Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial

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/d.

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.

Conflict of interest statement

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.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Kaplan-Meier Plot