Thermal Burns
Conditions
Keywords
fire/flame, scalds, contact
Brief summary
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.
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.
Interventions
Sponsors
MediWound Ltd
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 77 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Endpoint: Number of Participants With Complete Eschar Removal. | post application (post 2 h soaking) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Endpoint: Number of Participants With Surgical Excision Performed or Eschar Removal for NexoBrid vs SOC (FAS) | Post application (post 2 h soaking) for NexoBrid arm and immediately post surgical excision for SOC arm. | 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). |
| Secondary Endpoint: Comparison of Time (Days) to Complete Eschar Removal | 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. | 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) |
| Secondary Endpoint: Patient-Level Comparison of Actual Blood Loss (Volume in mL) Related to Eschar Removal for NexoBrid vs SOC (FAS) | 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. | Comparison of NexoBrid over SOC with regard to the blood loss (volume in mL) occurred during the eschar removal procedures. |
Countries
Belgium, Czechia, Georgia, Germany, Israel, Italy, Romania, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
NexoBrid | 75 |
| 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.
Gel Vehicle | 25 |
| 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.
Standard of Care (SOC) | 75 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 13 | 4 | 10 |
| Overall Study | Not Treated | 0 | 1 | 5 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 2 |
Baseline characteristics
| Characteristic | NexoBrid Gel | Gel Vehicle | Standard of Care (SOC) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 4 Participants | 5 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants | 21 Participants | 70 Participants | 159 Participants |
| Age, Continuous | 41.28 years STANDARD_DEVIATION 15.03 | 40.68 years STANDARD_DEVIATION 17.3 | 40.91 years STANDARD_DEVIATION 15.16 | 40.95 years STANDARD_DEVIATION 15.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 8 Participants | 8 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 17 Participants | 67 Participants | 145 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 3 Participants | 13 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 1 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) White | 61 Participants | 21 Participants | 59 Participants | 141 Participants |
| Sex: Female, Male Female | 26 Participants | 10 Participants | 16 Participants | 52 Participants |
| Sex: Female, Male Male | 49 Participants | 15 Participants | 59 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 77 | 0 / 24 | 0 / 68 |
| other Total, other adverse events | 49 / 77 | 16 / 24 | 39 / 68 |
| serious Total, serious adverse events | 9 / 77 | 3 / 24 | 9 / 68 |
Outcome results
Primary
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.
Time frame: post application (post 2 h soaking)
Population: Standard of Care (SOC) is not included as it was pre-specified in the statistical analysis plan that for the primary endpoint, NexoBrid Gel will be compared only to the Gel Vehicle
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NexoBrid Gel | Primary Endpoint: Number of Participants With Complete Eschar Removal. | 70 Participants |
| Gel Vehicle | Primary Endpoint: Number of Participants With Complete Eschar Removal. | 1 Participants |
p-value: <0.000195% CI: [35.549, 13984.356]Fisher Exact
Secondary
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)
Time frame: 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.
Population: Gel arm is not involved in comparison as defined in the statistical analysis plan. Only NexoBrid and SOC
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NexoBrid Gel | Secondary Endpoint: Comparison of Time (Days) to Complete Eschar Removal | 1.02 Days |
| Gel Vehicle | Secondary Endpoint: Comparison of Time (Days) to Complete Eschar Removal | 3.87 Days |
p-value: <0.0001Generalized Wilcoxon-Gehan Test
Secondary
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).
Time frame: Post application (post 2 h soaking) for NexoBrid arm and immediately post surgical excision for SOC arm.
Population: Gel arm is not involved in comparison as defined in the statistical analysis plan. Only NexoBrid and SOC
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NexoBrid Gel | Secondary Endpoint: Number of Participants With Surgical Excision Performed or Eschar Removal for NexoBrid vs SOC (FAS) | 3 Participants |
| Gel Vehicle | Secondary Endpoint: Number of Participants With Surgical Excision Performed or Eschar Removal for NexoBrid vs SOC (FAS) | 54 Participants |
p-value: <0.000195% CI: [0.003, 0.044]Chi-squared
Secondary
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.
Time frame: 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.
Population: Gel arm is not involved in comparison as defined in the statistical analysis plan. Only NexoBrid and SOC were compared
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NexoBrid Gel | Secondary Endpoint: Patient-Level Comparison of Actual Blood Loss (Volume in mL) Related to Eschar Removal for NexoBrid vs SOC (FAS) | 14.17 mL | Standard Deviation 512.4 |
| Gel Vehicle | Secondary Endpoint: Patient-Level Comparison of Actual Blood Loss (Volume in mL) Related to Eschar Removal for NexoBrid vs SOC (FAS) | 814.51 mL | Standard Deviation 1020.32 |
p-value: <0.000195% CI: [5974.41, 7037.19]Wilcoxon (Mann-Whitney)