Clinical trial
Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
Name
2024p000928
Description
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.
Trial arms
Trial start
2024-08-01
Estimated PCD
2028-07-01
Trial end
2028-12-31
Status
Not yet recruiting
Phase
Early phase I
Treatment
Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing
Percutaneous and intradermal skin testing will be performed in all participants. Concentrations for percutaneous testing; cefazolin (330 mg/ml), cefuroxime (90 mg/ml), cefotaxime (100 mg/ml), ceftazidime (100 mg/ml), ceftriaxone (100 mg/ml), cefepime (200 mg/ml), pre-pen (undiluted), penicillin G (10,000 U/ml), ampicillin (20 mg/ml) and histamine (6 mg/ml). Concentrations for the first intradermal testing; cefazolin (3.3mg/ml), cefuroxime (1 mg/ml), cefotaxime (1 mg/ml), ceftazidime (1 mg/ml), ceftriaxone (1 mg/ml), cefepime (2 mg/ml), pre-pen (undiluted), penicillin G (1000 U/ml), ampicillin (20 mg/ml), and histamine (0.1 mg/ml). Concentrations for the second intradermal testing; cefazolin (33mg/ml), cefuroxime (10 mg/ml), cefotaxime (10 mg/ml), ceftazidime (10 mg/ml), ceftriaxone (10 mg/ml), cefepime (20 mg/ml), pre-pen (undiluted), penicillin G (10,000 U/ml), ampicillin (20 mg/ml) and histamine (0.1 mg/ml). Histamine and saline will be used as positive and negative controls.
Arms:
Dissimilar cephalosporin first, Similar cephalosporin first
Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge
After double-blind skin testing, participants will undergo a 3-step double-blind placebo-controlled drug challenge to their culprit cephalosporin (the cephalosporin they are suspected to be allergic to, either cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime). The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge.
Arms:
Dissimilar cephalosporin first, Similar cephalosporin first
Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge
Participants will undergo a 3-step double-blind placebo-controlled drug challenge to a cephalosporin antibiotic that shares a similar side chain with their culprit. This will be cefepime for those allergic to ceftriaxone, cefaclor for those allergic to cephalexin, cefixime for those allergic to cefdinir, cefdinir for those allergic to cefixime, cephalexin for those allergic to cefaclor or cephadroxil, and ceftriaxone for those allergic to cefepime, cefuroxime, or cefpodoxime. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge.
Arms:
Dissimilar cephalosporin first, Similar cephalosporin first
Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge
Participants will undergo a 3-step double-blind placebo-controlled drug challenge to a cephalosporin antibiotic that has a dissimilar side chain to their culprit. This will be ceftriaxone for those allergic to cefazolin, and cefazolin for those allergic to any other cephalosporin. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge.
Arms:
Dissimilar cephalosporin first, Similar cephalosporin first
Amoxicillin double-blind placebo-controlled drug challenge
Participants will optionally undergo a 3-step double-blind placebo-controlled drug challenge to Amoxicillin. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge. The order of challenge to similar vs. dissimilar cephalosporin will be randomized as well.
Arms:
Dissimilar cephalosporin first, Similar cephalosporin first
Size
300
Primary endpoint
Proportion of participants with confirmed culprit cephalosporin allergy
Up to 7 weeks
Cephalosporin skin test sensitivity and specificity
Up to 7 weeks
Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects
Up to 7 weeks
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, and anaphylaxis) 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 systemic 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. Abnormal vital signs or unstable physical exam at Visit 1
13. Prison or jail inmates, pregnant women, severe cognitive impairment
14. 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
15. 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.
16. Inability or unwillingness of a participant to give written informed consent or comply with study protocol
Protocol
{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'CROSSOVER', 'interventionModelDescription': '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.', 'primaryPurpose': 'DIAGNOSTIC', 'maskingInfo': {'masking': 'QUADRUPLE', 'maskingDescription': 'Skin test reagents will be labeled blinded and prepared by a trained clinical trials pharmacy to maintain blinding. Drug challenges will be performed double-blind in a similar manner. The administrator, reader, and participant will all be blinded for each of these procedure types.', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 300, 'type': 'ESTIMATED'}}
Updated at
2024-05-10
1 organization
5 products
7 indications
Organization
Massachusetts General HospitalProduct
Beta-lactam antibioticIndication
Medication AllergyIndication
Cephalosporin AllergyIndication
Drug HypersensitivityIndication
Antibiotic AllergyIndication
Beta-Lactam Adverse ReactionIndication
Drug-Induced AnaphylaxisIndication
Cephalosporin ReactionProduct
Culprit cephalosporinProduct
Similar cephalosporinProduct
Dissimilar cephalosporinProduct
Amoxicillin