NOX1416 in Treatment of Chronic Non-Healing Diabetic Foot Ulcers (NTCDU)

The goal of this multi-center,randomized, placebo controlled, evaluator-blinded study is to assess the efficacy and safety of NOX1416 in the treatment of chronic, non-healing, diabetic foot ulcers (DFUs). Subjects will be randomized to receive treatment with NOX1416 or placebo as an adjunct to SOC.

The primary objective of the study is to evaluate the clinical benefit of daily NOX1416, as an adjunct to standard of care (SOC), in the treatment of chronic, non-healing DFUs. The secondary objective is to demonstrate efficacy, safety and tolerability of NOX1416 as adjunct to SOC. Each site will assign a physician (or designee) to serve as the "blinded-evaluator" to be responsible for assessing the study endpoints such as wound measurements and complete wound closure. The blinded-evaluator will not be involved in the clinical care of the subject.

A total of 30 subjects will be randomized 1:1 to receive either NOX1416 + SOC or Placebo + SOC. NOX1416 is a foam based gaseous nitric oxide (NO) product where NO is delivered through a microbubble foam. One pump each of Solution A (0.3g, containing Citric acid) and Solution B (0.3g, containing Sodium nitrite) will be dispensed, mixed for five seconds and applied immediately per each square centimeter of wound area using any sterile applicator. NOX1416 is topically applied directly onto the wound bed and left on the wound bed for a 5-minute period.

Subjects randomized to the NOX1416 treatment group will receive once a day application, for a total of 12 weeks with a double treatment, 10 minutes apart, on the first day. Similar to the NOX1416 treatment schedule, placebo will be topically applied directly onto the wound bed and left on the wound bed for a 5-minute period. Subjects randomized to the control group will receive once a day application, for a total of 12 weeks with a double treatment, 10 minutes apart, on the first day.

Standard of care will include evaluation to document, off-loading adequate arterial flow, wound cleaning, removal of necrotic, infected and/or nonviable tissue by debridement, maintenance of moist wound environment, and management of infection.

Eligibility Criteria:
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 2 diabetes undergoing therapy for glycemic control.
2. Subject has a glycosylated hemoglobin, HbA1c ≤ 12%. Note: Prior documented HbA1c within the last 3 months of the Screening Visit is acceptable.
3. Presence of at least one diabetic foot ulcer that meets all of the following criteria:

   1. A full-thickness ulcer of University of Texas Wound Classification (UTWCS) Grade I or II
   2. Ulcer is located on or below the malleoli
   3. Ulcer size (area) is ≥ 1 cm2 and ≤ 10 cm2 (post-debridement at time of randomization)
   4. Unresponsive to standard ulcer care and present for ≥1 month and ≤1 year (at time of screening)
   5. There is a minimum 1 cm margin between the qualifying Target Ulcer and any other ulcers on the specified foot, post-debridement)
   6. No exposed bone and no tunneling, undermining, or sinus tracts
   7. Ulcer must be non-healing as defined as \<35% reduction in size in response to standard of care during the two-week run-in Screening Period (between the first Screening Visit and Baseline) Note: Criterion 3(g) will be evaluated at the time of randomization. If the subject has more than one qualifying diabetic foot ulcer, the ulcer designated as the Target Ulcer will be at the discretion of the Investigator.
4. Subject has adequate vascular perfusion of the affected limb, confirmed by Ankle-Brachial Index (ABI) ≥ 0.6 and ≤ 1.2. ABI results within the last 3 months of Screening are acceptable. The assessment may also be performed between SV1 and SV2.

   Note: If the ABI measurement is \>1.20, confirmatory tests (Great toe pressure and/or TcPO2 at the foot) will be performed. A subject will be considered eligible for inclusion in this study if Great toe pressure ≥ 40mmHg or TcPO2 ≥ 40 mmHg at the foot. Prior documented flow study within the last 3 months of the Screening Visit is acceptable.
5. Clinically normal resting ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator.
6. Subject, if female of child-bearing potential, has a negative serum pregnancy test at screening, must not be breastfeeding, and willing to use acceptable methods of contraception (birth control pills, barriers, or abstinence) throughout the study.
7. Subject is able and willing to comply with study procedures and applicable dressing changes.
8. Subject demonstrates cognitive and physical ability to administer the treatment as determined by the clinician. If a caregiver will administer the treatment, the caregiver must demonstrate cognitive / physical ability.
9. 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: Osteomyelitis should be ruled out by clinical examination (probing of the wound) or X-ray findings, if necessary, by the Investigator.
2. Subject has ulcers secondary to a disease other than diabetes, e.g., fungal ulcerations, malignant ulcerations, and ulcerations due to venous or arterial insufficiency, or due to hematological disorders, in the opinion of the Principal Investigator.
3. Ulcer, which in the opinion of the Investigator is suspicious for cancer. Note: Ulcers present for \> 6 months would require biopsy to be performed to rule out malignancy.
4. Subjects with a gangrenous or ischemic toe that may need to be amputated in the opinion of the Investigator.
5. Body mass index (BMI) \> 40kg/m2
6. Laboratory values at Screening of:

   1. Hemoglobin \< 8.5 g/dL
   2. White Blood Cells (WBC) \< 3.0 X 109 cells/L and \> 11 x 109 cells/L
   3. Liver function studies \[Total bilirubin, aspartate aminotransferase (AST) and alanine transaminase (ALT)\] \> 3x the upper limit of normal
   4. Albumin \< 2.5 g/dL
   5. Renal function studies \[Serum Creatinine and Urea\] \> 3x the upper limit of normal
7. Presence of any clinically significant medical condition(s) that, in the opinion of the Investigator, could interfere with wound healing, including but not limited to the following:

   1. Vasculitis or connective tissue disease
   2. Buerger's disease, Raynaud's or other peripheral vascular disease.
   3. Clinically significant claudication or peripheral edema on the affected limb
   4. Acute or unstable Charcot foot
   5. Aplastic anemia or sickle cell anemia
   6. Current sepsis
   7. Severe heart diseases such as congestive heart failure (NYHA Class III or IV), coronary heart disease with ST segment elevation, myocardial infarction, or coronary artery bypass graft or percutaneous transluminal coronary angioplasty within the last 6 months
   8. Severe Liver disease
   9. End-stage renal disease
   10. Severe malnutrition
   11. Immunosuppression
   12. Acquired immune deficiency syndrome (AIDS) or HIV positive
   13. Past or present malignancy below the knee on the same limb as the Target Ulcer;
   14. History of radiation at the Target Ulcer site.
8. Subject is currently receiving (i.e., within 30 days of T1 visit) or scheduled to receive any of following medication or therapies during the course of the study.

   1. immunosuppressants (including chronic systemic corticosteroids)
   2. cytotoxic chemotherapy
   3. cytostatic therapy
   4. Lower limb revascularization surgery (e.g., angioplasty, artery bypass surgery,)
   5. application of bioengineered tissue or skin substitutes
   6. use of any investigational drug(s)
9. Subjects who have previously received NOX1416 treatment
10. Has a known hypersensitivity to any of the investigational drug components
11. Subject is susceptible to hemorrhaging or has a congenital or acquired predisposition to hemorrhaging.
12. Any reason that the subjects may need to be admitted to inpatient acute care in the opinion of the Investigator.
13. Has any other factor which may, in the opinion of the investigator, compromise participation and/or follow-up in the study.