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.).

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.

Smoking and dietary factors associated with moderate-to-severe acne in French adolescents and young adults: results of a survey using a representative sample.

BACKGROUND: Dietary factors and smoking play a role in acne. METHODS: CSA Santé conducted a survey in France in 2012. Each individual answered a questionnaire to report acne, with associated epidemiological variables. Data on subjects between 15 and 24 years of age were extracted. The characteristics of subjects reporting acne were compared to subjects reporting no acne, using univariate and multivariate analysis. RESULTS: The daily consumption of chocolate and sweets was independently and highly associated with acne, with an odds ratio of 2.38 (95% CI: 1.31-4.31). Smoking more than 10 cigarettes a day was highly associated with no acne, with an odds ratio of 0.44 (95% CI: 0.30-0.66). The regular use of cannabis was associated with acne, with an odds ratio of 2.88 (95% CI: 1.55-5.37). CONCLUSION: Chocolate, sweets and cannabis smoking are associated with acne. We found tobacco to be protective. We failed to investigate the respective roles of sugar, lipids and milk.

Consequences of acne on stress, fatigue, sleep disorders and sexual activity: a population-based study.

Acne is a common disease among young people, which could have a serious impact on quality of life. Based on a survey using the quotas method on a large sample of the French population, we studied the impact of acne on feelings of stress, fatigue upon waking, sleep disorders and sexual activity. We did not establish any relationship to sleep disorders, but clearly ascertained that people with acne (n = 1,375) feel more stressed and have less sexual intercourse. Hence, 18% of people from acne group declared to be stressed every day (13.9% in control group) and 37.5% had no sexual intercourse (20.4% in control group; n = 891). To our knowledge, this is the first study to show that fatigue upon waking is strongly associated with the presence of acne (65.4% versus 58.4%). This study emphasises the fact that acne could have a deep resounding impact on the lives of people suffering from the disease.

Haemangioma family burden: creation of a specific questionnaire.

To develop and validate a specific questionnaire to assess burden on families of children with infantile haemangioma (IH): the Haemangioma Family Burden questionnaire (HFB). Items were generated from a literature review and a verbatim report from parents. Subsequently, a study was implemented at the Necker Hospital and the Pellegrin Children's Hospital for psychometric analysis. The HFB was refined via item reduction according to inter-question correlations, consensus among experts and exploratory factor analysis. A 20-item questionnaire, grouped into 5 dimensions, was obtained. Construct validity was demonstrated and HFB showed good internal coherence (Cronbach's α: 0.93). The HFB was significantly correlated with the mental dimension of the Short-Form-12 (r = -0.75), and the Psychological General Well-Being Index (r = -0.61). HFB scores differed significantly according to the size and localization of the IH. A validated tool for assessing the burden on families of children with IH is now available.

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.

Efficacy and safety of a new 5% minoxidil formulation in male androgenetic alopecia: A randomized, placebo-controlled, double-blind, noninferiority study.

BACKGROUND: Androgenetic alopecia (AGA) is the most common cause of hair loss in men. Topical minoxidil solutions can help to treat AGA but have to be applied continuously to be effective. OBJECTIVES: A new minoxidil formulation with improved cosmetic characteristics (DC0120, Pierre-Fabre Dermatologie) was tested for noninferiority vs a comparator minoxidil product (ALOSTIL® , Johnson & Johnson) in stimulating hair growth in men with AGA. METHODS: Two 10 cm2 areas on the scalp of each subject were randomized to receive DC0120, the comparator, or one of their corresponding vehicles, applied twice per day for 16 weeks. Nonvellus target area hair count (TAHC) was measured within treatment areas at baseline (day 1) and after 8 and 16 weeks by digital phototrichogram. RESULTS: Two hundred and twenty subjects were included and randomized, of which 210 completed the study. The mean change in nonvellus TAHC between baseline and week 16 was +22.0 hairs/cm2 (95% CI: 18.1; 25.9) in the DC0120 group and +20.5 hairs/cm2 (95% CI: 16.6; 24.4) in the comparator group. The adjusted mean difference in TAHC changes between the two treatments was +1.5 hairs/cm2 (95% CI -2.3; 5.2), with the lower 95% confidence interval above the noninferiority threshold of -7 hairs/cm2 . This indicated that DC0120 was noninferior to the comparator. Both minoxidil treatments also increased nonvellus TAHC compared to vehicle groups at 8 and 16 weeks. No new safety signals were observed. CONCLUSIONS: DC0120 was as safe and effective as a similar marketed minoxidil product for stimulating hair growth in men with AGA.

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.

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.

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.