Thermal Burns
Conditions
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.
Interventions
DRUGNexoBrid
NexoBrid is an enzymatic debriding agent for Eschar Removal.
PROCEDUREStandard of Care
Surgical or Non-Surgical methods for Eschar Removal
Sponsors
MediWound Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
0 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Belgium, Georgia, Germany, Hungary, India, Italy, Netherlands, Poland, Romania, Slovakia, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Out of 153 patients that were screened for enrollment, 145 patients were enrolled, randomized and included in FAS analysis. Seven patients were excluded at screening and one patient withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| NexoBrid Gel 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.
NexoBrid: NexoBrid is an enzymatic debriding agent for Eschar Removal. | 72 |
| Standard of Care (SOC) Non surgical and Surgical Debridement
Standard of Care: Surgical or Non-Surgical methods for Eschar Removal | 73 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Missing | 0 | 1 |
| Overall Study | The patient was randomised but did not receive study drug treatment | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | NexoBrid Gel | Standard of Care (SOC) | Total |
|---|---|---|---|
| Age, Continuous Age (years) | 5.71 years STANDARD_DEVIATION 4.838 | 5.83 years STANDARD_DEVIATION 4.909 | 5.77 years STANDARD_DEVIATION 4.857 |
| Body Mass Index (BMI) | 16.88 kg/m^2 STANDARD_DEVIATION 4.368 | 17.09 kg/m^2 STANDARD_DEVIATION 4.108 | 16.99 kg/m^2 STANDARD_DEVIATION 4.226 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 7 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 66 Participants | 135 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 16 Participants | 33 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 51 Participants | 50 Participants | 101 Participants |
| Sex: Female, Male Female | 30 Participants | 25 Participants | 55 Participants |
| Sex: Female, Male Male | 42 Participants | 48 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 0 / 70 |
| other Total, other adverse events | 31 / 69 | 30 / 70 |
| serious Total, serious adverse events | 2 / 69 | 6 / 70 |
Outcome results
Primary
Time to Complete Eschar Removal (in Days)
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)
Time frame: 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.
Population: All patients who were randomised into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NexoBrid Gel | Time to Complete Eschar Removal (in Days) | 0.99 Days |
| Standard of Care | Time to Complete Eschar Removal (in Days) | 5.99 Days |
Comparison: Wilcoxon test statistic was estimated using generalized Wilcoxon-Gehan test stratified by center group, age group, % TBSA group, proportion of FT area group and number of TWs group. A negative (positive) statistic is associated with longer (shorter) time to the event when treated with NexoBrid vs. Standard of Care. P-value was calculated using the re-randomization test.p-value: 0.0008Generalized Wilcoxon-Gehan Test
Secondary
Blood Loss Related to Eschar Removal
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.
Time frame: 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
Population: Full analysis set (FAS): 145 patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NexoBrid Gel | Blood Loss Related to Eschar Removal | 32.26 mL | Standard Deviation 284.757 |
| Standard of Care | Blood Loss Related to Eschar Removal | 202.55 mL | Standard Deviation 409.147 |
p-value: 0.1374t-test, 2 sided
Secondary
Incidence of Autograft Performed in Deep Partial Thickness Wounds
Number of autografts performed in deep partial thickness wounds
Time frame: 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
Population: Main Analysis, Target Wound Level, Deep Partial Thickness Target Wounds Only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NexoBrid Gel | Incidence of Autograft Performed in Deep Partial Thickness Wounds | 21 autographs performed |
| Standard of Care | Incidence of Autograft Performed in Deep Partial Thickness Wounds | 26 autographs performed |
p-value: 0.054595% CI: [0.163, 1.054]t-test, 2 sided
Secondary
Incidence of Surgical Excision Performed for Eschar Removal
Number of patients who needed surgical excision for eschar removal
Time frame: 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.
Population: Incidence Rate = The proportion and number of patients who required surgical excision for eschar removal.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NexoBrid Gel | Incidence of Surgical Excision Performed for Eschar Removal | 6 Participants |
| Standard of Care | Incidence of Surgical Excision Performed for Eschar Removal | 47 Participants |
Comparison: Incidence of Surgical Excision for Eschar Removal for NexoBrid vs SOCp-value: <0.000195% CI: [0.007, 0.09]Fisher Exact
Secondary
Percent Area of Autograft Performed in DPT Wounds - Main Analysis, Patient Level.
Percent area of deep partial thickness wounds autografted
Time frame: Assessment will be performed by the investigator immediately after each autograft procedure was performed, before application of coverage.
Population: FAS, Patients with at least one DPT target wound.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NexoBrid Gel | Percent Area of Autograft Performed in DPT Wounds - Main Analysis, Patient Level. | 15.9 percent | Standard Deviation 38.57 |
| Standard of Care | Percent Area of Autograft Performed in DPT Wounds - Main Analysis, Patient Level. | 22.8 percent | Standard Deviation 43.72 |
p-value: 0.5045t-test, 2 sided