Evaluating the Efficacy of Perinatal Membrane Allografts in Addition to the Standard of Care for the Treatment of Non-healing Diabetic Foot Ulcers.

Patients with diabetes often develop ulcers on their lower extremities. While some ulcers can be managed using standard of care wound management techniques including debridement, moist dressings, infection control and off-loading, many develop into chronic, non-healing wounds. Chronic non-healing wounds can lead to higher risk of infection, amputation and decreased quality of life.

Advanced wound therapies aim to promote rapid and complete healing of chronic wounds. An example of an advanced wound therapy are perinatal tissue allografts. These include human amniotic / chorionic membranes, which have been confirmed by the United States Food & Drug Administration's Tissue Reference Group to meet the criteria for regulation solely under Section 361 of the Public Health Service Act as defined in Title 21 of the Code of Federal Regulations - Part 1271 for the management of diabetic foot ulcers.

The focus of this clinical trial is to determine the clinical utility of treating diabetic foot ulcers with weekly applications of perinatal tissue allografts in addition to standard of care wound management techniques compared to applying standard of care wound management only.

It is hypothesized that the addition of perinatal tissue allografts to standard of care treatment will result in a higher percentage of ulcers achieving complete closure (i.e. healing) compared to ulcer being treated with standard of care alone after 12 weeks of treatment.

To test this hypothesis the study will consist of patients who will undergo a 2-week screening phase and a 12-week treatment phase. Briefly, during the 2-week screening phase, patients meeting inclusion criteria will have an identified index wound managed with standard of care. Index wounds that are not reduced by more than 20% in the screening phase will be randomized into the treatment groups. During the 12-week treatment phase, index wounds will be treated weekly with either allograft and standard of care or standard of care alone.

Evaluation of data (outcome measures) associated with the trial will include intent to treat and per protocol analyses which will be performed by at least one blinded statistician and investigator.

Inclusion criteria

Potential subjects are required to meet all the following criteria for enrollment in the study.

• Subjects must be at least 18 years of age or older.
• Subjects must have a diagnosis of type 1 or 2 Diabetes mellitus.
• At randomization subjects must have a target ulcer with a minimum surface area of 1.0 cm2 and a maximum surface area of 20.0 cm2 measured post debridement.
• The target ulcer must have been present for a minimum of 4 weeks and a maximum of 52 weeks of standard of care, prior to the initial screening visit.
• The target ulcer must be located on the foot with at least 50% of the ulcer below the malleolus.
• The target ulcer must be Wagner 1 or 2 grade, extending at least through the dermis or subcutaneous tissue and may involve the muscle provided it is below the medial aspect of the malleolus. The ulcer may not include exposed tendon or bone.
• The affected limb must have adequate perfusion confirmed by vascular assessment. Any of the following methods performed within 3 months of the first screening visit are acceptable:

• ABI between 0.7 and ≤ 1.3;
• TBI ≥ 0.6;
• TCOM ≥ 40 mmHg;
• PVR: biphasic.
• If the subject has two or more ulcers, they must be separated by at least 2 cm. The largest ulcer satisfying the inclusion and exclusion criteria will be designated as the target ulcer.
• Target ulcers located on the plantar aspect of the foot must be offloaded for at least 14 days prior to enrollment.
• The potential subject must consent to using the prescribed offloading method for the duration of the study.
• The potential subject must agree to attend the weekly study visits required by the protocol.
• The potential subject must be willing and able to participate in the informed consent process.

Exclusion criteria

Potential subjects meeting any of the following criteria will be excluded from enrollment in the study.

• A subject known to have a life expectancy of < 6 months is excluded.
• The subject is excluded if the target ulcer is not secondary to diabetes.
• If the target ulcer is infected or if there is cellulitis in the surrounding skin, the subject is excluded.
• If there is evidence of osteomyelitis complicating the target ulcer, the subject is excluded.
• A potential subject cannot have an infection in the target ulcer or in a remote location that requires systemic antibiotic therapy.
• A subject receiving immunosuppressants (including systemic corticosteroids at doses greater than 10 mg of Prednisone per day or equivalent) or cytotoxic chemotherapy is excluded.
• The topical application of steroids to the ulcer surface within one month of initial screening is not permitted.
• A subject with a previous partial amputation on the affected foot is excluded if the resulting deformity impedes proper offloading of the target ulcer.
• The subject is excluded if the surface area of the target ulcer has reduced in size by more than 20% in the 2 weeks prior to the initial screening visit ("historical" run-in period). Photographic planimetry is not required for measurements taken during the historical run-in period (e.g. calculating surface area using length x width is acceptable).
• The subject is excluded if the surface area measurement of the Target ulcer decreases by 20% or more during the 2-week screening phase: the 2 weeks from the initial screening visit (S1) to the TV-1/randomization visit, during which time the subject received SOC.
• The potential subject has glycated hemoglobin (HbA1c) greater than or equal to 12% within 3 months of the initial screening visit.
• A subject with an acute Charcot foot, or an inactive Charcot foot, that impedes proper offloading of the target ulcer is excluded.
• Women who are pregnant or considering becoming pregnant within the next 6 months are excluded.
• A potential subject with end stage renal disease requiring dialysis is excluded.
• Participation in a clinical trial involving treatment with an investigational product within the previous 30 days.
• A subject who, in the opinion of the investigator, has a medical or psychological condition that may interfere with study assessments is excluded.
• A Subject treated with hyperbaric oxygen therapy or a Cellular Acellular, or Matrix-like Product (CAMP) in the 30 days prior to the initial screening visit is excluded.
• A subject is excluded if they are malnourished: a score of less than 17 on the Mini Nutritional Assessment (MNA).