Evaluating the Safety and Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing
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|ClinicalTrials.gov Identifier: NCT03644849|
Recruitment Status : Recruiting
First Posted : August 23, 2018
Last Update Posted : August 7, 2019
|First Submitted Date ICMJE||August 13, 2018|
|First Posted Date ICMJE||August 23, 2018|
|Last Update Posted Date||August 7, 2019|
|Actual Study Start Date ICMJE||September 28, 2018|
|Estimated Primary Completion Date||June 2020 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
||Efficacy of the carbon dioxide ablative fractional laser for healing postoperative lower extremity wounds.(Time, in weeks, till complete wound healing in days) [ Time Frame: 12 weeks (enrollment time per subject) ]
Time, in weeks, till complete wound healing in days. Complete wound healing is defined by reepithelization of the wound.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures
||Wound and peri-wound temperature associated with carbon dioxide ablative fractional laser for healing postoperative lower extremity wounds. [ Time Frame: 12 weeks (enrollment time per subject) ]
Wound temperature will be recorded in degrees Celsius through an infrared camera.
|Original Other Pre-specified Outcome Measures||Same as current|
|Brief Title ICMJE||Evaluating the Safety and Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing|
|Official Title ICMJE||A Single Center, Prospective, Double-blinded, Randomized, Placebo-controlled Trial Evaluating the Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing|
|Brief Summary||This study will evaluate the efficacy and safety of laser therapy on postoperative lower extremity wound healing over 12 months. The investigators will include adult patients who have underwent Mohs Micrographic Surgery on their lower extremities. Patients with poor immune systems, current pregnancies, uncontrolled diabetes, lower extremity venous or arterial disease will not be included in this study. After surgery patients will be randomized into two groups. One group will receive a single laser treatment immediately after their surgery on their wound while the other will not. The group not receiving laser therapy will undergo a sham laser therapy treatment. Immediately after therapy and 1, 2, 3, 4, 8, and 12 weeks postoperative patients will have a follow up visit. During these visits patients wound size will be recorded, a photograph will be taken, and the wound temperature will be measured. Patient will be given a diary to record any adverse events related to the wound.|
Background and Significance
With an aging population, the prevalence of cutaneous malignancies continues to pose significant burden in terms of morbidity and economic cost. It is estimated that 5.4 million new cases of non-melanoma skin cancers, i.e squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are diagnosed each year. As the incidence of skin cancer increases, the prevalence of postoperative lower extremity wounds also increases. Epidemiologic studies consistently find up to 10% of BCC and 20% of SCC occur on the lower extremity in both men and women, and the largest portion of malignant melanoma cases occurs on the legs of women. Lower extremity ulcers are a common postoperative complication of melanoma, BCC and SCC treatment, and impose an undue health care burden by negatively impacting patient quality of life and increasing costs. Recent reports suggest that lower extremity ulcers cost $10,000 per patient per year, and patients often reported social isolation and depression, thus making an improved treatment protocol for healing lower extremity wounds essential.
After an acute injury, normal wound healing is usually complete within four weeks and can be divided into 4 phases: coagulation, inflammation, formulation of granulation tissue, and remodeling or scar formation. The initial steps of coagulation and inflammation involve the inhibition of bleeding through activation of the coagulation cascade, release of growth factors and cytokines such as platelet-derived growth factor and transforming growth factor β, and recruitment of macrophages and fibroblasts. This facilitates removal of foreign bodies and bacteria while preparing the wound site for new tissue. Around 5-7 days inflammation subsides via apoptosis of proinflammatory cells followed by formation of granulation tissue through dermal and epidermal cell migration to the wound bed. Granulation tissue has a high metabolic demand that is supplied by angiogenesis (proliferation of new blood vessels). Angiogenesis occurs due to local hypoxia during acute tissue injury which stimulates the release of several factors such as vascular endothelial growth factor and fibroblast growth factor 2. Lastly matrix remodeling and scar formation result in the restoration of primarily normal epidermis by replacing the extracellular matrix containing collagen III to primarily collagen I and myofibroblast induced tissue contraction.
Lower extremity ulcers exhibit increased infection risk compared with other body sites, and are rarely amenable to surgical closure due to a lack of suitable local skin and poor tissue vascularity. As a result, many of these defects are allowed to heal via secondary intention healing (SIH).The lower extremity suffers from poor perfusion and hypovascularity, both of which impair wound healing in this anatomic site. Therefore, post-surgical wounds on the lower extremities frequently convert into chronic wounds, defined as wounds that fail to heal within four weeks and show no sign of improvement within eight weeks. This protracted healing course drains the medical system of resources and subjects the patient to significant discomfort and distress. The major problems reported from patients include pain, immobility, sleep disturbances, lack of energy, limitations in work and leisure activities, worry, frustration, and lack of self-esteem. Given the problems associated with allowing lower extremity ulcers to heal by second intent, strategies that improve ulcer healing would be beneficial, improving patient quality of life and preventing further complications.
Ablative fractional carbon dioxide lasers, such as the CO2RE® (Syneron Candela Corp, Wayland, MA), offer a multi-depth pulse technology that delivers a precise fractionated beam pattern to treat the epidermis and dermis simultaneously. This precision technology creates areas of superficial and deep ablation and coagulation to activate remodeling at several tissue depths. The CO2RE® is FDA-approved and has demonstrated efficacy in post-surgical scar treatment, although it has not been studied in acute, lower extremity ulcers.
While the use of AFLs for wounds is novel, there are sufficient reported studies to suggest it may be an efficacious intervention to facilitate the healing of lower extremity surgical wounds. AFLs create microscopic wounds that can reach greater dermal depths than previously attainable with fully ablative devices, and adjacent untreated skin may facilitate rapid healing. Histopathologic studies of normal skin treated with AFL demonstrate altered kinetics of growth factor and cytokine release, expression of heat shock proteins and matrix metalloproteinases. In 3D human organotypic full-thickness skin models, carbon dioxide AF therapy resulted in reduced expression of matrix metalloproteinases, and downregulation of pro-inflammatory cytokines. Therefore, carbon dioxide AFL may offer significant advantages over traditional non-ablative laser technologies.
The treatment for BCC and SCC is often surgical. Mohs Micrographic Surgery (MMS) is a surgical procedure in which skin cancer cells are removed. Once all visibly cancerous tissue is removed, the tissue is examined under a microscope to evaluate for the presence of cancer cells at the tissue edges. This allows the surgeon to determine if all of the cancer has been removed. After examining the specimen, multiple thin sections of tissue are removed around the margins of the wound and then examined under a microscope. If abnormal cells remain, further tissue excision is required. This process is continued until no cancerous cells remain. This technique allows for preservation of maximum amount of normal tissue and the pathologic confirmation of complete cancer excision. MMS is used when there is a high risk of recurrence, when the skin cancer is located in a sensitive area such as the nose or lower extremities, or the cancer is an aggressive subtype. Complications of MMS include infection, hypertrophic scar formation, hypergranulation tissue, and impaired wound healing that can result is ulcers persisting up to 7 months.
This project tests the highly innovative hypothesis that use of the AFL is both safe and efficacious for the treatment of post-surgical ulcers. This laser technology has demonstrated efficacy for treatment of lower extremity scars, but has not been adequately evaluated in ulcers. Due to a unique pattern of injury induced by fractional technology where healthy tissue in the vicinity of the ulcer is spared, the use of this technology may demonstrate significant benefits as compared to traditional non-ablative lasers and low level light systems previously used to treat ulcers.
Although our proposed study is highly novel, the feasibility of our proposed protocol is supported by the fact that the fractional carbon dioxide laser has been shown to improve wound healing in scar-related wounds and in post-traumatic wounds of the lower extremity. Based on this data, treating acute lower extremity ulcers with ablative fractional carbon dioxide laser is expected to improve healing times in lower extremity ulcers occurring as a result of cutaneous surgery. This work may lead to the use of ablative fractional laser to support the body's regenerative capacity on the lower extremity, improving patient quality of life and conserving healthcare resources. The investigators therefore hypothesize that ablative fractional laser treatment therapy after cutaneous surgery is a safe and efficacious treatment for lower extremity wounds.
In addition to the novelty of our proposed hypothesis, our study benefits from technical innovation in adjudicating ulcer healing, which has previously not been combined with carbon dioxide laser technology.
The first report of carbon dioxide AFL utilization in wounds was by Schumaker et. al in 2012. In their report they described three patients treated with a 10.6-um carbon dioxide AFL system for multiple traumatic scars related to blast injury. Incidentally they noted that chronic wounds in the treatment sites resolved within 2 weeks of initial therapy. Phillips et. al observed similar results in elderly individuals with post traumatic lower extremity ulcers. Their report demonstrated greater than 60% resolution of chronic lower-extremity ulcers 3 weeks after a single treatment with carbon dioxide AFL therapy. Most recently Krakowski et. al demonstrated near complete resolution of two chronic wounds by two months in pediatric patients after treatment with CO2 AFL at a pulse energy of 50 mJ and treatment density of 5%.
MMS performed on the nose, like lower extremities, are occasionally allowed to heal by second intent and can thus be predisposed to prolonged healing. Our preliminary studies demonstrate the effects of carbon dioxide AFL on these wounds. Two patients receiving MMS on the nasal ala were studied. One patient receiving carbon dioxide AFL therapy on his postoperative wound while the other did not. After three weeks the patient's postoperative wounds were assessed. The patient receiving laser therapy had complete epithelialization of his wound, while the patient with no treatment had incomplete epithelization. These results suggest the hypothesis that the carbon dioxide AFL may be a safe, efficacious treatment for ulcers of the lower extremity.
Our study is a prospective, double-blinded, randomized, placebo-controlled trial evaluating the efficacy of fractionated carbon dioxide therapy in postoperative lower extremity wound healing. This study, including analysis and submission for publication, will occur from July 2018 to June 2020. A cohort of 68 patients will be recruited from July 2018 to July 2020. Eligibility criteria will include patients older than 18 years, those with a lower extremity wound as a result of Mohs Micrographic Surgery at Saint Louis University Dermatology Des Peres, and a postoperative wound greater than 5mm in diameter. Patients must be able to understand the informed consent, willing to come to the office for treatments and capable of following post-treatment instructions. Exclusion criteria will include pregnancy, immunosuppression, uncontrolled diabetes (defined as >7% A1c in the last 3 months), peripheral vascular disease, venous insufficiency, or no desire/unable to undergo laser therapy.
After informed consent is obtained, a screening visit will be performed on their Mohs surgery day and patient eligibility will be determined. Then, patients will be randomized 1:1 to a treatment or control group via computer software. One arm will receive carbon dioxide AFL immediately postoperatively on the wound base. The second arm, which will serve as control, will receive sham laser therapy. Both patients will be given identical postoperative wound care instructions, including vaseline applied to the wound, a piece of telfa to overlay the wound, and paper tape to secure the dressing. Additionally, patients will be advised to avoid baths and application of any other products to their wound. These supplies will be given to the patients to eliminate wound care supplies as a confounding factor. Patients will be given a diary to record observations about their postoperative wound and to note any adverse events.
There will be one unblinded member of the team in this study which will be the clinician performing laser therapy or sham therapy, who will therefore not be involved in any data collection, but will be responsible for reporting any adverse events per IRB protocols at our institution. Other members of the research team member will be blinded to patient group assignment, and these members of the research team will collect data (see below) at subsequent visit. Additionally, patients will be blinded to treatment group. This will be achieved by having patients wear safety glasses which blind them and the wound site still anesthetized from the operation. Data collection will be done by a separate research team member who is blinded to the treatment groups.
Patient Visits and Data Collection
Patients will be seen at 7 separate visits. This will include weekly visits post-operatively for the first 4 weeks to monitor safety and efficacy endpoints and additionally at 8 and 12 weeks post-operatively. The patient's initial visit will include preoperative screening for eligibility, informed consent procedure, and recording of past medical history and physical exam. Once the patient is deemed eligible, enrolled, and signed informed consent, they will be randomized to either carbon dioxide AFL therapy or sham laser therapy. After the patient undergoes Mohs surgery with the resultant ulcer (the defect that typically forms after Mohs), the patient will undergo either carbon dioxide laser versus sham laser therapy.
The investigators will measure ulcer size, presence or absence of complete healing, wound temperature, a digital photograph, wound site pain, quality of life, and adverse events at each visit. Ulcer size will be recorded by placing transparent acetate paper with a grid over the wound site. This will then be traced with fine point marker. The cubic centimeters will be recorded along with the width (longest axis of the ulcer) and length (axis perpendicular to the width). Healing will be determined by one of the licensed research team members and will be defined by complete epithelialization in the absence of scab/eschar. Wound temperature will be recorded by non-invasive infrared thermographic camera. A digital photograph will be taken with a camera that has an attachment ensuring the same distance and angle at every visit. Wound pain will be graded on a scale from 1-10 with 1 being no pain to 10 being the worst pain of the patient's life. Quality of life will be determined by ED-5Q questionnaire. Adverse events will be recorded by eliciting an oral history and review of the patients diary. Adverse events will be recorded as presence of absence of specific outcomes. Outcomes that patients will be directly questioned about include: crusting (scaly or thickened scar), swelling, burning sensation, xerosis at treatment site, pruritus at treatment site, infection, bleeding, hypertrophic or keloid scarring, burns, or color changes at treatment site. These data points will be collected at every visit, and adjudicated by a member of the research team blinded to the treatment group. This member will be a licensed research team member.
Placebo treatment will consist of directing the laser system at the floor instead of the patient's wound site. The patients will be wearing safety glasses and will have their wound site still anesthetized from the operation therefore unaware if they are receiving the therapy. This group will serve as the control group to the treatment arm in the study.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
|Condition ICMJE||Leg Ulcer|
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||June 2020|
|Estimated Primary Completion Date||June 2020 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Immunosuppression will be defined as patients with HIV, AIDS, who have received an organ transplant, allogeneic bone marrow transplant, or peripheral stem cell transplant, and any other patients taking chronic doses of systemic immunosuppressive medication within 6 months prior to randomization. Examples of immunosuppressive medications include Tacrolimus, Azathioprine, Prednisone, or Methotrexate.
|Ages ICMJE||18 Years to 90 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03644849|
|Other Study ID Numbers ICMJE||29076|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Ramona Behshad, MD, St. Louis University|
|Study Sponsor ICMJE||St. Louis University|
|Collaborators ICMJE||Not Provided|
|Investigators ICMJE||Not Provided|
|PRS Account||St. Louis University|
|Verification Date||August 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP