Clinical trial NCT03452072: Efficacy and Safety of 0.25% Timolol Gel in Healing Surgical Open Wounds
Official title: Efficacy and Safety of 0.25% Timolol Gel in Healing Surgical Open Wounds: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Wound of Skin
Wound Heal
Wound Open
Surgical Wound
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2018-03-02
Enrollment: 88
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:

Case group:

1. Timolol 0.25% gel will be applied to wound bed immediately after surgery before dressing is applied
2. Starting the day after surgery: each day, the patient will cleanse the surgical site, apply 0.25% topical timolol gel (1 drop = 0.1ml for each cm2 of wound area), and re-cover wound with clean dressing
3. Daily routine continues for 12 weeks' post-surgery (even if the surgical defect has completely healed)

SOC group:

1. Vaseline will be applied to wound bed immediately after surgery before dressing is applied
2. Starting the day after surgery: each day, the patient will cleanse the surgical site, apply Vaseline, and re-cover wound with clean dressing
3. This daily routine continues for 12 weeks' post-surgery (even if the surgical defect has completely healed)
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 114 patients who have their skin cancer surgically removed resulting in open surgical wounds less or equal to 1.5 cm. The objective of this randomized safety study is to determine the safety and efficacy of 0.25% timolol in promoting wound healing in open surgical wounds less or equal to 1.5 cm.

Detailed description: Healing of a cutaneous defect by second intention is a complex process. Migration of fibroblasts, keratinocytes, and other cell types to the site of defect and their proliferation under stimulation by cytokines and growth factors occur during this process. The role of topical beta-blockers in promoting wound healing is currently emerging in the international literature (1-3). β2-Adrenergic receptors (B2AR) are the only subtype of beta-adrenoceptors expressed on skin (4-6). 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 (4-6). 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 (4-6). 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 (5-10).

Topical beta-blockers have been gaining increasing popularity and evidence over the last few years as enhancers of wound healing in acute and chronic open wounds. In particular, 0.25% timolol gel may represent a commercially available, safe and simple, painless-though perhaps moderately expensive-treatment for improving both acute and chronic open wounds, as well as for improving long-term cosmetic outcomes.

To assess the efficacy and safety of topically applied 0.25% timolol gel in promoting wound healing in surgical open wounds ≤1.5cm 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 reduction of open surgical wound;
2. Evaluating cosmetic outcomes of surgical wounds 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 patient discomfort during the healing process by means of a patient pain VAS;
4. Determining the side effects associated to 0.25% topical timolol versus SOC; and
5. Determining costs associated to the use of 0.25% topical timolol versus SOC.

Eligibility criteria: Inclusion Criteria:

1. Age greater than 18 years
2. Open surgical wound ≤1.5cm
3. No hypersensitivity with use of 0.25% timolol gel

Exclusion Criteria:

1. Age less than 18 years of age
2. Open surgical wound \>1.5cm
3. Pregnant women
4. Use of systemic retinoids within 1 month
5. Any hypersensitivity with use of 0.25% timolol gel

Primary outcomes:
measure: Change in histogram planimetry for open surgical wounds
timeFrame: 7 days' post-surgery, 15 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery
Secondary outcomes:
measure: Cosmetic outcomes of open surgical wound healing by blinded physician Vancouver Scar Scale assessment
timeFrame: 3 months' post-surgery, 6 months' post-surgery
measure: Study subject complete the Patient Scar Assessment via Visual Analogue Scale
timeFrame: 3 months' post-surgery, 6 months' post-surgery
measure: Determine side effects associated with 0.25% topical timolol for open surgical wounds
timeFrame: 7 days' post-surgery, 15 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:
affiliation: Brigham and Women's Hospital
name: Chrysalyne D Schmults, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References:
citation: Braun LR, Lamel SA, Richmond NA, Kirsner RS. Topical timolol for recalcitrant wounds. JAMA Dermatol. 2013 Dec;149(12):1400-2. doi: 10.1001/jamadermatol.2013.7135. No abstract available.
citation: Ali A, Herndon DN, Mamachen A, Hasan S, Andersen CR, Grogans RJ, Brewer JL, Lee JO, Heffernan J, Suman OE, Finnerty CC. Propranolol attenuates hemorrhage and accelerates wound healing in severely burned adults. Crit Care. 2015 May 4;19(1):217. doi: 10.1186/s13054-015-0913-x.
citation: Vestita M, Bonamonte D, Filoni A. Topical propranolol for a chronic recalcitrant wound. Dermatol Ther. 2016 May;29(3):148-9. doi: 10.1111/dth.12328. Epub 2016 Jan 22. No abstract available.
citation: Yesiloglu N, Yildiz K, Cem Akpinar A, Gorgulu T, Sirinoglu H, Ozcan A. Histogram Planimetry Method for the Measurement of Irregular Wounds. Wounds. 2016 Sep;28(9):328-333.
citation: Thomas B, Kurien JS, Jose T, Ulahannan SE, Varghese SA. Topical timolol promotes healing of chronic leg ulcer. J Vasc Surg Venous Lymphat Disord. 2017 Nov;5(6):844-850. doi: 10.1016/j.jvsv.2017.04.019. Epub 2017 Aug 7.
citation: Manahan MN, Peters P, Scuderi S, Surjana D, Beardmore GL. Topical timolol for a chronic ulcer--a case with its own control. Med J Aust. 2014 Jan 20;200(1):49-50. doi: 10.5694/mja13.10823. No abstract available.
citation: Lev-Tov H, Dahle S, Moss J, Isseroff RR. Successful treatment of a chronic venous leg ulcer using a topical beta-blocker. J Am Acad Dermatol. 2013 Oct;69(4):e204-5. doi: 10.1016/j.jaad.2013.06.003. No abstract available.
citation: Tang JC, Dosal J, Kirsner RS. Topical timolol for a refractory wound. Dermatol Surg. 2012 Jan;38(1):135-8. doi: 10.1111/j.1524-4725.2011.02200.x. Epub 2011 Oct 31. No abstract available.
citation: Zheng Z, Liu Y, Yang Y, Tang J, Cheng B. Topical 1% propranolol cream promotes cutaneous wound healing in spontaneously diabetic mice. Wound Repair Regen. 2017 May;25(3):389-397. doi: 10.1111/wrr.12546. Epub 2017 May 26.