Efficacy and Safety of Recombinant Human Platelet-Derived Growth Factor-BB (Becaplermin) in Patients with Chronic Venous Ulcers

Introduction The exact prevalence of venous ulcers is unknown, but estimates from the United States suggest that between 600,000 and 2.5 million individuals in the US suffer from these chronic, debilitating wounds,[1] while estimates indicate that between 0.15 percent and 1 percent of the European population suffer from this condition.[2,3] Thus, venous ulceration represents a common problem, particularly in the elderly population.[4] Venous ulcers are associated with a significant disease burden, as these ulcers are painful, are difficult to heal, and recur frequently. Current treatments range from compression therapy with stockings and bandages (to improve venous circulation) to skin grafting (to accelerate healing) and surgery to correct the underlying cause of venous insufficiency. Therefore, treatment strategies for venous ulcers are associated with substantial medical costs.[1] The indirect costs of venous ulceration can be substantial as well: an estimated two million work days are lost each year in the US because of leg ulcers.[5] Although the etiology of venous ulceration is unclear, it has been suggested that ulceration results from increased intraluminal pressure in the capillaries, which in turn results in the deposition of fibrin around the capillaries.[1,6] Subsequently, white blood cells (WBCs) become activated and release proteolytic enzymes, which may cause further tissue destruction. According to the “trap” hypothesis, which is another proposed mechanism, fibrin and other macromolecules eventually leak into the dermis where they bind to growth factors, making them unavailable for the tissue repair process.[6] This hypothesis suggests a potential role for topically applied growth factors in the treatment of venous ulcers. Platelet-derived growth factor (PDGF) plays an important role in the initiation and regulation of the healing process. Specifically, PDGF promotes the chemotactic recruitment and proliferation of cells involved in all stages of wound repair and enhances the formation of granulation tissue.[7] Recombinant human PDGF-BB (rhPDGF-BB) has activity similar to that of endogenous PDGF and has been shown to increase the incidence of complete healing of chronic wounds (i.e., diabetic foot ulcers and pressure ulcers) in several clinical studies.[8–12] Taken together, these findings suggest that rhPDGF-BB may be of benefit in patients with venous ulcers as well. This paper describes the results of two pilot studies conducted to evaluate the efficacy and safety of topically applied becaplermin gel (rhPDGF-BB; Regranex® 0.01%, Johnson & Johnson Wound Management Worldwide, Somerville, New Jersey) in patients with chronic, full-thickness, venous stasis leg ulcers. Methods This section describes the methods common to both studies with between-study differences noted where appropriate (i.e., the frequency of study medication administration and the type of compression therapy used). Study population. Men and women greater than or equal to 18 years of age with at least one chronic (i.e., greater than or equal to 4 wks to less than or equal to 3 yrs duration) full-thickness venous ulcer located on the gaiter area of the leg were eligible to participate in the study. Ulcer area was required to be between 2cm2 and 20cm2 postdebridement, as estimated by measurements of length and width. Venous etiology had to be proven, and deep vein thrombosis was ruled out by Doppler and/or Duplex scan. To exclude arterial insufficiency, the ankle/brachial index had to be greater than or equal to 0.8 on the target limb. Any infection of the target ulcer had to be well controlled with no evidence of necrotic or infected tissue or bone exposure after debridement. To ensure adequate nutritional status, patients were required to have serum albumin levels greater than or equal to 3.0g/dL. Finally, patients with diabetes had to have glycosylated hemoglobin (HbA1c) levels less than or equal to 9.9 percent. Patients were excluded from the study if they had more than two ulcers on the target limb or if the target ulcer was the result of electrical, chemical, or radiation burn insult, including patients with a history of radiation therapy where the field of treatment had included the target ulcer. The presence of osteomyelitis, active malignant disease of any kind, uncontrolled heart failure, or renal insufficiency (defined as serum creatinine greater than or equal to 3mg/dL) was reason for exclusion, as was the presence of any preexisting conditions or diseases that could interfere with the evaluation of becaplermin gel treatment. Women who were pregnant or nursing were not allowed to participate in the study, and all women of childbearing potential had to be using an acceptable method of birth control. The use of topical antibiotics, antiseptics, or other agents that might affect evaluation of the study medication within days prior to randomization was reason for exclusion from the study. Likewise, the use of systemic corticosteroids, the use of immunosuppressive or antineoplastic agents within 30 days prior to randomization, or the use of enzymatic debriding agents within seven days prior to randomization was not allowed. Both studies were conducted in accordance with the recommendations for ethical conduct outlined in the Declaration of Helsinki, and all patients provided written, informed consent prior to study participation. Study design. Patients enrolled in these multicenter, randomized, double-blind, placebo-controlled studies were treated with becaplermin gel 100mg/g or placebo gel for a maximum of 16 weeks or until ulcers were completely healed, whichever came first. Study medication was supplied in multi-use tubes and applied to the ulcers daily (in Study 1) or twice weekly (Study 2) in an amount sufficient to form a continuous thin layer that was approximately the thickness of a dime (1mm), and the ulcers were covered with nonadherent dressing (Adaptic®, Johnson & Johnson Wound Management Worldwide or Telfa®, The Kendall Company, Mansfield, Massachusetts) with or without gauze (Kerlix®, The Kendall Company). In addition, all patients received a standardized regimen of good wound care that included sharp debridement to remove all infected and necrotic tissue, compression therapy (30–40mmHg), and systemic treatment of infection, if present. Of note, different types of compression therapy were used in each study. Knee-high compression stockings were used in Study 1, while Study 2 employed either multilayer bandages, a multilayer compression system (Dyna-Flex,® Johnson & Johnson Wound Management Worldwide, Somerville, New Jersey), or a dry boot. These latter methods were selected based on their equivalent compression abilities and lack of ease for the patients to remove (unlike the compression stockings used in Study 1). At each study visit, measurements of the target ulcer size were made post-debridement, both by measuring length and width and by planimetry using acetate tracings. The primary efficacy endpoint was the incidence of complete healing. Secondary efficacy endpoints included time to healing and relative ulcer area at endpoint. Wound status was also assessed during the study using total wound evaluation score, which was a composite of six wound parameters (periwound erythema, periwound edema, purulence, necrotic tissue, fibrin, and serous drainage); each parameter was rated as absent, mild, moderate, or marked. Safety evaluations included the incidence of adverse events, changes from baseline in physical examination and laboratory findings, and determination of anti-PDGF antibodies. Statistical methods. The primary efficacy variable was the incidence of complete healing, as measured by a functional assessment score of 1 (defined as complete epithelization without drainage or scab) at study completion. The proportion of subjects with complete ulcer healing at endpoint was analyzed using a conditional logistic regression model, controlling for center and including terms for treatment group, baseline ulcer area, and treatment by baseline ulcer area. In Study 2, the treatment by baseline interaction was not significant, so it was excluded from the model. All hypothesis testing was two-sided. The main effects were tested at the 0.05 significance level; interaction was tested at the 0.01 level. Centers with insufficient enrollment (i.e., Efficacy results. In both studies, a greater percentage of patients treated with becaplermin achieved complete healing compared with that in the placebo-treated group, although not to a statistically significant degree. Further analysis showed that baseline ulcer size was probably an important covariate: the difference in the rate of complete healing between becaplermin and placebo treatment appeared to be larger in patients with ulcers greater than or equal to 5cm2. Ulcer duration also appeared to have an effect on healing with a trend toward improved healing observed in patients with ulcers of longer duration. The incidence of complete healing in the intent-to-treat populations of both studies is shown in Figure 1. In Study 1, complete healing of the target ulcer occurred in 36 percent (12/33) of patients treated with once-daily application of becaplermin gel compared with 34 percent (12/35) of patients treated with placebo gel (95% confidence interval: -0.21, 0.25). In Study 2, complete healing of the target ulcer was noted in 56 percent (18/32) of patients treated with twice-weekly application of becaplermin gel compared with 44 percent (14/32) of patients treated with placebo gel, an absolute difference of 12 percent (95% confidence interval: -0.12, 0.37). The benefits of becaplermin gel treatment were more apparent in patients with larger ulcers (Figure 2). When the incidence of complete healing was examined in patients with ulcers greater than or equal to 5cm2 at baseline in Study 1, complete healing was achieved in 46 percent (6/13) of patients treated with becaplermin gel compared with seven percent (1/15) of patients treated with placebo gel, an absolute difference of 39 percent (95% confidence interval: 0.10, 0.69). Similar results were observed in Study 2: in the subgroup of patients with ulcers greater than or equal to 5cm2 at baseline, the incidence of complete healing was 38 percent (5/13) in patients receiving becaplermin gel compared with 23 percent (3/13) of patients treated with placebo gel, for an absolute difference of 15 percent (95% confidence interval: -0.20, 0.50). The time to complete healing was also analyzed; however, no significant differences between treatment groups were observed (Figure 3). In Study 1, the Kaplan-Meier estimates of time to complete healing (25% quantile) were 92 days in patients treated with becaplermin gel and 80 days in those treated with placebo gel. In Study 2, the time to complete healing was 45 days in becaplermin-treated patients and 57 days in placebo-treated patients. Safety results. In Study 1, the percentage of patients who experienced at least one treatment-emergent, wound-related adverse event was 31 percent (11/35) in patients receiving becaplermin gel compared with 39 percent (14/36) in patients treated with placebo. In Study 2, these percentages were 53 percent (17/32) and 34 percent (11/32), respectively. The incidence of treatment-emergent, wound-related adverse events was generally similar for both treatment groups in both studies; slightly higher proportions of placebo-treated patients experienced infection (Study 1) and erythematous rash (Study 2) than did those treated with becaplermin gel. Conversely, infection was more common in becaplermin-treated patients in Study 2. A full listing of the incidence of treatment-emergent, wound-related adverse events occurring in greater than or equal to 5 percent of patients in each study is provided in Table 2. Few serious adverse events (i.e., those requiring additional treatment or hospitalization) were noted in the studies. In Study 1, no infection-related or target ulcer-associated serious adverse events occurred in patients treated with becaplermin gel. However, two patients (6%) receiving placebo experienced serious adverse events that were infection related and associated with the target ulcer (infection and cellulitis, respectively). In Study 2, three becaplermin-treated patients (9%) experienced serious target ulcer and infection-related adverse events (cellulitis, infection, and worsening ulcer condition, respectively) compared with one patient (3%) in the placebo group (infection). No deaths occurred in either study. Other clinically significant adverse events included the incidence of application site reactions and neoplasms. One application site reaction and one neoplasm (both in patients receiving placebo) occurred in Study 1, while no application site reactions and three neoplasms (2 in the placebo group, 1 in the becaplermin group) were observed in Study 2. The single event described as a neoplasm in the becaplermin-treated patient was hypertrophic granulation of the target ulcer. Treatment was continued without interruption, and the event resolved after sharp debridement of the ulcer. Ulcer recurrence was measured in both studies for a maximum follow-up period of 12 weeks. In Study 1, none of the placebo-treated patients whose ulcers had healed experienced recurrences, while one patient (8%) in the becaplermin group experienced a recurrence. In Study 2, the percentage of patients whose ulcers recurred was similar (33% in the becaplermin group vs. 29 percent in the placebo group). Physical examination and laboratory findings were comparable between groups in both studies. In addition, serum samples (drawn at baseline and upon study withdrawal or completion) from 58 patients in each study were analyzed for the presence of antibecaplermin antibodies using an enzyme-linked immunosorbent assay (ELISA), and there was no evidence of antibodies to becaplermin in any of the samples from either study. Discussion In both studies, complete ulcer healing was observed in a slightly larger percentage of patients treated with becaplermin gel than in those treated with placebo, although not to a statistically significant degree. Separation between treatment groups was greatest in Study 2, where 56 percent of patients treated with becaplermin gel 100mg/g twice weekly achieved complete healing, compared with 44 percent of those treated with placebo. The incidence of adverse events was generally similar between treatment groups in both studies, with slightly higher proportions of placebo-treated patients experiencing infection (Study 1) and erythematous rash (Study 2) and slightly more becaplermin-treated patients experiencing infection in Study 2. Taken together, these results suggest that becaplermin gel 100mg/g, in conjunction with good wound care that includes compression therapy at 30 to 40mmHg, is probably safe and may be beneficial in the treatment of patients with chronic venous leg ulcers, whether used daily or twice weekly. The slightly greater incidence of complete healing observed in Study 2 may indicate that the type of compression therapy used affects efficacy. This may be attributed in part to enhanced compliance with the compression method used in Study 2, as the compression wraps could not be removed by the patient and thus were worn 24 hours a day. In contrast, Study 1 utilized compression stockings, which were removed nightly by the patient. Only patients who slept lying flat were enrolled in Study 1, as body position was more important because of the absence of compression therapy at night. However, there is no information to confirm that this was the case, nor is it known how early in the day patients removed the stockings or whether they were fully compliant with placing them on each morning. Several factors may have contributed to the lack of conclusive results seen in these studies. First and foremost, both studies were designed as small pilot trials and were not powered for statistical significance. Second, becaplermin gel appeared to be of more benefit in patients with ulcers greater than or equal to 5cm2. However, less than half of the study populations had ulcers of this magnitude, making it difficult to draw meaningful conclusions. Therefore, it may be helpful to evaluate the use of becaplermin gel in patients with larger ulcers in the future. These findings have several implications for the design of future studies. First, these study results will allow the determination of an adequate sample size to demonstrate statistical significance. Second, because twice-weekly application appears to provide greater benefit than daily treatment and the use of the multilayer compression system appears to be a more effective method than compression stockings, methods chosen for use in future studies should reflect these findings. However, it is important to note that both factors may have contributed to the better outcomes observed in Study 2. In conclusion, becaplermin gel appears safe and well tolerated and may be beneficial in the treatment of patients with chronic venous ulcers. Although these studies were not powered for statistical significance, these encouraging results warrant further clinical investigation using appropriate study designs.