Clinical trial NCT03579160: Efficacy and Safety of 0.25% Timolol Gel in Enhancing Full Thickness Skin Grafts Healing and Cosmetic Outcomes
Official title: Efficacy and Safety of 0.25% Timolol Gel in Enhancing Full Thickness Skin Grafts Healing and Cosmetic Outcomes: A Randomized, Controlled Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Wound of Skin
Wound Heal
Surgical Wound
Full Thickness Skin Graft Healing
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2018-07-06
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Evaluating the need for further scar revision (via dermabrasion or pulsed dye laser (PDL))
timeFrame: 6-months' post-surgery
Secondary outcomes:
measure: Evaluating cosmetic outcomes of the receiving site of a FTSG via Vancouver Scar Scale (VSS)
timeFrame: 3 months' post-surgery and 6 months' post-surgery
measure: Evaluating cosmetic outcomes of the receiving site of a FTSG via patient Visual Analogue Scale (VAS)
timeFrame: 3 months' post-surgery and 6 months' post-surgery
measure: 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
timeFrame: 7 days post-surgery, and 14 days post-surgery
measure: 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
timeFrame: 7 days post-surgery, and 14 days post-surgery
measure: Evaluating change in patient discomfort during the healing process by means of a patient pain VAS
timeFrame: 7 days' post-surgery, 14 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery
measure: Determining change in the side effects associated with 0.25% timolol gel versus SOC via physician assessment
timeFrame: 7 days' post-surgery, 14 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery
measure: Determining change in the side effects associated with 0.25% timolol gel versus SOC via patient assessment
timeFrame: 7 days' post-surgery, 14 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery
Other outcomes:
Locations:
city: Boston
country: United States
facility: Mohs and Dermatologic Surgery Center, Brigham and Women's Hospital
state: Massachusetts
Study officials:
References: