Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Propranolol | Active Comparator | Propranolol |
|
| Atenolol | Active Comparator | Atenolol |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Propranolol | Drug | Initiated at a dosage of 1 mg/kg per day divided 3 times daily for 1 week, and then increased to 2 mg/kg per day divided 3 times daily from weeks 2 to 24. |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Primary Outcome Measure Was Any Response at 6 Months | Changes in IH size and color were classified as a complete response, nearly complete response, partial response or no response. The primary outcome measure was any response at 6 months in the intention-to-treat population of all patients who underwent randomization. The any response included compete, nearly complete and partial responses. A complete response was defined as no redundant tissue or telangiectasia was identified. A nearly complete response was defined as a minimal degree of telangiectasis, erythema and skin thickening. A partial response was defined as a size reduction or change in color that did not meet the nearly complete resolution criteria. | 6 month |
| Measure | Description | Time Frame |
|---|---|---|
| Hemangioma Activity Score (HAS) | HAS was measured at baseline and at 1, 4, 12, and 24 weeks, including the degree of deep swelling, the color of the hemangioma, and the ulceration assessment:
(2) Assessment of the ulceration. -0.5 point for an ulcer ≤1.0 cm2;
|
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Yi Ji, MD, PhD | West China Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| West China Hospital of Sichuan University | Chengdu | Sichuan | 610041 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25196392 | Background | 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. | |
| 24479731 | Background | 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. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Propranolol | Propranolol Propranolol: Initiated at a dosage of 1 mg/kg per day divided 3 times daily for 1 week, and then increased to 2 mg/kg per day divided 3 times daily from weeks 2 to 24. |
| FG001 | Atenolol | Atenolol Atenolol: Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 week, and then increased to 1 mg/kg per day in a single dose from weeks 2 to 24. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Propranolol | Propranolol Propranolol: Initiated at a dosage of 1 mg/kg per day divided 3 times daily for 1 week, and then increased to 2 mg/kg per day divided 3 times daily from weeks 2 to 24. |
| BG001 | Atenolol |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Primary Outcome Measure Was Any Response at 6 Months | Changes in IH size and color were classified as a complete response, nearly complete response, partial response or no response. The primary outcome measure was any response at 6 months in the intention-to-treat population of all patients who underwent randomization. The any response included compete, nearly complete and partial responses. A complete response was defined as no redundant tissue or telangiectasia was identified. A nearly complete response was defined as a minimal degree of telangiectasis, erythema and skin thickening. A partial response was defined as a size reduction or change in color that did not meet the nearly complete resolution criteria. | Posted | Count of Participants | Participants | 6 month |
|
Adverse events during the initial 6 months of treatment were compared between the 2 groups.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Propranolol | Propranolol Propranolol: Initiated at a dosage of 1 mg/kg per day divided 3 times daily for 1 week, and then increased to 2 mg/kg per day divided 3 times daily from weeks 2 to 24. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sleep disturbance | Nervous system disorders | Systematic Assessment | Severe sleep disturbance was defined as sleep disturbance that did not disappear or was not relieved after treatment administration was altered (eg, earlier evening dose or a decrease in daily dose) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yi jJi | Sichuan University | +86 02885423453 | jijiyuanyuan@163.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 1, 2017 | Oct 31, 2021 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D006391 | Hemangioma |
| D018324 | Hemangioma, Capillary |
| ID | Term |
|---|---|
| D009383 | Neoplasms, Vascular Tissue |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
Not provided
Not provided
| ID | Term |
|---|---|
| D011433 | Propranolol |
| D001262 | Atenolol |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Atenolol | Drug | Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 week, and then increased to 1 mg/kg per day in a single dose from weeks 2 to 24. |
|
|
| Baseline and at 1, 4, 12, and 24 weeks |
| Successful Initial Response | A successful initial response was defined as a HAS score decrease at 1 week after treatment. A successful initial response was assessed by using HAS in the intention-to-treat population. Previous studies demonstrated that HAS decreases over time after β-blocker treatment, with a dramatic drop occurring in the first week, indicating an immediate therapeutic response. HAS can reflect the rapid effect of β-blocker (either propranolol or atenolol) therapy shortly after initiation. | 1 week after treatment |
| Complete Ulceration Healing Time | The complete healing time of the ulceration was defined as the time from the first dosage of propranolol or atenolol until complete healing of the hemangioma ulceration (assessed up to 6 months). Ulceration is defined as a break in the integrity of the hemangioma surface epithelium (or skin) with or without infection. The information included the extent of ulceration, complications of ulceration, prior duration of ulceration (before treatment), concurrent treatments, and complete healing time. Prior duration of ulceration was defined as the time from the first sign of ulceration until before β-blocker treatment. The complete healing time of the ulceration was defined as the time from the first dosage of propranolol or atenolol until complete healing of the hemangioma ulceration. Concurrent treatments, including oral pain medication, oral antibiotics, topical ointment antibiotics and/or wound dressings, were permitted to treat ulcerated IH and were recorded. | from the first dosage of propranolol or atenolol until complete healing ofthe hemangioma ulceration. |
| Rebound Rate | Regrowth of more than 20% in hemangioma appearance (including changes in color and/or volume) after stopping the medication was considered significant rebound. The inclusion criteria for rebound analysis were as follows: (1) patients who completed 6 months of treatment and (2) patients who discontinued therapy or were tapering treatment after achieving an any response. The exclusion criteria were as follows: (1) patients who were noncompliant with treatment and (2) patients who did not respond to treatment. Whether a patient had hemangioma rebound was based on the site investigators' assessments after the week 24 treatment. In patients with significant rebound, reinitiation of systemic therapy (either propranolol or atenolol) was recommended. Minor rebound, which was defined as those patients in whose rebound was noted but no reinitiation of systemic therapy or further treatment was necessary, was not included in the analysis. | between weeks 24 and 96 |
| Number of Participants With Complete/Nearly Complete Response (96 Week) | A complete/nearly complete response at week 96 was considered median-term efficacy. | 96 week |
| 24374526 | Background | 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. |
| 24033364 | Background | 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. |
| 24011909 | Background | 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. |
| 21763565 | Background | 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. |
| 33856430 | Derived | 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. |
Atenolol
Atenolol: Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 week, and then increased to 1 mg/kg per day in a single dose from weeks 2 to 24.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | weeks |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | Atenolol | Atenolol Atenolol: Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 week, and then increased to 1 mg/kg per day in a single dose from weeks 2 to 24. |
|
|
|
| Secondary | Hemangioma Activity Score (HAS) | HAS was measured at baseline and at 1, 4, 12, and 24 weeks, including the degree of deep swelling, the color of the hemangioma, and the ulceration assessment:
(2) Assessment of the ulceration. -0.5 point for an ulcer ≤1.0 cm2;
| Posted | Mean | Standard Deviation | score on a scale | Baseline and at 1, 4, 12, and 24 weeks |
|
|
|
| Secondary | Successful Initial Response | A successful initial response was defined as a HAS score decrease at 1 week after treatment. A successful initial response was assessed by using HAS in the intention-to-treat population. Previous studies demonstrated that HAS decreases over time after β-blocker treatment, with a dramatic drop occurring in the first week, indicating an immediate therapeutic response. HAS can reflect the rapid effect of β-blocker (either propranolol or atenolol) therapy shortly after initiation. | Posted | Count of Participants | Participants | 1 week after treatment |
|
|
|
| Secondary | Complete Ulceration Healing Time | The complete healing time of the ulceration was defined as the time from the first dosage of propranolol or atenolol until complete healing of the hemangioma ulceration (assessed up to 6 months). Ulceration is defined as a break in the integrity of the hemangioma surface epithelium (or skin) with or without infection. The information included the extent of ulceration, complications of ulceration, prior duration of ulceration (before treatment), concurrent treatments, and complete healing time. Prior duration of ulceration was defined as the time from the first sign of ulceration until before β-blocker treatment. The complete healing time of the ulceration was defined as the time from the first dosage of propranolol or atenolol until complete healing of the hemangioma ulceration. Concurrent treatments, including oral pain medication, oral antibiotics, topical ointment antibiotics and/or wound dressings, were permitted to treat ulcerated IH and were recorded. | Posted | Mean | Standard Deviation | weeks | from the first dosage of propranolol or atenolol until complete healing ofthe hemangioma ulceration. |
|
|
|
| Secondary | Rebound Rate | Regrowth of more than 20% in hemangioma appearance (including changes in color and/or volume) after stopping the medication was considered significant rebound. The inclusion criteria for rebound analysis were as follows: (1) patients who completed 6 months of treatment and (2) patients who discontinued therapy or were tapering treatment after achieving an any response. The exclusion criteria were as follows: (1) patients who were noncompliant with treatment and (2) patients who did not respond to treatment. Whether a patient had hemangioma rebound was based on the site investigators' assessments after the week 24 treatment. In patients with significant rebound, reinitiation of systemic therapy (either propranolol or atenolol) was recommended. Minor rebound, which was defined as those patients in whose rebound was noted but no reinitiation of systemic therapy or further treatment was necessary, was not included in the analysis. | Data only included patients who attempted to discontinue β-blockers according to the treatment plan between weeks 24 and 96 | Posted | Count of Participants | Participants | between weeks 24 and 96 |
|
|
|
| Secondary | Number of Participants With Complete/Nearly Complete Response (96 Week) | A complete/nearly complete response at week 96 was considered median-term efficacy. | Posted | Count of Participants | Participants | 96 week |
|
|
|
| 0 |
| 190 |
| 5 |
| 190 |
| 128 |
| 190 |
| EG001 | Atenolol | Atenolol Atenolol: Initiated at a dosage of 0.5 mg/kg per day in a single dose for 1 week, and then increased to 1 mg/kg per day in a single dose from weeks 2 to 24. | 0 | 187 | 3 | 187 | 80 | 187 |
|
| Bronchiolitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Viral upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Bronchial hyperreactivity | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Sleep disturbance | Nervous system disorders | Systematic Assessment |
|
| Agitation | Psychiatric disorders | Systematic Assessment |
|
| Cool extremities | Blood and lymphatic system disorders | Systematic Assessment |
|
| Bradycardia | Cardiac disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Hypotension | Vascular disorders | Systematic Assessment |
|
| Bronchiolitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Decreased appetite | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Viral upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Bronchial hyperreactivity | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D011083 | Polycyclic Compounds |
| Week 4 |
|
| Week 12 |
|
| Week 24 |
|