Nadolol Versus Propranolol in Children With Infantile Hemangiomas

Nadolol Versus Propranolol in Children With Infantile Hemangiomas: a Randomized, Controlled, Double-blinded Trial

The purpose of this study is to assess the efficacy and safety of oral propranolol versus nadolol in patients with Infantile Hemangiomas (IH) in a randomized, controlled, double-blinded study.

Study Overview

• Status: Completed
• Conditions: Infantile Hemangioma
• Intervention / Treatment: Drug: Nadolol; Drug: Propranolol

Detailed Description

The study objective is to compare the efficacy and safety of oral propranolol in comparison with oral nadolol in patients with IH. Patients will be randomly assigned to either propranolol or dose equivalent nadolol. The duration of the study will be 24 weeks, however, patient will be monitored for up to 1 year post study enrolment. Both efficacy and safety will be closely monitored and captured.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 6 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1-6 months corrected age
• Written parental informed consent

• At least one of the following:

  • Size: hemangioma >1.5 cm on the face or >3 cm on other body parts
  • Causing or with potential for functional impairment (e.g. amblyogenic IH, ulcerated hemangioma)
  • Causing or with potential for cosmetic disfigurement (e.g. nasal tip, glabella location)

Exclusion Criteria:

• Contraindications to beta-blockers

  • Hypotension
  • Bradycardia
  • Hypoglycemia
  • Cardiac disease associated with decreased ejection fraction and/or > second degree heart block
  • Bronchospasm (including bronchial asthma)
  • Allergic rhinitis
• Corrected gestational age less than 1 month at screening
• Patients with PHACES cerebral arteriopathy at risk of stroke
• Patients and/or breastfeeding mothers receiving treatment with anti-arrhythmic agents, calcium channel blockers, ACE inhibitors, inotropic agents, vasodilators, hypoglycemic agents, neuroleptics, antiacids, benzodiazepines, thyroxine, warfarin
• Patients treated with an oral beta-blocker or other agent (e.g. systemic steroids, vincristine) within 2 weeks from randomization
• Patients treated with topical timolol within 1 week from randomization
• Vascular tumors other than infantile hemangioma (e.g. pyogenic granuloma, hemangioendothelioma)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nadolol group; 40 study participants will take Nadolol (oral liquid suspension)	Drug: Nadolol; Patients will be administered twice-daily doses of medication as follows: since Day 0- 0.5 mg/kg/day ; since Day 7-1.0 mg/kg/day and since Day 14- 1.5 mg/kg/day. In all subsequent visits the dosage will be adjusted based on the current weight rather than the baseline weight to maintain 1.5 mg/kg/day. Or the dose may be escalated (by 0.5 mg/kg/day at any following study visit) up to 3 mg/kg/day based on the clinical response to maintain the dose that led to at least 75% reduction in the hemangioma size until Week 24, when unblinding happen. At Week 24 paticipants can start weaning by 10% per week or continue with the last dose, depending on the investigator's decision. S/he will be monitored until Week 52.; Other Names: N/A (any brand )
Active Comparator: Propranolol group; 40 study paticipants will take Propranolol (oral liquid suspension)	Drug: Propranolol; Patients will be administered twice-daily doses of medication as follows: since Day 0- 0.5 mg/kg/day ; since Day 7-1.0 mg/kg/day and since Day 14- 1.5 mg/kg/day. In all subsequent visits the dosage will be adjusted based on the current weight rather than the baseline weight to maintain 1.5 mg/kg/day. Or the dose may be increased by investigator, based on clinical response by 0.5 mg/kg/day at any study visit (up to 3 mg/kg/day divided twice a day) to maintain the dose that lead to at least 75% reduction in the hemangioma size until Week 24, when unblinding happen. At Week 24 paticipants can start weaning by 10% per week or continue with the last dose, depending on the investigator's decision. S/he will be monitored until Week 52.; Other Names: N/A (any brand)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in the bulk (size/extent) and color of the infantile hemangioma (IH)at Week 24 compared to baseline using Visual Analog Scale (VAS).	A 100 mm visual analog scale (VAS) will be used to quantify changes in the visible bulk (size/extent) and color of the lesion by comparing clinical photographs at 24 weeks versus baseline	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in IH bulk using VAS at 4, 12, 52 weeks	A 100 mm visual analog scale (VAS) will be used to quantify changes in the visible bulk (size/extent) of the lesion by comparing clinical photographs at weeks 4, 12, and 52 versus baseline	4, 12, 52 weeks
Time and dose to reach the 50%, 75% and 100% tumor shrinkage	Time frame since the baseline and study medication dose, when patient's IH decreased in size by 50%, 75% and 100%.	52 weeks
Inter-rater reliability of the VAS scores	Two raters will assess the changes in IH for each study patient ( each visit). We will compare these results to assess inter-rater reliability.	52 weeks
Percentage of patients achieving functional correction at Week 4, 12, 24, 52	Percentage of patients achieving functional correction at Week 4, 12, 24, 52	4,12,24,52 weeks
Percent change in the volumetric changes of hemangioma	[(Length + Width)/2]3 X 0.07	24 and 52 weeks
Percentage of patients with residual changes (telangiectasias, discoloration, fibro-fatty changes, anetoderma)	Percentage of patients with residual changes	52 weeks
Frequency of observed and reported adverse events	Frequency of observed and reported adverse events	52 weeks

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Elena Pope, MD, Msc, The Hospital for Sick Children

Publications and helpful links

General Publications

• Pope E, Lara-Corrales I, Sibbald C, Liy-Wong C, Kanigsberg N, Drolet B, Ma J. Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial. JAMA Pediatr. 2022 Jan 1;176(1):34-41. doi: 10.1001/jamapediatrics.2021.4565.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: July 21, 2015
• First Submitted That Met QC Criteria: July 21, 2015
• First Posted (Estimate): July 22, 2015

Study Record Updates

• Last Update Posted (Actual): October 28, 2020
• Last Update Submitted That Met QC Criteria: October 27, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: hemangioma, propranolol, nadolol
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Skin Abnormalities; Neoplasms, Vascular Tissue; Hemangioma, Capillary; Port-Wine Stain; Hemangioma; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Propranolol; Nadolol
• Other Study ID Numbers: 1000048673

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No