Efficacy and Safety of 0.25% Timolol Gel in Enhancing Full Thickness Skin Grafts Healing and Cosmetic Outcomes

Study Overview
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Brief Summary
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The use of topical beta-blockers, such as 0.25% timolol, in promoting wound healing is currently emerging in the academic literature. The investigators will enroll 82 patients who have their skin cancer surgically removed resulting in the need of a full-thickness skin graft. The objective of this randomized safety study is to determine the safety and efficacy of 0.25% timolol in promoting wound healing in full-thickness skin grafts compared to standard of care.

Detailed Description
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The role of topical beta-blockers in promoting wound healing is currently emerging in the international literature. β2-Adrenergic receptors (B2AR) are the only subtype of beta-adrenoceptors expressed on skin. They can be found in secretory coil of apocrine glands, keratinocytes, fibroblasts and melanocytes. The distribution of these receptors provides insight on dermatological disorders that may be affected by β-blockers. Keratinocyte migration occurs by the facilitation of chemotaxis, the polarization of cells, and activation of extracellular signal-related kinases essential in the signaling of promigratory pathways. The B2AR activation inhibits keratinocyte migration by activating the serine/threonine phosphatase-2a, which downregulates phosphorylation of extracellular signal-related kinases necessary for migration. Therefore, B2AR antagonists prevent the phosphorylation of phosphatase-2a and have the downstream effect of extracellular signal-related kinase promotion, inducing a promigratory pathway in keratinocytes. Keratinocyte migration also occurs by galvanotaxis, a phenomenon in which cells migrate in response to electric stimuli. Keratinocytes can be stimulated to migrate with the formation of electrical poles and the application of electrical fields. The B2AR antagonists improve the ability of keratinocytes to respond to such migratory cues, whereas the B2AR agonists decrease keratinocytes' ability to respond, further implicating the use of topical timolol for recalcitrant wounds. Angiogenesis and dermal fibroblast proliferation are also regulated by B2ARs. The B2AR antagonists have been found to promote angiogenesis in chick chorioallantoic membrane assays and in vivo murine wound models. Dermal fibroblast migration is also increased (by 27%) when exposed to B2AR antagonists, and epidermal differentiation is improved with B2AR antagonists and β1- and β2-receptor antagonists. Full-thickness skin grafts (FTSG) are one of the most commonly performed procedures in dermatologic, plastic and burn surgery. Various experimental approaches to optimize the healing of FTSG receiving sites have been described; however, no clearly superior and easily applicable method has gained wide acceptance in daily practice. As indicated by preliminary evidence in other wound healing endeavors, 0.25% timolol gel may represent a commercially available, safe and simple, painless and relatively inexpensive treatment for improving healing of FTSG receiving site, as well as for improving cosmetic long term outcomes. To assess the efficacy and safety of topically applied 0.25% timolol gel in promoting wound healing in FTSG receiving site versus standard of care (SOC) by: Evaluating healing in response to treatment with 0.25% topical timolol gel versus SOC in terms of wound surface area and Graft Take Score at the receiving site of a FTSG at 7 and 14 days; Evaluating cosmetic outcomes of the receiving site of a FTSG in terms of blinded physician (Vancouver Scar Scale, VSS) and patient (Visual Analogue Scale, VAS) assessment at 3 and 6 months' follow up; Evaluating the need for further scar revision (dermabrasion or pulsed dye laser [PDL]) at the 6-month follow up; Evaluating patient discomfort during the healing process by means of a patient pain VAS; and Determining the side effects associated with 0.25% timolol gel versus SOC

Official Title
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Efficacy and Safety of 0.25% Timolol Gel in Enhancing Full Thickness Skin Grafts Healing and Cosmetic Outcomes: A Randomized, Controlled Trial

Conditions
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Wound of Skin, Wound Heal, Surgical Wound, Full Thickness Skin Graft Healing

Intervention / Treatment
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* Drug: 0.25% timolol gel with full-thickness skin grafts
* Other: Vaseline dressing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years of age Undergoing a procedure which results in the need of a FTSG Willing to provide written informed consent Exclusion Criteria: Age less than 18 years of age Pregnant women (Use of systemic drugs that can impede wound healing, such retinoids or immune-suppressive drugs) Severe coagulation disorders Severe, uncontrolled systemic comorbidities, such as diabetes, arthritis, etc. Hypersensitivity to 0.25% timolol gel Not willing to provide written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The protocol will begin post-surgery. Eligible subjects will be assigned by computer-based randomization to case (0.25% timolol gel) or control (standard of care [SOC]) group and treated as follows: Receiving site of FTSG/case group: During surgery: application of 0.25% timolol gel (2 drops per cm2) on wound bed before FTSG is placed During surgery: application of 0.25% timolol gel (2 drops per cm2) over FTSG after insetting of the graft After bolster removal (7 days): daily cleansing and daily 0.25% timolol (2 drops per cm2) application for 4 weeks Receiving site of FTSG/control group: FTSG surgery as per SOC After bolster removal (7 days): daily cleansing and daily Vaseline application for 4 weeks
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.25% Timolol gel applied to full-thickness skin graft<br>During surgery: application of 0.25% timolol gel (2 drops per cm2) on wound bed before FTSG is placed During surgery: application of 0.25% timolol gel (2 drops per cm2) over FTSG after insetting of the graft After bolster removal (7 days): daily cleansing and daily 0.25% timolol (2 drops per cm2) application for 4 weeks | Drug: 0.25% timolol gel with full-thickness skin grafts<br>* Timolol 0.25% gel will be applied to wound bed immediately after surgery before dressing is applied.<br>|
| Active Comparator: Standard of Care dressings<br>FTSG surgery as per SOC After bolster removal (7 days): daily cleansing and daily Vaseline application for 4 weeks | Other: Vaseline dressing<br>* Vaseline will be applied to wound bed immediately after surgery before dressing is applied.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluating the need for further scar revision (via dermabrasion or pulsed dye laser (PDL)) | A study physician will review the healed scar site to determine if there are potential cosmetic factors that could be improved through scar revision. If the patient is interested in having scar revision procedures, the study physician will offer a dermabrasion or PDL to treat the scar site. | 6-months' post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluating cosmetic outcomes of the receiving site of a FTSG via Vancouver Scar Scale (VSS) | Physician blinded to subject's treatment group uses VSS which documents scar appearance change over time via photos. VSS ranges from 0 (most desirable outcome) to 13 (least desirable). A lower score is considered a better outcome and a higher score is a worse outcome. VSS consists of 4 sub-scales, with each reporting a value. The pigmentation ranges from 0 (normal pigment) to 2 (hyperpigment); vascularity ranges from 0 (normal appearance) to 3 (purple appearance); pliability ranges from 0 (normal) to 5 (contracture); height ranges from 0 (normal/flat) to 3 (>5mm). Sub-scale scores are combined to give an overall VSS score. | 3 months' post-surgery and 6 months' post-surgery | 
| Evaluating cosmetic outcomes of the receiving site of a FTSG via patient Visual Analogue Scale (VAS) | Scar VAS rates subjects' graft cosmetic appearance. Each question ranges from 1 (no complaints w/ itch or pain/as normal skin) to 10 (worst imaginable itch or pain/very different from normal skin). Ranges from 6 (best outcome score) to 66 (worst outcome score); a lower score is considered a better outcome and a higher score is considered a worse outcome. | 3 months' post-surgery and 6 months' post-surgery | 
| Evaluating change in healing response to treatment with 0.25% topical timolol gel versus SOC in terms of wound surface area at the receiving site of a FTSG via Graft Take Score | The Graft Take Score will be used to assess amount of graft take at each visit. Graft take is considered Good if 90%+ of the graft site is healed and pink/purple in color; Moderate if there is 50% healing, pink or purple in color, and >50% of the graft has taken; and Poor if <50% graft take. | 7 days post-surgery, and 14 days post-surgery | 
| Evaluating change in healing response to treatment with 0.25% topical timolol gel versus SOC in terms of wound surface area at the receiving site of a FTSG via histogram planimetry | Histogram planimetry is more accessible than automated analysis software programs, and it is based on the pixel count of a selected irregular area which is divided by the pixel count of 1 cm2 to find a result in terms of cm2 or mm2. | 7 days post-surgery, and 14 days post-surgery | 
| Evaluating change in patient discomfort during the healing process by means of a patient pain VAS | Subjects will be asked to complete a Visual Analogue Scale for scar assessment to rate how they think their graft sites appear cosmetically compared to normal skin, and any complaints about how painful they sites are, and how itchy they feel. Each question ranges from 1 (no complaints with itch or pain/as normal skin) to 10 (worst imaginable itch or pain/very different from normal skin). The score ranges from 6 (best outcome score) to 66 (worst outcome score), thus a lower score is considered to have a better outcome and a higher score is considered a worse outcome. | 7 days' post-surgery, 14 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery | 
| Determining change in the side effects associated with 0.25% timolol gel versus SOC via physician assessment | A physician will assess for side effects and determine whether they are likely associated with the 0.25% topical timolol or part of the normal wound healing experience. | 7 days' post-surgery, 14 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery | 
| Determining change in the side effects associated with 0.25% timolol gel versus SOC via patient assessment | Patients will report any side effects they experience post-surgery | 7 days' post-surgery, 14 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery |