Clinical trial NCT06406114: Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
Official title: Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Drug Allergy
Cephalosporin Allergy
Drug Hypersensitivity
Antibiotic Allergy
Beta Lactam Adverse Reaction
Drug-Induced Anaphylaxis
Cephalosporin Reaction
Keywords: Allergy
Antibiotic
Cephalosporin
Penicillin
Beta-lactam
Drug challenge
Skin testing
Adverse reaction
Anaphylaxis
Perioperative anaphylaxis
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2024-05-09
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The proposed study is a multi-site clinical trial of cephalosporin allergy diagnostic testing to determine the optimal diagnostic approach through unbiased assessments, including double-blind skin testing and double-blind placebo-controlled drug challenges using a crossover design.
Primary purpose: DIAGNOSTIC

Brief summary: Cephalosporin antibiotics are commonly used but can result in allergic reactions and anaphylaxis. There is no clear diagnostic approach for cephalosporin-allergic patients, and guidance for the use of other antibiotics in allergic patients is based on side chain chemical similarity and limited skin testing evidence. This project includes a clinical trial and mechanistic studies to optimize the approach to cephalosporin allergy and advance future diagnostics.

Detailed description: Background:

In the United States, beta-lactam antibiotics are the leading cause of allergic reactions. Cephalosporin antibiotics, in particular, are the most common cause of drug-induced anaphylaxis and perioperative allergy. For penicillin allergy, the mechanism of allergy and the antigenic determinants are known; validated penicillin skin testing followed by drug challenge has a 100% negative predictive value to exclude an immunoglobulin (Ig)E-mediated reaction. For cephalosporin allergy, the antigenic determinants and mechanism are not known, and skin testing is not validated. The diagnostic test characteristics of skin testing with native cephalosporins remain unclear with no sensitivity nor specificity reported. Although beta-lactam cross-reactivity has been hypothesized to be from the similarity of the R1 side chains, rather than the beta-lactam ring, cross-reactivity estimates among beta-lactams vary. Furthermore, it is not known whether the variance in cross-reactivity is due to true allergy versus sensitization based on positive skin testing, given that drug challenges were not performed on skin-test-positive patients. While an IgE mechanism is assumed for cephalosporin allergy and supported by skin testing that has been positive, the biology has yet to be characterized, and some cephalosporin anaphylaxis can occur on the first exposure, which is inconsistent with an IgE mechanism. Given the complexity of cephalosporin structures and potential epitopes, there may be several distinct biologic pathways involved in cephalosporin allergy. Future diagnostics in cephalosporin allergy are reliant on determination of these biological pathways and finding key haptens.

Aims:

Current national practice guidelines related to cephalosporin allergy assessment are conditional and based on low-quality evidence. The overall goal is to identify the optimal diagnostic approach to cephalosporin allergy and determine beta-lactam cross-reactivity, while discovering the mechanism and antigenic determinants of cephalosporin allergy to advance future diagnostics. The investigators will do this through a clinical trial that will generate empirical evidence through novel trial procedures, double-blind skin testing, and double-blind placebo-controlled drug challenges. Specific aims are: 1) To determine the optimal approach to cephalosporin allergy evaluation; 2) To assess beta-lactam cross-reactivity in cephalosporin-allergic individuals; and 3) To investigate the antigenic determinants and mechanism of cephalosporin allergy.

Study Overview:

Enrolled and consented subjects will attend Visit 1 for baseline screening, sample collection, double-blind skin testing to a beta-lactam panel, and a double-blind placebo-controlled challenge to their culprit cephalosporin antibiotic. Results of the culprit cephalosporin challenge determine subject's study timeline. Subjects confirmed as non-allergic to their culprit cephalosporin will return for the End-of-Study Visit for venipuncture and blood collection, ending their participation in the study. Subjects who are confirmed as allergic to their culprit at Visit 1 will return for three additional visits; Visits 2 and 3 will include double-blind placebo-controlled challenges to a similar side chain and dissimilar side chain cephalosporin (as compared to the side chain of their culprit) to assess cross-reactivity. The order of these two challenges is randomized between Visit 2 and 3, and the order of whether a similar or dissimilar side chain cephalosporin is challenged first (in Visit 2) differentiates the comparator arms of this study. In Visit 4, subjects from both comparator arms will undergo a double-blind placebo-controlled challenge to a penicillin to assess cross-reactivity between cephalosporins and penicillins. After completion of this penicillin challenge, confirmed-allergic participants will return for an End-of-Study Visit. This visit will mark the end of their participation in the study. Venipuncture and sample collection will occur at each visit.

Eligibility criteria: Inclusion Criteria:

1. Age 18-70 years old.
2. Reaction history consistent with a potential immediate hypersensitivity reaction (pruritus, urticaria, erythema, angioedema, bronchospasm, wheezing, shortness of breath, anaphylaxis, or hypotension) to cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime.
3. English speaking or non-English speaking with translation services available.

Exclusion Criteria:

1. Severe concomitant medical condition (e.g., unstable coronary artery disease, congestive heart failure, severe chronic obstructive pulmonary disease, poorly controlled asthma, chronic renal failure, cirrhosis, or end-stage liver disease.)
2. History of Clostridioides difficile infection
3. Chronic spontaneous urticaria or systemic mastocytosis
4. Incident reaction required cardiopulmonary resuscitation
5. Reaction to 2 or more cephalosporin antibiotics
6. Active infection or antibiotic treatment within 7 days
7. Treatment with systemic antihistamines or corticosteroids within 7 days
8. Treatment with omalizumab or dupilumab within 60 days
9. Significant immunosuppression
10. Treatment with a beta-blocker or ACE inhibitor within 7 days
11. Use of investigational drugs within 60 days of participation
12. Anaphylaxis in the last 30 days
13. Penicillin anaphylaxis within the past year confirmed with positive penicillin skin tests
14. Prison or jail inmates, pregnant women, severe cognitive impairment
15. Current, diagnosed, mental illness or current, diagnosed, or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
16. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
17. Inability or unwillingness of a participant to give written informed consent or comply with study protocol

Primary outcomes:
measure: Proportion of participants with confirmed culprit cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Cephalosporin skin test sensitivity and specificity
timeFrame: Up to 7 weeks
measure: Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects
timeFrame: Up to 7 weeks
Secondary outcomes:
measure: Culprit cephalosporin skin test diagnostic characteristics
timeFrame: Up to 7 weeks
measure: Cephalosporin skin test diagnostic characteristic performance differences between risk groups
timeFrame: Up to 7 weeks
measure: Association between patient demographics and confirmed cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Association between patient allergy history and confirmed cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Proportion of nocebo responders
timeFrame: Up to 7 weeks
measure: Cephalosporin-specific antibody levels
timeFrame: Up to 54 months
measure: Cephalosporin-specific antibody binding
timeFrame: Up to 54 months
Other outcomes:
measure: Prevalence of nocebo response
timeFrame: Up to 7 weeks
measure: Graded severity of nocebo response reactions
timeFrame: Up to 7 weeks
measure: Cephalosporin skin test clinical statistics
timeFrame: Up to 7 weeks
measure: Tryptase levels in those with confirmed allergy
timeFrame: Up to 7 weeks
measure: Amoxicillin cross-reactivity in those with confirmed cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Amoxicillin skin test diagnostic characteristics in those with confirmed cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Similar cephalosporin skin test diagnostic characteristics in participants with confirmed cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Dissimilar cephalosporin skin test diagnostic characteristics in participants with confirmed cephalosporin allergy
timeFrame: Up to 7 weeks
measure: Graded severity of cephalosporin allergic reactions
timeFrame: Up to 7 weeks
measure: Proportion of delayed hypersensitivity reactions to cephalosporins
timeFrame: Up to 7 weeks
measure: Incidence of adverse events with cephalosporin diagnostic tests
timeFrame: Up to 7 weeks
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Rochester General Hospital
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: Massachusetts General Hospital
name: Kimberly G Blumenthal, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas Southwestern Medical Center
name: David A Khan, MD
role: PRINCIPAL_INVESTIGATOR
References: