NOX1416 in Treatment of Chronic Non-Healing Diabetic Foot Ulcers

Inclusion Criteria:

Subjects will be eligible for enrollment in the study only if they meet ALL the following criteria at time of Screening:

1. Male or female subjects aged 18 to 80 years (inclusive) with Type 1 or Type 2diabetes requiring treatment with oral medications and/or insulin replacementtherapy

2. Subject has a glycosylated hemoglobin, HbA1c ≤ 12%. Note: Prior documented HbA1cwithin the last 3 months of the Screening Visit is acceptable.

3. Presence of at least one diabetic foot ulcer that meets all of the followingcriteria:

4. A full-thickness ulcer of University of Texas Wound Classification (UTWCS)Grade IA or IIA

5. At least 50% of the ulcer is located below the malleoli

6. Ulcer size (area) is ≥ 1 cm2 and ≤ 10 cm2 (post-debridement at time ofrandomization)

7. Unresponsive to standard ulcer care for ≥ 4 weeks (at time of screening)

8. There is a minimum 1 cm margin between the qualifying Target Ulcer and anyother ulcers on the specified foot, post-debridement)

9. No exposed bone and no tunneling, undermining, or sinus tracts

10. The index ulcer has a clean base and is free of necrotic debris at time ofplacement of treatment product.

11. Index ulcer and/or index ulcer limb may have had prior infection, butinfection(s) must be adequately treated and controlled as defined by IDSAGuidelines Grade level 1.

12. Ulcer must be non-healing as defined as < 25% reduction in size in response tostandard of care during the two-week run-in Screening Period (between the firstScreening Visit and Baseline) Note: Criterion 3(i) will be evaluated at thetime of randomization. If the subject has more than one qualifying diabeticfoot ulcer, the ulcer designated as the Target Ulcer will be at the discretionof the Investigator.

13. Adequate circulation to the affected foot as demonstrated by a dorsum transcutaneousoxygen measurement (TCOM) or a skin perfusion pressure (SPP) measurement of ≥ 30mmHg or an ABI between 0.7 and ≤ 1.3, or TBI of >0.6 within 3 months of the firstScreening Visit. The assessment may also be performed between SV1 and SV2.

14. Subject does not smoke or use tobacco products.

15. Subject, if female of child-bearing potential, has a negative urine pregnancy testat screening, must not be breastfeeding, and willing to use acceptable methods ofcontraception (birth control pills, barriers, or abstinence) throughout the study.

16. Subject is able and willing to comply with study procedures and applicable dressingchanges.

17. Subject demonstrates cognitive and physical ability to administer the treatment asdetermined by the clinician. If a caregiver will administer the treatment, thecaregiver must demonstrate cognitive and physical ability.

18. The index ulcer has been offloaded with protocol defined offloading devicethroughout the study run-in period for at least 14 days prior to randomization (Run-in period defined as Screening through TV1/Randomization).

19. A signed and dated informed consent form has been obtained from the subject.

Exclusion Criteria:

Subjects meeting ANY of the following criteria at time of Screening will be excluded from enrollment:

1. Ulcers with exposed bone or associated with osteomyelitis. Note: Osteomyelitisshould be ruled out by clinical examination (probing of the wound) or X-rayfindings, if necessary, by the Investigator.

2. Subject has ulcers secondary to a disease other than diabetes, e.g., fungalulcerations, malignant ulcerations, and ulcerations due to venous or arterialinsufficiency, or due to hematological disorders, in the opinion of the PrincipalInvestigator.

3. Ulcer, which in the opinion of the Investigator, is suspicious for cancer.

4. Subjects with a gangrenous or ischemic toe that may need to be amputated in theopinion of the Investigator.

5. Body mass index (BMI) > 40kg/m2

6. Methemoglobin > 5% at SV1

7. Laboratory values at Screening of:

• Hemoglobin < 8.5 g/dL

• White Blood Cells (WBC) < 3.0 X 109 cells/L and > 11 x 109 cells/L

• Liver function studies [Total bilirubin, aspartate aminotransferase (AST) andalanine transaminase (ALT)] > 3x the upper limit of normal

• Albumin < 2.5 g/dL

• Renal function studies [Estimated Glomerular Filtration Rate] < 45

8. Presence of any clinically significant medical condition(s) that, in the opinion ofthe Investigator, could interfere with wound healing, including but not limited tothe following:

• Vasculitis or connective tissue disease

• Buerger's disease, Raynaud's or other peripheral vascular disease.

• Clinically significant claudication or peripheral edema on the affected limb

• Acute or unstable Charcot foot

• Aplastic anemia or sickle cell anemia

• Current sepsis

9. Past or present malignancy below the knee on the same limb as the Target Ulcer;

10. History of radiation at the Target Ulcer site.

11. Subject is currently receiving (i.e., within 30 days of T1 visit) or scheduled toreceive any of following medication or therapies during the course of the study.

• Immunosuppressants (including chronic systemic corticosteroids)

• Cytotoxic chemotherapy

• Cytostatic therapy

• Lower limb revascularization surgery (e.g., angioplasty, artery bypasssurgery,)

• application of bioengineered tissue or skin substitutes

• use of any investigational drug(s)

12. Subjects who have previously received NOX1416 treatment

13. Subject is unable to comply with offloading device.

14. Revascularization surgery on the lower extremity on which the index ulcer is locatedwithin 30 days of Screening Visit (SV1).

15. Has a known hypersensitivity to any of the investigational drug components

16. Subject is susceptible to hemorrhaging or has a congenital or acquiredpredisposition to hemorrhaging.

17. Subject has a history of self-harm or suicidal ideation.

18. Any reason that the subjects may need to be admitted to inpatient acute care in theopinion of the Investigator.

19. Has any other factor which may, in the opinion of the investigator, compromiseparticipation and/or follow-up in the study.