Evaluating the Safety and Efficacy of GrafixPL™PRIME for the Treatment of Chronic Venous Leg Ulcers

The present study is a multi-center, prospective, randomized, open-label trial to evaluate
the efficacy of GrafixPL™PRIME plus standard compression therapy for the treatment of chronic
venous leg ulcers (VLUs). GrafixPL™PRIME is a commercially available product.

At the screening visit, patients will have their blood drawn and a urine sample will have to
be provided. Throughout visits, culture swabs of the wound will be taken.

Approximately 30 patients (15 in each treatment group) at this site will be randomized at a
1:1 ratio to GrafixPL™PRIME plus standard compression therapy or standard compression therapy
alone for up to 12 weeks. Allowing for a randomized not treated patient population of 2%, the
study is planned for 196 evaluable patients.

Subjects will be in the study for up to 38 weeks.

Subjects randomized to Cohort A: (GrafixPL™PRIME plus standard compression therapy) or Cohort
B: (standard compression therapy only). Randomization means that you are put into a group by
chance. It is like flipping a coin. Which group you are put in is done by a computer. Neither
you nor the researchers will choose what group you will be in. You will have an equal chance
of being placed in any group. Neither you nor the investigator will know what group you are
in.

Treatment Regimen: All Subjects will receive standard compression therapy weekly throughout
the study starting with Screening Visit 1. Multi-layer compression materials will be
provided.

All subjects will be asked to complete a Cardiff Wound Impact Schedule (CWIS) survey and a
Work Productivity and Activity Impairment Questionnaire every visit after their screening
visits.

Cohort A: (GrafixPL™PRIME plus standard compression therapy)

Subjects randomized to GrafixPL™PRIME plus standard compression therapy will receive
applications of GrafixPL™PRIME plus standard compression therapy once weekly for up to 12
weeks. Subjects randomized to standard compression therapy alone will receive standard
compression therapy once weekly for up to 12 weeks. Both GrafixPL™PRIME plus standard
compression therapy and standard compression therapy alone subjects will return for weekly
visits until the ulcer has closed or until the End of Treatment Visit. Subjects randomized to
treatment with GrafixPL™PRIME plus standard compression therapy will receive GrafixPL™PRIME
plus standard compression therapy on Days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70 and 77
(plus or minus 3 days) unless ulcer closure is achieved within the 12 week Treatment Phase.
If ulcer closure is not achieved, subjects will continue in the study until the End of
Treatment Visit. If ulcer closure is achieved, subjects will be followed for up to 168 days
(plus or minus 7 days) after the End of Treatment Visit in the Follow-Up Phase.

Cohort B: (standard compression therapy only)

Subjects in the standard compression therapy alone group whose ulcers are not closed at the
End of the Treatment Visit will be offered GrafixPL™PRIME plus standard compression therapy
in the Crossover Extension Treatment Phase. Subjects randomized to standard compression
therapy alone will receive standard compression therapy on Days 0, 7, 14, 21, 28, 35, 42, 49,
56, 70, and 77 (plus or minus 3 days) unless ulcer closure is achieved within the 12 week
Treatment Phase. Those who do not achieve ulcer closure within the 12 week Treatment Phase
are eligible for the Crossover Extension Treatment Phase for up to 12 weeks of treatment with
GrafixPL™PRIME plus standard compression therapy.

These subjects are eligible for up to 12 treatments (once weekly for 12 weeks) of
GrafixPL™PRIME plus standard compression therapy. Subjects randomized to GrafixPL™PRIME plus
standard compression therapy in the Treatment Phase whose ulcers do not close are not
eligible for the Crossover Extension Treatment Phase.

The maximum duration of patient participation in this study is expected to be approximately
38 weeks from the initial Screening Visit to completion of the Follow-Up Visits.

Inclusion Criteria:

1. 18 years or older, as of the date of screening

2. An Index Ulcer that is chronic (defined as present for greater than or equal to 4
weeks, but not present for more than 52 weeks at Screening Visit 1)

3. Index Ulcer is located on the leg, below the knee and above the malleoli (ulcer may be
inclusive of the malleoli)

4. The Index Ulcer is between 1 cm squared and 25 cm squared, inclusive, at the Screening
and Baseline Visits. The longest dimension of the index ulcer cannot exceed 10 cm at
the Baseline Visit.

5. The Index Ulcer has had compression for greater than or equal to 2 weeks at Screening
Visit 1.

6. The Index Ulcer extends into the dermis or subcutaneous tissue without evidence of
exposed muscle, tendon, bone, or joint capsule.

7. Patient has adequate circulation to the foot, as documented up to 14 days prior to
Screening Visit 1 by either:

- Ankle Brachial Index (ABI) > 0.80 and <1.30, or

- In patients with non-compressible ankle vessels defined as an ABI greater than or
equal to 1.30, a Toe Brachial Index (TBI) greater than or equal to 0.50, or

- In patients with non-compressible ankle vessels defined as an ABI greater than or
equal to 1.30 and TBI cannot be performed (e.g., toe is absent, ulcers are
present, or site cannot perform a TBI), a Doppler waveform in the posterior
tibial or dorsalis pedis arteries at the ankle consistent with adequate flow in
the foot (biphasic or triphasic) and other diagnostic confirmation of adequate
flow (e.g., duplex imaging, normal pulse volume recording [PVR] testing).

8. Confirmed diagnosis of venous insufficiency, as documented up to 30 days prior to
enrollment (Baseline Day 0), by either:

- Duplex ultrasonography, or

- Principal Investigator [PI] clinical assessment to include clinical signs and
symptoms of venous ulcerations (e.g., hyperpigmentation of surrounding skin,
varicosities, and/or lipodermatosclerosis).

In the inclusion criteria above, the word or is meant to include the case where both or
multiple criteria are met as well as the case where just a single criterion is met.

Exclusion Criteria:

1. Index Ulcer is of non-venous pathophysiology

2. Gangrene is present on any part of the affected limb

3. Patient is unable to tolerate standard compression therapy

4. Glycated hemoglobin A1c (HbA1c) level of >14% in any patient with type 1 or type 2
diabetes mellitus, as documented up to 14 days prior to Screening Visit 1

5. Patient is receiving intravenous (IV) corticosteroids, immunosuppressive or cytotoxic
agents at any time during the screening period

6. Patient has an ulcer within 5 cm of the Index Ulcer identified for study
consideration.

7. Patient is Human Immunodeficiency Virus (HIV) positive or has Acquired Immune
Deficiency Syndrome (AIDS)

8. Current evidence of infection at the Index Ulcer, including cellulitis and/or pus
drainage from the ulcer site at the time of Screening and Baseline Visits.

9. Evidence of osteomyelitis at the time of Screening and Baseline Visits.

10. Patient has active malignancy other than non-melanoma skin cancer

11. Patient's Index Ulcer has decreased by greater than or equal to 30% between Screening
Visit 1 and the Baseline Visit during the screening period

12. Patient has untreated alcohol or substance abuse at the time of Screening Visit 1

13. Pregnant women and women who who are breastfeeding

14. Patient is currently enrolled in or has participated in another investigational
device, drug, or biological trial within 30 days prior to Screening Visit 1

15. Patient has had within 14 days of Screening Visit 1, or is currently undergoing, or is
planning for ulcer treatments with growth factors, living skin, dermal substitutes or
other advanced biological therapies

16. Patient is an employee, or an immediate family member of an employee, of the sponsor
company or site research staff conducting the study

17. Patients who have already been randomized in Protocol 360 at any center or may not be
considered for screening or for re-entry into the trial at any center, even after the
End of Treatment Study Visit

18. Patients with a history of poor compliance, or an unwillingness or inability to adhere
to the requirements of the protocol

In the exclusion criteria above, the word or is meant to include the case where both or
multiple criteria are met as well as the case where just a single criterion is met.