Borate-based Bioactive Glass Fiber Matrix (BBGFM) in the Treatment of Venus Leg Ulcers (VLU)

A Phase IV, Post-market, Randomized, Controlled, Open-label, Multicenter Clinical Trial Designed to Evaluate the Safety and Effectiveness of MIRRAGEN® Advanced Wound Matrix Plus Standard of Care Compared With Standard of Care Alone in Achieving Complete Wound Closure in Participants With Venous Leg Ulcers by 12 Weeks.

The goal of this clinical trial is to learn if Borate-based Bioactive Glass Fiber Matrix (BBGFM) can help heal Venous Leg Ulcers (VLU) that have not closed with standard treatment. The main question it aims to answer is:

1. Does BBGFM help Venus Leg Ulcers heal completely in 12 weeks?

Researchers will compare BBGFM plus Standard of Care (SOC) to SOC alone to see if BBGFM works to heal wounds.

Participants will:

• Have BBGFM applied to their wound (if assigned to the BBGFM group) for up to 12 applications
• Visit the clinic each week for wound checks and tests

Other study purposes include looking at:

• The time it takes for the wound to heal
• Changes in wound size over time
• The durability of wound healing after closure
• The use of healthcare resources related to wound care
• Any adverse events (side effects) or reactions related to the treatment
• Changes in pain levels
• Changes in quality of life

Inclusion Criteria:

Patients are required to meet the following inclusion criteria before entering the study:

1. Male or Female, 18 years of age or older

2. Participant has a medical diagnosis of venous leg ulcer or venous insufficiency with a lower extremity wound. Venous etiology confirmed by duplex ultrasound of the affected limb performed within 90 days prior to randomization, demonstrating superficial and/or deep venous reflux (≥0.5 seconds) in the examined venous segments and no evidence of acute deep venous thrombosis.7, 8

3. Participant has a venous leg ulcer present for ≥4 weeks and ≤18 months prior to screening, as documented in the medical record.

4. The target wound must demonstrate ≤50% reduction in wound area following minimum of 28 consecutive days of continuous therapeutic compression at Randomization (Day 1).

   a. For participants with clinical site medical records documenting a wound measurement, wound photography, and continuous therapeutic compression for >14 days prior to the Screening Visit, an accelerated 14-day screening period will be followed.

   i. A documented wound measurement in medical record obtained >14 days prior to Screening Visit will serve as the reference measurement. The same wound measurement method (e.g., manual planimetry or a digital wound measurement system) must be used for all comparative assessments prior to randomization.

   ii. At Screening Visit: The target wound must demonstrate ≤50% reduction in wound area following 14 consecutive days of SOC continuous therapeutic compression at screening compared with the reference measurement.

   iii. At Randomization: After completion of a 14 day run in period of continuous therapeutic compression, the target wound must demonstrate ≤50% reduction at Randomization (Day 1) compared with the reference measurement (>28 days prior to randomization).

   b. For participants without qualifying clinical site medical records, a traditional 28-day screening period will be followed.

   i. The wound measurement obtained at Screening Visit will be the reference measurement.

   ii. At Randomization: After completion of a 28 day run in period of continuous therapeutic compression, the target wound must demonstrate ≤50% reduction in wound area at Randomization (Day 1) compared with the reference measurement (>28 days prior to randomization).

5. Target wound is between 2.0 cm² to ≤20.0 cm² at Randomization. Wound area will be measured at each visit using standardized digital planimetric measurement (standardized camera distance/lighting and calibration); historical and screening percent area change calculations must use the same method.

6. Adequate arterial perfusion demonstrated by one of the following:

   • ABI ≥0.7 and ≤1.3 OR TBI ≥0.6, obtained within 30 days prior to randomization
   • If ABI is >1.3 (noncompressible) or borderline, TBI or arterial duplex must be obtained to confirm adequate perfusion
   • Tcom ≥40mmHg

7. Target wound must be free of necrotic debris prior to application of MIRRAGEN® or standard of care (target wound bed is adequately debrided such that no adherent necrotic eschar or slough obscures wound bed assessment, and the wound is suitable for study product application per Investigator). 9, 10

8. Females of childbearing potential must have a negative serum β-hCG at Screening, performed within 14 days prior to Randomization, and a negative urine pregnancy test at Randomization (Day 1) prior to receipt of study treatment. If the initial serum βhCG result is more than 14 days old at the time of Randomization, the serum β hCG test must be repeated to ensure it remains within the 14-day window.

9. Target wound must be non-infected at Screening and Randomization. Non-infected is defined as absence of ≥2 local clinical signs (swelling/induration, erythema beyond margin, increased warmth, new/increased pain/tenderness, or purulent exudate) and absence of systemic signs (fever or leukocytosis), consistent with Wound Healing Society (WHS) guidelines. Any infection present before or during the run-in period must be treated, and resolution must be documented prior to Randomization.

10. If two or more wounds are present, the wounds must be separated by at least 2 cm.

11. Participant has no more than 5 other wounds on the index leg.

12. CEAP classification is not required as an eligibility criterion. Doppler waveform assessment (biphasic or triphasic signal) will not be used as an eligibility criterion. If there is more than one wound present, the largest qualifying wound will be the target wound.

13. Participant is able and willing to follow the protocol requirements.

Exclusion Criteria:

Patients will be excluded if they meet any of the following exclusion criteria:

1. Participant does not have a diagnosis of venous leg ulcer or venous insufficiency with a wound located on the lower extremity.

2. Participant has a known life expectancy of <1 year.

3. Participant is unable to comply with protocol treatment.

4. Participant has comorbid conditions, such as serious cardiovascular, renal, liver, pulmonary, autoimmune, palliative care, or inherited blood disorders. that may compromise participant's safety or wound healing in the opinion of the Investigator.

5. Participant actively (or having a history) being treated for malignant disease, or history of malignancy or radiation therapy at the site of wound.

6. HbA1c >12% (HbA1c must be ≤12% at screening, measured within 30 days prior to Randomization (Christman et al. 2011, Snyder et al. 2010), or renal failure defined as eGFR <30 mL/min/1.73m² (CKD stage 4-5) at Screening, or end-stage renal disease requiring dialysis).

7. Known contraindications to bioabsorbable advanced wound matrix

8. Concurrent participation in alternative clinical trial that involves investigational drug or cellular, acellular, and matrix-like products that may interfere with wound treatment and/or healing

9. Participant is pregnant or breastfeeding.

10. History of immunosuppressant treatment (systemic corticosteroids >10mg/ day), cytotoxic chemotherapy, or topical steroid application to the wound for >2 weeks within 30 days prior to Randomization, or anticipated use of any of the above during the course of the study

11. Wound previously treated with cellular, acellular, or matrix-like products, tissue engineered constructs, or scaffold materials within 30 days prior to Randomization

12. Wound depth with visible exposed bone or hardware

13. Hyperbaric oxygen therapy (HBO) or Negative Pressure Wound Therapy (NPWT) within 28 days prior to Randomization

14. Planned or recent (within 30 days prior to Screening) revascularization surgery/procedure or venous intervention of the target wound limb, including arterial revascularization (endovascular or open bypass), or anticipated need for revascularization during the treatment period, as determined by vascular assessment

    1. For arterial procedure: including but not limited to endovascular or open bypass
    2. For venous procedures: including but not limited to endovenous ablation, surgical ligation/stripping, or perforator vein procedures

15. Target wound suspicious of neoplasm in the opinion of the Principal Investigator

16. Multiple venous leg ulcers on the same leg with <2 cm² separation from the target wound

17. Inability to tolerate the protocol-approved compression therapy

18. Stage II or Stage III lymphedema as defined by the Society of Lymphology

19. Body mass index (BMI) >45 kg/m² at Screening. Participants with BMI >45 kg/m² will be excluded due to the potential for impaired mobility, difficulties with consistent application or tolerance of therapeutic compression, and increased risk of confounding factors that may adversely affect venous leg ulcer healing.