The Use of Penicillin Allergy Clinical Decision Rule to Enable Direct Oral Penicillin Challenge

Study Overview
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Brief Summary
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Whilst validated tools exist to enable inpatient penicillin assessment and de-labelling, limited evidence is available regarding the safety and efficacy in the outpatient clinic. The ability to deliver point-of-care penicillin allergy testing for a large cohort of patients, without skin testing, will improve patient access to testing and utilization of preferred penicillin antibiotics.

Detailed Description
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Patient-reported penicillin allergies result in poor health outcomes for patients and drive inappropriate antibiotic prescribing, antimicrobial resistance and healthcare costs. Our group has internally and externally validated a novel penicillin allergy clinician decision rule (PEN-FAST) that is able to identify low risk penicillin allergies with a negative predictive value of 96% (95%; 94-98%). Therefore, whilst validated tools exist to enable inpatient penicillin assessment and de-labelling, limited evidence is available regarding the safety and efficacy in the outpatient clinic. The ability to deliver point-of-care penicillin allergy testing for a large cohort of patients, without skin testing, will improve patient access to testing and utilization of preferred penicillin antibiotics.

Official Title
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The Use of Penicillin Allergy Clinical Decision Rule to Enable Direct Oral Penicillin Challenge - An International Multicenter Randomized Control Trial - The PALACE Study

Conditions
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Hypersensitivity, Immediate, Hypersensitivity, Delayed, Hypersensitivity Response

Intervention / Treatment
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* Other: Direct oral penicillin challenge
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients referred to the outpatient allergy clinic for a penicillin allergy history; Willing and able to give consent. Exclusion Criteria: Patient age is < 18 years; Patients with a PEN-FAST score less than 3 Pregnancy; Any other illness that, in the investigator's judgement, will substantially increase the risk associated with subject's participation in this study; Patients with history of type A adverse drug reaction, drug-associated anaphylaxis, idiopathic urticaria/anaphylaxis, mastocytosis, serum sickness, blistering skin eruption or acute interstitial nephritis; Patients where the allergy history was not able to be confirmed with patient; Patients on concurrent antihistamine therapy; Patients receiving more than stress dose steroids (i.e. > 50mg QID hydrocortisone [or steroid equivalent]).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Direct oral challenge in patients with PEN-Fast less than 3 Eligible patients referred to the outpatient clinic reporting a penicillin allergy will be identified and assessed with a standard clinical history and the calculation of the PEN-FAST score. PEN-FAST is a three-point clinical assessment tool recently externally validated in a multicenter study, with a PEN-FAST score of < 3 associated with 96.7% negative predictive value. Intervention: The patient will receive a single dose of oral penicillin, following baseline vital signs (i.e. temperature, heart rate, blood pressure, respiratory rate, skin check). Nursing staff will repeat vital signs as needed and after oral challenge while observing for signs of an immune mediated adverse reaction. If at any stage an antibiotic associated adverse event is noted, standard of care treatment is offered by the attending clinicians (ex. adrenalin for immediate hypersensitivity reaction).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Direct oral antibiotic challenge<br>Direct oral antibiotic (penicillin) challenge in patients with PEN-Fast less than 3. | Other: Direct oral penicillin challenge<br>* The patient will receive a single dose of oral penicillin, following baseline vital signs.<br>|
| Active Comparator: Standard of care<br>Standard of care: skin testing and, if negative, oral challenge. | Other: Standard of care<br>* Routine management as per the treating clinicians that include skin prick and intradermal beta-lactam testing, followed by oral penicillin challenge in the setting of negative skin testing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference in the proportion of positive oral challenges (i.e. immune-mediated reaction) |  | up to 48H after oral challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients referred to the outpatient allergy clinic that are eligible for intervention (i.e randomization) as per protocol [Eligibility to screened ratio] |  | Before randomization | 
| Feasibility of recruitment defined as the proportion of patients consenting to participate in the study as per protocol from eligible patients. [Recruitment to eligibility ratio]. |  | Before randomization | 
| Feasibility of intervention delivery defined as the proportion of patients randomized to the intervention arm who had the intervention delivered as per protocol. [Intervention to recruitment ratio] |  | Before randomization | 
| The proportion of patients with a penicillin allergy who experience an antibiotic associated immune mediated adverse event OR severe adverse drug reaction as per protocol definitions. |  | Up to 48h after the drug challenge | 
| The proportion of patients with a penicillin allergy who experience an antibiotic associated non-immune mediated adverse event. |  | Up to 48h after the drug challenge | 
| The proportion of patients that will respect the protocol (protocol compliance) |  | Up to 48h after the drug challenge | 
| Proportion of patient with positive Penicillin Skin Testing |  | Up to 48h after the drug challenge | 
| Proportion of patients with non-immune mediated positive oral provocation |  | Up to 48h after the drug challenge | 
| Proportion of patients with severe adverse reaction - anaphylaxis/death |  | Up to 48h after the drug challenge | 
| Time from randomization to delabelling |  | Up to 48h after the drug challenge | 
| Number of appointments required for Penicillin delabelling |  | Up to 48h after the drug challenge | 
| Assessment with the Pre-Questionnaire and the 6 months follow-up Questionnaire |  | Up to 6 months after the drug challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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penicillin, Low Risk allergy, direct oral challenge, standard of care, outpatient clinic