Nitric Oxide Footbath for Treatment of Diabetic Foot Ulcers

It is hypothesized that a single, relatively short exposure (three times a week for a half hour) of a nitric oxide releasing solution (NORS) for four (4) week period will be well tolerated and may have other beneficial secondary outcomes for individuals presenting with diabetic foot ulcers.

Inclusion criteria

• Non-hospitalized, ambulatory patients with controlled diabetes mellitus as determined by physician diagnosis recorded in the medical record. Diabetes may be treated with insulin, oral hypoglycemic agents or diet alone. Patient glycaemic control (HbA1c) should be less than or equal to 12 % within 2 weeks of enrollment;
• Must be ≥ 19 years of age unless local laws dictate otherwise;
• Participants must be considered reliable, willing and able to give signed informed consent, and sign the informed consent form.
• Participant is willing to be randomized and able to comply with the protocol
• Participants must have either:

i) 1 or more full thickness ulcers on the foot below the malleoli with a surface area exceeding 0.5 cm2 (50 mm2) after debridement (full thickness means extending through the epidermis and dermis but not involving tendon, bone, or joint capsule); or ii) 1 or more partial thickness ulcers (i.e., do not completely penetrate the dermis) of forefoot or digits; or iii) 1 or more ulcers of the forefoot or digits have granulation tissue at their base.

• Participants must have localized mild infection of at least 1 ulcer that would ordinarily be treated on an outpatient basis. Mild infection of an ulcer is defined by the presence of at least 2 manifestations of inflammation (purulence, erythema, pain, tenderness, warmth, or induration) which is limited to the skin or superficial subcutaneous tissues. If there is more than one ulcer meeting eligibility, the Investigator will determine which ulcer will be followed for the course of the study.
• Mild infection defined by IDSA criteria34:

i) "Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and without systemic signs as described below).

ii) If erythema, must be >0.5 cm to ≤2 cm around the ulcer. Exclude other causes of an inflammatory response of the skin (e.g., trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis)."

• Participants who have been previously treated or are currently under treatment for a localized infection of an ulcer may be enrolled if there has been an inadequate response to treatment and the ulcer is still infected as described above.
• Participants must have a radiograph (appropriate views as determined by the investigator) within the 2 weeks prior to entry showing no evidence of cortical destruction consistent with osteomyelitis in the affected foot.
• Participants must have either:

i) A palpable dorsalis pedis or posterior tibial pulse in the affected foot; or ii) If the pulse is congenitally absent or not palpable due to edema, a Dopplerable dorsalis pedis or posterior tibial pulse measured at ≥ 30 mm Hg; or iii) If there are no palpable pulses, non Dopplerable pulses, rest pain, or claudication on walking less than one block are present, the patient may be enrolled only if a vascular surgeon has determined that vascular surgery, angioplasty or amputation is not warranted.

• Participants must have no more than a reduced wound area of ≤30% documented by the PI, during the 2 weeks of screening, in which patients received institutional standard of care (SOC)
• Participants may not be taking or have received any other investigational therapy or approved therapy (i.e., drug or device) for investigational use within the 30 days prior to entry.
• Female Participants must be postmenopausal for at least 6 months; surgically sterilized (hysterectomy or tubal ligation); or, if of child-bearing potential, must have a negative pregnancy test prior to entry and must be willing to use one highly effective birth control method which include: hormonal contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy and tubal ligation or to use two forms of effective birth control methods which include: barrier methods of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge). The Participants must have used the birth control method for at least 2 complete menstrual cycles prior to study entry.

Exclusion criteria

• Participants with limb threatening infection, extensive cellulitis (≥2 cm beyond the ulcer), lymphangitis, fasciitis, deep tissue infection, an abscess, or other evidence of local complications of infection.
• Participants with symptoms of systemic infection (e.g., severe hyperglycemia, ketoacidosis, azotemia).
• Participants requiring concurrent local or systemic antimicrobials during the study period for any infection, including diabetic foot ulcer.
• Participants who are currently treated by dialysis, awaiting dialysis or who have an estimated glomerular filtration rate of ≤20 mL/min/173 m2.
• Participants who are expected to be unable to care for their ulcer because of hospitalization, vacation, disability, etc. during the study period.
• Participants with known active alcohol or substance abuse within the 6 months preceding study entry.
• Participants who are receiving systemic corticosteroids (in a dose equivalent to ≥ 20 mg of prednisone per day) immunosuppressive radiation therapy, or cytotoxic agents
• Participants who require treatment for a primary or metastatic malignancy (other than squamous or basal cell carcinoma of the skin).
• Participants with a systemically immunocompromising disease, such as acquired immune deficiency syndrome or known human immunodeficiency virus (HIV) positivity.
• Participants who have an unexplained fever or chills during the week prior to enrollment.
• Participants with other conditions considered by the investigator to be reasons for disqualification that may jeopardize patient safety or interfere with the objectives of the trial (e.g., acute illness or exacerbation of chronic illness, lack of motivation, history of poor compliance).
• Women who are breast feeding, pregnant or attempting to become pregnant.