A Post Marketing Study of Apligraf in Non-healing Wounds of Subjects With Venous Leg Ulcers

Subjects with a ≥5 cm2, non-infected target ulcer that has not reduced in area by ≥ 40%
since the Screening visit will be randomized at Day 0 to either Apligraf or Control. After
enrollment of 25 subjects, randomization will be discontinued and all remaining subjects
will receive Apligraf.

Once the target ulcer is assessed by the Investigator as healed at a study visit, the
subject's participation in the study is completed (eg, assessed as healed at Week 3, subject
would not be required to complete any subsequent study visits).

Apligraf Group (Day 0 to Week 4) Prior to all applications, Apligraf will be fenestrated
(perforated) in a standardized manner using a #11 blade with 6 fenestrations per 44 cm2.

For those subjects randomized to the Apligraf group, after Apligraf application, the
dressing regimen will include a foam dressing (eg. Mepilex) and a 4 layered compression
bandage system (eg. Profore) which will be changed weekly by the Investigator.

After the initial Apligraf application at study Day 0, Apligraf may be applied weekly
thereafter for an additional 4 weeks at study Weeks 1, 2, 3, and 4, if, upon visual
inspection, adherent Apligraf wound coverage is < 100%.

At Week 4, the area of the target ulcer will be compared to the area of the target ulcer at
Day 0 to determine if the target ulcer is PTH or NPTH.

Apligraf subjects that do not achieve CWC by Week 5 will enter the Follow-Up Phase at that
time.

Control Group (Day 0 to Week 4 [PTH] or Day 0 to Week 8 [NPTH] Beginning at Day 0, subjects
randomized to the Control group will receive the standard dressing regimen which includes a
foam dressing (e.g. Mepilex®) and a four layered compression bandage system (e.g. Profore™)
which will be changed weekly by the Investigator.

At study Week 4, the size of the ulcer will be compared to the size at study Day 0 to
determine if the ulcer is demonstrating "Predicted to Heal" (PTH), defined as >40% reduction
in ulcer surface area compared with study Day 0, or "Not Predicted to Heal (NPTH), defined
as <40% reduction in ulcer surface area compared with study Day 0.

Control PTH subjects that do not achieve CWC by Week 4 will continue to receive Control
treatment and will enter the Follow-Up Phase at Week 5.

Control NPTH subjects will receive Apligraf beginning at Week 4. Prior to all applications,
Apligraf will be fenestrated (perforated) in a standardized manner using a #11 blade with 6
fenestrations per 44 cm2. After the initial Apligraf application at Week 4, Apligraf may be
applied weekly thereafter for an additional 4 weeks at study Weeks 5, 6, 7, and 8 if upon
visual inspection, adherent Apligraf wound coverage is < 100%. After Apligraf application,
the standard dressing regimen will be applied over the target ulcer. The dressing will be
changed weekly by the Investigator. At Week 8, the area of the target ulcer will be compared
to the area of the target ulcer at Week 4 to determine if the target ulcer is PTH or NPTH.

Control NPTH subjects that do not achieve CWC by Week 9 will enter the Follow-up Phase at
that time.

Inclusion Criteria:

1. Subject has at least 1 clinically non-infected full-thickness venous leg ulcer (VLU)
at least 5 cm2 in size.

2. Subject is at least 18 years of age or older.

3. Subject must have read, understood and signed an institutional review board (IRB)
approved Informed Consent Form.

4. Subject must be able and willing to follow study procedures and instructions.

Exclusion Criteria:

1. Subjects who require VAC® (Vacuum Assisted Closure™) therapy on or after Day 0 Study
visit.

2. Subject has arterial disease as determined by an Ankle Brachial Index (ABI)
measurement of <0.65.

3. Subject with any systemic or congenital condition like uncontrolled diabetes
mellitus, positive HIV test, or any disorder(s) that may compromise wound healing.

4. Subjects with carcinomas located at the target ulcer with biopsy confirmed active
malignancy. (Subjects with other carcinoma locations would not be excluded from entry
into the study.)

5. Subjects who are currently receiving, or have received at any time within 30 days
prior to Screening visit, non-inhaled corticosteroids except topical steroids not at
the target ulcer (Inhaled steroid therapy is acceptable on study.), immunosuppressive
agents, radiation therapy, hemodialysis, peritoneal dialysis or chemotherapy.
(Anticipated use of the above agents or therapies would exclude subject from entry
into the study.)

6. Clinical vasculitis, severe rheumatoid arthritis, and other collagen vascular
diseases.

7. Signs and symptoms of cellulitis or osteomyelitis at the target ulcer.

8. Avascular target ulcer beds. (Ulcers of mixed etiology such as arterial disease with
VLU will be excluded.)

9. Target ulcer with exposed bone, tendon or fascia.

10. Known hypersensitivity to bovine collagen or to the components of the Apligraf
agarose shipping medium.

11. Subject enrolled in any wound or investigational study (drug, biologic or device) for
any disease within 30 days of the Screening visit.

12. Subject previously treated with Apligraf, Dermagraft® or any other cell therapy at
the target ulcer site within 30 days of the Screening visit.

13. Subject with a history of alcohol or substance abuse within the previous year, which
could interfere with study compliance such as inability to attend scheduled study
visits.

14. Subject who is a current smoker or has not ceased smoking 6 months prior to the
Screening visit, or in the opinion of the Investigator, has a smoking history that
may compromise wound healing.

15. Subject 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.

16. Target ulcer has not decreased in size by > 40% from Screening to Day 0.

17. Confirmed gene expression overlap between the subject's cells (buccal swab) and the
cells contained in Apligraf.