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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypersensitivity, Immediate; Hypersensitivity, Delayed; Hypersensitivity Response
• Intervention / Treatment: Other: Direct oral penicillin challenge; Other: Standard of care

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.

• Study Type: Interventional
• Enrollment (Actual): 382
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3000
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Center
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • McGill University Health Centre (MUHC)
• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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]).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Direct oral antibiotic challenge; Direct oral antibiotic (penicillin) challenge in patients with PEN-Fast less than 3.	Other: Direct oral penicillin challenge; The patient will receive a single dose of oral penicillin, following baseline vital signs.
Active Comparator: Standard of care; Standard of care: skin testing and, if negative, oral challenge.	Other: Standard of care; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Austin Health

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Actual): December 2, 2022
• Study Completion (Actual): December 2, 2022

Study Registration Dates

• First Submitted: June 25, 2020
• First Submitted That Met QC Criteria: June 29, 2020
• First Posted (Actual): July 1, 2020

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 2, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: outpatient clinic; penicillin; standard of care; Low Risk allergy; direct oral challenge
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity, Delayed; Anti-Infective Agents; Anti-Bacterial Agents; Penicillins
• Other Study ID Numbers: PALACE1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No