a Prospective, Multicenter, Randomized Controlled Trial, With a Non-randomized Sentinel Cohort, Evaluating the Efficacy of Bioxheal, a Single-layer Placental-derived Biologic in Nonhealing Diabetic Foot Ulcers

Phase 3, multicenter, prospective, open-label, randomized controlled study conducted at up to 30 U.S. clinical centers. A non-randomized sentinel cohort (5 completed participants required, with up to 10 participants enrolled) will first receive BIOxHEAL plus SOC to assess early safety. Following DSMB review and FDA authorization to proceed, 243 participants will be randomized 2:1 to BIOxHEAL plus SOC or SOC alone, with randomization stratified by baseline ulcer area and ulcer duration. BIOxHEAL is administered topically once weekly for up to 12 weeks or until complete ulcer closure. Complete closure is confirmed approximately 2 weeks later. Participants are subsequently followed for 3 months.

• Standard of Care (Other): Protocol-defined standard of care (SOC) for diabetic foot ulcers, performed at each study visit: wound cleansing with sterile saline, sharp debridement as clinically indicated, a non-adherent silicone primary dressing with an absorbent secondary dressing to maintain a moist wound environment, offloading for plantar and pressure-bearing ulcers (Foot Defender boot, Total Contact Cast, or Medical Monitor-approved equivalent), and diabetes education and nutritional support, including smoking cessation counseling for current smokers.
• BIOxHEAL (human amniotic membrane allograft) (Biological): BIOxHEAL is an investigational, sterile, single-use biologic derived from human amniotic membrane. BIOxHEAL is administered topically to the target ulcer once weekly in combination with protocol-defined standard of care for up to 12 weeks or until complete ulcer closure. Each unit is individually packaged for single-patient, one-time use.

Primary outcomes

• Proportion of target ulcers with complete wound closure at Week 12 [Baseline to Week 12]: Complete closure is defined as 100% epithelialization, assessed by the Investigator and confirmed by blinded, independent wound evaluators. Compared between BIOxHEAL plus standard of care and standard of care alone.

Secondary outcomes

• Proportion of target ulcers with complete wound closure at Week 8 [Baseline to Week 8.]: Complete closure is defined as 100% epithelialization, assessed by the Investigator and confirmed by blinded, independent wound evaluators. Compared between BIOxHEAL plus standard of care and standard of care alone.
• Proportion of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) [From first treatment through the end of follow-up (at least 3 months after complete wound healing, or after Visit 13 if not healed), assessed up to approximately 6 months]: Number and proportion of participants with TEAEs, including SAEs and AESIs. Compared between BIOxHEAL plus standard of care and standard of care alone.
• Mean change in Wound Quality-of-Life (wQOL) score from baseline to Week 12 [Baseline to 12 weeks]: Change in wQOL questionnaire score. Compared between BIOxHEAL plus standard of care and standard of care alone.
• Proportion of participants with major and minor lower extremity amputations, and number and frequency of amputations [From first treatment through the end of the follow-up period, assessed up to approximately 6 months]: Number and frequency of major and minor lower extremity amputations occurring during the study period.
• Proportion of participants with completely closed diabetic foot ulcers at any time during the study [From first treatment until complete wound closure (100% epithelialization) is first confirmed, assessed up to approximately 6 months]: Complete closure is defined as 100% epithelialization, assessed by the Investigator and confirmed by blinded, independent wound evaluators. Compared between BIOxHEAL plus standard of care and standard of care alone.

Other outcomes

• Number of sentinel cohort participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and adverse events of special interest (AESIs) during the treatment period [From first treatment through the end of the treatment period (up to 12 weeks)]: Early safety assessment in the non-randomized sentinel cohort, in which all participants receive BIOxHEAL plus standard of care. Safety data from the first 5 participants who complete the treatment period are reviewed by the DSMB and the FDA before randomization begins. The DSMB monitors for risks associated with tissue-based products, including localized inflammatory responses, graft rejection, or unexpected infections.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

Participants must be at least 18 years of age or older. Participants must have a diagnosis of type 1 or 2 diabetes mellitus. At randomization (or enrollment for the sentinel cohort), participants must have a target ulcer with a minimum surface area of 1.0 cm2 and a maximum surface area of 25.0 cm2 measured post debridement.

The target ulcer must have been present for a minimum of 4 weeks and a maximum of 52 weeks of standard of care prior to the initial screening visit.

The target ulcer must be located on the foot with at least 50% of the ulcer below the malleolus.

The target ulcer must be Wagner Grade 1 extending at least through the dermis or subcutaneous tissue.

The affected limb must have adequate perfusion confirmed by vascular assessment. Any of the following methods performed within 3 months of the first screening visit are acceptable:

ABI greater than or equal to 0.7 and less than or equal to 1.3 TBI greater than or equal to 0.6 TCOM greater than or equal to 40 mmHg Arterial Doppler ultrasound with biphasic dorsalis pedis and posterior tibial vessels at the level of the ankle on the extremity where the index ulcer is located If the participant has two or more ulcers, they must be separated by at least 2 cm. The largest ulcer satisfying the inclusion and exclusion criteria will be designated as the target ulcer.

The participant must consent to using the prescribed offloading method for the duration of the study.

The participant must agree to attend the weekly study visits required by the protocol.

The participant must be willing and able to participate in the informed consent process.

The participant must have a suitable living environment to manage prescribed offloading and wound care management.

Exclusion Criteria:

Known life expectancy of less than 6 months. Target ulcer is not secondary to diabetes. Wagner Grade 2 to 5 ulcers. Target ulcer is infected, or there is cellulitis in the surrounding skin.

Evidence of osteomyelitis complicating the target ulcer, based on clinical assessment supported by at least one of the following:

Imaging (for example, plain radiography, MRI, or nuclear medicine study) consistent with osteomyelitis Positive bone culture Abnormal inflammatory markers (for example, ESR, CRP) in conjunction with clinical signs highly suggestive of osteomyelitis per Investigator judgment - Documentation of the basis for diagnosing or excluding osteomyelitis must be available in the participant's source documents Infection in the target ulcer or in a remote location that requires systemic antibiotic therapy.

Receiving immunosuppressants (including systemic corticosteroids at doses greater than 10 mg of prednisone per day or equivalent) or cytotoxic chemotherapy.

Topical application of steroids to the ulcer surface within one month of initial screening.

Previous partial amputation on the affected foot, if the resulting deformity impedes proper offloading of the target ulcer.

Glycated hemoglobin (HbA1c) greater than or equal to 12% within 3 months of the initial screening visit.

The surface area of the target ulcer has reduced in size by more than 40% between Screening Visit 1 and Treatment Visit 1 during the protocol-defined screening period.

Acute Charcot foot, or an inactive Charcot foot, that impedes proper offloading of the target ulcer.

Women who are pregnant or considering becoming pregnant within the next 6 months.

Male or female participants who are unwilling or unable to comply with the required contraceptive measures for the duration of study participation.

End stage renal disease requiring dialysis. Serum creatinine level greater than 3.0 mg/dL. Aspartate aminotransferase (AST, GOT) and/or alanine aminotransferase (ALT, GPT) greater than 3 times the upper limit of normal.

A medical or psychological condition that, in the opinion of the investigator, may interfere with study assessments.

Treated with hyperbaric oxygen therapy or a Cellular and/or Tissue Product (CTP) in the 30 days prior to the initial screening visit.

Mini Nutritional Assessment (MNA) screening score below 12.

• Charles Zelen, DPM, Study director, Professional Education & Research Institute (PERI)