Efficacy and Safety of 0.25% Timolol Gel in Healing Surgical Open Wounds

January 10, 2022 updated by: Chrysalyne D Schmults, MD, MSCE, Brigham and Women's Hospital

Efficacy and Safety of 0.25% Timolol Gel in Healing Surgical Open Wounds: A Randomized Controlled Trial

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

88

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Massachusetts
      • Boston, Massachusetts, United States, 02130
        • Mohs and Dermatologic Surgery Center, Brigham and Women's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 0.25% Timolol gel under the paraffin gauzes
  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. This daily routine continues for 12 weeks' post-surgery (even if the surgical defect has completely healed in the interim)
Timolol 0.25% gel will be applied to wound bed immediately after surgery before dressing is applied. 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
Active Comparator: Standard of Care dressings
  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 in the interim)
Vaseline will be applied to wound bed immediately after surgery before dressing is applied. Starting the day after surgery: each day, the patient will cleanse the surgical site, apply Vaseline, and re-cover wound with clean dressing

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in histogram planimetry for open surgical wounds
Time Frame: 7 days' post-surgery, 15 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery
Histogram planimetry is more accessible and less expensive 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, 15 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cosmetic outcomes of open surgical wound healing by blinded physician Vancouver Scar Scale assessment
Time Frame: 3 months' post-surgery, 6 months' post-surgery
A physician blinded to the treatment group the subject is in will self-administer the Vancouver Scar Scale (VSS) which documents change in scar appearance over time via standardized photographs. The VSS ranges from 0 (most desirable outcome) to 13 (least desirable outcome), thus, a lower score is considered to have a better outcome and a higher score is considered a worse outcome. The VSS consists of four sub-scales, with each sub-scale reporting a value. The "pigmentation sub-scale" ranges from 0 (normal pigmentation) to 2 (hyperpigmentation); the "vascularity sub-scale" ranges from 0 (normal appearance) to 3 (purple appearance); the "pliability sub-scale" ranges from 0 (normal pliability) to 5 (contracture); and the "height sub-scale" ranges from 0 (normal [flat]) to 3 (>5mm). Sub-scale scores are combined to give an overall VSS assessment score.
3 months' post-surgery, 6 months' post-surgery
Study subject complete the Patient Scar Assessment via Visual Analogue Scale
Time Frame: 3 months' post-surgery, 6 months' 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. 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 PSAS 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.
3 months' post-surgery, 6 months' post-surgery
Determine side effects associated with 0.25% topical timolol for open surgical wounds
Time Frame: 7 days' post-surgery, 15 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery
Patients will report and side effects they experience post-surgery. A physician will also 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, 15 days' post-surgery, 30 days' post-surgery, 3 months' post-surgery, 6 months' post-surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Chrysalyne D Schmults, MD, MSCE, Brigham and Women's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 20, 2018

Primary Completion (Actual)

December 29, 2020

Study Completion (Actual)

June 30, 2021

Study Registration Dates

First Submitted

February 16, 2018

First Submitted That Met QC Criteria

February 28, 2018

First Posted (Actual)

March 2, 2018

Study Record Updates

Last Update Posted (Actual)

January 12, 2022

Last Update Submitted That Met QC Criteria

January 10, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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