Drug AllergyPhase 2DACATNCT06406114
Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
A Phase 2 study testing Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing in people with Drug Allergy and Cephalosporin Allergy, run by Massachusetts General Hospital at 6 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Drug Allergy, Cephalosporin Allergy, Drug Hypersensitivity
- What is being tested?
- Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 300 participants
- Where
- 6 sitesUnited States
- Study dates
- 5 May 2025to 31 Dec 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-70 years old.
- 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.
- English speaking or non-English speaking with translation services available.
Who cannot join
- 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.)
- History of Clostridioides difficile infection
- Chronic spontaneous urticaria or systemic mastocytosis
- Incident reaction required cardiopulmonary resuscitation
- Reaction to 2 or more cephalosporin antibiotics
- Active infection or antibiotic treatment within 7 days
Show all 17Show fewer
- Treatment with systemic antihistamines or corticosteroids within 7 days
- Treatment with omalizumab or dupilumab within 60 days
- Significant immunosuppression
- Treatment with a beta-blocker or ACE inhibitor within 7 days
- Use of investigational drugs within 60 days of participation
- Anaphylaxis in the last 30 days
- Penicillin anaphylaxis within the past year confirmed with positive penicillin skin tests
- Prison or jail inmates, pregnant women, severe cognitive impairment
- 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
- 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.
- Inability or unwillingness of a participant to give written informed consent or comply with study protocol
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
6 sites in 1 country
United States6 sites, 6 recruiting
- Recruiting
Massachusetts General Hospital
Boston, Massachusetts, 02114
Aleena Banerji, MD, 6177263850, ABANERJI@mgh.harvard.edu
Noah Im, BS, 617-726-2974, noim@mgh.harvard.edu
- Recruiting
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
David A Khan, MD, 214-406-5119, Dave.Khan@UTSouthwestern.edu
Sophia Lopez, BS, 469-444-0531, Sophia.Lopez@UTSouthwestern.edu
- Recruiting
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
Elizabeth Phillips, MD, 6153100339, elizabeth.j.phillips@vumc.org
April O'Connor, RN, 615-957-6057, april.oconnor@vumc.org
- Recruiting
Rochester General Hospital
Rochester, New York, 14621
Allison C Ramsey, MD, 585-922-8350, allison.ramsey@rochesterregional.org
Dawn Shefflin, RN, 585-922-8314, dawn.sheflin@rochesterregional.org
- Recruiting
University of California, San Francisco
San Francisco, California, 94143
Monica Tang, MD, 415-514-8044, dacat@ucsf.edu
Lina Kamil, 916-743-8466, Lina.Kamil@ucsf.edu
- Recruiting
Mayo Clinic Arizona
Scottsdale, Arizona, 14607
Alexei Gonzalez-Estrada, MD, 904-953-2451, gonzalez.alexei@mayo.edu
Renee Nunez, BS, 480-574-1826, Nunez.Renee@mayo.edu
About this study
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.
Read the 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.
- Conditions
- Drug Allergy, Cephalosporin Allergy, Drug Hypersensitivity, Antibiotic Allergy, Beta Lactam Adverse Reaction, Drug-Induced Anaphylaxis
- Being tested
- Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing, Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge, Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge, Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge, Amoxicillin double-blind placebo-controlled drug challenge
- Keywords
- Allergy, Antibiotic, Cephalosporin, Penicillin, Beta-lactam, Drug challenge, Skin testing, Adverse reaction, Anaphylaxis, Perioperative anaphylaxis
- Medical subject headings
- Drug Hypersensitivity, Hypersensitivity, Anaphylaxis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testingDrug
Percutaneous and intradermal skin testing will be performed in all participants. Concentrations for percutaneous testing; cefazolin (330 mg/ml), cefuroxime (90 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), 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), 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.
Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challengeDrug
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.
Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challengeDrug
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.
Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challengeDrug
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.
Amoxicillin double-blind placebo-controlled drug challengeDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Similar cephalosporin first | Experimental | In visit 2, confirmed-allergic subjects will have a double-blind placebo-controlled drug challenge to a similar side chain cephalosporin, followed by a double-blind placebo-controlled challenge to a dissimilar side chain cephalosporin in visit 3. The randomization of which cephalosporin (similar or dissimilar side chain) is challenged in visits 2 and 3 differentiates the two arms. Receives: Drug: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing; Drug: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge; Drug: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge; Drug: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge; Drug: Amoxicillin double-blind placebo-controlled drug challenge |
| Dissimilar cephalosporin first | Experimental | In visit 2, confirmed-allergic subjects will have a double-blind placebo-controlled drug challenge to a dissimilar side chain cephalosporin, followed by a double-blind placebo-controlled challenge to a similar side chain cephalosporin in visit 3. The randomization of which cephalosporin (similar or dissimilar side chain) is challenged in visits 2 and 3 differentiates the two arms. Receives: Drug: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing; Drug: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge; Drug: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge; Drug: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge; Drug: Amoxicillin double-blind placebo-controlled drug challenge |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of participants with confirmed culprit cephalosporin allergy
Placebo-controlled drug challenges will be used to confirm or disprove participant's cephalosporin allergies, and the proportion of included participants with confirmed allergies will be measured.
Measured: Up to 7 weeks
Cephalosporin skin test sensitivity and specificity
Challenge results will be used as a reference standard to determine the sensitivity and specificity of cephalosporin skin testing.
Measured: Up to 7 weeks
Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects
The proportion of participants with confirmed cross-reactivity to dissimilar/similar cephalosporins than their culprit will be determined.
Measured: Up to 7 weeks
Secondary outcomes (7)
Culprit cephalosporin skin test diagnostic characteristics
The diagnostic testing characteristics of culprit cephalosporin skin tests will be evaluated, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.
Measured: Up to 7 weeks
Cephalosporin skin test diagnostic characteristic performance differences between risk groups
Allergy history risk will be measured using a validated Drug Allergy History Tool. The PPV, NPV, and false positive rate of skin testing will then be compared through regression modeling to show differences in diagnostic characteristic performance between high-risk and low-risk groups.
Measured: Up to 7 weeks
Association between patient demographics and confirmed cephalosporin allergy
Participant demographic traits will be collected and their associations with confirmed cephalosporin allergy will be presented as odds ratios with 95% confidence intervals.
Measured: Up to 7 weeks
Association between patient allergy history and confirmed cephalosporin allergy
A validated Drug Allergy History Tool will be used to collect participant's allergy history, and associations of allergy history with confirmed cephalosporin allergy will be presented as odds ratios with 95% confidence intervals.
Measured: Up to 7 weeks
Proportion of nocebo responders
The rate of nocebo response in those undergoing cephalosporin drug challenges will be measured.
Measured: Up to 7 weeks
Cephalosporin-specific antibody levels
Cephalosporin drug- and hapten-specific antibody levels will be evaluated from serum using ELISA.
Measured: Up to 54 months
Cephalosporin-specific antibody binding
Cephalosporin drug antibody binding epitopes will be presented using nanoallergens to evaluate rates of antibody binding and cell degranulation to gain a mechanistic understanding of cephalosporin allergy.
Measured: Up to 54 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2024
- Study start5 May 2025
- Primary completion1 Jul 2028 (estimated)
- Study completion31 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Drug AllergyStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kimberly Blumenthal, MD, MSc, Mayo Clinic
- Investigators
- Kimberly G Blumenthal, MD, MSc, Principal investigator, Mayo ClinicDavid A Khan, MD, Principal investigator, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06406114
- Sponsor's protocol ID
- 2024p000928
- Other IDs
- U01AI184071
- Acronym
- DACAT
- Status last verified
- Jan 2026
- First submitted
- 17 Apr 2024
- Last updated
- 4 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will include demographics, clinical and procedure outcomes, and laboratory results. Investigators will preserve and share de-identified individual participant-level data (IPD) through submission to a controlled-access public repository. Investigators will apply the Safe Harbor method for de-identification of participant data. Participant informed consent forms will reflect this plan. To facilitate the use and interpretation of these data, the study protocol, data collection forms, case report forms, data dictionary, manual of operations, statistical analysis plan, and source code will be shared. Investigators will use Persistent Unique Identifiers (PIDs) to improve data findability across all dissemination outputs. PIDs used will include ORCID iDs for people, DOIs for outputs (e.g., datasets, protocols), and Research Resource IDentifiers (RRIDs) for resources. Investigators will also use indexed metadata to make scientific data easily findable.
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
- ClinicalTrials.gov ID
- NCT06406114
- Acronym / sponsor ID
- DACAT / 2024p000928
- Conditions
- Drug Allergy, Cephalosporin Allergy, Drug Hypersensitivity, Antibiotic Allergy, Beta Lactam Adverse Reaction, Drug-Induced Anaphylaxis
- Keywords
- Allergy, Antibiotic, Cephalosporin, Penicillin, Beta-lactam, Drug challenge, Skin testing, Adverse reaction
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- 5 May 2025 (actual)
- Primary completion
- 1 Jul 2028 (estimated)
- Study completion
- 31 Dec 2028 (estimated)
- First posted
- 9 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Similar cephalosporin first | Experimental | Drug: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing, Drug: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge, Drug: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge, Drug: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge, Drug: Amoxicillin double-blind placebo-controlled drug challengeIn visit 2, confirmed-allergic subjects will have a double-blind placebo-controlled drug challenge to a similar side chain cephalosporin, followed by a double-blind placebo-controlled challenge to a dissimilar side chain cephalosporin in visit 3. The randomization of which cephalosporin (similar or dissimilar side chain) is challenged in visits 2 and 3 differentiates the two arms. |
| Dissimilar cephalosporin first | Experimental | Drug: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing, Drug: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge, Drug: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge, Drug: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge, Drug: Amoxicillin double-blind placebo-controlled drug challengeIn visit 2, confirmed-allergic subjects will have a double-blind placebo-controlled drug challenge to a dissimilar side chain cephalosporin, followed by a double-blind placebo-controlled challenge to a similar side chain cephalosporin in visit 3. The randomization of which cephalosporin (similar or dissimilar side chain) is challenged in visits 2 and 3 differentiates the two arms. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Age 18-70 years old.
- 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.
- English speaking or non-English speaking with translation services available.
Key exclusion criteria (17 listed)
- 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.)
- History of Clostridioides difficile infection
- Chronic spontaneous urticaria or systemic mastocytosis
- Incident reaction required cardiopulmonary resuscitation
- Reaction to 2 or more cephalosporin antibiotics
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testingPercutaneous and intradermal skin testing will be performed in all participants. Concentrations for percutaneous testing; cefazolin (330 mg/ml), cefuroxime (90 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), 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), 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. | Drug | 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 challengeAfter 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. | Drug | Dissimilar cephalosporin first, Similar cephalosporin first |
| Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challengeParticipants 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. | Drug | Dissimilar cephalosporin first, Similar cephalosporin first |
| Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challengeParticipants 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. | Drug | Dissimilar cephalosporin first, Similar cephalosporin first |
| Amoxicillin double-blind placebo-controlled drug challengeParticipants 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. | Drug | Dissimilar cephalosporin first, Similar cephalosporin first |
Primary outcome
Proportion of participants with confirmed culprit cephalosporin allergy
Time frame: Up to 7 weeks
Placebo-controlled drug challenges will be used to confirm or disprove participant's cephalosporin allergies, and the proportion of included participants with confirmed allergies will be measured.
Cephalosporin skin test sensitivity and specificity
Time frame: Up to 7 weeks
Challenge results will be used as a reference standard to determine the sensitivity and specificity of cephalosporin skin testing.
Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects
Time frame: Up to 7 weeks
The proportion of participants with confirmed cross-reactivity to dissimilar/similar cephalosporins than their culprit will be determined.
7 secondary outcomes
Culprit cephalosporin skin test diagnostic characteristics
Time frame: Up to 7 weeks
Cephalosporin skin test diagnostic characteristic performance differences between risk groups
Time frame: Up to 7 weeks
Association between patient demographics and confirmed cephalosporin allergy
Time frame: Up to 7 weeks
Association between patient allergy history and confirmed cephalosporin allergy
Time frame: Up to 7 weeks
Proportion of nocebo responders
Time frame: Up to 7 weeks
Cephalosporin-specific antibody levels
Time frame: Up to 54 months
Cephalosporin-specific antibody binding
Time frame: Up to 54 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2026.
- Individual participant dataSharing planned: Yes. Data will include demographics, clinical and procedure outcomes, and laboratory results. Investigators will preserve and share de-identified individual participant-level data (IPD) through submission to a controlled-access public repository. Investigators will apply the Safe Harbor method for de-identification of participant data. Participant informed consent forms will reflect this plan. To facilitate the use and interpretation of these data, the study protocol, data collection forms, case report forms, data dictionary, manual of operations, statistical analysis plan, and source code will be shared. Investigators will use Persistent Unique Identifiers (PIDs) to improve data findability across all dissemination outputs. PIDs used will include ORCID iDs for people, DOIs for outputs (e.g., datasets, protocols), and Research Resource IDentifiers (RRIDs) for resources. Investigators will also use indexed metadata to make scientific data easily findable.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Kimberly G Blumenthal, MD, MSc principal investigator
Mayo Clinic
David A Khan, MD principal investigator
University of Texas Southwestern Medical Center
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing in people with Drug Allergy and Cephalosporin Allergy, run by Massachusetts General Hospital at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 4 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Cara Yelverton, BSc, PhD (6177242415, cyelverton@mgh.harvard.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of participants with confirmed culprit cephalosporin allergy (time frame: Up to 7 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2026.