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

• ClinicalTrials.gov Identifier: NCT04454229
• Recruitment Status: Completed
• First Posted: July 1, 2020
• Last Update Posted: March 6, 2023
• Sponsor: Austin Health
• Information provided by (Responsible Party): Ana Copaescu, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hypersensitivity, Immediate; Hypersensitivity, Delayed; Hypersensitivity Response	Other: Direct oral penicillin challenge; Other: Standard of care	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 382 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

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).

• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• 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
• Actual Study Start Date: July 1, 2021
• Actual Primary Completion Date: December 2, 2022
• Actual Study Completion Date: December 2, 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. The difference in the proportion of positive oral challenges (i.e. immune-mediated reaction) [ Time Frame: up to 48H after oral challenge ]

Secondary Outcome Measures :

1. Proportion of patients referred to the outpatient allergy clinic that are eligible for intervention (i.e randomization) as per protocol [Eligibility to screened ratio] [ Time Frame: Before randomization ]
2. 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]. [ Time Frame: Before randomization ]
3. 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] [ Time Frame: Before randomization ]
4. 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. [ Time Frame: Up to 48h after the drug challenge ]
5. The proportion of patients with a penicillin allergy who experience an antibiotic associated non-immune mediated adverse event. [ Time Frame: Up to 48h after the drug challenge ]
6. The proportion of patients that will respect the protocol (protocol compliance) [ Time Frame: Up to 48h after the drug challenge ]
7. Proportion of patient with positive Penicillin Skin Testing [ Time Frame: Up to 48h after the drug challenge ]
8. Proportion of patients with non-immune mediated positive oral provocation [ Time Frame: Up to 48h after the drug challenge ]
9. Proportion of patients with severe adverse reaction - anaphylaxis/death [ Time Frame: Up to 48h after the drug challenge ]
10. Time from randomization to delabelling [ Time Frame: Up to 48h after the drug challenge ]
11. Number of appointments required for Penicillin delabelling [ Time Frame: Up to 48h after the drug challenge ]
12. Assessment with the Pre-Questionnaire and the 6 months follow-up Questionnaire [ Time Frame: Up to 6 months after the drug challenge ]

Eligibility Criteria

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

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]).

Contacts and Locations

Locations

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Australia, Victoria

Austin Health

Heidelberg, Victoria, Australia, 3084

Peter MacCallum Cancer Center

Melbourne, Victoria, Australia, 3000

Royal Melbourne Hospital

Melbourne, Victoria, Australia, 3000

Canada, Quebec

McGill University Health Centre (MUHC)

Montreal, Quebec, Canada, H3G 1A4

Sponsors and Collaborators

Austin Health

  Study Documents (Full-Text)

Documents provided by Ana Copaescu, McGill University Health Centre/Research Institute of the McGill University Health Centre:

Statistical Analysis Plan  [PDF] December 10, 2022

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Ana Copaescu, Physician-Scientist Immunology and Allergy, McGill University Health Centre/Research Institute of the McGill University Health Centre
• ClinicalTrials.gov Identifier: NCT04454229
• Other Study ID Numbers: PALACE1
• First Posted: July 1, 2020
• Last Update Posted: March 6, 2023
• Last Verified: March 2023

• 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

Keywords provided by Ana Copaescu, McGill University Health Centre/Research Institute of the McGill University Health Centre:

penicillin; Low Risk allergy; direct oral challenge; standard of care; outpatient clinic

Additional relevant MeSH terms:

Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity, Delayed; Immune System Diseases; Penicillins; Anti-Bacterial Agents; Anti-Infective Agents