Timolol Option for Ulcerated Hemangiomas (TOUCH Trial) (TOUCH)

The Efficacy of Timolol 0.5% Gel Forming Solution for the Treatment of Ulcerated Hemangiomas

The purpose of this study is to determine whether Timolol 0.5% Gel Forming Solution is safe and effective in promoting wound healing of infantile ulcerated hemangiomas compared with standard conservative management with topical antibiotic.

Study Overview

• Status: Withdrawn
• Conditions: Infantile Hemangiomas
• Intervention / Treatment: Drug: Timolol 0.5% Gel Forming Solution (GFS); Drug: Mupirocin 2% Ointment

Detailed Description

Ulceration is the most common complication associated with infantile hemangiomas. Ulceration and the delay in wound healing places patients at risk for infection, bleeding, pain and permanent scarring. Currently, the care of ulcerated hemangiomas is extremely difficult and patients are often subject to multiple treatment modalities.

In the past two years, the leading advance in the treatment of hemangiomas has been the use of the non-selective, oral beta-blocker propranolol to arrest growth and promote involution of hemangiomas. Recent literature also suggests beta-blockers may have a role in helping ulcerated wounds re-epithelialize.

The use of a topical non-selective beta-blocker on isolated ulcerated hemangiomas may promote early healing and reduce the number of complications associated with ulceration. Investigation is needed to explore the safety and tolerability of applying a topical beta-blocker on an ulcerated hemangioma and whether topical beta-blockade may be more efficacious than conservative care with topical antibiotics.

In this study, infants will be randomized to either receive a topical antibiotic (topical mupirocin 2% ointment twice per day) or a topical beta-blocker (Timolol 0.5% Gel Forming Solution) according to a dose-escalation schedule. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed. Photographs and safety and efficacy measurements will be taken at each visit to assess response to therapy.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 8 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infants weighing between 4-12kg
• Infants with corrected gestational age 44 weeks - 8 months of age
• Infant with an ulcerated hemangioma
• Informed consent

Exclusion Criteria:

• Ulceration larger than 16cm2
• Ulcerated hemangioma with active bleeding or infection at time of enrollment
• Disease threatening hemangioma meeting criteria for oral propranolol
• Previous treatment with topical/oral corticosteroid or propranolol
• Medical history of congenital heart disease with decreased cardiac output, stroke/cerebral vasculopathy, active reactive airway disease or metabolic disorder
• History of an allergic reaction to Mupirocin or Timolol
• Currently taking medication that would interact with beta-blockers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Timolol 0.5% Gel Forming Solution (GFS); Half of enrolled subjects will receive topical Timolol	Drug: Timolol 0.5% Gel Forming Solution (GFS); Dose-based escalation schedule for topical application: 4-8 kg: Day 0-7: 1 drop every other day; Day 7-14: 1 drop daily; Day 14 - Day 60: 1 drop twice per day 8-12 kg: Day 07: 1 drop daily; Day 7-14: 1 drop twice per day; Day 14 - Day 60: 2 drops twice per day; Other Names: Timolol 0.5% topical
Active Comparator: Mupirocin 2% ointment; Half of enrolled subjects will receive Mupirocin	Drug: Mupirocin 2% Ointment; Topical application twice per day for 60 days; Other Names: Mupirocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to Wound Re-epithelization	At 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Ulcer Surface Area and Depth		At 3 months
Investigator's Global Evaluation of Disease	A scoring system developed to measure clinical improvement of ulcerated hemangioma.	At 3 months
Timolol Serum Level		Measured at 1 month into therapy
Evaluate number of participants with changes in Glucose levels after drug is applied	Glucose monitoring will be performed for patients receiving Timolol 0.5% GFS before and 1 hour after drug is applied in clinic. Glucose values < 60 mg/dL will be considered significant. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed.	Baseline, day 7, day 14
Evaluate number of participants with evidence of changes in blood pressure following administration of Timolol 0.5% GFS	Blood pressure monitoring will be performed for patients receiving Timolol 0.5% GFS before and 1 hour after drug is applied in clinic. Blood pressure values < 3rd percentile (systolic or diastolic) will be considered significant for hypotension. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed.	Baseline, day 7, day 14
Pain scores (presence or absence) on the Wong-Baker faces scale	Investigators will question caregivers about common complications of ulcerated hemangiomas (pain, infection, bleeding) at each visit throughout the study. Pain will be assessed using the Wong-Baker faces scale. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed.	Baseline, day 7, day 14, 1 month, 2 months
Number of participants with presence or absence of Infection	Investigators will question caregivers about common complications of ulcerated hemangiomas (pain, infection, bleeding) at each visit throughout the study. Infection will be clinically assessed by presence of drainage or exudate, and/or culture positivity. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed.	Baseline, day 7, day 14, 1 month, 2 months
Number of participants with presence (or absence) of active bleeding	Investigators will question caregivers about common complications of ulcerated hemangiomas (pain, infection, bleeding) at each visit throughout the study. Infection will be clinically assessed by presence of active bleeding. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed.	Baseline, day 7, day 14, 1 month, 2 months
Evaluate number of participants with changes in Heart Rate after drug is applied	Glucose and vital sign monitoring will be performed for patients receiving Timolol 0.5% GFS before and 1 hour after drug is applied in clinic. Heart rate values < 3rd percentile will be considered significant and indicative of bradycardia. Subjects will be seen in clinic on day 7, day 14, 1 month and 2 months into therapy and 1 month after therapy is completed.	Baseline, day 7, day 14

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Society for Pediatric Dermatology
• Investigators: Principal Investigator: Albert C. Yan, MD, Children's Hospital of Philadelphia, Chair of Pediatric Dermatology; Principal Investigator: Vikash S. Oza, MD, Children's Hospital of Philadelphia, Attending Physician; Principal Investigator: Patrick McMahon, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. 2010 May;146(5):564-5. doi: 10.1001/archdermatol.2010.67. No abstract available.
• Sivamani RK, Pullar CE, Manabat-Hidalgo CG, Rocke DM, Carlsen RC, Greenhalgh DG, Isseroff RR. Stress-mediated increases in systemic and local epinephrine impair skin wound healing: potential new indication for beta blockers. PLoS Med. 2009 Jan 13;6(1):e12. doi: 10.1371/journal.pmed.1000012.
• Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, Lipsker D, Dupuis E, Ezzedine K, Vergnes P, Taieb A, Leaute-Labreze C. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics. 2009 Sep;124(3):e423-31. doi: 10.1542/peds.2008-3458. Epub 2009 Aug 10.
• Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol. 2011 Apr;164(4):886-8. doi: 10.1111/j.1365-2133.2010.10177.x. No abstract available.
• Chamlin SL, Haggstrom AN, Drolet BA, Baselga E, Frieden IJ, Garzon MC, Horii KA, Lucky AW, Metry DW, Newell B, Nopper AJ, Mancini AJ. Multicenter prospective study of ulcerated hemangiomas. J Pediatr. 2007 Dec;151(6):684-9, 689.e1. doi: 10.1016/j.jpeds.2007.04.055. Epub 2007 Aug 24. Erratum In: J Pediatr. 2008 Apr;152(4):597.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: March 10, 2011
• First Submitted That Met QC Criteria: August 1, 2011
• First Posted (Estimate): August 3, 2011

Study Record Updates

• Last Update Posted (Estimate): January 17, 2014
• Last Update Submitted That Met QC Criteria: January 16, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Timolol; Hemangioma; Infantile Hemangioma; Ulcerated Hemangioma; Beta blocker; Vascular anomaly
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Skin Abnormalities; Neoplasms, Vascular Tissue; Ulcer; Hemangioma, Capillary; Port-Wine Stain; Hemangioma; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Timolol; Mupirocin
• Other Study ID Numbers: 10-007923