Enhancing Patient Centricity and Advancing Innovation in Clinical Research with Virtual Randomized Clinical Trials (vRCTs).

The current public health crisis has highlighted the need to accelerate healthcare innovation. Despite unwavering levels of cooperation among academia, industry, and policy makers, it can still take years to bring a life-saving product to market. There are some obvious limitations, including lack of blinding or masking and small sample size, which render the results less applicable to the real world. Traditional randomized controlled trials (RCTs) are lengthy, expensive, and have a low success rate. There is a growing acknowledgement that the current process no longer fully meets the growing healthcare needs. Advances in technology coupled with proliferation of telehealth modalities, sensors, wearable and connected devices have paved the way for a new paradigm. Virtual randomized controlled trials (vRCTs) have the potential to drastically shorten the clinical trial cycle while maximizing patient-centricity, compliance, and recruitment. This new approach can inform clinical trials in real time and with a holistic view of a patient's health. This paper provides an overview of virtual clinical trials, addressing critical issues, including regulatory compliance, data security, privacy, and ownership.

Real-time bacterial fluorescence imaging accurately identifies wounds with moderate-to-heavy bacterial burden.

OBJECTIVE: Clinical evaluation of signs and symptoms (CSS) of infection is imperative to the diagnostic process. However, patients with heavily colonised and infected wounds are often asymptomatic, leading to poor diagnostic accuracy. Point-of-care fluorescence imaging rapidly provides information on the presence and location of bacteria. This clinical trial (#NCT03540004) aimed to evaluate diagnostic accuracy when bacterial fluorescence imaging was used in combination with CSS for identifying wounds with moderate-to-heavy bacterial loads. METHODS: Wounds were assessed by study clinicians using NERDS and STONEES CSS criteria to determine the presence or absence of moderate-to-heavy bacterial loads, after which the clinician prescribed and reported a detailed treatment plan. Only then were fluorescence images of the wound acquired, bacterial fluorescence determined to be present or absent and treatment plan adjusted if necessary. RESULTS: We examined 17 VLUs/2 DFUs. Compared with CSS alone, use of bacterial fluorescence imaging in combination with CSS significantly improved sensitivity (22% versus 72%) and accuracy (26% versus 74%) for identifying wounds with moderate-to-heavy bacterial loads (≥104 CFU/g, p=0.002). Clinicians reported added value of fluorescence images in >90% of study wounds, including identification of wounds incorrectly diagnosed by CSS (47% of study wounds) and treatment plan modifications guided by fluorescence (73% of study wounds). Modifications included image-guided cleaning, treatment selection, debridement and antimicrobial stewardship. CONCLUSION: Findings from this pilot study suggest that when used in combination with CSS, bacterial fluorescence may: (1) improve the diagnostic accuracy of identifying patients with wounds containing moderate-to-heavy bacterial loads and (2) guide more timely and appropriate treatment decisions at the point-of-care.

A Post-marketing Surveillance Study of Chronic Wounds Treated With a Native Collagen Calcium Alginate Dressing.

Chronic wounds (ie, wounds that fail to progress through a normal, orderly, timely sequence of repair) continue to pose significant clinical and economic burdens. A prospective, descriptive, 3-week post-marketing surveillance study was conducted across 3 wound care centers in the United States to evaluate the effectiveness of a collagen calcium alginate dressing on chronic wounds in conjunction with standard care (SC) practices (eg, offloading, debridement, compression) to support healing. Eligible participants had to be >18 years of age, have at least 1 chronic wound, and no known sensitivity to collagen. Demographic characteristics were recorded at the screening visit on case report forms. At each visit, wound-related pain was assessed using the Visual Analog Scale along with wound characteristics including size (using digital planimetry), wound exudate (minimal, moderate, heavy), and odor (none, mild). Participants were monitored for adverse events as well as infection based on signs and symptoms in and around the local wound bed, the deeper structures, and the surrounding skin. An intention-to-treat approach was used for all analyses. If an observation was missing, the last observation carried forward principle was used. For wounds that healed, pain and exudate were set to 0 (no pain/exudate) at visit 4. Descriptive, paired t tests and the Wilcoxon signed rank test were used to analyze the data. Of the 31 participants (15 men, 16 women, mean age 66.6 years), most (13, 42%) had a diabetic foot ulcer or venous leg ulcer (10, 32%); median duration of all wounds was 148 days. Thirty (30) patients completed the study. The mean number of comorbidities was 10.6 ± 6.3, and patients used a mean of 9.3 ± 5.64 prescription or over-the-counter medications. For all wounds combined, mean wound area was 4.8 ± 8.38 cm2 at baseline. At week 3, a decrease in wound area of 38.1% was noted (median: 45% ± 42.54; P = .006); 3 wounds healed completely. The change in wound exudate level from visit 1 to visit 4 was statistically significant (P = .006). No adverse events or infections occurred. In this population, the use of etiology-appropriate SC and a collagen calcium alginate dressing resulted in a decrease in wound area after 3 weeks of care. Longer-term studies to confirm these observations and controlled clinical studies to compare the effects of this dressing to other nongauze dressing treatments are needed.

Randomized Controlled Trial Comparing Collagen/Oxidized Regenerated Cellulose/Silver to Standard of Care in the Management of Venous Leg Ulcers.

OBJECTIVE: To assess healing outcomes in venous leg ulcers (VLUs) treated with a combination of collagen, oxidized regenerated cellulose, and silver in conjunction with standard of care (SOC; intervention group) compared with SOC alone (control group). Standard of care included ADAPTIC nonadhering dressing (Acelity, San Antonio, Texas) and compression. DESIGN AND SETTING: Randomized controlled trial that followed patients in 3 US facilities for 12 weeks or until complete healing. PATIENTS AND INTERVENTION: Forty-nine patients with VLUs were randomized to either the intervention group (n = 22) or the control group (n = 27). MAIN OUTCOME MEASURE: Wound healing over 12 weeks. MAIN RESULTS: Intent-to-treat analysis showed a mean percentage wound area reduction at 12 weeks of 85.6% (SD, 28.6%) for the intervention group and 72.5% (SD, 77.8%) for the control group. There was a higher healing rate in the intervention group compared with patients who received SOC only at both week 4 (23% vs 11%) and week 12 (64% vs 59%). There were no adverse events related to the study therapy. CONCLUSIONS: Although the results were not significant, there was a trend toward faster healing in the intervention group. The results of this study indicate that collagen/oxidized regenerated cellulose/silver is a suitable and safe adjunctive intervention for use with SOC to manage VLUs.

A new approach to clinical research: Integrating clinical care, quality reporting, and research using a wound care network-based learning healthcare system.

The disparity between ideal evidence from randomized controlled trials and real-world evidence in medical research has prompted the United States Food and Drug Administration to consider the use of real-world data to better understand safety and effectiveness of new devices for a broader patient population and to prioritize real-world data in regulatory decision making. As the healthcare system transitions from volume- to value-based care, there is a growing need to harness the power of real-world data to change the paradigm for wound care clinical research and enable more generalizable clinical trials. This paper describes the implementation of a network-based learning healthcare system by a for-profit consortium of wound care clinics that integrates wound care management, quality improvement, and comparative effectiveness research, by harnessing structured real-world data within a purpose-built electronic health record at the point of care. Centers participating in the consortium submit their clinical data and quality measures to a qualified clinical data registry for wound care, enabling benchmarking of their data across this national network. The common definitional framework of the purpose-built electronic health record and the 21 wound-specific quality measures help to standardize the potential sources of bias in real-world data, making the consortium data useful for comparative effectiveness research. This consortium can transform wound care clinical research and raise the standards of care, while helping physicians achieve success with the Merit-Based Incentive Payment System.

Defining a new diagnostic assessment parameter for wound care: Elevated protease activity, an indicator of nonhealing, for targeted protease-modulating treatment.

It is widely accepted that elevated protease activity (EPA) in chronic wounds impedes healing. However, little progress has occurred in quantifying the level of protease activity that is detrimental for healing. The aim of this study was to determine the relationship between inflammatory protease activity and wound healing status, and to establish the level of EPA above which human neutrophil-derived elastase (HNE) and matrix metalloproteases (MMP) activities correlate with nonhealing wounds. Chronic wound swab samples (n = 290) were collected from four wound centers across the USA to measure HNE and MMP activity. Healing status was determined according to percentage reduction in wound area over the previous 2-4 weeks; this was available for 211 wounds. Association between protease activity and nonhealing wounds was determined by receiver operating characteristic analysis (ROC), a statistical technique used for visualizing and analyzing the performance of diagnostic tests. ROC analysis showed that area under the curve (AUC) for HNE were 0.69 for all wounds and 0.78 for wounds with the most reliable wound trajectory information, respectively. For MMP, the corresponding AUC values were 0.70 and 0.82. Analysis suggested that chronic wounds having values of HNE >5 and/or MMP ≥13, should be considered wound healing impaired. EPA is indicative of nonhealing wounds. Use of a diagnostic test to detect EPA in clinical practice could enable clinicians to identify wounds that are nonhealing, thus enabling targeted treatment with protease modulating therapies.

Use of a fluorescence angiography system in assessment of lower extremity ulcers in patients with peripheral arterial disease: A review and a look forward.

The prevalence of chronic wounds is sharply rising throughout the world due to an aging population and increases in the incidence of obesity, diabetes, and cardiovascular diseases. People with diabetes, hypertension, and hyperlipidemia are at increased risk for developing peripheral arterial disease (PAD). PAD affects 8 to 12 million people over the age of 40 years in the United States and it is a major contributing factor to the development of lower extremity ulcers. Although a number of noninvasive diagnostic tests are available to detect PAD in lower extremities, they have several clinical limitations. In this review, current understanding of the pathophysiology of commonly seen lower extremity ulcers is described and vascular assessments typically used in practice are evaluated. In addition, application of the LUNA Fluorescence Angiography System (Novadaq, Bonita Springs, FL) for the screening and treatment of complex nonhealing wounds in patients with PAD is discussed.