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Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile HemangiomaA Randomized Clinical Trial

Educational Objective
To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with infantile hemangiomas.

1 Credit CME

JAMA Pediatrics

Published Online: November 8, 2021

Original Investigation

Article Information and Disclosures

Elena Pope, MD, MSc¹;

Irene Lara-Corrales, MD, MSc¹;

Cathryn Sibbald, MD, MSc¹;

Carmen Liy-Wong, MD²;

Nordau Kanigsberg, MD²;

Beth Drolet, MD³;

Author Affiliations

¹Division of Pediatric Dermatology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
²Division of Dermatology and Rheumatology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
³Department of Dermatology, University of Wisconsin–Madison
⁴Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada

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Key Points

Question Is nadolol noninferior to propranolol in the management of infantile hemangioma?

Findings In this randomized clinical trial, infantile hemangiomas treated with nadolol showed a larger change in size and color compared with propranolol, demonstrating that nadolol was noninferior to propranolol.

Meaning Nadolol may be an efficacious and safe alternative to propranolol in the treatment of infants with infantile hemangiomas.

Abstract

Importance Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic β-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events.

Objective To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH.

Design, Setting, and Participants This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement.

Interventions Oral propranolol and nadolol in escalating doses up to 2 mg/kg per day.

Main Outcomes and Measure Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale.

Results The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions.

Conclusions and Relevance Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required.

Trial Registration ClinicalTrials.gov Identifier: NCT02505971

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Article Information

Accepted for Publication: August 18, 2021.

Published Online: November 8, 2021. doi:10.1001/jamapediatrics.2021.4565

Correction: This article was corrected on January 31, 2022, to change mg/kg/d to mg/kg per day.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Pope E et al. JAMA Pediatrics.

Corresponding Author: Elena Pope, MD, MSc, Division of Pediatric Dermatology, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON M5J 1X8, Canada (elena.pope@sickkids.ca).

Author Contributions: Drs Pope and Ma had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pope, Lara-Corrales.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Pope.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Pope, Lara-Corrales, Ma.

Obtained funding: Pope.

Administrative, technical, or material support: Pope, Lara-Corrales.

Supervision: Pope, Lara-Corrales.

Conflict of Interest Disclosures: Dr Pope reports serving as an advisory board member for Boeringher Ingelheim, Novartis, Sanofi Genzyme, and Timber outside the submitted work. Dr Lara-Corrales reports personal fees from Pierre Fabre during the conduct of the study as well as personal fees from Amgen, Ipsen, Novartis, Pfizer, and Sanofi Genzyme and grants from AbbVie, Clementia, Mayne Pharma, and Sanofi Genzyme outside the submitted work. Dr Kanigsberg reports personal fees from Pierre Fabre advisory committee outside the submitted work. Dr Drolet reports grants from Venthera and personal fees from Venthera outside the submitted work and has a patent for PCT/US2020/034270 issued for a new topical treatment of infantile hemangioma. No other disclosures were reported.

Funding/Support: This study was supported by Physician Services Inc, Ontario, Canada.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Hanna Fadzeyedeva, SickKids research coordinator; Harini Balasundaram and Nicole Travis, Children’s Hospital of Eastern Ontario research coordinators; Michelle Lee, Jackie Su, and Melanie Audette, the clinic nurses who contributed to patient monitoring and photography; and George Tomlinson for his help with statistical interpretation. The research coordinators were compensated for their contributions; other individuals were not. Finally, we thank the families who agreed to allow their children to participate in the study.

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AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.