Evaluating the Efficacy and Safety of 4% 5-Fluorouracil Cream in Patients with Actinic Keratosis: An Expert Opinion.

Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors' expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.

Severity of Local Skin Reactions with 4% 5-Fluorouracil Plus Emollient versus 4% 5-Fluorouracil Alone in Patients with Actinic Keratosis: A Single-Blind Randomised Trial.

INTRODUCTION: Topical 5-fluorouracil (5-FU)-containing treatments are effective for actinic keratosis (AK); however, they frequently lead to transient local skin reactions (LSRs), which often result in treatment non-adherence. METHODS: The aim of this international, phase IV clinical trial was to investigate whether addition of an emollient to topical 4% 5-FU would reduce the frequency and severity of LSRs over 4 weeks of treatment (intervention group) compared with 4% 5-FU alone (control group) in patients with AK. The primary objective was to assess the severity of LSRs (i.e. erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) at week 4 of treatment (or before, in case of a major local reaction). Key secondary objectives were LSR total scores at weeks 2 and 8, the scores of individual LSR items at each visit, and the proportions of patients with 100% and ≥ 75% AK lesion clearance at week 8. RESULTS: In total, 141 patients were included in the efficacy analysis (71 in the intervention group and 70 in the control group). There were no statistically or clinically significant differences between the treatment groups in terms of LSR total score at week 4 (overall and by subgroups defined by the number of lesions and patient age at baseline), scores of individual LSR items at any time point, and AK lesion clearance rates at week 8. LSR scores with topical 4% 5-FU alone were lower than expected. Skin reactions were the most common treatment-emergent adverse events in both groups, leading to treatment discontinuation in nine patients (12.3%) in the intervention group and seven (9.9%) in the control group. No new safety signals were observed with the addition of an emollient to 4% 5-FU. CONCLUSIONS: Daily emollient applications during the 4-week treatment course did not impact the safety and efficacy profile of 4% 5-FU.

Evaluation of a Novel Skin Emollient Cream on Skin Lipidome and Lipid Organization.

INTRODUCTION: The stratum corneum (SC) matrix is composed of free fatty acids, cholesterol, and ceramides (CERs), which play a key role in the skin barrier function. Changes in the composition and content of skin lipids will affect the function of the skin barrier. The effect of a glycerol/petrolatum-based emollient (G/P-emollient) cream on the lipid profiles of isolated ex vivo human SC and the SC of a reconstructed human epidermis (RHE) model was measured. METHODS: The spatial organization of the cream and the isolated SC intercellular matrix were studied using X-ray diffraction. The inter-bilayer distances in the multi-lamellar lipid structures and lattice type were analyzed using small-angle X-ray scattering and wide-angle X-ray scattering (WAXS), respectively. Lipidomic analysis using shotgun lipidomics was performed on RHE models to quantify CER classes and chain lengths. This technology enables the analysis of thousands of lipids in a single biological sample. RESULTS: The crystallized components of the cream are lipids, which were mainly packed in orthorhombic lattices, as well as hexagonal lattices and were similar to the SC structure. The cream penetrated the SC but did not alter the WAXS profile. It increased the amount of higher carbon number CERs (>42 carbons) and decreased lower carbon number CERs (<42 carbons). All chain length of CERs and acyl-CER classes (CER EOS, EOH, EOP, EOdS) were increased as the total CER classes. A decrease of the CER C34 for hydroxylated and non-hydroxylated CERs was also observed. The cream altered the S and P CER forms (increased the NP/NS and AP/AS ratios), indicating it could reduce the relative feedback mechanism observed in inflammatory pathologies, for example, atopic dermatitis. The cream increased CER NP, which is decreased in dry skin. CONCLUSION: G/P-emollient cream may be beneficial for skin pathologies by modifying SC lipids, balancing CER levels and ratios, and improving the barrier function. Importantly, the cream structure mimics that of the SC and penetrated the lower SC layers without compromising its lamellar structure.

Early initiation of treatment with oral propranolol for infantile hemangioma improves success rate.

BACKGROUND/OBJECTIVES: Early referral and treatment of infantile hemangioma (IH) is a major challenge for treatment success. However, there is a lack of data supporting a specific threshold for initiating treatment with oral propranolol. The aim of this analysis was to find factors, such as age at treatment initiation, leading to a higher success rate with oral propranolol treatment. METHODS: Based on data from the pivotal phase 2-3 clinical trial of oral propranolol in IH, we used Generalized Additive Model (GAM) charts with Generalized Linear Models (GLM), then a rule discovery algorithm, to identify sub-groups presenting a high probability of occurrence of the predefined outcome (i.e., success [complete or nearly complete resolution of the target hemangioma] at 6 months of treatment). RESULTS: Our analyses identified that patients who started oral propranolol 3 mg/kg/day before the age of 10 weeks had a success rate of 86%, higher than the 60% success rate for all patients that received the same regimen commencing after 10 weeks of age. CONCLUSIONS: Treatment initiation before 10 weeks of age was associated with a significantly higher rate of treatment success with oral propranolol 3 mg/kg/day. Infants with IH requiring treatment should be referred to an expert center and treated as soon as possible.

EczemaPred: A computational framework for personalised prediction of eczema severity dynamics.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease leading to substantial quality of life impairment with heterogeneous treatment responses. People with AD would benefit from personalised treatment strategies, whose design requires predicting how AD severity evolves for each individual. OBJECTIVE: This study aims to develop a computational framework for personalised prediction of AD severity dynamics. METHODS: We introduced EczemaPred, a computational framework to predict patient-dependent dynamic evolution of AD severity using Bayesian state-space models that describe latent dynamics of AD severity items and how they are measured. We used EczemaPred to predict the dynamic evolution of validated patient-oriented scoring atopic dermatitis (PO-SCORAD) by combining predictions from the models for the nine severity items of PO-SCORAD (six intensity signs, extent of eczema, and two subjective symptoms). We validated this approach using longitudinal data from two independent studies: a published clinical study in which PO-SCORAD was measured twice weekly for 347 AD patients over 17 weeks, and another one in which PO-SCORAD was recorded daily by 16 AD patients for 12 weeks. RESULTS: EczemaPred achieved good performance for personalised predictions of PO-SCORAD and its severity items daily to weekly. EczemaPred outperformed standard time-series forecasting models such as a mixed effect autoregressive model. The uncertainty in predicting PO-SCORAD was mainly attributed to that in predicting intensity signs (75% of the overall uncertainty). CONCLUSIONS: EczemaPred serves as a computational framework to make a personalised prediction of AD severity dynamics relevant to clinical practice. EczemaPred is available as an R package.

The Overall Number of Actinic Keratosis Lesions Is Not Predictable by the Number of Visible Lesions: Consequences for Field-Directed Therapies.

Actinic keratoses are keratotic lesions occurring on skin areas extensively damaged by sunlight. Using data from a previously published Phase III randomized, controlled clinical trial in patients with at least 5 actinic keratoses, we explored the potential link between the number of visible actinic keratosis lesions before any treatment and the total number of lesions of the field cancerization as revealed by 5-fluorouracil cream. Our analysis suggests that the baseline number of visible actinic keratoses is a poor indicator of the real number of lesions in the field of cancerization, reinforcing the need to explain the field cancerization concept to patients. (Curr Ther Res Clin Exp. 2022; 82:XXX-XXX) © 2022 Elsevier HS Journals, Inc.

Intensity of Local Skin Reactions During 5-Fluorouracil Treatment Related to the Number of Actinic Keratosis Lesions: A Post Hoc, Exploratory Analysis.

INTRODUCTION: Actinic keratoses (AK) are epithelial lesions caused by chronic skin exposure to ultraviolet light that can progress into squamous cell carcinoma. Although several treatments are effective, they are associated with severe skin reactions, which might be related to the extent of the disease. This study aimed to examine the relationship between the severity of local skin reactions during treatment with 5-fluorouracil 4% cream and the number of AK lesions at baseline. METHODS: This post hoc analysis pooled data from two multicentre randomised phase III studies (HD-FUP3B-048, HD-FUP3B-049) in patients with AK treated with topical 5-fluorouracil 4% once daily (OD) or 5% twice daily (BID) for 4 weeks. First, we compared the severity, assessed using a numerical rating scale, of the local skin reactions between 5-fluorouracil 4% and 5%. Then, we investigated the relationship between the number of lesions at baseline and severe skin reactions with 5-fluorouracil 4% OD. RESULTS: Safety data were included from 397 patients who had received 5-fluorouracil 4% (348 in study HD-FUP3B-048, 49 in study HD-FUP3B-049) OD and 342 (HD-FUP3B-048) who had received 5-fluorouracil 5% BID. For most skin reactions, severe ones were more common in patients treated with 5-fluorouracil 5% cream BID than in those treated with 5-fluorouracil 4% cream OD (P < 0.05). With 5-fluorouracil 4% OD, the incidence of severe erythema was significantly higher in patients with at least 10 lesions (46%) than in patients with 5-10 lesions (28%; P < 0.001). Similar results were observed for the other local skin reactions. CONCLUSION: Treatment with 5-fluorouracil 4% cream OD was associated with less severe local skin reactions than 5-fluorouracil 5% BID. The number of AK lesions at baseline seems to have predictive value regarding the severity of local skin reactions that appear during treatment.

In order to prevent recurrence of actinic keratosis lesions and their progression to invasive squamous cell carcinoma, topical treatment of actinic keratosis often involves treating the field of cancerisation to clear visible and subclinical lesions. The occurrence of local adverse skin reactions during treatment can affect patient adherence to therapy and therefore compromise efficacy. A thorough understanding of the relationships between changes in lesions, actinic keratosis remission and tolerability of topical treatments over time is necessary to manage patient expectations, ensure treatment adherence and optimise clinical outcomes. This exploratory study used pooled data from two pivotal phase III studies to compare local skin reaction severity between 5-fluorouracil 4% cream applied once daily and 5-fluorouracil 5% cream applied twice daily, then to examine the relationship between the severity of local skin reactions during treatment and the number of actinic keratosis lesions at baseline. Local skin reactions appeared to be more severe in patients with more than 10 actinic keratosis lesions at baseline than in those with 5 to 10 lesions. Using a cut-off value of 10 lesions pre-treatment, healthcare practitioners can forewarn patients accordingly of potentially more severe local adverse skin reactions in order to motivate them to complete their treatment, thus ensuring treatment efficacy. If patients are likely to experience intolerable severe skin reactions, practitioners can plan to introduce an appropriate rescue treatment.

Combined effects of glycerol and petrolatum in an emollient cream: A randomized, double-blind, crossover study in healthy volunteers with dry skin.

BACKGROUND: The stratum corneum plays an important protective physiological role in providing a barrier to preventing skin desiccation and penetration of external agents. Emollients are used commonly to improve barrier function and skin hydration. AIMS: The primary objective of this study was to evaluate the effect of an emollient, V0034CR cream, and its active ingredients, to restore the cutaneous barrier. Secondary objectives included assessment of the moisturizing activity of each product and tolerance. The study was not designed to evaluate therapeutic benefit. METHODS: In this randomized, double-blind, 4-arm crossover, clinical pharmacology study, the full emollient V0034CR, its vehicle formulation alone, or with glycerol, or petrolatum, was applied to the forearms of healthy volunteers (n = 51) with dry skin (Kligman score of 2 or 3). Cutaneous permeability by Trans Epidermal Water Loss (TEWL) and skin moisture content by corneometry were serially measured for 12 hours following application. An analysis of variance with repeated measures was performed on the evolution of TEWL and corneometry. RESULTS: V0034CR emollient significantly reduced mean TEWL compared to vehicle (P = .0018) and vehicle + glycerol (P = .0001) and significantly increased mean corneometry scores compared to vehicle (P < .0001) and vehicle + petrolatum (P < .0001). CONCLUSIONS: The emollient V0034CR presented combined effects, with the petrolatum component improving skin barrier function, with a reduction in TEWL, and the glycerol component improving skin hydration.

A high-emollient liquid cleanser for very dry and atopic-prone skin: Results of an in-use tolerance and efficacy study conducted under dermatological, pediatric, and ophthalmological supervision.

BACKGROUND: Emollients play a key role in the treatment of eczematous lesions and xerosis such as in atopic dermatitis. However, studies that show the actual benefits of cleansers are few and far between. AIMS: This study aims to evaluate the tolerance and efficacy of a high-emollient liquid cleanser (HELC) designed for very dry and atopic-prone skin, in the absence of any additional skin care. The product is a soap-free and fragrance-free liquid cleanser, containing mild surfactants and a ternary system of selected emollients: glycerin, vaseline, and paraffin. METHODS: In-use study was conducted under dermatological, pediatric, and ophthalmological supervision in 50 subjects (infants, children, and adults) with "dry to very dry and atopic-prone" skin. The primary objective of this monocentric, open, and intra-individual study was to assess the dermatological and ophthalmological tolerance of HELC after 21 days of using it at least once a day on the face and body. The secondary objectives were to evaluate its efficacy based on a clinical score (SCORAD), assess its short- and long-term moisturizing effect by measuring hydration rates (Corneometer® ), and ascertain its cosmetic acceptability through a subjective evaluation questionnaire. RESULTS: The study validates the good dermatological and ophthalmological tolerance of HELC. Its efficacy was demonstrated by improvements in the SCORAD and moisturizing scores. Furthermore, the product was very well accepted by the subjects. CONCLUSION: The fragrance-free HELC tested in this study for 21 days on "dry to very dry and atopic-prone skin" improves skin dryness and pruritus while ensuring good tolerance.

Central Effects of Beta-Blockers May Be Due to Nitric Oxide and Hydrogen Peroxide Release Independently of Their Ability to Cross the Blood-Brain Barrier.

Propranolol is the first-line treatment for infants suffering from infantile hemangioma. Recently, some authors raised the question of potential neurologic side effects of propranolol due to its lipophilic nature and thus its ability to passively cross the blood-brain barrier (BBB) and accumulate into the brain. Hydrophilic beta-blockers, such as atenolol and nadolol, where therefore introduced in clinical practice. In addition to their classical mode of action in the brain, circulating factors may modulate the release of reactive oxygen/nitrogen species (ROS/RNS) from endothelial cells that compose the BBB without entering the brain. Due to their high capacity to diffuse across membranes, ROS/RNS can reach neurons and modify their activity. The aim of this study was to investigate other mechanisms of actions in which these molecules may display a central effect without actually crossing the BBB. We first performed an oral treatment in mice to measure the accumulation of propranolol, atenolol and nadolol in different brain regions in vivo. We then evaluated the ability of these molecules to induce the release of nitric oxide (NO) and hydrogen peroxide (H2O2) ex vivo in the hypothalamus. As expected, propranolol is able to cross the BBB and is found in brain tissue in higher amounts than atenolol and nadolol. However, all of these beta-blockers are able to induce the secretion of signaling molecules (i.e., NO and/or H2O2) in the hypothalamus, independently of their ability to cross the BBB, deciphering a new potential deleterious impact of hydrophilic beta-blockers in the brain.

Efficacy of Propranolol Between 6 and 12 Months of Age in High-Risk Infantile Hemangioma.

BACKGROUND AND OBJECTIVES: There is no consensus on optimal treatment duration for propranolol in infantile hemangioma (IH). We evaluated the efficacy and safety of oral propranolol solution administered for a minimum of 6 months up to a maximum of 12 months of age in high-risk IH. METHODS: This single-arm, open-label, phase 3 study was conducted in patients aged 35 to 150 days with high-risk IH in 10 hospitals between 2015 and 2017. The study comprised a 6-month initial treatment period (ITP) plus continuation up to 12 months of age if complete success was not achieved, a follow-up, and a retreatment period. Patients received oral propranolol twice daily (3 mg/kg per day). The primary end point was the success rate at the end of the ITP. Furthermore, the persistence of IH response and efficacy of retreatment was evaluated. RESULTS: The success rate after 6 months of treatment was 47%, increasing to 76% at the end of the ITP. Of the patients who achieved success, 68% sustained success for 3 months without treatment, and 24% required retreatment. Of the 8 patients who were retreated, 7 achieved success. Adverse events, reported by 80% of patients, were mild, which were expected in this population or known propranolol side effects. CONCLUSIONS: Oral propranolol administered beyond 6 months and up to 12 months of age meaningfully increases the success rate in high-risk IH. Success was sustained in most patients up to 3 months after stopping treatment. Retreatment was efficacious, and the safety profile satisfactory.

Propranolol pharmacokinetics in infants treated for Infantile Hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg-1 day-1 given twice daily (BID) in infants (77-243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty-seven plasma concentrations from 22 infants were used in the population analysis. Weight effect was tested on apparent clearance and volume of distribution. Monte-Carlo simulations were performed for 4 dosing regimens: BID dosing with irregular or strict 12-hour intervals and 2 different 3 time daily dosing (TID) regimens. The best model was a one-compartment model with first-order absorption and elimination rates. The weight affected the clearance but not the volume. Typical oral clearance was estimated at 3.06 L hour-1 kg-1 (95% CI: 1.14-8.61 L hour-1 kg-1), close to adult clearance data. When regular BID dosing was compared to TID or irregular BID regimens, simulated median Cmin and Cmax were <20% different. To conclude, a model using a weight allometric function on clearance was established and confirmed that the dose in mg/kg should be used without adaptation by range of age in treatment of complicated IH. The simulations support the use of a BID dosing preferably to a TID dosing thanks to close Cmin and Cmax at steady state between both regimen and showed the possibility of irregular BID dosing, allowing early administration in the evening when needed.

Burden of Infantile Hemangioma on Family: An International Observational Cross-Sectional Study.

BACKGROUND/OBJECTIVES: Infantile hemangioma (IH) is the most frequent benign tumor of infancy resulting from vascular proliferation. Data regarding the burden on families of children with IHs are limited. This study aimed to characterize IHs and provide a comprehensive evaluation of the burden of IHs on parents of children requiring systemic treatment in the United States and Europe. METHODS: This noninterventional cross-sectional study included infants with newly diagnosed IH requiring systemic treatment. A parent or family member completed two questionnaires (Family Member questionnaire; Hemangioma Family Burden [HFB] questionnaire). RESULTS: A total of 693 individuals were evaluable in five countries. IHs were observed in more girls than boys (66%-83% female) and the mean age at inclusion was 0.44 to 1.4 years. Approximately half of patients had superficial IHs, approximately 70% of cases affected the head, and approximately 80% of cases were moderate or severe. Most patients received propranolol treatment. Their child's IH affected more than 70% of parents in each country, but fewer than 10% were offered psychological support. Approximately half of all parents reported that their child's IH affected their professional life. The global HFB score was significantly (p < 0.001) greater with greater IH severity. More than 90% of parents in each country were satisfied with the care of their child's disease. CONCLUSIONS: This international study using the validated HFB questionnaire provides further insight into the burden of IH and highlights potential areas for future focus in assisting families with affected children.

Prevention of Flares in Children with Atopic Dermatitis with Regular Use of an Emollient Containing Glycerol and Paraffin: A Randomized Controlled Study.

BACKGROUND/OBJECTIVES: Emollients are part of the standard treatment for atopic dermatitis (AD), although there is limited evidence that regular use of emollients as management therapy reduces the frequency of flares and corticosteroid consumption. The objective of this study was to evaluate the benefit of emollient use in the management of mild to moderate AD in children by assessing the ability of two different emollients (particularly V0034CR) to prevent flares and to reduce the use of corticosteroids. METHODS: In this randomized, open-label study, patients with a current flare were treated with a potent topical corticosteroid. After flare resolution, patients were centrally randomized to V0034CR emollient, reference emollient, or no emollient (1:1:1 ratio) for 12 weeks. New flares were medically assessed before being treated with a moderately potent corticosteroid. RESULTS: A total of 335 children 2 to 6 years of age were randomized. At 12 weeks, the percentage of patients with one or more flares was statistically significantly lower with V0034CR (35.1%) than without emollient (67.6%; p < 0.001). Fewer patients treated with V0034CR required any corticosteroids or immunosuppressants (23.6%) than patients with no emollient (43.3%) at 12 weeks. The difference was significant at all time points (p = 0.002). Patients treated with emollients had a longer time to first flare, fewer flares, higher complete remission rates, less corticosteroid consumption, lower Investigator Global Assessment scores, and lower Scoring Atopic Dermatitis scores than those who were not. V0034CR was well tolerated, with no specific safety concerns. CONCLUSION: Regular emollient use in children with mild to moderate AD reduces flares and corticosteroid consumption.

Regression of cutaneous xerosis with emollient treatment in sub-Saharan African patients.

Emollients have proven effective in improving cutaneous xerosis in various populations; however, no clinical data are available for African patients. The observational study "Xerafrica" was conducted by dermatologists in seven sub-Saharan countries to assess the evolution of xerosis after an 8-week treatment with an emollient. Patients were children above 3 years or adults. Secondary objectives were to assess pruritus, improvement in symptoms, quality of life, satisfaction, and tolerance. An analysis of 185 patients was made. After 8 weeks of emollient treatment, the relative reduction of the "Scaling Roughness Redness Cracks" (SRRC) score was -83.9% and -80.4% in children and adults, respectively. The effect was significantly stronger when topical steroids were co-prescribed with the emollient and in patients with co-dermatosis. To a lesser extent, the effect of emollient was also observed at week 4. Similarly, pruritus and quality of life strongly improved during follow-up. Skin lesions improved in almost all patients, with a high level of satisfaction noted by both dermatologists and patients. The "Xerafrica" study addressed, for the first time, the treatment of xerosis by emollients in an African population. In this specific context, the emollient markedly reduced xerosis as soon as 4 weeks and resolved it almost totally by 8 weeks. The study confirms, under real-life conditions, the efficacy and tolerability of an emollient in improving xerosis.

Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review.

BACKGROUND AND OBJECTIVES: Given the widespread use of propranolol in infantile hemangioma (IH) it was considered essential to perform a systematic review of its safety. The objectives of this review were to evaluate the safety profile of oral propranolol in the treatment of IH. METHODS: We searched Embase and Medline databases (2007-July 2014) and unpublished data from the manufacturer of Hemangiol/Hemangeol (marketed pediatric formulation of oral propranolol; Pierre Fabre Dermatologie, Lavaur, France). Selected studies included ≥10 patients treated with oral propranolol for IH and that either reported ≥1 adverse event or effect (AE) or planned to capture AEs. Data capture was standardized and extracted study design, demographic characteristics, IH characteristics, intervention, and safety outcomes. AEs were assigned a system organ class and preferred term. RESULTS: A total of 83 of 398 identified literature records met the inclusion criteria, covering 3766 propranolol-treated patients. The manufacturer's data for 3 pooled clinical trials (435 propranolol-treated patients) and 1 Compassionate Use Program (1661 patients) were included. AE data were reported for 1945 of 5862 propranolol-treated patients. The most frequently reported AEs included a range of sleep disturbances, peripheral coldness, and agitation. The most serious AEs (atrioventricular block, bradycardia, hypotension, bronchospasm/bronchial hyperreactivity, and hypoglycemia-related seizures) were managed by decreasing doses or temporary/permanent discontinuation of propranolol. Limitations included the variety of included study designs; monitoring, collection, and reporting of AE data; small sample sizes for some articles; and the wide scope of review. CONCLUSIONS: Oral propranolol is well tolerated if appropriate pretreatment assessments and within-treatment monitoring are performed to exclude patients with contraindications and to minimize serious side effects during treatment.

A randomized, controlled trial of oral propranolol in infantile hemangioma.

BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).