Cellular Versus Acellular Grafts for Diabetic Foot Ulcers: Altering the Protocol to Improve Recruitment to a Comparative Efficacy Trial
Diabetic foot ulcers (DFUs) have a substantial impact on public health. The standard of care (SOC) for DFUs consists of a multidisciplinary approach involving glycemic control, wound care with debridement of necrotic tissue, application of a moist dressing, infection control, use of off-loading devices, and patient education. New therapeutic devices aim to target the extracellular matrix (ECM) that is impaired in DFU; however, there is insufficient data on the effectiveness of such therapies along with lack of evidence on their long-term effectiveness. We hypothesized that there is no difference in healing between the cellular matrix and an acellular matrix relative to SOC. To test this hypothesis, we conducted a randomized, single-blind clinical trial in patients with nonhealing DFUs that included 3 treatment arms: (1) SOC, (2) SOC plus a bioengineered ECM with living fibroblasts, and (3) SOC plus a bioengineered ECM devoid of cells. Our trial currently is closed for enrollment, as we have reached our target population size. Amendments to the protocol were made to help reach this threshold.
Resident Pearl
- Deciding on the appropriate wound care regimen for diabetic foot ulcers is difficult given the vast amount of wound products on the market. This head-to-head clinical trial compared the use of an expensive cellular matrix and an inexpensive acellular matrix relative to the standard of care. We hope that this study will help to guide therapy based on cost-effectiveness of wound adjuncts without compromising patient care.
Results
Study Protocol Amendments
Given the number of diabetic patients in the US veteran population, we anticipated that there would be enough participants meeting the inclusion and exclusion criteria; however, because of the difficulty with recruitment, the initial study criteria were modified. The study was initially designed to incorporate DFUs with a minimum size of 1.0 cm2.12
Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A1C (HbA1C). The study was originally established to include participants with an HbA1C level of 10% of total hemoglobin or below.12 Unfortunately, the majority of the potential participants had values substantially higher, and thus could not be enrolled in the trial, requiring another amendment to the study protocol in 2014, which was approved to include patients with an HbA1C level less than 12% of total hemoglobin. This change contributed considerably to the noted increase in enrollment rates in 2015, which almost doubled relative to enrollment under the original exclusion criteria (Figure).
The study has screened more than 600 patients. Among them, 137 were assessed for eligibility; 71 were excluded for various reasons, including screen failure (eg, decrease in wound size by >40% during the 2-week screening phase), loss to follow-up, and adverse events. Sixty-six participants reached the primary outcome at week 12, while 55 participants completed the study (19 in the SOC group; 18 in the cellular matrix group; 18 in the acellular matrix group).
,We have stopped enrolling patients from all sites and the community, as we have reached our target enrollment.
Comment
One of the challenges of clinical trials is the recruitment of an adequate number of participants within an appropriate time frame, which is explained by Lasagna’s Law,18 a well-described phenomenon whereby the investigator overestimates the number of potential participants available to meet the inclusion criteria. This so-called funnel-effect was partly encountered in our selection process. A review of the veteran population with DFUs seemed to be more than adequate to fulfill the sample size; however, some important participant-related factors also played a substantial role.
In addition, the Veterans’ Affairs network centralizes health information, making it readily available to all providers participating in their care. As a result, patients with diabetes mellitus typically are seen by a primary care physician along with an endocrinologist, a diabetic nurse, and/or a dietician. Despite the collaboration with an interdisciplinary team, the glycemic control of the participants remains an issue along with other psychosocial factors that are deterrents in patient compliance. As a result, patients with poorly controlled diabetes and an HbA1C level above 10% (and less than 12%) of total hemoglobin who were initially excluded from the study were reincluded after modifying the inclusion criteria. Some patients were interested in joining the study, but physical limitations (eg, impaired mobility) prompted their decision not to join the trial, even though they met all the inclusion criteria.
As far as research-related factors that could affect participation, it is notable that most of the patients were retired; thus, the interventions did not cause additional burden of taking time off from work or loss of productivity. Although randomization could be a deterrent in many clinical trials, the majority of patients were willing to participate without demanding to be assigned to a particular treatment group.
There are many factors that are intertwined and can lead to enrollment and/or attrition rates. It was critical for our team to make some adjustment without compromising the controlled nature of a randomized trial.
Acknowledgment
The authors wish to acknowledge Huong Le, DPM, MPH, who was the coauthor of the study protocol.
