Wednesday, March 5, 2014
New Drug a Possible Breakthrough for Diabetic Foot Ulcers?
Treatment with polydeoxyribonucleotide (PDRN), an adenosine A2A-receptor agonist, nearly doubled the rate of complete healing of difficult-to-treat Wagner 1 or 2 diabetic foot ulcers compared with placebo, achieved earlier ulcer closure, and resulted in an "impressive" reduction in ulcer area as early as 8 weeks after the start of therapy, a new study indicates.
The results are published online ahead of print in the Journal of Clinical Endocrinology & Metabolism .
Diabetic foot ulcers are a leading cause of hospitalization and readily become chronic, with poor healing, explained lead author Francesco Squadrito, MD, of the University of Messina, Italy. "If ulcers can be prevented, up to 85% of amputations may also be prevented… The opportunity to have a treatment proven effective…is a breakthrough in this field," he told Medscape Medical News.
Emphasizing the wider clinical significance of the study findings, Dr. Squadrito noted that these results suggest "the possibility of a proven effective drug, relatively inexpensive at around $250 for 8 weeks of therapy, with a high safety profile, that can be [used] at home."
Asked to comment, David Armstrong, MD, professor of surgery and director, Southern Arizona Limb Salvage Alliance, University of Arizona College of Medicine, Phoenix, said the new data were rather encouraging.
"It appears, at first evaluation, that delivery of A2A-receptor agonists may result in a higher proportion of…healing than placebo. The use of a combined intramuscular route at home and a 2-day-per-week intralesional administration, likely in the clinic, is rather novel," he observed. "I think I speak for all of us in the field when I say that we look forward to further works that may confirm these initial findings."
However, Andrew Boulton, MD, from the University of Manchester, United Kingdom, and current president of the European Association for the Study of Diabetes (EASD), said that he did not feel the results were a major advance and that a technique called "enforced offloading" would be equally effective.
Other experts said that this does not mean that PDRN does not hold some promise but that future studies will need to ensure that participants receive adequate offloading, the standard of care for such wounds.
Study Details: PDRN Improves Outcomes, Appears Safe
The Italian researchers explain that diabetic foot is the principal cause of hospital admission for people with diabetes in the developed world and presents a high morbidity, often leading to pain, suffering, poor quality of life, and lower-leg amputations. Diabetic foot ulcers readily become chronic, and chronic ulcers have biological properties that differ substantially from acute ones.
In their prospective, randomized, double-blind, placebo-controlled clinical trial, patients from 2 centers in southern Italy with chronic, hard-to-heal diabetic foot ulcers were recruited; half of them received placebo (n = 106) and the remainder PDRN (n = 110).
The researchers ensured that all patients had adequate blood supply to the foot, to avoid the scenario whereby healing differences could be due to poor circulation. Participants were treated by daily intramuscular injection of PDRN (5.625 mg in a 3-mL vial), or placebo, for 5 days of the week and by the perilesional route (5.625 mg in a 3-mL vial), or placebo, for 2 days over a period of 8 weeks. The first perilesional administration was performed by an experienced physician in the hospital setting, and thereafter the subjects (or their caregivers) were carefully instructed to perform the perilesional and intramuscular treatment at home between each visit.
The primary end point was complete ulcer healing; secondary end points were days needed to complete ulcer closure and the reepithelialization of wound surface.
Among patients who completed the 8 weeks of treatment (101 PDRN and 91 placebo), complete ulcer healing was observed in 37.3% of those treated with PDRN compared with 18.9% of those who received placebo (P = .0027).
Closure of foot ulcers was twice as likely in patients on PDRN compared with placebo (hazard ratio, 2.20; P = .004), and the median time to complete wound healing was 30 days for patients on PDRN and 49 days for those on placebo (P = .0027). The median epithelialized area of the ulcers was also significantly greater in the treatment group, at 82.2%, vs 49.3% in patients on placebo (P = .001).
No difference was observed between patient groups in the incidence of serious adverse events, indicating that PDRN is safe, at least in the treatment of diabetic ulcers, say the researchers.
Lack of Adequate Offloading May Have Skewed Results
But many of those polled by Medscape Medical News felt that the results may have been affected by the lack of adequate offloading.
Dr. Boulton said: "The healing rate in the active-treatment group was only 37%. These are predominantly plantar neuropathic lesions that would heal equally well with enforced offloading."
And Lee C. Rogers, DPM, medical director of the Amputation Prevention Center at Sherman Oaks Hospital, Los Angeles, California, agreed that the study failed to provide adequate offloading, the standard of care in such cases."In a clinical trial, these [offloading] devices are typically provided to patients without charge," he observed.
But this critique does not mean PDRN has no potential, he added, rather that future studies would require better adherence to standard of care and adequate offloading. PDRN "has a unique mechanism of action, and the delivery of the drug avoids some of the pitfalls in other diabetic foot ulcer treatments," he pointed out.
Meanwhile, Richard Leigh, DPodM, head of podiatry at the Royal Free Hospital, London, United Kingdom, agreed that problems with offloading might have skewed the results.
He pointed out that there are 4 main reasons for ulcers not to heal — ischemia, infection, necrosis, and pressure/shear force — and that the researchers have gone to some lengths to rule out ischemia (ankle-brachial pressure index and partial pressure O2), clinical infection, and debrided and necrotic tissue in participants. "Therefore, the only remaining reason for diabetic foot ulcer chronicity is pressure."
Dr. Leigh further noted that trial patients were not tested for peripheral symmetrical polyneuropathy, which may have been helpful, because those without pain sensation were more likely to refuse offloading devices due to failure to feel the wound.
"However, it is likely that the participants were neuropathic and were wearing inappropriate (non-offloading) footwear, which is why the wounds became chronic in the first instance and why they probably didn't heal in the trial."
"The easiest way to have conducted the trial would have been to decide on an offloading device that could be used by all participants and exclude patients who did not wear them," he added.
His colleague Janice Tsui, DPodM, also at the Royal Free Hospital, concurred. "I agree…that appropriate offloading is the most important aspect of the treatment of these ulcers, but this is difficult to achieve in all patients," she said. And "the authors have pointed this out and have reported compliance rates of both the treatment and placebo patient groups."
Dr Leigh also spoke to the issue of reepithelialization of the ulcer, which was assessed using a method called Visitrack (Smith & Nephew, London). But this does not assess granulation, and the researchers claim the potential healing ability of PDRN is due to its ability to increase granulating tissue. The latter could have been measured with 3D photography, he noted.
"This suggests that many of these nonhealing wounds were already granulated but not reepithelializing — again, a possible pressure problem. If the researchers wanted to look at PDRN as a stimulator of granulation tissue, they should have excluded participants with Wagner grade 1 ulcers; however, these made up around 70% [of ulcers] in both arms of the study," he observed.
New Therapeutic Approaches Desperately Needed
In response to the comments about offloading, Dr. Squadrito replied that the use of offloading devices was strongly and repeatedly recommended during the study. "However, it is well-known that patients do not easily agree to compliance with these devices. In addition, these hard-to-heal ulcers are quite difficult to treat, and the 37% was an elevated percentage with efficacy far beyond the expectation.
"The offloading procedure and the standardized methods were reinforced across the centers," he added. And since the offloading procedure was recommended also in the placebo group, "a significant drug's effect can be easily acknowledged," he told Medscape Medical News.
Dr. Squadrito also stressed that novel therapeutic approaches are much needed in the treatment of diabetic foot ulcers, which still represent a major issue in people with diabetes. Currently, diabetic foot ulcers are managed with bandages, therapeutic footwear, and hyperbaric chamber treatment, which, he pointed out, was "expensive, has several side effects, and is not available in rural areas."
Indeed, low oxygen levels at the wound site explain why hyperbaric oxygen therapy is effective, he and his colleagues note, and hypoxia is also responsible for the upregulation of adenosine A2A receptors, which make PDRN so effective because it activates adenosine A2A receptors, enhancing, in turn, new blood vessel formation.
So with the exception of hyperbaric oxygen therapy and possibly negative-pressure wound therapy, "there is no scientific evidence, at the highest level, suggesting the use of a more effective therapy," Dr. Squadrito said.
Dr. Tsui agrees: "Diabetic foot ulceration is a significant health issue and a challenge to manage. Wound-healing studies are difficult to do, but the authors have used a range of outcome measures to show the potential efficacy of PDRN. This is a well-designed study and despite the limitations…which the authors have discussed….the improvement in all the outcome measures in the PDRN group suggests this treatment deserves further investigation."
And, she added, "I would be interested to see if PDRN treatment may benefit patients with a degree of underlying vascular insufficiency not easily amenable to revascularization, as this group of patients has poorer outcomes."
Dr. Squadrito said the next step will be a phase 4 study involving more centers in Italy and possibly the European registration of the product to make PDRN in diabetic foot ulcer more widely available. PDRN is the active fraction of a preparation used in Italy as a tissue repair and stimulating agent and is extracted from the sperm of trout bred for feeding purposes, he and his colleagues explain. The manufacturer (Placentex, Mastelli, Sanremo, Italy) has filed a request for claims on ulcer healing, Dr. Squadrito added.
The researchers are also planning another randomized controlled trial involving patients with ulcers of grade 3 to 5. This study will compare the efficacy and safety of PDRN with hyperbaric oxygen therapy.
Drs. Squadrito, Armstrong, Boulton, Rogers, Leigh, and Tsui have reported no relevant financial relationships.
J Clin Endocrinol Metab. Published online January 31, 2014. Abstract