Table 1.

Inclusion and exclusion criteria

Inclusion criteria

● Have diagnosis of diabetes mellitus

● Male or female subject of any race aged 18 years or older

● Lower extremity ulcer located anywhere on the foot up to the ankle

- Of more than 30 days duration and less than 2 years duration (medically documented)

- Surface area between 0.5cm2 and 20cm2 (as measured with the Silhouette imaging system at randomization). The ulcer with largest surface area meeting inclusion criteria will be selected as the index ulcer

- If two ulcers are present with the same surface area, the ulcer of the longest duration will be selected as the index ulcer

● Documented ankle–brachial index (ABI) between 0.8 and 1.2 on the study limb or toe pressure over 65 mmHg within 6 months of screening phase

● Documented biopsy report to rule out malignancy of ulcer of > 6 months’ duration

Exclusion criteria

● Ulcer of non-diabetic etiology, such as venous, arterial, and burn wounds

● Index ulcer is less than 3 cm in distance from any other ulcer on the same extremity

● There are more than three ulcers on the study foot

● Index ulcer presents with any of the following: cellulitis, osteomyelitis, exposed bone, tendon or fascia, purulent exudates, or gangrene

● Index ulcer shows evidence of infection (defined as a moderate or severe rating of all of the following clinical signs/symptoms: 1) increased warmth, 2) increased pain, 3) erythema, and 4) malodorous exudate at screening or at randomization (visit 1), OR total organism count > 1 × 105 colony forming units (CFU) from the screening visit study ulcer culture sample)

● Index ulcer surface area has decreased or increased > 40% between screening and at randomization (visit 1) as assessed by the Silhouette imaging system

● Has medically documented history of HIV

● Has active malignancy on the study limb

● Has uncontrolled diabetes mellitus as defined by glycosylated hemoglobin A1C > 12% within 3 months of screening

● Has immunodeficiency as defined by serum IgG, IgA, and IgM less than one-half the lower limit of normal

● Has severe protein malnutrition as defined by serum albumin < 2.5 g/dL

● Has chronic renal insufficiency requiring dialysis

● Has serum aspartate aminotransferase (AST, SGOT, GOT) or serum alanine aminotransferase (ALT, SGPT, GPT) levels greater than twice the upper limit of normal

● Has fatigue, palpitations, dyspnea, and/or angina at rest

● Has a medically documented or self-reported history, within the previous 12 months from date of screening visit, of alcohol or drug abuse, particularly methadone or heroin

● Has received previous treatment with the following during the 60 days prior to screening: immunosuppressive agents, radiation, chemotherapy, growth factors (epidermal growth factor, tumor necrosis factor, transforming growth factor, platelet derived growth factor, etc.) at the site of the study ulcer, split- or full-thickness skin graft at the site of the study ulcer, biologically active (or engineered) cellular or acellular product(s) at the site of the study ulcer, investigational drug or device

● Has been hospitalized for treatment of a diabetic foot ulcer within the previous 30 days from screening

● Has history of bradycardia (heart rate less than 60)

● Has ESR > 70 mm/h and CRP > 100 mg/L at time of screening

● Has medically documented history of hypotension/orthostatic hypotension and/or symptomatic hypotension (systolic blood pressure below 90 and diastolic blood pressure less than 60). (Note that there is no standard testing regimen protocol for orthostatic hypotension, even for patients starting on oral timolol)

● Currently taking asthma or COPD medications (as documented in chart)

● Has a medically documented diagnosis of myasthenia gravis, untreated hyperthyroidism, type 1 and/or type 2 heart block

● Female who is pregnant or refuses to use adequate contraceptive methods and is of childbearing age during the trial

● Prisoners, institutionalized individuals, or vulnerable population