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.
- AE —
- adverse event
- BID —
- twice daily
- CI —
- confidence interval
- FAS —
- full analysis set
- HFB —
- Haemangioma Family Burden
- HR —
- heart rate
- IH —
- infantile hemangioma
- ITP —
- initial treatment period
- PP —
- per protocol
- QoL —
- quality of life
- SF-36 —
- 36-item short-form
- TEAE —
- treatment-emergent adverse event
- TESAE —
- treatment-emergent serious adverse event
What’s Known on This Subject:
Propranolol is the first-line therapy in the treatment of infantile hemangioma (IH). Efficacy and safety have been demonstrated in a placebo-controlled study (complete and/or near complete resolution in 60% of patients after 6 months of treatment at 3 mg/kg per day) in which high-risk IH were excluded.
What This Study Adds:
This study reveals that in high-risk IH, extending propranolol treatment beyond 6 months up to a maximum of 12 months of age produces a clinically meaningful increase in the success rate. The safety profile of propranolol remains satisfactory.
Infantile hemangiomas (IHs) are benign vascular tumors characterized by endotheliallike cell proliferation,1 with an estimated incidence of 4% to 5%.2 Although most IHs have an uncomplicated clinical course, some are associated with complications that can be life altering or life- and function threatening.3–5 Permanent sequelae can be psychologically distressing.6 In a large US cohort study involving 1058 children with IH, 24% experienced complications, with the most common being ulceration and, to a lesser extent, threat to vision and airway obstruction.4
In 2008, several cases of successful IH treatment with oral propranolol were reported.7 Since then, several retrospective, observational,8–10 and early small placebo-controlled studies11,12 revealed the efficacy of oral propranolol for the treatment of IH. This was recently confirmed in a large, pivotal, randomized, placebo-controlled study with an adaptive design in which researchers selected 3 vs 1 mg/kg per day for 6 months as the most effective regimen.13 Propranolol is now the first-line therapy for IH, and although there is currently no consensus on the optimal treatment duration, treatment up to 12 months of age has been proposed for patients who do not fully respond to 6 months of treatment.14–17
Because the pivotal study was performed in comparison with a placebo, patients with high-risk IH were excluded for ethical reasons.13 Therefore, we evaluated the efficacy and safety of oral propranolol in patients with high-risk IH when administered for a minimum of 6 months and up to a maximum of 12 months of age. Furthermore, because rebound growth is reported in ∼25% of patients after stopping propranolol,18,19 the persistence of IH response and the efficacy of retreatment was evaluated along with the impact of treatment on parents’ quality of life (QoL).
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines and approved by local ethics committees and competent authorities in the participating countries. Parents and/or guardians provided written informed consent according to national regulations. The study is registered with the European Union Clinical Trials Register (European Union Drug Regulating Authorities Clinical Trials database number 2014 005555-80).
Between June 29, 2015, and February 21, 2017, patients were recruited across 10 centers (hospitals and clinics) in Spain and Poland. Eligible participants were male and female infants aged 35 to 150 days (corrected age for premature infants) with high-risk IH in the proliferative phase. High-risk IHs were defined as those that were either life-threatening, at risk for functional impact (in the following locations: periorbital, nasal, labial, laryngotracheal, or limb joints), disfiguring (IH diameter >5 cm or in the following locations: glabella, nasal, philtrum, central chin, central cheek, or labial with mouth deformities), or ulcerated nonresponsive to standard wound care measures. Key noninclusion criteria included having a congenital hemangioma; Kasabach-Merritt syndrome and posterior fossa, hemangioma, arterial lesions, cardiac abnormalities and/or aortic coarctation, and eye abnormalities syndrome; asthma; bronchospasm; hypoglycemia; hyperkaliemia; and bradycardia and previous hemangioma treatment (see Supplemental Information for detailed eligibility criteria).
Study Design and Treatments
In this multicenter, phase 3, open-label, single-arm study, we assessed the efficacy and safety of oral propranolol (Hemangiol, propranolol hydrochloride, 3.75 mg/mL oral solution; Pierre Fabre Dermatologie, Boulogne-Billancourt, France) administered twice daily (BID) at a dose of 3 mg/kg per day. The study consisted of an initial treatment period (ITP), a follow-up, and a retreatment period. During the ITP, patients received oral propranolol for a minimum of 6 months. If treatment success was not achieved by month 6, treatment was continued (continuation period) until success or up to 12 months of age. Patients who achieved success in the ITP were managed for 3 months with no treatment. If rebound growth occurred within the follow-up period, treatment was reinitiated at the investigator’s discretion until success for 6 months maximum. Initiation and reinitiation of treatment in each study period were started with a 2-week dose titration phase (1 mg/kg per day from days 1 to 7 and 2 mg/kg per day from days 8 to 14). During treatment periods, the total daily dose of propranolol was administered BID (dose was divided equally between morning and late afternoon at least 9 hours apart).
During the ITP, scheduled visits were on day 1 (inclusion visit and baseline), day 8, day 15, month 1, month 2, month 3, month 4, month 5, month 6, and every 2 months thereafter during the continuation period (continuation visits 1 and 2). During the follow-up period, visits were at month 1 and month 3 (follow-ups 1 and 2). During the retreatment period, visits were on day 1 (reinitiation visit), day 8, day 15, month 2, month 4, and month 6 (retreatment visits 1–6).
Outcome Measures and Clinical Assessments
Treatment success was assessed by the investigator at each postbaseline visit and was defined as the resolution of the target IH and absence of functional impact. Qualitative assessment was performed by the investigator at each visit, who documented the size of the superficial and deep component, color intensity, tenseness, elevation of the superficial component, presence of a deep component, and distortion of local anatomic landmarks (Supplemental Information). Resolution was defined as IH disappearance even if a minimal degree of telangiectasias, erythema, skin thickening, soft tissue swelling, and/or palpable component persisted or sequelae were present. Functional impact was assessed by using the Hemangioma Severity and Hemangioma Dynamic Complication scales (ulceration, feeding difficulties, torticollis, cartilage distortion or destruction, airway involvement, visual compromise, and pain, each on a scale of 4–6),20 where 0 represented the absence of complications (Supplemental Information). The evolution of the target IH (improvement, stabilization, or worsening) was assessed by the investigator at each postbaseline visit and compared with the baseline as well as the previous visit.
QoL and disease burden on the parent and/or guardian were assessed respectively by using the 36-item short-form (SF-36)21 and Haemangioma Family Burden (HFB)22 questionnaires, which was performed at enrollment, month 1, month 3 (SF-36 only), month 6, the end of ITP (in the case of treatment continuation beyond 6 months), and the end of the follow-up period. From the SF-36, 8 scale scores were calculated, from which a summary measure for both physical and mental health was determined. From the HFB questionnaire, 6 dimension scores were calculated, from which a total score was calculated.
Safety was primarily assessed by analysis of adverse events (AEs) and recorded throughout the study from signatures of informed consent. AEs were coded by using the Medical Dictionary for Regulatory Activities version 19.0 and recorded as either treatment-emergent adverse events (TEAEs), meaning AEs that occurred or worsened while on the study treatment or up to 5 days after the last day of study treatment or each treatment period, or non-TEAEs. All AEs were classified according to seriousness, severity, and relationship to the study drug. In addition, physical examinations, blood pressure, heart rate (HR), height, and weight measurements were performed at each visit. Blood pressure and HR were monitored closely for 2 hours after dose administration at initiation and/or reinitiation of treatment and each titration period.
The primary end point was treatment success (yes or no) at the end of the ITP. Patients being withdrawn prematurely (before the end of the ITP) for inefficacy or safety reasons with a related AE leading to definitive study drug discontinuation and/or receiving prohibited treatments for the target IH were considered treatment failures. Secondary end points included treatment success (yes or no) after 6 months of treatment and at each visit throughout the study, time (in days) to first sustained success from day 1 up to the end of the study, reinitiation of treatment (reinitiation or no reinitiation), QoL (SF-36 and HFB questionnaires), and the assessment of safety (primarily, AEs). Other prespecified secondary end points are presented in the Supplemental Information.
The sample size was based on a 60% success rate at the end of treatment (achieved in the pivotal study13), an α risk of 5% in 2-sided conditions, and a half-width confidence interval (CI) of the success rate set at 15% (meaning the lower limit of the CI would be >45%, which is above the rate of resolution without treatment).23 Assuming a dropout of 10%, 45 evaluable patients were required.
The full analysis set (FAS), or all patients who received at least 1 dose of study treatment, was the primary analysis set for all planned efficacy, QoL, and safety analyses. The per protocol (PP) set (patients from the FAS without major protocol deviation or other source of bias and minimal treatment exposure of 6 months) was used for a supportive efficacy analysis of the primary end point. Two sensitivity analyses were conducted on the primary end point: 1 on the FAS, without imputation for missing data, and 1 on the subset of patients in the FAS who completed the ITP. All statistical results were descriptive (qualitative variables: number, percentage, and 95% CI; continuous data: number, mean, SD, median, lower and upper quartiles, minimum, and maximum). No statistical tests were performed. Last observation carried forward imputation was used for an analysis of the primary variable and the secondary variable, success at 6 months, in the FAS. Time to sustained success and/or improvement was estimated by using the Kaplan-Meier method. SAS software version 9.4 (SAS Institute, Inc, Cary, NC) was used.
The FAS included 45 enrolled patients who received at least 1 dose of the study drug (Fig 1). Two patients were prematurely withdrawn during the ITP: 1 patient for lack of efficacy and 1 patient because of the parent and/or guardian’s decision. Therefore, 43 patients completed the study (study completers were those who completed the ITP). Of these, 34 patients entered the follow-up period, and 8 entered the retreatment period. The PP population consisted of 40 patients; 5 patients in the FAS were excluded for major protocol deviations, the most frequent being treatment interruption >30 days.
Demographic and baseline characteristics met the expected population profile observed in previous studies17,24: patients were predominantly girls (33 of 45; 73%) and had facial IHs (35 of 45; 78%), and most IHs were localized (28 of 45; 62%). The mean largest diameter for the superficial component was 3.88 cm (SD 2.90 cm; range 0.1 to 12.5 cm), and the mean for the deep component was 3.49 cm (SD 3.09 cm; range 0.5 to 14.0 cm). The mean age at first propranolol administration was 91.9 days (SD 38 days). The rate of patients who were initiated between 35 and 90 days of age was 58% (Table 1). Treatment compliance was high during the initial (96%) and retreatment (100%) periods.
Primary End Point
Treatment success was achieved by 34 patients (76%; 95% CI 61.7%–86.3%) by the end of the ITP. The results of the primary efficacy analysis were confirmed in both the supportive and sensitivity analyses (Supplemental Table 3).
Secondary End Points
After 6 months of treatment, success was achieved by 21 patients (47%; 95% CI 32.7%–61.1%; Fig 2). Sustained success (first visit for which success was obtained and maintained at each scheduled subsequent visit) from day 1 up to the end of follow-up was reported in 23 patients (51%), with a median time to success of 290 days (range of 64 to 307 days).
Of the 34 patients who achieved treatment success during the ITP, 11 had rebound growth, 8 of whom were judged by the investigator as requiring retreatment. By the end of the retreatment period, 7 of the 8 patients had achieved success. The duration of initial treatment did not appear to influence whether patients required retreatment; of the 8 patients who were retreated, 5 had completed the minimum 6 months only, and 3 had continued until 12 months of age. Investigators continued treatment in 9 patients without success, with Hemangiol or off-label propranolol, but this being out of the framework of the study, no data on the duration of treatment or outcome were collected.
QoL of the parent and/or guardian was not impacted at baseline; the SF-36 mean mental and physical component summary scores were 49.1 (SD 9.0) and 55.1 (SD 6.5), respectively, versus the normal US reference score of 50.10 Nevertheless, mean values of all SF-36–scaled scores increased (ie, improved) slightly from baseline at almost all assessment time points, revealing a marginal impact of treatment on parent’s QoL. This improvement from baseline was reflected in the mental component summary score (mean change of 3.2 [SD 8.7] and 2.8 [SD 6.4] at the end of the ITP and follow-up periods, respectively) and, to a lesser extent, in the physical component summary score (mean change of 0.9 [SD 4.6] and −0.1 [SD 4.8] at the end of the ITP and follow-up periods, respectively). The median values of all HFB questionnaire dimension scores and the total score decreased (ie, burden decreased) from baseline at each assessment time point. The median total score change from baseline was 8.9 (first quartile −20.5; third quartile −4.4) and 7.1 (first quartile 16.6; third quartile 2.8) at the end of the ITP and follow-up periods, respectively, and was mainly attributed to the large decrease in emotional and psychological dimension scores (median change of −22.2 for both dimensions and time points, equivalent to a 50% decrease). This revealed a decrease in the burden perceived by the parents and/or guardians after treatment despite there being no impact on family or social life at baseline (median scores were 0).
No deaths were reported. Overall, 36 patients (80%) experienced 233 TEAEs (Supplemental Table 4). Of these, 13 were treatment-emergent serious adverse events (TESAEs) and were experienced by 8 patients (18%). None of the TESAEs were considered by the investigator to be treatment related, and all were resolved by the end of study. The TESAEs were respiratory syncytial virus bronchiolitis, ulcerated hemangioma, and hemangioma (ulcerated, recorded hemangioma [pain and blooded]) in 1 patient; pneumonia and respiratory failure (respiratory insufficiency) in 1 patient; and events of inguinal hernia, upper respiratory tract infection, dehydration, somnolence, bronchitis, choking, thermal burn, and gastroenteritis rotavirus (each reported in 1 patient).
Almost all nonserious TEAEs were of mild or moderate severity; only 1 patient experienced 2 severe TEAEs (inguinal hernia and laparoscopic surgery). The most commonly reported events (≥10% of patients; Table 2) were either expected in infants (pyrexia, conjunctivitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, and teething), known propranolol side effects (vomiting and bradycardia), or both (bronchitis). Bradycardia was experienced by 8 patients (14 events of mild severity, 11 of which were reported during the closely monitored up-titration period) and were mostly due to an HR decrease of ≥30 beats per minute from baseline; HR values remained above the age group lower limit of normal. All bradycardia events were asymptomatic, and patients recovered without corrective medication or changes in the study treatment dose.
Overall, 17 patients (38%) had TEAEs that were considered treatment related. All were nonserious, with bronchitis, bradycardia, IH enlarged and/or worsening (3 patients each), vomiting, and nightmare (2 patients each) being the only to occur in >1 patient.
During the retreatment period, all 8 patients who required retreatment experienced 22 TEAEs. All were nonserious, and most were of mild severity. Only 2 were suspected to be related to the study treatment: 1 event of upper respiratory tract infection of mild severity and 1 event of IH of moderate severity. Both events were resolved by the end of the study.
No patients experienced TEAEs that led to definitive discontinuation of the study treatment. However, 35 TEAEs in 17 patients (38%) led to temporary treatment discontinuation, including 5 TESAEs in 4 patients (all respiratory related: respiratory syncytial virus bronchitis, pneumonia, respiratory failure [respiratory insufficiency], upper respiratory tract infection, and bronchitis). All were mild or moderate in severity, not suspected to be related to the treatment, and resolved by the end of treatment.
This single-arm study of 45 patients revealed that 3 mg/kg per day (BID) of oral propranolol is effective in treating high-risk IH with a favorable safety profile. At the end of the minimal treatment duration of 6 months, 47% of patients achieved treatment success, increasing to 76% when treatment was continued up to 12 months of age. This result was confirmed by both supportive PP and sensitivity analyses. Building on the results of the pivotal study13 (60% of patients achieved treatment success at month 6), our study further reveals the efficacy of propranolol treatment in high-risk IH patients and that treatment up to 12 months of age is an optimized treatment choice for those who do not fully respond within 6 months.
Two-thirds of patients (68%) were able to sustain success for 3 months without treatment, which was deemed an acceptable follow-up period because rebound growth has been reported to occur in most patients within 2 months after stopping propranolol treatment.18 The rate of rebound growth (32%) was consistent with that of previous reports.18,19 However, the proportion of patients who were judged as requiring retreatment in our study (24%) was higher than in the retrospective studies (15%19 and 12%18 of patients required retreatment or modification of systemic therapy) and the pivotal study (10%13 of patients required retreatment). However, these studies were not restricted to high-risk IH patients only, who are more likely to require treatment. The efficacy of retreatment in those who had rebound growth was also confirmed; 7 of 8 patients achieved success after propranolol readministration for a maximum duration of 6 months. This study also reveals that propranolol treatment may lighten the perceived burden of disease on parents.
Of the important risks identified with propranolol use (hypotension, bronchospasm or bronchial hyperreactivity reactions, hypoglycemia, bradycardia, and hyperkalemia),25 only bradycardia (mainly, a decrease of HR to ≥30 beats per minute from baseline and observed during the closely monitored up-titration period) was commonly reported (in >10% of patients) and would be expected as a consequence of β blockade. The events of bradycardia were mild and asymptomatic. No TEAEs led to definitive treatment discontinuation, and those that led to temporary discontinuation were resolved and considered to be not treatment related. The safety profile of the retreatment period was similar to that of the overall study, revealing that continuing treatment beyond 6 months does not increase safety risks.
The limitations of this study are the noncontrolled design in real-use conditions on a limited number of patients. This is justified by the wide acceptance of propranolol as a first-line IH treatment because of its favorable risk/benefit ratio and ethical limitations that prevent the use of a placebo in high-risk patients. The power calculation and statistical methodology were based on a conservative approach in terms of spontaneous resolution of IH; therefore, the number of patients is deemed sufficient to accurately document the success rate at the end of the ITP. All other results should be regarded within a descriptive perspective.
Treatment with oral propranolol at a dose of 3 mg/kg per day (BID) for a duration of at least 6 months and up to 12 months of age was efficacious in most patients with high-risk IH. Extending treatment beyond 6 months up to a maximum of 12 months of age produced a clinically meaningful increase in the success rate. The treatment effect was persistent in most patients for up to 3 months without treatment, and in those patients requiring retreatment, propranolol was efficacious. The safety profile was satisfactory, with no unexpected safety signals.
We acknowledge all physicians and parents of patients who participated in this trial, Eric Garrigue for his contribution in the initial stages of the study, Marius Rylski (Pierre Fabre, Warsaw, Poland) for the management of the study in Poland, and all the participants from the sponsor study team and the Contract Research Organizations (CROs) for their invaluable contribution. We also thank Dominique Helberg of Scinopsis (Brighton, United Kingdom) for her editorial support.
- Accepted May 30, 2018.
- Address correspondence to Eulalia Baselga, MD, Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Mas Casanova 90, 08041 Barcelona, Spain. E-mail:
This trial has been registered with the European Union Clinical Trials Register (www.clinicaltrialsregister.eu) (European Union Drug Regulating Authorities Clinical Trials database number 2014 005555-80).
FINANCIAL DISCLOSURE: Other than the items listed under Potential Conflict of Interest, the authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by the Institut de Recherche Pierre Fabre (dermatology).
POTENTIAL CONFLICT OF INTEREST: Drs Zaim, Menon, Lebbé, Bouroubi, Delarue, and Voisard and Ms Gautier are current employees of Pierre Fabre; Dr Baselga received research support for this study from Laboratoires Pierre Fabre (and has previously received honoraria and/or reimbursement from Laboratoires Pierre Fabre for the role of consultant, speaker, and/or investigator); Dr Torrelo has been paid for lecturing for Pierre Fabre; and the other authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2018 by the American Academy of Pediatrics