Timolol for the Prevention of Proliferation of Infantile Hemangioma (TiPPIH Trial)

Study Overview
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Brief Summary
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The purpose of this trial is to see if a topical beta blocker is effective in preventing the proliferation of infantile hemangioma.

Detailed Description
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Infantile hemangiomas (IH) are among the most common, benign vascular tumors of infancy with an estimated prevalence of 4-5% of the population. IH are not found at birth but become evident within the first few weeks of life. They are characterized by a rapid proliferative phase that can last up to 4-6 months or longer and then a period of minimal or absent growth before an involutive phase where they may resolve with minimal or no scarring over multiple years. Although frequently thought of as benign lesions, hemangiomas can occur in locations to cause functional impairment of vital organs, can lead to ulcerations, scarring or disfigurement, and can lead to life-threatening complications. Management of these problematic IH includes laser, long-term systemic corticosteroids, interferon, Vincristine, surgery, and most recently systemic propranolol. Pulsed-dye laser is the only treatment approved by the FDA; it has been useful for superficial hemangiomas but has little effect on subcutaneous or deep-seated hemangiomas. The proposed therapeutic effects of propranolol are vasoconstriction, decreased expression of vascular endothelial growth factor (VEGR) and basic fibroblast growth factors (bFGF) genes through downregulation of Raf/mitogen-activated protein kinase pathway, and apoptosis of capillary endothelial cells. For periorbital lesions that may cause amblyopia or anisometropia, topical Timolol has been reported to be of benefit. There is one retrospective review that is proof of concept that shows that topical timolol is safe and effective treatment for 6 cases of IH. The advantage of a topical therapy is the decreased risk of systemic side effects compared with oral or intravenous administration. The disadvantage is that limited penetration may preclude effectiveness for the thicker or deeper lesions. Being of low birth weight as well as prematurity are known risk factors for IH. In the premature infant development clinic at the University of Texas Health Science Center in San Antonio infants less than 1500 grams birth weight are followed for three years following discharge from the Newborn Intensive Care Unit (NICU); approximately 16% of these infants have hemangiomas. Therefore the investigators find it reasonable to start treatment with a topical beta blocker at an early stage of hemangioma to prevent the growth and proliferation and hence the possible severe effects associated with growth and thus impairment of vital organs/tissues.

Official Title
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Phase 1 Study of Topical Beta Blocker to Prevent the Proliferative Stage of Infantile Hemangioma

Conditions
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Infantile Hemangioma, Very Low Birth Weight Infants

Intervention / Treatment
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* Drug: topical 0.5% Timolol maleate
* Drug: Control (placebo) group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Babies admitted to NICU or seen in follow clinic that have a diagnosis of hemangioma that is verified by Principal Investigator (PI) or Co-Principal Investigators. Exclusion Criteria: Babies with PHACES (Posterior fossa, Hemangioma, Arterial lesions, Cardiac abnormalities, Eye abnormalities) syndrome Babies with cardiac conditions that may predispose to heart block Babies with persistent hypoglycemia Babies on medications that may interact with beta blockers Babies who are hemodynamically unstable and are requiring pressors to maintain blood pressure Babies who are on systemic corticosteroid therapy

Ages Eligible for Study
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Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Timolol<br>Application of 1-2 drops of Timolol maleate 0.5% ophthalmic aqueous solution to hemangioma twice daily. | Drug: topical 0.5% Timolol maleate<br>* topical 0.5% Timolol aqueous solution, 1-2 drops to cover the hemangioma, twice daily<br>|
| Placebo Comparator: Placebo<br>Application of 1-2 drops of placebo gel twice daily to hemangioma. | Drug: Control (placebo) group<br>* Aqueous placebo, 1-2 drops to cover the hemangioma, twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects in treatment group compared to placebo group with at least 50% improvement in the extent of hemangioma as compared to each other with respect to changes from baseline photographs. | hemangioma once detected will be measured and photographed. Measurements and photographs will be obtained every 2 weeks while the patient is in hospital and monthly after discharged until end point of 6 months. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare treatment group to placebo group assessments | Difference in color of the hemangioma of the treatment group versus control group | 6 months | 
| Compare treatment group to placebo group assessments | More significant Retinopathy of Prematurity findings between treatment group versus control group | 6 months | 
| Compare treatment group to placebo group assessments | Frequency of adverse events (e.g. hypotension, behavioral changes, etc.) collected by investigator and reported by NICU staff and parents. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infantile hemangioma, very low birth weight infants, premature infants