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

Tracking Information

• First Submitted Date: June 25, 2020
• First Posted Date: July 1, 2020
• Last Update Posted Date: March 6, 2023
• Actual Study Start Date: July 1, 2021
• Actual Primary Completion Date: December 2, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 29, 2020): The difference in the proportion of positive oral challenges (i.e. immune-mediated reaction) [ Time Frame: up to 48H after oral challenge ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 20, 2022)

• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• The proportion of patients that will respect the protocol (protocol compliance) [ Time Frame: Up to 48h after the drug challenge ]
• Proportion of patient with positive Penicillin Skin Testing [ Time Frame: Up to 48h after the drug challenge ]
• Proportion of patients with non-immune mediated positive oral provocation [ Time Frame: Up to 48h after the drug challenge ]
• Proportion of patients with severe adverse reaction - anaphylaxis/death [ Time Frame: Up to 48h after the drug challenge ]
• Time from randomization to delabelling [ Time Frame: Up to 48h after the drug challenge ]
• Number of appointments required for Penicillin delabelling [ Time Frame: Up to 48h after the drug challenge ]
• Assessment with the Pre-Questionnaire and the 6 months follow-up Questionnaire [ Time Frame: Up to 6 months after the drug challenge ]

Original Secondary Outcome Measures (submitted: June 29, 2020)

• 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 ]
• 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 ]
• 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 ]
• 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 ]
• The proportion of patients that will respect the protocol (protocol compliance) [ Time Frame: Up to 48h after the drug challenge ]
• Proportion of patient with positive Penicillin Skin Testing [ Time Frame: Up to 48h after the drug challenge ]
• Proportion of patients with non-immune mediated positive oral challenges [ Time Frame: Up to 48h after the drug challenge ]
• Proportion of patients with severe adverse reaction - anaphylaxis/death [ Time Frame: Up to 48h after the drug challenge ]
• Time from randomization to delabelling [ Time Frame: Up to 48h after the drug challenge ]
• Number of appointments required for Penicillin delabelling [ Time Frame: Up to 48h after the drug challenge ]
• Assessment with the Drug Hypersensitivity Quality of Life Questionnaire [ Time Frame: Up to 48h after the drug challenge ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

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

Condition

• Hypersensitivity, Immediate
• Hypersensitivity, Delayed
• Hypersensitivity Response

Intervention

• Other: Direct oral penicillin challenge
  The patient will receive a single dose of oral penicillin, following baseline vital signs.
• 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.

Study Arms

• Experimental: Direct oral antibiotic challenge
  Direct oral antibiotic (penicillin) challenge in patients with PEN-Fast less than 3.
  Intervention: Other: Direct oral penicillin challenge
• Active Comparator: Standard of care
  Standard of care: skin testing and, if negative, oral challenge.
  Intervention: Other: Standard of care

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 2, 2023): 382
• Original Estimated Enrollment (submitted: June 29, 2020): 380
• Actual Study Completion Date: December 2, 2022
• Actual Primary Completion Date: December 2, 2022 (Final data collection date for primary outcome measure)

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]).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, United States

Administrative Information

• NCT Number: NCT04454229
• Other Study ID Numbers: PALACE1
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Ana Copaescu, McGill University Health Centre/Research Institute of the McGill University Health Centre
• Original Responsible Party: Ana Copaescu, Austin Health, Investigator, Allergy-Immunology Fellow
• Current Study Sponsor: Austin Health
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Austin Health
• Verification Date: March 2023