Deep Partial Thickness Wounds
timeFrame: 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
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Maricopa Special Health Care District
state: Arizona
city: Gainesville
country: United States
facility: University Of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: The University of South Florida Board of Trustees
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Boston
country: United States
facility: Shriners Hospital for Children
state: Massachusetts
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Portland
country: United States
facility: Legacy Emanuel Hospital & Health Center dba Legacy Research Institute
state: Oregon
city: Philadelphia
country: United States
facility: Drexel University
state: Pennsylvania
city: Charleston
country: United States
facility: Shawn Jekins Children's Hospital
state: South Carolina
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Gent
country: Belgium
facility: University Hospital, Department of Plastic Surgery
city: Tbilisi
country: Georgia
facility: S. Khechinashvili University Hospital
city: Berlin
country: Germany
facility: Unfallkrankenhaus Berlin Zentrum für Schwerbrandverletzte mit Plastischer Chirurgie
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart - Olgahospital
city: Budapest
country: Hungary
facility: MRE Bethesda Gyermekkórháza
city: Miskolc
country: Hungary
facility: B.A.Z Megyei Kórház és Egyetemi Oktatókórház
city: Pécs
country: Hungary
facility: Klinikai Kozpont Gyermekgyogyaszati Klinika
city: New Delhi
country: India
facility: Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Marg
state: Delhi
city: Mysuru
country: India
facility: Krishna Rajendra Hospital
city: New Delhi
country: India
facility: Vardhman Mahavir Medical College (VLCC) and Safdarjung Hospital
city: Verona
country: Italy
facility: Universitary Integrated Hospital Verona (AOUI Verona),
city: Beverwijk
country: Netherlands
facility: Acute Burn Care &Trauma Surgery, Dept Surgery/Burn Center, Rode Kruis Ziekenhuis, LUMC University Leiden
city: Kraków
country: Poland
facility: Uniwersytecki Szpital Dzieciecy w Krakowie
city: Warszawa
country: Poland
facility: Szpital Dzieciecy im.prof.dr.med Jana Bogdanowicza, Oddzial Chirurgii i Urologii Dzieciecej z Pododdzialem Leczenia Oparzen
city: Iasi
country: Romania
facility: Spitalul Clinic de Urgenta pentru Copii "Sfanta Maria"
city: Târgu-Mureş
country: Romania
facility: Spitalul Clinic de Urgenta Tg- Mures
city: Bratislava
country: Slovakia
facility: Univerzitná nemocnica Bratislava, Klinika popálenin a rekonštrukčnej chirurgie
city: Madrid
country: Spain
facility: La Paz University Hospital
city: Valencia
country: Spain
facility: Boulevar Sur s/n
city: Kharkiv
country: Ukraine
facility: 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'
city: Odesa
country: Ukraine
facility: Communal institution "Odessa Regional Clinical Medical Center"
city: Birmingham
country: United Kingdom
facility: Birmingham Children´s Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
affiliation: MediWound Ltd
name: Lior Rosenberg, Prof.
role: STUDY_CHAIR
affiliation: MediWound Ltd
name: Yaron Shoham, Dr.
role: STUDY_DIRECTOR
References:
citation: Rosenberg L, Krieger Y, Bogdanov-Berezovski A, Silberstein E, Shoham Y, Singer AJ. A novel rapid and selective enzymatic debridement agent for burn wound management: a multi-center RCT. Burns. 2014 May;40(3):466-74. doi: 10.1016/j.burns.2013.08.013. Epub 2013 Sep 26.