Most chronic (long-lasting) wounds of the leg (also known as venous ulcers) fail to heal in a reasonable period of time. Although researchers have made great progress in understanding how the body repairs wounds, attempts to develop new treatments have been disappointing. In general, treatments based on recent findings about the details of wound repair have not greatly reduced the number of people who have chronic wounds. The long-term goal of this study is to evaluate a new approach for healing a chronic wound. Current methods of directly applying substances that are involved in wound healing to a chronic wound do not cause enough healing. We think that PDGF-B (platelet-derived growth factor B), a factor associated with wound healing, will dramatically enhance healing if we inject a genetically engineered virus into the wound that causes cells in the wound to produce PDGF-B in large quantities.

Condition	Treatment or Intervention	Phase
Varicose Ulcer	Drug: PDGF-B/Ad5	Phase I

Most chronic wounds of the leg fail to heal in a reasonable period of time. In fact, despite considerable advances in elucidating the molecular basis of wound repair, attempts to develop new therapies have been disappointing. In general, therapies based on recently elucidated mechanisms of wound repair have had minimal effect on the overall number of individuals with a treated healed chronic wound. The long-term goal of this study is to evaluate a new approach for healing a chronic wound. Current methods of applying cytokines as a topical protein to treat chronic wounds result in an inadequate response. We hypothesize that PDGF-B, a growth factor associated with wound healing, will dramatically enhance wound healing when produced in large quantities in the wound bed via adenovirus-mediated gene overexpression by the cells of the wound bed.

This study consists of two trials. The goal of Trial A, a dose-escalation trial, is to determine the maximum tolerated dose (MTD) of PDGF-B/Ad5, an adenovirus vector designed to overexpress PDGF-B, with respect to local and systemic toxicity and biologic feasibility. Our primary objective is to evaluate the acute safety, both local and systemic, of an intra-ulcer injection of PDGF-B/Ad5, thereby determining the recommended dose. After we evaluate the patients, we will treat them with a single intra-ulcer injection of PDGF-B/Ad5 in the wound. We will give patients only one dose, which we will administer during a 72-hour inpatient stay in a research unit at the Hospital of the University of Pennsylvania.

This study will use a standard three-six dose-escalation scheme. The MTD is defined as the highest dose for which fewer than two of six subjects experience a severe adverse reaction. We will closely monitor each patient for clinical adverse reactions resulting from treatment with PDGF-B/Ad5. We will grade toxicity according to the National Cancer Institute's Common Toxicity Criteria Scale.

The primary objective of Trial B is to evaluate the safety and biologic feasibility of the MTD of PDGF-B/Ad5 reported in Trial A in a standard 24-week trial for treatment of a venous leg ulcer. For this study, we will treat 15 consecutive patients using the MTD. We will give all patients a single intra-ulcer injection of PDGF-B/Ad5 and a limb compression bandage to be changed weekly. We will follow study participants for 24 weeks, which is the length of most FDA-approved venous leg ulcer trials.

Ages Eligible for Study:  18 Years   -   90 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Patient must have a venous leg ulcer.
• Patient must have failed at least 6 weeks of limb compression.
• Wound must be free of necrotic debris.
• Wound must be greater than 5 cm2 and less than 20 cm2.
• Wound must be more than 6 months old.
• Affected limb must have an ankle-brachial index (ABI) > 0.85.
• Patient must be more than 18 years old.

Exclusion Criteria:

• Any active cancer or cancer in remission for less than 10 years.
• Patients with life expectancy of less than 6 months.
• Liver function tests (ALT, AST, ALK PHOS and bilirubin) greater than 1.5x upper limit of normal for the reference lab.
• Patients with intercurrent organ damage or medical problems.
• Pregnant or lactating females.
• Any requirement for systemic corticosteroids or immunosuppressives, or history of corticosteroid or immunosuppressive use in the 4 weeks previous to study entry.
• Seropositive for hepatitis B surface antigen or hepatitis C antibody.
• Any concurrent medical illness that may be exacerbated by PDGF-B/Ad5 administration.

David J. Margolis, MD      215-898-4938    dmargoli@cceb.med.upenn.edu

Pennsylvania
      University of Pennsylvania, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting

Study chairs or principal investigators

David J. Margolis, MD,  Principal Investigator,  University of Pennsylvania   

Study ID Numbers:  NIAMS-044; N01 AR-9-2238
Record last reviewed:  November 2004
Record first received:  January 18, 2000
ClinicalTrials.gov Identifier:  NCT00000431
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-11-08