Study of VF001-DP in Patients With Chronic Venous Leg Ulcers

Objective: The objective of this study is to demonstrate the effectiveness and safety of
VF001-DP as an adjunct to standard care (SC) in the treatment of chronic venous leg ulcers
(VLUs) compared to Placebo with SC over the course of the 12‑week Treatment Phase.

Design: This study is a multi-center, randomized, double-blind, placebo-controlled
dose‑response study designed to evaluate VF-001-DP as an adjunct to SC, versus Placebo and SC
in the treatment of chronic VLUs. The SC therapy for VLUs is a moisture retentive ulcer
dressing and multi‑layer compression therapy. Mepitel® and Coban2® have been chosen to be
used as SC in this trial.

The study will have three (3) phases: Screening (2 weeks), Treatment Phase (12 weeks) and
Follow-Up (12 weeks).

Only patients whose study ulcer does not exhibit more than 30% change (increase or decrease)
in ulcer size post-debridement between Screening Phase Visit (S1) and Treatment Phase Visit
(T1) and who continue to meet eligibility criteria at T1 will be randomized to receive either
the Active Treatment group (VF001-DP low or high dose plus SC) or the Control Treatment group
(Placebo plus SC) in a ratio of 1:1:1.

Treatment: Eligible patients will be assigned to one of the following treatment groups:

- Placebo and SC

- VF001-DP (14 micrograms per treatment) and SC (low dose [LD])

- VF001-DP (140 micrograms per treatment) and SC (high dose [HD]).

The investigational product (IP), i.e., VF001-DP and placebo, will be supplied in 1 mL
syringes each containing 0.5 mL of either VF001-DP or Placebo.

The IP contains parts of normal vitronectin and Insulin-like growth factor 1 (IGF-I) combined
in a single protein (vitronectin, amino acids 1-64 of the human sequence and IGF-I amino
acids 1‑70 of the human sequence), 14 μg or 140 μg protein in 0.5 mL of Phosphate Buffered
Saline, pH 7.2. VF001-DP is manufactured utilizing an expression vector system in yeast to
Good Manufacturing Practice (GMP) and is not made with and does not include any products of
human or animal origin.

Number of Patients: It is planned to recruit 168 patients (56 per treatment group) at 26
centres in USA for this study.

Inclusion Criteria:

1. At least 18 years old.

2. Ankle-Brachial Pressure Index (ABI) ≥0.80. (Calculations will be made using
measurements from both posterior tibial and dorsalis pedis arteries as well as both
arms).

3. Presence of VLUs extending through the full thickness of the skin but not down to
muscle, tendon or bone. In the case of more than one ulcer, the largest ulcer
(compliant with study criteria) will be chosen as the study ulcer and treated in the
study. Other ulcerations, if present on the same leg must be at least 2 cm apart from
the study ulcer.

4. Venous disease confirmed by Doppler ultrasonography to demonstrate reflux of >0.5
seconds in saphenous (great or small), calf perforators or the deep venous system.
Patients with prior venous surgery (i.e., varicose vein stripping, endovenous
ablation) may be included if they still demonstrate significant reflux in a remaining
venous segment and the ulcer continues to suffer poor healing because of venous
hypertension.

5. Ulcer which has been present and treated with standard care (moisture retentive ulcer
dressings and compression bandaging not limited to Mepitel® and Coban2®) for at least
one month prior to the initial Screening Visit.

6. Moderate severity ulcer at the T1 visit (post-debridement) complying with the
following requirements of the Margolis Predictive Score Baseline Wound Area and Wound
Duration:

1. 1(a) 2.5 cm2 to not-more-than 5 cm2 and not‑less-than 6 months or;

2. 1(b) Not-less-than 5 cm2 to not-more-than 15 cm2 and not-more-than 6 months

7. Ulcer with a clean, granulating base free of adherent slough at the T1 visit
(post-debridement).

8. Female patients of childbearing potential, willing to use acceptable methods of
contraception (birth control pills, barriers, or sexual abstinence). A urine pregnancy
test must be performed, and negative at the T1 visit.

9. Patient able to understand the study procedures and willing to participate in the
clinical study and able to comply with study visit schedule.

10. Provide signed informed consent.

Exclusion Criteria

1. Ulcer(s) deemed by the Investigator to be caused by a medical condition other than
venous insufficiency. These may include, but are not limited to: fungal ulcerations,
malignant ulcerations, diabetic (neuropathic) ulcerations, and ulcerations due to
arterial insufficiency.

2. Increase or decrease by >30% in the study ulcer surface area at the T1 visit
post-debridement as compared to the S1 visit study ulcer surface area
post-debridement.

3. Ulcer exhibits clinical signs and symptoms of infection at S1to T1 in which case
infection should be treated and the patient may after treatment be re-assessed for
eligibility to enter into the study.

4. Known allergy to any of the protocol-stipulated treatment procedures, or non‑tolerance
of multi-layer compression therapy.

5. Ulcer which has undergone continuing high level of compression therapy for ≥12 months

6. Ulcer, which in the opinion of the Investigator is suspicious for cancer.

7. A history of more than 2 weeks' treatment with immunosuppressants (including systemic
corticosteroids), cytotoxic chemotherapy, or application of topical steroids to the
ulcer surface within one month prior to initial screening, or treatments with such
medications during the screening period, or anticipated requirement of such
medications during the course of the study.

8. IGF-1 treatment or treatment with a product containing IGF-1.

9. Treatment with Pentoxifylline (Trental®) within 30-days of S1 visit.

10. Treatment with any investigational drug(s) or therapeutic device(s) within 30 days
preceding screening (i.e., S1); or anticipated (patient or physician anticipates) use
of any of these therapies during the course of the study.

11. Malignant disease not in remission for 5 years or more, other than basal cell
carcinoma, squamous cell carcinoma of the skin or cervical carcinoma in situ, that
have been successfully treated without evidence of recurrence or metastases.

12. History of radiation at the ulcer site.

13. As determined by medical history, presence of one or more medical conditions including
renal, hepatic, hematologic, active auto-immune or immune diseases that, in the
opinion of the Investigator, would make the patient an inappropriate candidate for
this ulcer healing study.

14. Known history of having Acquired Immunodeficiency Syndrome (AIDS) or with a history of
known infection with Human Immunodeficiency Virus (HIV).

15. Previous participation in any VF001-DP study within the past 6 months.

16. Ulcer has been previously treated with tissue engineered materials (e.g., Apligraf® or
Dermagraft®) or other scaffold materials (e.g., Oasis®, Matristem®) within the last 30
days prior to S1.

17. Ulcer which in the opinion of the Investigator might require negative pressure ulcer
therapy or hyperbaric oxygen during the course of the study.

18. New York Heart Association Class III and IV congestive heart failure, as defined by
the following criteria:

1. Class III: Symptoms with moderate exertion

2. Class IV: Symptoms at rest

19. Uncontrolled diabetes mellitus, defined as Hemoglobin A1C >10% confirmed by the
Investigator.

20. Ulcer on the dorsum of the foot or with more than 50% of the ulcer below the malleolus
is excluded.

21. Known history of acromegaly.

22. Any other medical or psychological condition (including relevant laboratory
abnormalities at screening) that, in the opinion of the Investigator, may suggest a
new and/or insufficiently understood disease, may present an unreasonable risk to the
study patient as a result of his/her participation in this clinical trial, may make
patient's participation unreliable, or may interfere with study assessments. The
specific justification for patients excluded under this criterion will be noted in
study documents (chart notes, CRFs, etc).

23. Women unwilling to use adequate birth control, if of reproductive potential and
sexually active. Adequate birth control is defined as agreement to consistently
practice an effective and accepted method of contraception throughout the duration of
the study.

24. Pregnancy or breast-feeding.