Full Thickness Skin Graft Healing, Surgical Wound, Wound Heal, Wound of Skin
Conditions
Brief summary
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
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: 1. 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; 2. 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; 3. Evaluating the need for further scar revision (dermabrasion or pulsed dye laser \[PDL\]) at the 6-month follow up; 4. Evaluating patient discomfort during the healing process by means of a patient pain VAS; and 5. Determining the side effects associated with 0.25% timolol gel versus SOC
Interventions
DRUG0.25% timolol gel with full-thickness skin grafts
Timolol 0.25% gel will be applied to wound bed immediately after surgery before dressing is applied.
OTHERVaseline dressing
Vaseline will be applied to wound bed immediately after surgery before dressing is applied.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Blinded physician will assess outcomes from pictures
Intervention 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: 1. During surgery: application of 0.25% timolol gel (2 drops per cm2) on wound bed before FTSG is placed 2. During surgery: application of 0.25% timolol gel (2 drops per cm2) over FTSG after insetting of the graft 3. 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: 1. FTSG surgery as per SOC 2. After bolster removal (7 days): daily cleansing and daily Vaseline application for 4 weeks
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Age ≥18 years of age 2. Undergoing a procedure which results in the need of a FTSG 3. Willing to provide written informed consent
Exclusion criteria
1. Age less than 18 years of age 2. Pregnant women 3. (Use of systemic drugs that can impede wound healing, such retinoids or immune-suppressive drugs) 4. Severe coagulation disorders 5. Severe, uncontrolled systemic comorbidities, such as diabetes, arthritis, etc. 6. Hypersensitivity to 0.25% timolol gel 7. Not willing to provide written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Healed Wound Surface in 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 | 7 days post-surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Successful (Completely Healed) Graft in Response to Treatment With 0.25% Topical Timolol Gel Versus SOC Using a Blinded Physician Assessment Score at the Receiving Site of a FTSG at 7 Days | 7 days post-surgery | 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. |
| Patient Discomfort During the Healing Process by Means of a Patient Pain VAS | 7 days' post-surgery | 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. The score ranges from 1 to 10. A lower score is considered to have a better outcome and a higher score is considered a worse outcome. |
| Number of Participants With Side Effects Associated With 0.25% Timolol Gel Versus SOC Via Physician Assessment | 7 days' post-surgery | 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. |
| Number of Participants With Side Effects Associated With 0.25% Timolol Gel Versus SOC Via Patient Assessment | 7 days' post-surgery | Patients will report any side effects they experience post-surgery |
Countries
United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 82 years STANDARD_DEVIATION 13.86 |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 |
| other Total, other adverse events | 0 / 3 | 0 / 5 |
| serious Total, serious adverse events | 0 / 3 | 0 / 5 |
Outcome results
None listed