NuShield/Affinity for the Treatment of Neuropathic Diabetic Foot Ulcers

This is a three (3)-arm evaluation in 100 patients over 3 facilities with diabetic foot
ulcers (DFU). Patients will be treated with NuShield or Affinity together with standard
therapy or with standard care alone. For the purposes of this evaluation, standard therapy
will consist of extensive debridement of nonviable tissue, saline-moistened non-occlusive
dressing, off-loading to decrease pressure on extremity, aggressive treatment of infection
and arterial revascularization if indicated. The patients will receive NuShield or Affinity
plus standard therapy to determine optimal application method. The evaluation duration is 4
weeks with 8-week and 12-week follow-up visits. Patients with diabetic neuropathic foot
ulcers of at least 4 weeks duration and free of clinical signs of infection at the time of
treatment may be eligible for inclusion. At Week -1, each patient will undergo aggressive,
surgical debridement. The site should be free of fibrin, necrotic and callous tissue. Digital
imaging and planimetery of the target ulcer will be performed pre- and post initial
debridement and at each subsequent visit as per the evaluation schedule. This evaluation is
designed to investigate the potential of an allogeneic placental-derived amniotic membrane to
accelerate healing of lower extremity DFU when used in conjunction with standard therapy.
This potential will be measured as an increase in the rate of healing (daily decrease in
percent wound area/volume compared to initial debrided ulcer area/volume) of patients treated
with NuShield or Affinity plus standard wound care compared to patients treated with standard
good wound care alone. Studies by Margolis and co-workers have demonstrated that the use of
this surrogate marker, measured at 4 and 8 weeks of care, is predictive (>70%) of wound
healing in patients with DFU at the 20th week of care. [Kantor 1998; Margolis 2003] The
secondary endpoint will be patients achieving complete closure (100%) by week 12.

Inclusion Criteria:

1. Subject is or greater than 18 years old.

2. Type 1 or Type 2 diabetes.

3. Subject has plantar ulcers of greater than or equal to 4 weeks duration at
presentation, unresponsive to standard wound care.

4. Subject's ulcer size >0.5cm2 and < 20cm2 area post-debridement.

5. Subject has well controlled glucose levels, with HbA1c < 10%.

6. Subject has adequate lower extremity perfusion, with Ankle-Brachial Index > 0.8 (note:
this is an ABI-equivalent, based on biphasic or triphasic color duplex - PVR or MRA.
Diabetics often have peripheral vascular calcification or poorly compressible vessels
resulting in abnormally high Ankle-Brachial Indices.) or dorsum transcutaneous oxygen
test (TcPO2) > 30 mmHg. Presence of tibial and plantar pulses is preferred.

7. Subject should have no evidence of unresolved gross soft-tissue infection or boney
pathology (i.e. osteomyelitis).

8. Subject should have no evidence of underlying co-morbid conditions that would
adversely affect wound healing such as: Cancer, Raynaud's syndrome, severe venous
insufficiency or uncorrected arterial insufficiency, etc.

9. Subject should not be on medications that compromise healing: cytotoxic
chemotherapeutics, etc

Exclusion Criteria:

1. Patients with evidence of skin cancer within or adjacent to the ulcer site.

2. Patients who have signs and symptoms of boney pathology (i.e. osteomyelitis) following
debridement.

3. Patients with ulcers on the calcaneus.

4. Patients who have significant arterial disease as determined by ABI, duplex Doppler
sonography (PVR) or magnetic resonance angiography (MRA): Ankle-Brachial Index < 0.8
(note: this is an ABI-equivalent, based on biphasic or triphasic color duplex - PVR or
MRA. Diabetics often have peripheral vascular calcification or poorly compressible
vessels resulting in abnormally high ABIs); dorsum transcutaneous oxygen test (TcPO2)
< 30 mmHg; absence of tibial or plantar pulses.

5. Patients who have documented clinically significant medical conditions, which would
impair wound healing. This includes:

- Renal impairment (creatinine >2.5 mg/dL);

- Hepatic impairment (2XULN);

- Hematological disorders (abnormities of formed elements);

- Neurologic disorders resulting in significant impairment of sensory and motor
functions as judged by the investigator;

- Patients with signs and symptoms of cellulitis;

- Patients with ulcers with sinus tracts associated with an ongoing infection;

- Patients with active deep vein thrombosis;

- Patients with uncontrolled diabetes, as demonstrated by increased HbA1C (> 10%);

- Immunocompromised patients (e.g., lymphoma, AIDS, myelodysplastic disorders)

- Patients with a history of basal cell carcinomas or actinically induced squamous
cell carcinomas which have been effectively treated are not excluded, except if
the skin cancer was in the exact location of the target ulcer.

6. Patients with active systemic cancer receiving active cancer therapy

7. Patients who are currently receiving, or have received within 1 week prior to study
entry:

- Adriamycin (doxorubicin), bleomycin, serolimus (Rapamune, rapamycin) and
anti-TNFα cytotoxic/immunosuppressive agents;

- Radiation therapy at the ulcer site;

- Topical growth factors at the target site (i.e., Regranex®).

8. Patients enrolled in wound or drug investigational agent study for any disease within
the past 4 weeks.

9. Patients previously treated with amniotic membrane, PRP/PRFM, stem cell therapy,
Apligraf, OrCel, Dermagraft, Graft Jacket, Oasis, stem cell therapy or any other
advanced therapy at the target site for 1 month prior to enrollment.

10. Pregnant or breast-feeding.

11. Patients, who in the opinion of the investigator, for any reason other than those
listed above, will not be able to complete the study per protocol.