Clinical trial NCT06303128: Penicillin Allergy Delabeling After a One-Dose Versus Two-Dose Graded Direct Oral Challenge
Official title: Penicillin Allergy Delabeling After a One-Dose Versus Two-Dose Graded Direct Oral Challenge
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Penicillin Allergy
Keywords: low-risk allergy
amoxicillin
drug allergy
direct oral challenge
Lead sponsor: Texas Tech University Health Sciences Center
Sponsor class: OTHER
Collaborators: name: Texas Tech University Health Sciences Center
First posted: 2024-03-12
Enrollment: 380
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: - Low-risk penicillin allergic patients ("low-risk" determined by a PEN-FAST score of 2 or less) will be recruited. Clinically stable patients will be randomly assigned in a double-blinded manner to receive either a one-dose or graded two-dose direct oral challenge with amoxicillin in an outpatient setting. Those assigned to receive one dose of amoxicillin will receive a placebo in place of a second dose of amoxicillin. Both groups will receive the same cumulative dose of amoxicillin (250mg) by the end of the trial. Baseline vital signs will be obtained and tracked throughout the trial. Patients will also be monitored for development of signs of allergic reactions during the trial, with administration of appropriate treatment should the need arise.
Primary purpose: DIAGNOSTIC

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of successfully "delabeled" subjects in one-dose versus two-dose groups
timeFrame: 5 days (at time of first follow up phone call)
Secondary outcomes:
measure: Analysis of adverse reactions
timeFrame: 2 hours (during direct oral challenge) and 5 days (at time of first follow up phone call)
measure: Analysis of medical and allergic history
timeFrame: Reported at time of direct oral challenge
measure: Validation of penicillin allergy delabeling
timeFrame: 6 months
measure: Analysis of demographic data
timeFrame: Reported at time of direct oral challenge
Other outcomes:
Locations:
city: Lubbock
country: United States
facility: Texas Tech University Health Sciences Center
state: Texas
Study officials:
affiliation: Texas Tech University Health Sciences Center
name: James A Tarbox, MD
role: PRINCIPAL_INVESTIGATOR
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