Clinical trial NCT04454229: The Use of Penicillin Allergy Clinical Decision Rule to Enable Direct Oral Penicillin Challenge
Official title: The Use of Penicillin Allergy Clinical Decision Rule to Enable Direct Oral Penicillin Challenge - An International Multicenter Randomized Control Trial - The PALACE Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypersensitivity, Immediate
Hypersensitivity, Delayed
Hypersensitivity Response
Keywords: penicillin
Low Risk allergy
direct oral challenge
standard of care
outpatient clinic
Lead sponsor: Austin Health
Sponsor class: OTHER_GOV
First posted: 2020-07-01
Enrollment: 382
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: DIAGNOSTIC

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Adult patients referred to the outpatient allergy clinic for a penicillin allergy history;
2. Willing and able to give consent.

Exclusion Criteria:

1. Patient age is \< 18 years;
2. Patients with a PEN-FAST score less than 3
3. Pregnancy;
4. Any other illness that, in the investigator's judgement, will substantially increase the risk associated with subject's participation in this study;
5. 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;
6. Patients where the allergy history was not able to be confirmed with patient;
7. Patients on concurrent antihistamine therapy;
8. Patients receiving more than stress dose steroids (i.e. \> 50mg QID hydrocortisone \[or steroid equivalent\]).

Primary outcomes:
measure: The difference in the proportion of positive oral challenges (i.e. immune-mediated reaction)
timeFrame: up to 48H after oral challenge
Secondary outcomes:
measure: Proportion of patients referred to the outpatient allergy clinic that are eligible for intervention (i.e randomization) as per protocol [Eligibility to screened ratio]
timeFrame: Before randomization
measure: 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].
timeFrame: Before randomization
measure: 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]
timeFrame: Before randomization
measure: 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.
timeFrame: Up to 48h after the drug challenge
measure: The proportion of patients with a penicillin allergy who experience an antibiotic associated non-immune mediated adverse event.
timeFrame: Up to 48h after the drug challenge
measure: The proportion of patients that will respect the protocol (protocol compliance)
timeFrame: Up to 48h after the drug challenge
measure: Proportion of patient with positive Penicillin Skin Testing
timeFrame: Up to 48h after the drug challenge
measure: Proportion of patients with non-immune mediated positive oral provocation
timeFrame: Up to 48h after the drug challenge
measure: Proportion of patients with severe adverse reaction - anaphylaxis/death
timeFrame: Up to 48h after the drug challenge
measure: Time from randomization to delabelling
timeFrame: Up to 48h after the drug challenge
measure: Number of appointments required for Penicillin delabelling
timeFrame: Up to 48h after the drug challenge
measure: Assessment with the Pre-Questionnaire and the 6 months follow-up Questionnaire
timeFrame: Up to 6 months after the drug challenge
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Montreal
country: Canada
facility: McGill University Health Centre (MUHC)
state: Quebec
Study officials:
References:
citation: Trubiano JA, Vogrin S, Chua KYL, Bourke J, Yun J, Douglas A, Stone CA, Yu R, Groenendijk L, Holmes NE, Phillips EJ. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020 May 1;180(5):745-752. doi: 10.1001/jamainternmed.2020.0403.
citation: Devchand M, Urbancic KF, Khumra S, Douglas AP, Smibert O, Cohen E, Sutherland M, Phillips EJ, Trubiano JA. Pathways to improved antibiotic allergy and antimicrobial stewardship practice: The validation of a beta-lactam antibiotic allergy assessment tool. J Allergy Clin Immunol Pract. 2019 Mar;7(3):1063-1065.e5. doi: 10.1016/j.jaip.2018.07.048. Epub 2018 Aug 29.
citation: Trubiano JA, Smibert O, Douglas A, Devchand M, Lambros B, Holmes NE, Chua KY, Phillips EJ, Slavin MA. The Safety and Efficacy of an Oral Penicillin Challenge Program in Cancer Patients: A Multicenter Pilot Study. Open Forum Infect Dis. 2018 Nov 17;5(12):ofy306. doi: 10.1093/ofid/ofy306. eCollection 2018 Dec.
citation: Copaescu AM, James F, Vogrin S, Rose M, Chua K, Holmes NE, Turner NA, Stone C, Phillips E, Trubiano J. 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. BMJ Open. 2022 Aug 8;12(8):e063784. doi: 10.1136/bmjopen-2022-063784.