Original Investigation
July 17, 2023
Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial
Ana Maria Copaescu, Sara Vogrin, Fiona James, et al
JAMA Intern Med. Published online July 17, 2023. doi:10.1001/jamainternmed.2023.2986
Question Is direct oral penicillin challenge in adults with a low-risk penicillin allergy, defined as a PEN-FAST score less than 3, safe and effective compared with the standard-of-care penicillin skin testing followed by an oral penicillin challenge?
Findings In this randomized clinical trial of 382 patients across 6 centers in 3 countries, a positive penicillin oral challenge consistent with an immune-mediated reaction occurred in 0.5% of both the direct oral challenge intervention group and the control group, with an upper 1-sided confidence interval below the noninferiority margin of 5 percentage points.
Meaning In adult patients with a low-risk penicillin allergy, direct oral penicillin challenge is a safe and effective procedure that may facilitate the removal of a larger number of penicillin allergy labels.
Abstract
Importance Fewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling.
Objective To determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy.
Design, Setting, and Participants This parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies.
Interventions Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm).
Main Outcome and Measure The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp).
Results A total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, −1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, −0.45 pp; 95% CI, −4.87 to 3.96 pp). No serious adverse events occurred.
Conclusions and Relevance In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label.
Trial Registration ClinicalTrials.gov Identifier: NCT04454229
