Penicillin Allergy Delabeling After a One-Dose Versus Two-Dose Graded Direct Oral Challenge

April 28, 2025 updated by: James Tarbox, MD

The goal of this clinical trial is to learn about dosing when testing to see if a penicillin allergy label can be removed from adults that had been labeled as "penicillin-allergic" previously. The main question it aims to answer is:

- In penicillin-allergic patients that are at low risk of having an allergic reaction, is a one-dose oral challenge with amoxicillin (a penicillin-based antibiotic) as safe and effective as a two-dose oral challenge?

Participants will, after being identified as having a low-risk penicillin allergy, be administered oral amoxicillin in a controlled setting and then monitored for an allergic reaction. Researchers will compare participants that took one dose of amoxicillin to participants that took two doses of amoxicillin (a small dose and then a larger dose) to see if either group was more likely to develop an allergic reaction.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Anywhere from 5-15% of patients have a reported penicillin allergy listed in their medical record. However, most patients with this listed allergy had reactions with characteristics that would qualify their penicillin allergy as low-risk of having a subsequent serious reaction (when considering initial reaction symptoms, time since initial reaction and if treatment was required). Of patients with penicillin allergy listed, it has been demonstrated that >90% can tolerate penicillin after further evaluation, indicating a significant number of patients with an unnecessary penicillin allergy label.

Penicillin allergy delabeling is a practice commonly performed by allergists to test patients for safe removal of penicillin allergy from their medical records. The protocol of penicillin allergy delabeling has historically consisted of a skin test, followed by a two-step graded direct oral challenge, in which patients are given a smaller, then larger, oral dose of amoxicillin, a penicillin-containing medication. The patient is monitored closely throughout the process for reaction to penicillin and, if necessary, treatment is given for management of reaction symptoms. This method, though functional, takes time and resources to delabel patients.

As our understanding of penicillin drug allergy evolves, it may be possible to reduce the number of steps (and therefore resources) necessary to safely remove penicillin allergy labels. New data suggests that skin testing may not be a necessary step in penicillin allergy delabeling in a subset of low-risk patients. It has also been demonstrated in several studies that a single-dose direct oral challenge (rather than a two-step graded dose) is safe. A recent pilot study also showed that penicillin allergy delabeling can be safely performed in a primary care setting without the direct supervision of an allergist.

Per the authors' literature review, no prospective studies have directly compared the safety and efficacy of a single-dose versus a two-dose graded direct oral challenge. We propose a non-inferiority study in which patients classified as having a low-risk penicillin allergy are randomized into two groups and then receive either a single-dose or the traditional two-dose graded direct oral challenge to be able to evaluate these two treatment protocols in a side-by-side fashion. The results will contribute to our understanding of if a single-dose direct oral challenge can be safely used in place of the traditional two-dose graded direct oral challenge, thus reducing barriers for implementation in a primary care setting.

Patients with penicillin allergy that express interest through publicly posted recruitment materials will be screened to determine if they meet criteria for a "low-risk" allergy through the PEN-FAST screening tool, a recently developed, externally validated penicillin allergy risk assessment calculator. Those that meet the low-risk criteria and other eligibility criteria will be scheduled for an outpatient delabeling appointment. Participants will be randomly assigned in a double-blinded manner to receive either a two-dose graded direct oral challenge (DOC) with amoxicillin or a one-dose DOC placebo, followed by amoxicillin. Each group will receive the same cumulative dose of amoxicillin by the end of the challenge. Participants assigned to the two-dose graded DOC will be administered 62.5mg amoxicillin (25% of the full dose), followed by 187.5mg amoxicillin. Patients assigned to the one-dose DOC will be administered a placebo (Syrpalta or similar, a syrup used in drug compounding), followed by 250mg amoxicillin.

Doses will be given 30 minutes apart from one another. Both groups will be observed for a minimum of 1 hour after administration of the final dose of amoxicillin. Vital signs will be taken immediately before starting the trial, 30 minutes after administration of the first dose, and 60 minutes after administration of the second dose. If patients develop a reaction at any point in the trial, they will be treated according to the type and severity of their symptoms in an appropriate and standardized manner.

As both single-dose and graded two-dose challenges have been used in clinical practice to remove penicillin allergy labels in the past, if no reaction occurs, patients can have their penicillin allergy removed from their chart. Patients will be contacted around 5 days after the challenge to evaluate for any delayed reactions. If, at the 5-day phone call, patients have not had any other reactions suspected to be related to amoxicillin, their penicillin allergy label will be removed at that time. Patients will also be contacted around 6 months after the DOC to evaluate for any reactions to antibiotics received since successful delabeling. The two groups will then be compared to determine if the one-dose challenge is noninferior to the standard graded two-dose challenge (based upon the rate of successful delabeling without adverse reactions).

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

Study Type

Interventional

Enrollment (Estimated)

380

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Texas
      • Lubbock, Texas, United States, 79430
        • Recruiting
        • Texas Tech University Health Sciences Center
        • Contact:
        • Sub-Investigator:
          • Joshua A Peterson, MD
        • Sub-Investigator:
          • Nicole Welch, MD
        • Sub-Investigator:
          • KaKa L Adams, MD
        • Sub-Investigator:
          • Sierra Sullivan, MD
        • Principal Investigator:
          • Jacob Nichols, MD
        • Principal Investigator:
          • James A Tarbox, MD
        • Contact:
        • Sub-Investigator:
          • Watsachon Pangkanon, MD
        • Sub-Investigator:
          • Nattanicha Chaisrimaneepan, MD
        • Sub-Investigator:
          • Safa Mohamed, MD
        • Sub-Investigator:
          • Maireigh McCullough, MD
        • Sub-Investigator:
          • Diego Olavarria Bernal, MD
        • Sub-Investigator:
          • Miriam Paz Sierra, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Expresses interest in participating by calling or filling out information form on study website
  • Reports an allergy to one of the following medications: penicillin VK, penicillin G, amoxicillin, ampicillin, dicloxacillin, flucloxacillin, nafcillin, oxacillin, amoxicillin- clavulanate, ampicillin-sulbactam. Subjects with an unspecified penicillin allergy are also eligible to participate.

Exclusion Criteria:

  • Penicillin allergy deemed to be more than "low-risk" per PEN-FAST (score ≥ 3 points)
  • History of acute kidney injury (acute interstitial nephritis), severe liver impairment (drug- induced liver injury), serum sickness, or isolated drug fever attributed to a penicillin- based antibiotic
  • Anaphylaxis for any reason in the last year
  • Cognitive impairment where a collateral history could not be obtained and/or patient does not have capacity to consent for themselves
  • Pregnant (self-reported)
  • Any illness or condition that would increase the risk of participation in the study, per the evaluating clinician's judgment
  • Active treatment of or history of acute angle closure glaucoma
  • On H1- or H2-blockers (i.e. diphenhydramine, hydroxyzine, chlorpheniramine, cetirizine, levocetirizine, loratadine, fexofenadine or famotidine, ranitidine, cimetidine, nizatidine, respectively) within 72 hours of initiating direct oral challenge (will be counseled to discontinue prior to testing)
  • Actively receiving greater than stress dose steroid (hydrocortisone >50mg four times a day or steroid equivalent)
  • Actively receiving any antibiotic
  • Relative contraindication: Patients on beta blockers and angiotensin converting enzyme inhibitors (ACE inhibitors) will have an open dialog with the study team regarding the risks and benefits of testing a low-risk penicillin allergy patient. A joint decision will be made based on the patient's preference and the physician's comfort level.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: One-dose group
Patients assigned to this group will receive a liquid placebo followed by full-dose liquid amoxicillin 250mg PO thirty minutes later.
Drug: Amoxicillin 250 MG
Liquid amoxicillin 250mg PO
Other Names:
  • One-dose group
Drug: Placebo
Given prior to amoxicillin 250mg in one-dose group
Other Names:
  • Liquid placebo (Syrpalta or similar) for one-dose group
Active Comparator: Graded, two-dose group
Patients assigned to this group will receive liquid amoxicillin (25% of 250mg dose), followed by liquid amoxicillin 187.5mg PO (75% of 250mg dose) thirty minutes later.
Drug: Amoxicillin 62.5mg
Given first in two-dose group, liquid amoxicillin 62.5mg PO
Other Names:
  • Two-dose group, dose 1 of 2
Drug: Amoxicillin 187.5mg
Given second in two-dose group, liquid amoxicillin 187.5mg PO
Other Names:
  • Two-dose group, dose 2 of 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of successfully "delabeled" subjects in one-dose versus two-dose groups
Time Frame: 5 days (at time of first follow up phone call)
Percentage of subjects that successfully complete either the one-dose or graded two-dose direct oral challenge with amoxicillin without adverse reactions during the challenge, as determined by no reaction reported at first follow up phone call.
5 days (at time of first follow up phone call)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Analysis of adverse reactions
Time Frame: 2 hours (during direct oral challenge) and 5 days (at time of first follow up phone call)
Percentage of subjects that report adverse reactions during direct oral challenge and at 5-day follow-up phone call, including type of reaction, timing, severity, treatment required (if any), and classification of degree of causality.
2 hours (during direct oral challenge) and 5 days (at time of first follow up phone call)
Analysis of medical and allergic history
Time Frame: Reported at time of direct oral challenge
For further stratification of primary outcome, other medical and allergic history items including: reported penicillin allergy label, history of cephalosporin allergy, PEN-FAST score, time (in years) since index reaction, time (in hours) between administration of medication and index reaction, treatment required for index reaction, antibiotics tolerated since index reaction, history of other atopic conditions, and use of beta blockers/ACE inhibitors.
Reported at time of direct oral challenge
Validation of penicillin allergy delabeling
Time Frame: 6 months
Data from 6-month follow up phone call including: percentage of successfully delabeled patients able to tolerate penicillin-derived antibiotics since DOC and any associated reactions, percentage of patients confident in taking a penicillin derivative should it be required in the future.
6 months
Analysis of demographic data
Time Frame: Reported at time of direct oral challenge
For further stratification of primary outcome, demographic data, including age, gender, race/ethnicity, urban vs. rural and other measures of socioeconomic status. This will allow us to analyze differences in reaction rates between different groups, as well as psychological differences between groups when considering patient confidence in their allergy label being removed.
Reported at time of direct oral challenge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

James Tarbox, MD

Collaborators

Texas Tech University Health Sciences Center

Investigators

  • Principal Investigator: James A Tarbox, MD, Texas Tech University Health Sciences Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 3, 2024

Primary Completion (Estimated)

July 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

March 4, 2024

First Submitted That Met QC Criteria

March 4, 2024

First Posted (Actual)

March 12, 2024

Study Record Updates

Last Update Posted (Actual)

May 1, 2025

Last Update Submitted That Met QC Criteria

April 28, 2025

Last Verified

April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-FY2024-61

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 provide a methodologically sound proposal to achieve aims 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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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