Catherine N. Tchanque-Fossuo, MD, MS

Guidelines on Skin Cancer Surgeries During the COVID-19 Pandemic

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention issued recommendations to decrease the spread of SARS-CoV-2 and optimize the use of personal protective equipment (PPE) for frontline workers.¹ In the field of dermatologic surgery, the American College of Mohs Surgery, the National Comprehensive Cancer Network, the American Society for Dermatologic Surgery, and the American Academy of Dermatology made recommendations to postpone nonessential and nonurgent procedures.^2-4 The initial guidelines of the American College of Mohs Surgery advised cancellation of all elective surgeries and deferred treatment of most cases of basal cell carcinoma for as long as 3 months; low-risk squamous cell carcinoma (SCC) and melanoma in situ treatment was deferred for as long as 2 or 3 months.³ Additional recommendations were made to reserve inpatient visits for suspicious lesions and high-risk cancers, postpone other nonessential and nonurgent appointments, and utilize telemedicine whenever possible.⁵

These recommendations led to great uncertainty and stress for patients and providers. Although numerous important variables, such as patient risk factors, severity of disease, availability of PPE and staff, and patient-to-provider transmission were considered when creating these guidelines, the patient’s experience likely was not a contributing factor.

COVID-19 Transmission During Mohs Surgery

There have been concerns that surgeons performing Mohs micrographic surgery (MMS) might be at an increased risk for COVID-19, given their close contact with high-risk sites (ie, nose, mouth) and cautery-generated aerosols; most of the estimated transmission risk associated with MMS has been based on head and neck surgery experience and publications.^6-8 Tee and colleagues⁹ recently published their institution’s MMS COVID-19 preventive measures, which, to their knowledge, have prevented all intraoperative transmission of SARS-CoV-2, even in disease-positive patients. Currently, evidence is lacking to support a high risk for SARS-CoV-2 transmission during MMS when proper PPE and personal hygiene measures as well as strict infection control protocols—presurgical COVID-19 testing in high-risk cases, COVID-19 screening optimization, visitor restrictions, and appropriate disinfection between patients—are in place.

The Impact of Postponing Treatment on Patients

Although studies have focused on the effects of the COVID-19 pandemic on physicians practicing MMS,¹⁰ little is known about the effects of delays in skin cancer treatment on patients. A survey conducted in the United Kingdom investigating the patient’s perspective found that patients expressed worry and concern about the possibility that their MMS would be postponed and greatly appreciated continuation of treatment during the pandemic.¹¹

Other medical specialties have reported their patient experiences during the pandemic. In a study examining patient perception of postponed surgical treatment of pelvic floor disorders due to COVID-19, nearly half of survey respondents were unhappy with the delay in receiving care. Furthermore, patients who reported being unhappy were more likely to report feelings of isolation and anxiety because their surgery was postponed.¹² In another study involving patients with lung cancer, 9.1% (N=15) of patients postponed their treatment during the COVID-19 pandemic because of pandemic-related anxiety.¹³

With the goal of improving care at our institution, we conducted a brief institutional review board–approved survey to evaluate how postponing MMS treatment due to the COVID-19 pandemic affected patients. All MMS patients undergoing surgery in June 2020 and July 2020 (N=99) were asked to complete our voluntary and anonymous 23-question survey in person during their procedure. We obtained 88 responses (response rate, 89%). Twenty percent of surveyed patients (n=18) reported that their MMS had been postponed; 78% of those whose MMS was postponed (n=14) indicated some level of anxiety during the waiting period. It was unclear which patients had their treatment postponed based on national guidelines and which ones elected to postpone surgery.

Tips for Health Care Providers

Patient-provider communication highlighting specific skin cancer risk and the risk vs benefit of postponing treatment might reduce anxiety and stress during the waiting period.¹⁴ A study found that COVID-19 posed a bigger threat than most noninvasive skin cancers; therefore, the authors of that study concluded that treatment for most skin cancers could be safely postponed.¹⁵ Specifically, those authors recommended prioritizing treatment for Merkel cell carcinoma, invasive SCC, and melanoma with positive margins or macroscopic residual disease. They proposed that all other skin cancers, including basal cell carcinoma, SCC in situ, and melanoma with negative margins and no macroscopic residual disease, could be safely delayed for as long as 3 months.¹⁵

For patients with multiple risk factors for COVID-19–related morbidity or mortality, delaying skin cancer treatment likely has less risk than contracting the virus.¹⁵ This information should be communicated with patients. Investigation of specific patient concerns is warranted, and case-by-case evaluation of patients’ risk factors and skin cancer risk should be considered.

Based on the current, though limited, literature, delaying medical treatment can have a negative impact on the patient experience. Furthermore, proper precautions have been shown to limit intraoperative transmission of SARS-CoV-2 during MMS, but research is lacking. Practitioners should utilize shared decision-making and evaluate a given patient’s risk factors and concerns when deciding whether to postpone treatment. We encourage other institutions to evaluate the effects that delaying MMS has had on their patients, as further studies would improve understanding of patients’ experiences during a pandemic and potentially influence future dermatology guidelines.

Guidelines on Skin Cancer Surgeries During the COVID-19 Pandemic

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention issued recommendations to decrease the spread of SARS-CoV-2 and optimize the use of personal protective equipment (PPE) for frontline workers.¹ In the field of dermatologic surgery, the American College of Mohs Surgery, the National Comprehensive Cancer Network, the American Society for Dermatologic Surgery, and the American Academy of Dermatology made recommendations to postpone nonessential and nonurgent procedures.^2-4 The initial guidelines of the American College of Mohs Surgery advised cancellation of all elective surgeries and deferred treatment of most cases of basal cell carcinoma for as long as 3 months; low-risk squamous cell carcinoma (SCC) and melanoma in situ treatment was deferred for as long as 2 or 3 months.³ Additional recommendations were made to reserve inpatient visits for suspicious lesions and high-risk cancers, postpone other nonessential and nonurgent appointments, and utilize telemedicine whenever possible.⁵

These recommendations led to great uncertainty and stress for patients and providers. Although numerous important variables, such as patient risk factors, severity of disease, availability of PPE and staff, and patient-to-provider transmission were considered when creating these guidelines, the patient’s experience likely was not a contributing factor.

COVID-19 Transmission During Mohs Surgery

There have been concerns that surgeons performing Mohs micrographic surgery (MMS) might be at an increased risk for COVID-19, given their close contact with high-risk sites (ie, nose, mouth) and cautery-generated aerosols; most of the estimated transmission risk associated with MMS has been based on head and neck surgery experience and publications.^6-8 Tee and colleagues⁹ recently published their institution’s MMS COVID-19 preventive measures, which, to their knowledge, have prevented all intraoperative transmission of SARS-CoV-2, even in disease-positive patients. Currently, evidence is lacking to support a high risk for SARS-CoV-2 transmission during MMS when proper PPE and personal hygiene measures as well as strict infection control protocols—presurgical COVID-19 testing in high-risk cases, COVID-19 screening optimization, visitor restrictions, and appropriate disinfection between patients—are in place.

The Impact of Postponing Treatment on Patients

Although studies have focused on the effects of the COVID-19 pandemic on physicians practicing MMS,¹⁰ little is known about the effects of delays in skin cancer treatment on patients. A survey conducted in the United Kingdom investigating the patient’s perspective found that patients expressed worry and concern about the possibility that their MMS would be postponed and greatly appreciated continuation of treatment during the pandemic.¹¹

Other medical specialties have reported their patient experiences during the pandemic. In a study examining patient perception of postponed surgical treatment of pelvic floor disorders due to COVID-19, nearly half of survey respondents were unhappy with the delay in receiving care. Furthermore, patients who reported being unhappy were more likely to report feelings of isolation and anxiety because their surgery was postponed.¹² In another study involving patients with lung cancer, 9.1% (N=15) of patients postponed their treatment during the COVID-19 pandemic because of pandemic-related anxiety.¹³

With the goal of improving care at our institution, we conducted a brief institutional review board–approved survey to evaluate how postponing MMS treatment due to the COVID-19 pandemic affected patients. All MMS patients undergoing surgery in June 2020 and July 2020 (N=99) were asked to complete our voluntary and anonymous 23-question survey in person during their procedure. We obtained 88 responses (response rate, 89%). Twenty percent of surveyed patients (n=18) reported that their MMS had been postponed; 78% of those whose MMS was postponed (n=14) indicated some level of anxiety during the waiting period. It was unclear which patients had their treatment postponed based on national guidelines and which ones elected to postpone surgery.

Tips for Health Care Providers

Patient-provider communication highlighting specific skin cancer risk and the risk vs benefit of postponing treatment might reduce anxiety and stress during the waiting period.¹⁴ A study found that COVID-19 posed a bigger threat than most noninvasive skin cancers; therefore, the authors of that study concluded that treatment for most skin cancers could be safely postponed.¹⁵ Specifically, those authors recommended prioritizing treatment for Merkel cell carcinoma, invasive SCC, and melanoma with positive margins or macroscopic residual disease. They proposed that all other skin cancers, including basal cell carcinoma, SCC in situ, and melanoma with negative margins and no macroscopic residual disease, could be safely delayed for as long as 3 months.¹⁵

For patients with multiple risk factors for COVID-19–related morbidity or mortality, delaying skin cancer treatment likely has less risk than contracting the virus.¹⁵ This information should be communicated with patients. Investigation of specific patient concerns is warranted, and case-by-case evaluation of patients’ risk factors and skin cancer risk should be considered.

Based on the current, though limited, literature, delaying medical treatment can have a negative impact on the patient experience. Furthermore, proper precautions have been shown to limit intraoperative transmission of SARS-CoV-2 during MMS, but research is lacking. Practitioners should utilize shared decision-making and evaluate a given patient’s risk factors and concerns when deciding whether to postpone treatment. We encourage other institutions to evaluate the effects that delaying MMS has had on their patients, as further studies would improve understanding of patients’ experiences during a pandemic and potentially influence future dermatology guidelines.

Guidelines on Skin Cancer Surgeries During the COVID-19 Pandemic

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention issued recommendations to decrease the spread of SARS-CoV-2 and optimize the use of personal protective equipment (PPE) for frontline workers.¹ In the field of dermatologic surgery, the American College of Mohs Surgery, the National Comprehensive Cancer Network, the American Society for Dermatologic Surgery, and the American Academy of Dermatology made recommendations to postpone nonessential and nonurgent procedures.^2-4 The initial guidelines of the American College of Mohs Surgery advised cancellation of all elective surgeries and deferred treatment of most cases of basal cell carcinoma for as long as 3 months; low-risk squamous cell carcinoma (SCC) and melanoma in situ treatment was deferred for as long as 2 or 3 months.³ Additional recommendations were made to reserve inpatient visits for suspicious lesions and high-risk cancers, postpone other nonessential and nonurgent appointments, and utilize telemedicine whenever possible.⁵

These recommendations led to great uncertainty and stress for patients and providers. Although numerous important variables, such as patient risk factors, severity of disease, availability of PPE and staff, and patient-to-provider transmission were considered when creating these guidelines, the patient’s experience likely was not a contributing factor.

COVID-19 Transmission During Mohs Surgery

There have been concerns that surgeons performing Mohs micrographic surgery (MMS) might be at an increased risk for COVID-19, given their close contact with high-risk sites (ie, nose, mouth) and cautery-generated aerosols; most of the estimated transmission risk associated with MMS has been based on head and neck surgery experience and publications.^6-8 Tee and colleagues⁹ recently published their institution’s MMS COVID-19 preventive measures, which, to their knowledge, have prevented all intraoperative transmission of SARS-CoV-2, even in disease-positive patients. Currently, evidence is lacking to support a high risk for SARS-CoV-2 transmission during MMS when proper PPE and personal hygiene measures as well as strict infection control protocols—presurgical COVID-19 testing in high-risk cases, COVID-19 screening optimization, visitor restrictions, and appropriate disinfection between patients—are in place.

The Impact of Postponing Treatment on Patients

Although studies have focused on the effects of the COVID-19 pandemic on physicians practicing MMS,¹⁰ little is known about the effects of delays in skin cancer treatment on patients. A survey conducted in the United Kingdom investigating the patient’s perspective found that patients expressed worry and concern about the possibility that their MMS would be postponed and greatly appreciated continuation of treatment during the pandemic.¹¹

Other medical specialties have reported their patient experiences during the pandemic. In a study examining patient perception of postponed surgical treatment of pelvic floor disorders due to COVID-19, nearly half of survey respondents were unhappy with the delay in receiving care. Furthermore, patients who reported being unhappy were more likely to report feelings of isolation and anxiety because their surgery was postponed.¹² In another study involving patients with lung cancer, 9.1% (N=15) of patients postponed their treatment during the COVID-19 pandemic because of pandemic-related anxiety.¹³

With the goal of improving care at our institution, we conducted a brief institutional review board–approved survey to evaluate how postponing MMS treatment due to the COVID-19 pandemic affected patients. All MMS patients undergoing surgery in June 2020 and July 2020 (N=99) were asked to complete our voluntary and anonymous 23-question survey in person during their procedure. We obtained 88 responses (response rate, 89%). Twenty percent of surveyed patients (n=18) reported that their MMS had been postponed; 78% of those whose MMS was postponed (n=14) indicated some level of anxiety during the waiting period. It was unclear which patients had their treatment postponed based on national guidelines and which ones elected to postpone surgery.

Tips for Health Care Providers

Patient-provider communication highlighting specific skin cancer risk and the risk vs benefit of postponing treatment might reduce anxiety and stress during the waiting period.¹⁴ A study found that COVID-19 posed a bigger threat than most noninvasive skin cancers; therefore, the authors of that study concluded that treatment for most skin cancers could be safely postponed.¹⁵ Specifically, those authors recommended prioritizing treatment for Merkel cell carcinoma, invasive SCC, and melanoma with positive margins or macroscopic residual disease. They proposed that all other skin cancers, including basal cell carcinoma, SCC in situ, and melanoma with negative margins and no macroscopic residual disease, could be safely delayed for as long as 3 months.¹⁵

For patients with multiple risk factors for COVID-19–related morbidity or mortality, delaying skin cancer treatment likely has less risk than contracting the virus.¹⁵ This information should be communicated with patients. Investigation of specific patient concerns is warranted, and case-by-case evaluation of patients’ risk factors and skin cancer risk should be considered.

Based on the current, though limited, literature, delaying medical treatment can have a negative impact on the patient experience. Furthermore, proper precautions have been shown to limit intraoperative transmission of SARS-CoV-2 during MMS, but research is lacking. Practitioners should utilize shared decision-making and evaluate a given patient’s risk factors and concerns when deciding whether to postpone treatment. We encourage other institutions to evaluate the effects that delaying MMS has had on their patients, as further studies would improve understanding of patients’ experiences during a pandemic and potentially influence future dermatology guidelines.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

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 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C 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 HbA_1C 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. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

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 HbA_1C 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. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

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.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

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 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C 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 HbA_1C 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. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

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 HbA_1C 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. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

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.

Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.^1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.^1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.⁶ The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.⁷ The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.^4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.⁹ With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.¹⁰

The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.^8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al¹² published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.^13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.^13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.¹⁵ The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.^16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.^14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.

This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,¹² focusing on elements that required modification during the trial’s duration.

Methods

Study Protocol
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.

Study Products
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.¹² The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.¹²

Randomization
The inclusion and exclusion criteria were previously outlined.¹² After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.¹²

Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.¹² Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.¹²

Statistical Analysis
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al¹² discussed the statistical analysis in more detail.

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 cm².¹²The study investigators noted that within the veteran population, many diabetic patients with DFUs had ulcers that were too small to meet the inclusion criteria; thus, these patients could not be captured in the trial. However, those small ulcers would stall for months, which prompted the decision to change this major exclusion criterion to allow patients with a wound size greater than 0.5 cm² (versus 1.0 cm²) to be recruited. Enrollment of participants also was extended to include nonveterans.

Another limiting criterion was the percentage of total hemoglobin level for hemoglobin A_1C (HbA_1C). The study was originally established to include participants with an HbA_1C 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 HbA_1C 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. The criterion for minimum ulcer size of 1.0 cm² was comparable to other trials⁸ but was a major limiting factor in our study. Many participants already were established with either the podiatry or multispecialty wound clinics, and they had small DFUs, which were stalling for months. Thus, by decreasing the lesion size needed for inclusion, our trial benefited from this subset population.

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 HbA_1C 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. Some research-related factors that were an impediment to patient enrollment included the time to travel and the associated expenses, but our trial was designed to offer a small stipend for travel reimbursement (up to $400) to mitigate such factors.

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.