Efficacy and Safety of Propranolol Versus Atenolol on the Proliferative Phase of Infantile Hemangioma

March 12, 2022 updated by: Yi Ji, West China Hospital
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 Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

377

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Sichuan
      • Chengdu, Sichuan, China, 610041
        • West China Hospital of Sichuan University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 5 months (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Propranolol
Drug: 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.
Other Names:
  • Oral propranolol
Active Comparator: Atenolol
Drug: 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.
Other Names:
  • Oral atenolol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hemangioma Activity Score (HAS)
Time Frame: Baseline and at 1, 4, 12, and 24 weeks

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:

  1. 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.

  2. 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.
Baseline and at 1, 4, 12, and 24 weeks
Successful Initial Response
Time Frame: 1 week after treatment

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
Time Frame: from the first dosage of propranolol or atenolol until complete healing ofthe hemangioma ulceration.
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
Time Frame: between weeks 24 and 96
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)
Time Frame: 96 week
A complete/nearly complete response at week 96 was considered median-term efficacy.
96 week

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

West China Hospital

Investigators

  • Principal Investigator: Yi Ji, MD, PhD, West China Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2013

Primary Completion (Actual)

September 1, 2018

Study Completion (Actual)

September 1, 2018

Study Registration Dates

First Submitted

January 7, 2015

First Submitted That Met QC Criteria

January 16, 2015

First Posted (Estimate)

January 19, 2015

Study Record Updates

Last Update Posted (Actual)

June 16, 2022

Last Update Submitted That Met QC Criteria

March 12, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2014-229

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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