Evaluation of Safety and Efficacy of realSKIN® (Skin Xenotransplant) for Complete Closure of Severe Burn Wounds

Study Overview
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Brief Summary
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This is a Phase 1/2, Open-label, Multi-center, Clinical Trial to evaluate the safety, tolerability, and efficacy of realSKIN® to provide temporary wound closure of severe and extensive deep-partial or full-thickness burn wounds until definitive wound closure can be achieved via permanent autografting. Approximately 25 total subjects will be enrolled. Subjects who meet eligibility criteria and provide written informed consent will receive realSKIN® placement at a single burn wound site. The designated realSKIN® product size will be placed on the burn wound following wound site preparation, including necessary debridement and tangential excision as determined by burn surgeon and secured in place via suturing or stapling. The remaining burn wound will be covered with human cadaver allograft and treated according to local standard of care with care to avoid any overlap or significant contact of the two temporary wound dressings. The Investigator will assess the wounds and identify the matched pair of burn sites then the treatments will be randomly assigned to the sites. realSKIN® will remain in place until intentional removal per Investigator's direction consistent with subject's overall clinical course, or if it is deemed to no longer provide effective wound closure and barrier function to the wound bed. The Investigator will follow local standard of care relevant to wound care and dressing changes while the realSKIN® is in place. Standard of care burn management will be provided by the Investigator. Routine vital sign assessments, photography, laboratory tests (hematology, chemistry, and urinalysis), physical exams, and adverse event monitoring will occur while realSKIN® is in place and for up to 1 year following initial placement. Subjects will be monitored via a passive and active screening program using blood samples collected at time points throughout the study period, as adapted from FDA Guidance for Industry. The risk of transmission of infectious disease is expected to be extremely low and while limited human trial data are available there have been no reports of transmission of porcine microorganisms to humans, and to date, there have been no adverse events (AEs) related to the use of realSKIN® observed or reported, and independent analysis of PERV data and medical records by the Safety Review Committee has indicated no evidence of zoonotic transmission in this trial.

Detailed Description
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Product Name: realSKIN® Chemical Name: alpha-1,3-galactosyltransferase knock-out (GalT-KO) porcine (Sus scrofa) epidermal and dermal layers. Chemical Structure: realSKIN® a biologically active, split-thickness, xenotransplantation skin product. realSKIN® is derived from specialized, genetically engineered (alpha 1,3 galactosyltransferase knockout [GalT-KO]), Designated Pathogen Free (DPF), porcine donors, containing vital, metabolically active (i.e., non-terminally sterilized) porcine cells within the dermal and epidermal tissue layers. Proposed Indication: realSKIN is indicated for the treatment of mixed-depth, full-thickness burn wounds requiring hospitalization, surgical excision, and skin grafting. Drug Type: realSKIN® is classified as a Live Biotherapeutic Product (LBP). (Guidance to Industry, Early Clinical Trials with Live Biotherapeutic Products, Section 1.b.) Active Ingredient: Live (i.e. non-terminally sterilized) porcine cells, including endothelial cells of intact vasculature and those comprising the dermal and epidermal tissue layers Product Structure: realSKIN® has an approximate thickness of 0.022 inches (0.55mm) and is currently provided in one investigational size: approximately 5x15 cm2 (22.5g/75 cm2). Formulation: Each lot or releasable batch of realSKIN® is derived from a single source animal and each batch is independently processed and tested for various adventitious agents, histology, morphology, sterility, and purity. Route of Administration: Surgical engraftment, via sutures or staples Dosing Regimen: Surgical engraftment, via sutures or staples, to provide wound closure of severe and extensive deep-partial and full-thickness burn wounds requiring hospitalization, surgical excision, and skin grafting. The amount is of temporary wound dressing is based on the depth and size (TBSA) of the burn injury. Drug's Mechanism of Action: Patients with severe burns are at high risk of mortality due to a devastating sequela of complications such as increased capillary leak and release of inflammatory cytokines, infection from opportunistic pathogens, immune-compromise, hypovolemia, hypothermia, electrolyte and pH imbalances, and other detrimental deviations to pre-injury homeostasis as a result of a disruption in the skin barrier that contributes to organ failure and often death. realSKIN® provides a temporary barrier against infection, helps prevent fluid loss, and helps restore the functional skin barrier prior to definitive wound closure with the placement of an autograft. realSKIN®'s inclusion of viable epithelial, epidermal, and dermal porcine cells permits revascularization of the wound bed, critical for efficient re-epithelialization and wound healing. This mechanism of action closely mirrors today's clinical standard, human cadaver allograft. The same progression of wound healing processes occurs in both human cadaver allograft and realSKIN®. This mechanism of action distinguishes realSKIN® from traditional xenografts products on the market today, which are terminally sterilized, rendering the cells inactive, limiting their therapeutic capability. Drug Packaging: Each realSKIN® product is individually packaged in a clear plastic, externally threaded, 10-ml polypropylene vial with threaded seal-cap, stored on a rolled, sterile nylon mesh backing on the dermal-side of the realSKIN® product that serves to support and protect the graft during processing and transport. Within this container, each realSKIN® product is individually immersed in 7-ml of sterile cryoprotective medium with 5% dimethyl sulfoxide (DMSO) (CryoStor CS5, BioLifeSolutions). Source animal serum is NOT included or used in this process. The contents are cryopreserved via controlled rate, phase freezer and stored at -80o C until use. All packaging materials are removed prior to the surgical procedure and dressing placement.

Official Title
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An Open-label Phase 1/2 Study to Evaluate the Safety, Tolerability, and Efficacy of realSKIN® (Skin Xenotransplant) for Complete Closure of Severe and Extensive Deep-Partial and Full-Thickness BurnWounds

Conditions
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Deep Full-thickness Burn Injury (Disorder)

Intervention / Treatment
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* Biological: realSKIN (skin xenotransplant)
* Biological: Human Cadaver Allograft


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject provides written informed consent to participate in this study Males or females age greater than 18 years old Females must have a negative serum pregnancy test at Screening and at Baseline and must not be nursing Male and female subjects must agree to use a protocol-approved method of contraception for a minimum of 3 months following Xeno-Skin® placement, which includes a barrier method plus one or more of the following: Hormonal contraceptives (e.g., birth control pills, skin patches, vaginal rings, and the Depo- Provera shot) Intrauterine device (IUD) Male or female condoms with spermicide Diaphragm with spermicide Permanent tubal occlusive birth control system Total Body Surface Area (TBSA) <30%, to include deep-partial thickness or full-thickness burn wounds Burn injuries would otherwise require debridement and tangential excision Burn injury requiring temporary grafting with human cadaver allograft skin, based on clinical judgment prior to definitive wound closure via autologous grafting Sufficient area of burn wound for Xeno-Skin® placement and not located on face or hands or having an engraftment site centered on high-impact areas such as joints, weight-bearing areas (e.g. soles of feet), or the inguinal region, per Investigator's judgment Exclusion Criteria: Pregnant or lactating women Documented history of infection with human immunodeficiency virus (HIV) or other condition(s) that in the opinion of the Investigator may compromise patient safety or study objectives Immunosuppressive medication regimens e.g. antineoplastics, high dose steroids (> 10 mg prednisone/day), TNF alpha inhibitors, calcineurin inhibitors (cyclosporine, tacrolimus), anti-proliferative agents, and other immunomodulators Known allergy to penicillins (such as ampicillin), ceftazidime or aztreonam, glycopeptide antibiotics (such as vancomycin) or amphotericin B Active malignancy, including those requiring surgery, chemotherapy, and/or radiation in the past 5 years. Non-metastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed Use of any experimental or investigational drugs within 30 days prior to placement of Xeno-Skin® Previously received a porcine or other xenogeneic tissue product, including but not limited to: glutaraldehyde fixed porcine or bovine bioprosthetic heart valve replacements and glutaraldehyde fixed porcine dermal matrix (e.g., EZ Derm) BMI > 40 kg/m2 HbA1c ≥ 7.0% Treatment with systemic corticosteroids within 30 days before screening (not including inhaled steroids) Electrical, chemical, or radiation burns History of chronic end stage renal disease defined as an MDRD CrCl < 15 mL/min, or receiving chronic dialysis History of chronic liver disease or cirrhosis (Child-Pugh Score C). Evidence of acute or chronic hepatitis B infection based on documented HBV serology testing Known documented history of Hepatitis B, Hepatitis C, Treponema pallidum, Cytomegalovirus, herpes or varicella zoster Note: Successfully treated hepatitis C patients without evidence of end stage liver disease is allowed. If HCV antibody reactive, then HCV RNA must be undetectable. Recent (within 3 months prior to study enrollment) MI, unstable angina leading to hospitalization, uncontrolled, CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack (TIA), endovascular procedure or surgical intervention for peripheral vascular disease or plans to undergo a major surgical or interventional procedure (eg, PCI, CABG, carotid or peripheral revascularization) Presence of venous or arterial vascular disorder directly affecting the area of burn wound Pre-existing haemolytic anemia Chronic malnourishment as determined by Investigator Significant pulmonary compromise Systemic anticoagulation at the time of treatment or INR > 2 Documented evidence of wound infection at Screening or Baseline Evidence of sepsis and/or end organ damage Acute lung injury Life expectancy of less than 180 days Subject who is unable to self-consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase 1/2, Open-label, Multi-center, Clinical Trial to evaluate the safety, tolerability, and efficacy of realSKIN® to provide complete wound closure of severe and extensive deep-partial or full-thickness burn wounds. Approximately 25 total subjects will be enrolled. The designated realSKIN® product size will be placed on the burn wound following wound site preparation, including necessary debridement and tangential excision as determined by burn surgeon and secured in place via suturing or stapling. The remaining burn wound will be covered with human cadaver allograft and treated according to local standard of care with care to avoid any overlap or significant contact of the two temporary wound dressings. The Investigator will assess the wounds and identify the matched pair of burn sites then the treatments will be randomly assigned to the sites.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Treatment: realSKIN (skin xenotransplant)<br>In the experimental arm, patients are treated with the investigational drug, realSKIN®, in a side-by-side comparison to the active comparator, thus, each patient serves as their own control. The designated realSKIN® product size will be placed on the burn wound and secured in place via suturing or stapling. The Investigator will assess the wounds and identify the matched pair of burn sites then the treatments will be randomly assigned to the sites. | Biological: realSKIN (skin xenotransplant)<br>* 3+3 Dose-escalation Study Design; 2 dosage strengths will be utilized during this Phase 1/2 Trial; an expansion cohort (9 patients) receive the highest dose.<br>|
| Active Comparator: Active Comparator: Human Allograft Skin<br>In the active comparator arm, patients are treated with human cadaver allograft, in a side-by-side comparison to the investigational drug, thus, each patient serves as their own control. The allograft active comparator will be placed adjacently to the investigational drug, in the same anatomical location, on wound sites following debridement and secured via suture or staples. All other treatment aspects were consistent with the standard of care. The Investigator will assess the wounds and identify the matched pair of burn sites then the treatments will be randomly assigned to the sites. | Biological: Human Cadaver Allograft<br>* HCA is used as a temporary wound dressing between debridement and definitive closure in many well-resourced contexts.<br>* Other names: HCA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Temporary Wound Closure | To assess the capability of realSKIN® to improve wound healing by providing supportive care until definitive closure can be accomplished by functioning as a barrier, much like human skin, as compared to similar wound site(s) treated with human cadaver allograft (HCA). | Prior to autograft placement (within 14 days) | 
| Long-term Safety and Tolerability | To further demonstrate the long-term safety and tolerability of realSKIN®, to include evidence that Xeno-Skin® does not significantly impede wound healing. | Prior to autograft placement (continued follow up through 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definitive Wound Closure | To assess the quality of healing, to include scarring, contour and feel of healed skin, or normalization of skin markings or pigmentation, at wound treatment sites that received temporary closure with realSKIN®, as compared to that of wound treatment site(s) that received temporary closure with human cadaver allograft (HCA). | Post autograft placement (continued follow up through 1 year) | 
| Improved Wound Healing | To assess the capability of realSKIN® to improve wound healing by providing supportive care until definitive closure can be accomplished by functioning as a barrier, much like human skin, as compared to similar wound site(s) treated with human cadaver allograft (HCA). | Post autograft placement (continued follow up through 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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xenotransplant, skin, burns, temporary, allograft, porcine, closure, dressing, live biotherapeutic, xenograft, pig, genetically engineered, alpha-Gal, GalT-KO