Evaluation of Skin Testing Reagents for Penicillin Allergy

Study Overview
=================
Brief Summary
-----------------
A self- or parent-reported history of penicillin allergy excludes approximately 10% of the US population from receiving penicillin (Kerr 1994, Kagy, Blaiss 1998, Solensky et al. 2000, Neugut et al. 2001). Yet approximately 80% of patients labeled as allergic to the penicillins can safely take these antibiotics without fear of a life-threatening reaction (Gadde et al. 1993, Macy et al. 1997). The outcomes of this erroneous classification of patients include unnecessary denial of an effective and well-tolerated class of antibiotics, which are often the treatment of choice. The primary aim of skin testing with the Penicillin Skin Test Kit is to identify subjects at very low risk of developing acute IgE-dependent reactions when given a penicillin or cross-reacting drug. The negative predictive value (NPV) of skin testing is assessed by oral challenge with a penicillin.

Detailed Description
-----------------
This is a prospective, open-label investigation of skin testing with the Penicillin Skin Test Kit in subjects at least 18 years of age with a self-reported history of possible IgE-dependent penicillin hypersensitivity. At screening on Day 1, subjects and their parents/legal guardians (if applicable) will sign the informed consent form/ pediatric assent form. Following consent/assent, demographic information and medical history will be obtained, including prior and current medication use. Subjects will also be asked if they have had a respiratory infection in the past 2 weeks or antibiotics within the past 4 weeks. A physical examination will be performed, along with measurements of vital signs and, in subjects >5 years of age with active asthma, peak expiratory flow rate (PEFR). A urine pregnancy test will be obtained for all female subjects of childbearing potential. The skin test procedure will first involve puncture testing. Skin test reagents will include the Penicillin Skin Test Kit, histamine (positive control), and sodium chloride (negative control). Subjects who have negative skin puncture test results to any of the drug antigens contained within the Penicillin Skin Test Kit will then undergo intradermal testing in duplicate. Subjects who have a positive reaction to one or more puncture or intradermal tests contained within the Penicillin Skin Test Kit will be discharged from the study. However, subjects with any positive skin test to drug antigens in the Penicillin Skin Test Kit will be asked to return for retesting (puncture and intradermal) in 4 weeks. Subjects who have negative puncture and intradermal test results will be given the oral amoxicillin challenge, which will be comprised of a single, full oral dose of amoxicillin. The purpose of the oral amoxicillin challenge is to confirm lack of allergy and confirm the NPV (Negative Predictive Value) of skin testing. Subjects will be monitored at the study site for 1 hour following oral amoxicillin challenge and then sent home. The study site will follow-up by telephone with all subjects (or their parents/legal guardians in the case of young children) ≥72 hours after administration of the oral amoxicillin challenge. Adverse events (AEs) will be recorded from administration of the Penicillin Skin Test throughout the 3-day study period as spontaneously reported by subjects or observed by the site staff. Two normal subjects (i.e., no history of penicillin allergy) will be skin tested at each site to provide data on skin test specificity.

Official Title
-----------------
Confirmatory Study to Examine Negative Predictive Value (NPV) and Safety of Skin Testing With PRE-PEN, a Minor Determinant MIxture (MDM) of Penicillin Antigens, and Amoxicillin Reagent Against an Oral Challenge With Amoxicillin

Conditions
-----------------
History of IgE Dependent Reaction to a Penicillin Product

Intervention / Treatment
-----------------
* Drug: Penicillin skin test kit


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must have provided written, informed consent prior to performance of any procedures. Subject can be male or female and must be generally healthy and at least 18 years of age. Subject must have a reported history of possible IgE dependent reaction to a penicillin or its semi-synthetic derivatives, including one or more of the following: anaphylaxis, decreased blood pressure and/or diminished consciousness, upper or lower airway obstruction, angioedema, urticaria, and/or generalized pruritic rash. Exclusion Criteria: Subject who has exhibited a systemic allergic reaction to previous skin-test administration of PRE-PEN, MDM, or individual penicillin metabolites (benzylpenicillin, benzylpenicilloate, or benzylpenilloate). Subject who is pregnant or lactating. Subject who has had a respiratory infection within the past 2 weeks or has taken antibiotics of any kind during the past 2 weeks (except for topical antibiotics for acne). Subject who has taken an oral H1-antihistamine within 72 hours prior to skin testing. Subject who has taken hydroxyzine or doxepin within 7 days prior to skin testing. Subject who has had a penicillin reaction, including semisynthetic penicillins, within the last 6 weeks prior to skin testing. Subject who has received an investigational drug within 30 days prior to skin testing or who plans to participate in a study in which an investigational drug will be administered within the 30 days following skin testing. Subjects who have planned hospitalizations or medical or surgical procedures during the 72 hours following the oral amoxicillin challenge. Subjects who plan to take any new prescription or over-the-counter medications or herbal supplements during the 72 hours following the oral amoxicillin challenge. Subject who has had a previous adverse reaction to penicillin or semisynthetic derivative and subsequently tolerated a penicillin or semisynthetic derivative without an adverse experience. Subject who, in the investigator's opinion, has any other social or medical condition (e.g. fever, rash) that may place the subject at increased risk or may confound the interpretation of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: all subjects<br>Intervention: Penicillin skin test kit Subjects with negative intradermal tests will be given single oral amoxicillin challenge dose and followed for 72 hours for IgE dependent reactions. | Drug: Penicillin skin test kit<br>* Allergy skin testing is done by puncture and intradermal. If all tests negative, subjects receive an oral amoxicillin challenge.<br>* Other names: amoxicillin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Negative Predictive Value | The primary endpoint was the negative predictive value (NPV), which was estimated as p = percentage of n history-positive subjects with negative skin tests from the Penicillin Allergy Skin Test Kit (as confirmed with an overall negative result for the skin puncture/intradermal testing) who do not experience an IgE-dependent hypersensitivity reaction within 72 hours of the oral amoxicillin challenge. | 72 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
penicillin allergy