HemangiomaPhase 3NCT02342275
Efficacy and Safety of Propranolol Versus Atenolol on the Proliferative Phase of Infantile Hemangioma
A Phase 3 study testing Propranolol and Atenolol in people with Hemangioma, run by West China Hospital at 1 site in China.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 24 weeksHealthy volunteers can take part
- Conditions the study is for
- Hemangioma
- What is being tested?
- Propranolol and Atenolol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 377 participants
- Where
- 1 siteChina
- Study dates
- Oct 2013to Sep 2018
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 24 weeks
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- 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)
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Hemangioma
- Being tested
- Propranolol, Atenolol
- Keywords
- Infantile hemangioma, Propranolol, Atenolol, Efficacy, Safety
- Medical subject headings
- Hemangioma, Hemangioma, Capillary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PropranololDrug
Also called Oral 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.
AtenololDrug
Also called Oral 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.
| Study group | Role | What they receive |
|---|---|---|
| Propranolol | Active comparator | Propranolol Receives: Drug: Propranolol |
| Atenolol | Active comparator | Atenolol Receives: Drug: Atenolol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6 month
Secondary outcomes (5)
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:
- Assessment of the degree of swelling. It was scored as follows:
- 6 points if the swelling was tense;
- 4 points if the swelling was'neutral;
- 2 points when the swelling was reduced by 50% or more at follow-up; or
- 0 point when there was no more visible swelling at a follow-up.
- Assessment of the color of the IH.
- 5 points if the hemangioma lesion was bright red all over;
- 3 points if the hemangioma lesion was matte red or reddish-purple;
- 1 point if the hemangioma lesion was totally or partially gray;
- 0 points if the hemangioma lesion was totally or partially skin-colored after involution. (2) Assessment of the ulceration. -0.5 point for an ulcer ≤1.0 cm2;
- One point for an ulcer >1.0 cm2 but <25 cm2;
- Two points for an ulcer ≥25 cm2. The HAS score= (Swelling score + color score)/2 +Ulceration score.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 96 week
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jan 2015 (estimated)
- Study startOct 2013
- Primary completionSep 2018
- Study completionSep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for HemangiomaStudies of the same condition, open and under way.
- More trials run by West China HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Care provider, Investigator, Outcomes assessor
- Enrolment
- 377 participants (actual)
Sponsor and investigators
- Lead sponsor
- West China Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Yi Ji, West China Hospital
- Investigators
- Yi Ji, MD, PhD, Principal investigator, West China Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02342275
- Sponsor's protocol ID
- 2014-229
- Status last verified
- Mar 2022
- First submitted
- 7 Jan 2015
- Last updated
- 16 Jun 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 25196392Ji 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.
PubMed 24479731Ji 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.
PubMed 24374526Ji 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.
PubMed 24033364de 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.
PubMed 24011909Raphael 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.
PubMed 21763565Ji 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.
PubMed 33856430
Study at a glance
From the registry record, last updated by the sponsor on 16 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy and Safety of Propranolol Versus Atenolol on the Proliferative Phase of Infantile Hemangioma
- ClinicalTrials.gov ID
- NCT02342275
- Acronym / sponsor ID
- 2014-229
- Conditions
- Hemangioma
- Keywords
- Infantile hemangioma, Propranolol, Atenolol, Efficacy, Safety
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 377 participants (actual)
- Lead sponsor
- West China HospitalUniversity, hospital or other
- Study start
- Oct 2013
- Primary completion
- Sep 2018 (actual)
- Study completion
- Sep 2018 (actual)
- First posted
- 19 Jan 2015 (estimated)
- Results
- Posted 16 Jun 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Propranolol | Active comparator | Drug: PropranololPropranolol |
| Atenolol | Active comparator | Drug: AtenololAtenolol |
Who may qualify
- Ages
- Up to 24 weeks
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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)
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PropranololAlso: Oral propranololInitiated 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. | Drug | Propranolol |
| AtenololAlso: Oral atenololInitiated 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. | Drug | Atenolol |
Primary outcome
The Primary Outcome Measure Was Any Response at 6 Months
Time frame: 6 month
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.
5 secondary outcomes
Hemangioma Activity Score (HAS)
Time frame: Baseline and at 1, 4, 12, and 24 weeks
Successful Initial Response
Time frame: 1 week after treatment
Complete Ulceration Healing Time
Time frame: from the first dosage of propranolol or atenolol until complete healing ofthe hemangioma ulceration.
Rebound Rate
Time frame: between weeks 24 and 96
Number of Participants With Complete/Nearly Complete Response (96 Week)
Time frame: 96 week
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jun 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 25196392Ji 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.
- Background: PubMed 24479731Ji 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.
- Background: PubMed 24374526Ji 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.
- Background: PubMed 24033364Ji 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.
- Background: PubMed 24011909de 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.
- Background: PubMed 21763565Raphael 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.
- Derived from this study: PubMed 33856430Ji 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yi Ji, MD, PhD principal investigator
West China Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Propranolol and Atenolol in people with Hemangioma, run by West China Hospital at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Jun 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Primary Outcome Measure Was Any Response at 6 Months (time frame: 6 month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02342275, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jun 2022.