Risk-stratified Testing for Safe Removal of Penicillin Allergy Labels

The aim of this clinical trial is to analyze the negative predictive capacity and safety of risk-stratified direct drug provocation tests for patients with self-reported penicillin allergies. Patients reporting immediate or delayed penicillin allergies and defined as low-risk by the PEN-FAST score will receive drug provocation tests without prior skin testing.

Study Overview

• Status: Recruiting
• Conditions: Hypersensitivity, Immediate; Hypersensitivity, Delayed; Penicillin Allergy; Hypersensitivity Response
• Intervention / Treatment: Other: standard of care; Other: Direct Oral challenge

Detailed Description

The PEN-FAST clinical decision rule is an internationally validated scoring system (0-5 points) that identifies low-risk patients (= a score of 0-2 points) with self-reported penicillin allergies with a negative predictive value (NPV) of over 95%. Performing direct drug provocation tests without prior skin testing on these low-risk patients was shown to be non-inferior in terms of safety and prediction of immediate allergic reactions. However, several studies have questioned the negative predictive capacity of the PEN-FAST score. In these studies, misclassifications of the PEN-FAST score were mainly based on positive skin test findings that can show false-positive results.

This study aims to validate the NPV and safety of direct drug provocation tests using the PEN-FAST score.

Participants with a PEN-FAST score of 0-2 points will directly receive a two-dose challenge (50%-50%) or single challenge (100%) with the culprit penicillin and will be monitored for at least 4 hours. No skin tests will be performed prior to the drug provocation test. Patients will be instructed to contact the hospital after the drug provocation test to monitor any delayed allergic reactions.

The outcomes will be compared to those of patients with a PEN-FAST score of 0-2 points who do not wish to skip the skin tests and who will, in parallel, receive the standard-of-care testing.

Currently, this study is approved as a single-site study.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Deniz Göcebe, MD; Phone Number: +4962215639539; Email: Deniz.Goecebe@med.uni-heidelberg.de
• Study Contact Backup: Name: Knut Schäkel, MD; Email: Knut.Schaekel@med.uni-heidelberg.de

Study Locations

• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Recruiting
      • University Hospital Heidelberg, Dermatology
      • Contact: Deniz Göcebe, MD; Phone Number: +4962215639539; Email: Deniz.Goecebe@med.uni-heidelberg.de
      • Contact: Deniz Göcebe
    • Heidelberg, Baden-Württemberg, Germany, 69120
      • Recruiting
      • University Hospital Heidelberg, Division of Infectious Diseases and Tropical Medicine
      • Contact: Elham Khatamzas, MD; Phone Number: +4962215622999; Email: Elham.Khatamzas@med.uni-heidelberg.de
      • Contact: Elham Khatamzas, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult outpatients or inpatients with a penicillin allergy label
2. Willing and able to give consent.
3. PEN-FAST score of 0-2 points

Exclusion Criteria:

1. Age <18 years
2. Concurrent immunosuppressive therapy with 20 mg of prednisolone per day or steroid equivalent
3. Concurrent antihistamine therapy
4. Pregnancy
5. Significantly impaired general condition
6. Unstable or therapeutically inadequately controlled bronchial asthma
7. History of stem cell transplantation
8. History of acute interstitial nephritis
9. Chronic urticaria
10. Mastocytosis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Direct drug provocation test	Other: Direct Oral challenge; Patients will receive a 1-step or 2-step challenge with the suspected penicillin and will be monitored for any allergic reaction within the first four hours. Patients will be instructed to contact the hospital after the drug provocation test to inquire delayed allergic reactions.
Active Comparator: Standard of care; Standard of care Skin testing and measurement of allergen-specific IgE, if negative, drug provocation test.	Other: standard of care; The patient will receive skin prick test and patch test (if a delayed allergy is suspected). Allergen-specific IgE will be measured. If all negative, drug provocation tets will be performed identical to the experimental group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The difference in the proportion of patients with any positive finding in skin tests, allergen-specific IgE or drug provocation test between the two groups	Percentage of subjects that retain their allergy label as they show at least one positive finding in skin tests, allergen-specific IgE or drug provocation test.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Negative predictive capacity of skin tests and allergen-specific IgE	Negative predictive values of each test alone and combined	7 days
Analysis of medical and allergic history	(supposed) allergic symptoms	1 day
Penicillin allergy label	Identification of culprit penicillin	1 day
Analysis of demographic data	Age, sex	1 day
Analysis of adverse reactions	Detailed analysis of any (supposed) allergic reactions following drug provocation test	7 days
Analysis of medical and allergic history	year of (supposed) allergic reaction	One day
Analysis of medical and allergic history	time between administration and (supposed) allergic reaction	One day
Analysis of medical and allergic history	treatment required for (supposed) allergic reaction	One day
Analysis of medical and allergic history	current medication	One day
Analysis of internal hospital risk stratification system	Measurement of score of internal hospital risk stratification system	One day
Analysis of medical and allergic history	(supposed) allergic symptoms	One day

Collaborators and Investigators

• Sponsor: Deniz Göcebe

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.
• Copaescu AM, Vogrin S, James F, Chua KYL, Rose MT, De Luca J, Waldron J, Awad A, Godsell J, Mitri E, Lambros B, Douglas A, Youcef Khoudja R, Isabwe GAC, Genest G, Fein M, Radojicic C, Collier A, Lugar P, Stone C, Ben-Shoshan M, Turner NA, Holmes NE, Phillips EJ, Trubiano JA. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023 Sep 1;183(9):944-952. doi: 10.1001/jamainternmed.2023.2986.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: December 22, 2024
• First Submitted That Met QC Criteria: December 22, 2024
• First Posted (Actual): January 1, 2025

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: April 9, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: penicillin allergy; PEN-FAST; allergy delabeling
• Additional Relevant MeSH Terms: Immune System Diseases; Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions; Hypersensitivity; Hypersensitivity, Delayed; Drug Hypersensitivity; Hypersensitivity, Immediate
• Other Study ID Numbers: S-656/2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the article that is planned to be published, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Researchers who offer a well-structured and scientifically sound approach to realizing the objectives detailed in the approved proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

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