Use of a penicillin allergy clinical decision rule to enable direct oral penicillin provocation: an international multicentre randomised control trial in an adult population (PALACE): study protocol

Abstract

Introduction: Penicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by skin testing and 96%-99% of low-risk penicillin allergy labels can be removed by direct oral challenge. An internally and externally validated clinical assessment tool for penicillin allergy, PEN-FAST, can identify a low-risk penicillin allergy without the need for skin testing; a score of less than 3 has a negative predictive value of 96.3% (95% CI, 94.1 to 97.8) for the presence of a penicillin allergy. It is hypothesised that PEN-FAST is a safe and effective tool for assessing penicillin allergy in an outpatient clinic setting.

Methods and analysis: This is an international, multicentre randomised control trial using the PEN-FAST tool to risk-stratify penicillin allergy labels in adult outpatients. The study's primary objective is to evaluate the non-inferiority of using PEN-FAST score-guided management with direct oral challenge compared with standard care (defined as prick and intradermal skin testing followed by oral penicillin challenge). Participants will be randomised 1:1 to the intervention arm (direct oral penicillin challenge) or standard of care arm (skin testing followed by oral penicillin challenge, if skin testing is negative). The sample size of 380 randomised patients (190 per treatment arm) is required to demonstrate non-inferiority.

Ethics and dissemination: The study will be performed according to the guidelines of the Helsinki Declaration and is approved by the Austin Health Human Research Ethics Committee (HREC/62425/Austin-2020) in Melbourne Australia, Vanderbilt University Institutional Review Board (IRB #202174) in Tennessee, USA, Duke University Institutional Review Board (IRB #Pro00108461) in North Carolina, USA and McGill University Health Centre Research Ethics Board in Canada (PALACE/2022-7605). The results of this study will be published and presented in various scientific forums.

Trial registration number: NCT04454229.

Keywords: IMMUNOLOGY; INFECTIOUS DISEASES; Protocols & guidelines; Public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

PEN-FAST clinical decision rule. aForms of severe delayed reactions include potential Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and acute generalised exanthematous pustulosis. Patients with a severe delayed rash with mucosal involvement should be considered to have a severe cutaneous adverse reaction. Acute interstitial nephritis, drug-induced liver injury, serum sickness and isolated drug fever were excluded phenotypes from the derivation and validation cohorts. bIncludes unknown.

Figure 2

Overview of the study design. ■Penicillin unspecified, penicillin VK/G, amoxicillin, amoxicillin/clavulanate, ampicillin, semisynthetic antistaphylococcal penicillins. ∆Skin prick testing followed by intradermal testing using standard beta-lactam panel.