Clinical trial NCT02342275: Efficacy and Safety of Propranolol Versus Atenolol on the Proliferative Phase of Infantile Hemangioma
Official title: Efficacy and Safety of Propranolol Versus Atenolol on the Proliferative Phase of Infantile Hemangioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemangioma
Keywords: Infantile hemangioma
Propranolol
Atenolol
Efficacy
Safety
Lead sponsor: West China Hospital
Sponsor class: OTHER
First posted: 2015-01-19
Enrollment: 377
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the efficacy of orally administered propranolol versus atenolol in the treatment of potentially disfiguring or functionally threatening IHs.

Detailed description: Currently, propranolol is the preferred treatment for problematic proliferating infantile hemangiomas (IHs). Although propranolol is clearly efficacious, rare side effects, such as hypoglycemia, may be life-threatening. The possibility of propranolol resistance and treatment failure is also important, and highlights the need for employing more established techniques in certain cases.

Nonselective β-adrenergic antagonists, such as propranolol and timolol, are competitive antagonists of catecholamines at the β1- and β2-adrenergic receptors (β-ARs). β2-AR blockade may result in hypoglycemia as a result of decreased glycogenolysis, gluconeogenesis, and lipolysis. Moreover, bronchial hyperreactivity is a direct effect of nonselective β-blockers, resulting in bronchospasms due to pulmonic β2-AR blockade. A solution to minimize many of the side effects of nonselective β-blocker therapy may be the use of more selective β1-blockers such as metoprolol or atenolol, which, at low dosages, have little β2 activity. Unfortunately, there is a paucity of clinical data comparing the efficacy of selective and non-selective β-blocker. Furthermore, because of the broad heterogeneity of IH (e.g., proliferating versus involuting), confounding with other pharmacologic exposures (e.g., corticosteroids), associated complications (e.g., ulceration) and comorbid medical anomalies (e.g., PHACE) that can influence efficiency after IH treatment, observational studies are unable to definitively establish the clinical utility of β-blockers in IH. Thus, questions regarding the efficacy of the subtypes of β-blockers must be answered in randomized controlled trials, which may provide the only way to overcome the selection and ascertainment bias.

The purpose of this study is to compare the efficacy of orally administered propranolol versus atenolol in the treatment of potentially disfiguring or functionally threatening IHs.

Eligibility criteria: Inclusion Criteria:

* Patients younger than 24 weeks.
* Presenting a hemangioma with the following characteristics:
* Subcutaneous and/or cutaneous
* Minimum diameter of 1.5 cm on face, 3 cm outside face and 1.5 cm if it is ulcerated.
* Consent of both parents (or the person having parental authority in families)

Exclusion Criteria:

* Infant presenting contraindications for the administration of propranolol or atenolol.
* Hemangioma has been previous treated with corticosteroids, laser, cryotherapy, or only other treatments.
* Patients with an inability to participate or to follow the study treatment and assessment plan.

Primary outcomes:
measure: The Primary Outcome Measure Was Any Response at 6 Months
timeFrame: 6 month
Secondary outcomes:
measure: Hemangioma Activity Score (HAS)
timeFrame: Baseline and at 1, 4, 12, and 24 weeks
measure: Successful Initial Response
timeFrame: 1 week after treatment
measure: Complete Ulceration Healing Time
timeFrame: from the first dosage of propranolol or atenolol until complete healing ofthe hemangioma ulceration.
measure: Rebound Rate
timeFrame: between weeks 24 and 96
measure: Number of Participants With Complete/Nearly Complete Response (96 Week)
timeFrame: 96 week
Other outcomes:
Locations:
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
Study officials:
affiliation: West China Hospital
name: Yi Ji, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action. Br J Dermatol. 2015 Jan;172(1):24-32. doi: 10.1111/bjd.13388. Epub 2014 Dec 17.
citation: Ji Y, Chen S, Li K, Li L, Xu C, Xiang B. Signaling pathways in the development of infantile hemangioma. J Hematol Oncol. 2014 Jan 31;7:13. doi: 10.1186/1756-8722-7-13.
citation: Ji Y, Chen S, Li K, Xiao X, Zheng S. Propranolol: a novel antihemangioma agent with multiple potential mechanisms of action. Ann Surg. 2015 Feb;261(2):e52-3. doi: 10.1097/SLA.0000000000000450. No abstract available.
citation: Ji Y, Chen S, Li K, Xiao X, Xu T, Zheng S. Upregulated autocrine vascular endothelial growth factor (VEGF)/VEGF receptor-2 loop prevents apoptosis in haemangioma-derived endothelial cells. Br J Dermatol. 2014 Jan;170(1):78-86. doi: 10.1111/bjd.12592.
citation: de Graaf M, Raphael MF, Breugem CC, Knol MJ, Bruijnzeel-Koomen CA, Kon M, Breur JM, Pasmans SG. Treatment of infantile haemangiomas with atenolol: comparison with a historical propranolol group. J Plast Reconstr Aesthet Surg. 2013 Dec;66(12):1732-40. doi: 10.1016/j.bjps.2013.07.035. Epub 2013 Sep 4.
citation: Raphael MF, de Graaf M, Breugem CC, Pasmans SGMA, Breur JMPJ. Atenolol: a promising alternative to propranolol for the treatment of hemangiomas. J Am Acad Dermatol. 2011 Aug;65(2):420-421. doi: 10.1016/j.jaad.2010.11.056. No abstract available.
citation: Ji Y, Chen S, Yang K, Zhang X, Zhou J, Li L, Xiang B, Qiu T, Dai S, Jiang X, Lu G, Qiu L, Kong F, Zhang Y. Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2021 Jul 1;147(7):599-607. doi: 10.1001/jamaoto.2021.0454.