RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas in 5- to 24-Week-Olds

Chan, Hsien; McKay, Colette M.; Adams, Susan; Wargon, Orli

doi:10.1542/peds.2012-3828

Cited by 133 publications

(115 citation statements)

References 34 publications

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“…26,27 One study comparing ophthalmic timolol and imiquimod reported no differences in effects. 28 Two studies using laser as a comparator reported mixed results: no differences in average overall improvement in 1 study comparing timolol and timolol plus laser modalities 30 and greater response to timolol in superficial IH, with greater response of mixed IH to timolol plus laser in another.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22] One cohort study compared oral propranolol (2 mg/kg/day) and intralesional bleomycin (0.5 mg/kg) 23 ; and 1 RCT and 1 cohort study evaluated oral propranolol (2-3 mg/kg/day) and other β-blockers (1-4 mg/kg/ day). 24,25 Three cohort studies and 2 RCTs assessed topical timolol (0.5%) compared with placebo or observation or another agent, [26][27][28][29][30] and 1 RCT and 1 cohort study evaluated different steroids, including oral prednisone and intralesional triamcinolone. 31,32 Studies included a total of 1265 children with IH (ages ranging from 2 weeks to 9 years), and most were fair quality.…”

Section: Study Selection and Study Characteristicsmentioning

confidence: 99%

“…15,16,18,20,23,25,26,[29][30][31] Two studies rated improvement as greater or less than either 50% 32 or 75%. 21 The additional studies reported percent reduction, 27 change in total surface area, 19 or mean percentage decrease in size. 17 Fourteen studies explicitly reported using masked assessors to rate changes in IH.…”

Section: Study Selection and Study Characteristicsmentioning

confidence: 99%

“…17 Fourteen studies explicitly reported using masked assessors to rate changes in IH. [15][16][17][19][20][21][22]24,25,27,[29][30][31][32] All studies included IH in multiple anatomic locations, and lesion types (when reported) also varied, with the exception of most studies of topical timolol, which generally included only superficial lesions. Supplemental Table 5 outlines key study characteristics.…”

Section: Study Selection and Study Characteristicsmentioning

confidence: 99%

“…[33][34][35] A senior reviewer resolved discrepancies in quality assessment. We considered 4 studies as good quality 15,19,27,31 and 5 as poor quality. 23,24,26,29,32 Two investigators also graded the strength of the body of evidence (confidence in the estimate of effect) by using methods based on the Methods Guide for Effectiveness and Comparative Effectiveness Reviews.…”

Section: Assessment Of Study Quality and Strength Of Evidencementioning

confidence: 99%

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Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis

Chinnadurai¹,

Fonnesbeck

Snyder

et al. 2016

Pediatrics

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STUDY SELECTION: Two reviewers assessed studies using predetermined inclusion criteria. DATA EXTRACTION:One reviewer extracted data with review by a second. RESULTS:We included 18 studies in a network meta-analysis assessing relative expected rates of IH clearance associated with β-blockers and steroids. Oral propranolol had the largest mean estimate of expected clearance (95%; 95% Bayesian credible interval [BCI]: 88%-99%) relative to oral corticosteroids (43%, 95% BCI: 21%-66%) and control (6%, 95% BCI: 1%-11%). Strength of evidence (SOE) was high for propranolol's effects on reducing lesion size compared with observation/placebo. Corticosteroids demonstrated moderate effectiveness at reducing size/volume (moderate SOE for improvement in IH). SOE was low for effects of topical timolol versus placebo. LIMITATIONS:Methodologic limitations of available evidence may compromise SOE. Validity of meta-analytic estimates relies on the assumption of exchangeability among studies, conditional on effects of the intervention. Results rely on assumed lack of reporting bias. CONCLUSIONS:Propranolol is effective at reducing IH size compared with placebo, observation, and other treatments including steroids in most studies. Corticosteroids demonstrate moderate effectiveness at reducing IH size/volume. The meta-analysis estimates provide a relative ranking of anticipated rates of lesion clearance among treatments. Families and clinicians making treatment decisions should also factor in elements such as lesion size, location, number, and type, and patient and family preferences. Dr Chinnadurai contributed to the conceptualization and design of the original review and meta-analysis and helped assess studies, verify data, develop the analysis, and draft the initial manuscript; Dr Fonnesbeck contributed to the conceptualization and design of the original review and meta-analysis, conducted the metaanalysis, and helped verify data and draft the initial manuscript; Drs Likis and McPheeters contributed to the conceptualization and design of the original review and meta-analysis and helped assess studies, develop the analysis, and draft the initial manuscript; Drs Morad and Snyder contributed to the conceptualization and design of the original review and meta-analysis and helped assess studies, verify data, develop the analysis, and draft the initial manuscript; Ms Sathe contributed to the conceptualization and design of the original review and meta-analysis and helped evaluate studies, extract and verify data, develop the analysis, and draft the initial manuscript; and all authors approved the fi nal manuscript as submitted. Infantile hemangiomas (IH) are the most common tumors of childhood. IH are benign but possess potential for permanent local tissue damage, ulceration, infection, bleeding, functional impact, and pain. Because of historical inconsistencies in naming conventions, the true prevalence of IH is unclear, but it is estimated that they affect ∼4% to 5% of children, 1 with higher prevalence in females and Caucasians. 2,3 ...

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Section: Discussionmentioning

confidence: 99%

Section: Study Selection and Study Characteristicsmentioning

confidence: 99%

Section: Study Selection and Study Characteristicsmentioning

confidence: 99%

Section: Study Selection and Study Characteristicsmentioning

confidence: 99%

Section: Assessment Of Study Quality and Strength Of Evidencementioning

confidence: 99%

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Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis

Chinnadurai¹,

Fonnesbeck

Snyder

et al. 2016

Pediatrics

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Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage

et al. 2021

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IMPORTANCETreatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for treatment with oral propranolol. To our knowledge, no studies have determined whether beginning early treatment with timolol for IH is better than in other proliferative stages.OBJECTIVE To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the early treatment of IH in infants younger than 60 days.DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, double-blind, placebo-controlled, phase 2a pilot clinical trial included patients aged 10 to 60 days with focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth). Patients were randomly assigned to treatment with topical timolol maleate solution, 0.5%, or placebo twice daily for 24 weeks. Changes in lesion size (volume, thickness) and color were evaluated from photographs taken at 2, 4, 8, 12, 24, and 36 weeks. Vital signs and adverse effects were recorded at each visit. The study was carried out from November 2015 to January 2017, and data analyses were completed in September 2019. MAIN OUTCOMES AND MEASURESThe primary outcome of complete or nearly complete IH resolution and the secondary outcomes of changes in lesion thickness, volume, and color were evaluated by a blinded investigator. RESULTSOf the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days; 55 (80%) were female; and 51 (74%), 11 (16%), 6 (9%), and 1 (1%) had superficial, mixed, abortive, or deep IHs, respectively. The IHs were localized, segmental, or indeterminate in 60 (87%), 7 (10%), and 2 (3%) patients, respectively. The IHs were located on the head and/or neck (n = 23 [33%]) or other body sites (n = 46 [67%]). The study was completed by 26 of 33 (79%) patients receiving timolol and 31 of 36 (86%) receiving placebo. There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37). The odds ratio of complete or almost complete response vs no response at week 24 was 1.33 (95% CI, 0.45-3.89). There were no between-group differences in IH size (volume, thickness). An improvement in color was observed at week 4 in the timolol group, and timolol was well tolerated with no systemic adverse effects. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, results demonstrated that topical timolol is well tolerated for the treatment of early proliferative IH but provides limited benefit in lesion resolution when given during the early proliferative stage.

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Interventions for infantile haemangiomas of the skin

Novoa

Baselga

Beltrán

et al. 2018

Cochrane Database of Systematic Reviews

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We found there to be a limited evidence base for the treatment of infantile haemangiomas: a large number of interventions and outcomes have not been assessed in RCTs.Our key results indicate that in the management of IH in children, oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harms. We found no evidence of a difference between oral propranolol and topical timolol maleate with regard to reducing haemangioma size, but we are uncertain if there is a difference in safety. Oral propranolol is currently the standard treatment for this condition, and our review has not found evidence to challenge this. However, these results are based on moderate- to very low-quality evidence.The included studies were limited by small sample sizes and risk of bias in some domains. Future trials should blind personnel and participants; describe trials thoroughly in publications; and recruit a sufficient number of children to deduce meaningful results. Future trials should assess patient-reported outcomes, as well as objective outcomes of benefit, and should report adverse events comprehensively. Propranolol and timolol maleate require further assessment in RCTs of all types of IH, including those considered problematic, as do other lesser-used interventions and new interventions. All treatments should be compared against propranolol and timolol maleate, as beta blockers are approved as standard care.

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RCT of Timolol Maleate Gel for Superficial Infantile Hemangiomas in 5- to 24-Week-Olds

Cited by 133 publications

References 34 publications

Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis

Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis

Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage

Interventions for infantile haemangiomas of the skin

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