TGF-beta3 in the treatment of pressure ulcers: A preliminary report

Advances in Skin & Wound Care,  Mar/Apr 2001  by Hirshberg, James,  Coleman, James,  Marchant, Beverly,  Rees, Riley S

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ABSTRACT

OBJECTIVE: To determine the safety, tolerability, and efficacy of TGF-63 in the treatment of chronic, nonhealing pressure ulcers.

DESIGN: A subset analysis of data from a randomized, blind, parallel, placebocontrolled trial involving 270 patients.

SETTING: University of Michigan Wound Care Center.

PATIENTS: A total of 14 patients (6 women and 8 men aged >=18 years) with pressure ulcers were randomly assigned to 1 of 3 groups to receive once daily topical application of recombinant TGF-(beta)3 or placebo gel for a period of no more than 16 weeks. Group 1 (n=4) received 1.0 (mu)g/cm^sup 2^ of TGF-beta, Group 2 (n=5) received 2.5 (mu)g/cm^sup 2^ of TGF-(beta)3, and Group 3 (n=5) received placebo gel. All subjects received standardized wound care as well. Weekly evaluations were performed for efficacy, determined by relative wound surface areas and volumes, and were compared with initial baseline values and safety parameters.

MAIN OUTCOME MEASURE: Reduction in pressure ulcer area and volume.

MAIN RESULTS: Group 2 had a significantly increased rate of wound healing at the fourth visit (P

CONCLUSION: The findings of this study indicate that the topical application of TGF-(beta)3 is safe and useful in the treatment of pressure ulcers and is most effective at the earliest stages of therapy.

ADV SKIN WOUND CARE 2001;14:91-5

The management of pressure ulcers (PUs) is a sizeable clinical problem.1-4 Despite the heightened awareness of health care providers about the risks for PUs and the technologic advances in support systems, the prevalence of Stage III and Stage IV PUs has not declined in recent decades.5-9

Recently, there has been a great deal of interest in biologic agents as potential adjuvants in the treatment of chronic wounds. Clinical trials using plateletderived growth factors (PDGF) have shown success in the treatment of diabetic foot ulcers and PUs.10,11 Encouraging results have been demonstrated in animal studies using transforming growth factor beta (TGF-beta) for diabetic ulcers and poorly vascularized wounds.12-14

TGF-beta is a polypeptide cytokine secreted by a variety of cells involved in wound repair.15,16 It has shown healing efficacy in venous wounds in animals and humans after topical application.17 TGF-(beta)3 is a recombinant form of the TGF human molecule. To date, no studies have evaluated the efficacy of usingTGF-(beta)3 in the treatment of PUs in humans. The present study examined the effectiveness of topical applications of TGF-(beta)3 on PUs in 3 groups of patients.

METHODS

Study design and population

This pilot study represents a subset analysis of the University of Michigan Wound Care Center's data from a larger (270 patients), randomized, blind, parallel, placebo-controlled trial of the safety, efficacy, and tolerability of the topical application of TGF-(beta)3.

To be eligible for the trial, the patient's PU surface area had to be between 15 cm^sup 2^ and 120 cm^sup 2^ and the calcium alginate mold weight had to be 10 grams or more, following debridement at the baseline visit. If more than I full-thickness PU was present, the PU closest to a volume of 40 cm^sup 3^ was designated as the target ulcer. The target ulcer had to have been present for at least 4 weeks. In addition, patients were required to have a serum albumin concentration of 2.5 grams/dL or more. Prior to randomization, debridement of the target ulcer was performed to remove any nonviable tissue. A biopsy confirmed that the target ulcer bed had bacterial counts of less than 10^sup 5^ per gram of tissue and no evidence of beta-hemolytic streptococci or malignancy.

Patients were excluded from the trial if (1) the target ulcer had osteomyelitis, determined by clinical evaluation, X-ray, and/or bone biopsy; (2) the target ulcer's calcium alginate mold weight was 10 grams or less after debridement; (3) topical antibiotics or disinfectants were applied to the target ulcer during cleansing; (4) autolytic or enzymatic debriding agents were used on the target ulcer; or (5) an experimental, nonapproved, or investigational drug was used within the past month or during the trial. Additional exclusion criteria were malignancy at any PU site, administration of systemic corticosteroids of more than 20 mg per day, or administration of other immunosuppressive therapy. Patients whose target ulcer failed to heal with previous cytokine therapy or who had received radiation therapy at the target ulcer site were also excluded from the trial. In addition, women who were pregnant, nursing, or of childbearing age and not using an accepted method of birth control were excluded.

The protocol was approved by the University of Michigan Institutional Review Board; all patients gave written informed consent prior to participating in the study.

Subset analysis was conducted on 14 patients (6 women and 8 men) age 18 years or older who met the inclusion criteria. The patients had between 1 and 3 chronic full-thickness PUs located on the trunk that were Stage III or Stage IV as defined by the National Pressure Ulcer Advisory Pane18,19; the PUs did not have bone exposure.