A Phase 2 interventional study of Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing and Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge in Drug Allergy, Cephalosporin Allergy and Drug Hypersensitivity, sponsored by Massachusetts General Hospital. Recruiting at 6 sites in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2026-09-04.
Sponsored by Massachusetts General Hospital · Phase 2, Interventional, and Diagnostic
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.
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.
57 studies on the registry are indexed under Drug Hypersensitivity; 18 are open to participants now.
This study's planned enrollment of 300 is above the median of 100 across 27 interventional studies indexed under Drug Hypersensitivity.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
COPD
Chronic obstructive pulmonary disease: long-term lung disease that makes it hard to breathe out, including emphysema and chronic bronchitis.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
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Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
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
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.
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
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.
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.
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.
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.
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.
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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 7 weeks
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 7 weeks
Proportion of nocebo responders
The rate of nocebo response in those undergoing cephalosporin drug challenges will be measured.
Time frame: Up to 7 weeks
Cephalosporin-specific antibody levels
Cephalosporin drug- and hapten-specific antibody levels will be evaluated from serum using ELISA.
Time frame: 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.
Time frame: Up to 54 months
Prevalence of nocebo response
The prevalence of nocebo responses to drug challenges will be measured to understand how often these responses occur during cephalosporin challenges.
Time frame: Up to 7 weeks
Graded severity of nocebo response reactions
Respiratory, mucocutaneous, and cardiovascular symptoms and clinical presentation of nocebo response reactions will be collected and graded using the United States Drug Allergy Registry (USDAR) grading scale to determine the average severity of nocebo reactions. This scale is scored as either NR (no reaction) or values 0-4 indicating the severity of the reaction, with 0 being the mildest and 4 being the most severe.
Time frame: Up to 7 weeks
Cephalosporin skin test clinical statistics
The average diameter size of the wheal and flare during cephalosporin skin tests will be determined.
Time frame: Up to 7 weeks
Tryptase levels in those with confirmed allergy
In participants with confirmed cephalosporin allergy, tryptase levels will be evaluated and compared to determine if tryptase levels are associated with reaction grades.
Time frame: Up to 7 weeks
Amoxicillin cross-reactivity in those with confirmed cephalosporin allergy
Among those with confirmed cephalosporin allergy, the proportion with cross-reactivity to amoxicillin will be determined.
Time frame: Up to 7 weeks
Amoxicillin skin test diagnostic characteristics in those with confirmed cephalosporin allergy
Among those with confirmed cephalosporin allergy, the skin test diagnostic characteristics with amoxicillin will be determined, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.
Time frame: Up to 7 weeks
Similar cephalosporin skin test diagnostic characteristics in participants with confirmed cephalosporin allergy
Among those with confirmed cephalosporin allergy, the skin test diagnostic characteristics with a similar side-chain cephalosporin will be determined, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.
Time frame: Up to 7 weeks
Dissimilar cephalosporin skin test diagnostic characteristics in participants with confirmed cephalosporin allergy
Among those with confirmed cephalosporin allergy, the skin test diagnostic characteristics with a dissimilar side-chain cephalosporin will be determined, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.
Time frame: Up to 7 weeks
Graded severity of cephalosporin allergic reactions
Respiratory, mucocutaneous, and cardiovascular symptoms and clinical presentation of cephalosporin allergic reactions will be collected and graded using the United States Drug Allergy Registry (USDAR) grading scale to determine the average severity of cephalosporin reactions. This scale is scored as either NR (no reaction) or values 0-4 indicating the severity of the reaction, with 0 being the mildest and 4 being the most severe.
Time frame: Up to 7 weeks
Proportion of delayed hypersensitivity reactions to cephalosporins
The proportion of participants with delayed hypersensitivity reactions to cephalosporins will be recorded.
Time frame: Up to 7 weeks
Incidence of adverse events with cephalosporin diagnostic tests
The incidence rate of allergic and nonallergic adverse events (as graded by the United States Drug Allergy Registry (USDAR) grading scale \[grades NR for no reaction and then grades 0-4 with four being the most severe reaction\] and National Cancer Institute's Common Terminology Criteria for Adverse Events \[grades 1 to 5, with grades 1 being the mildest and grade 5 being death\]) in cephalosporin skin tests and drug challenges will be determined.
Time frame: Up to 7 weeks
Plan to share: 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.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Analytic code
Time frame: All scientific data generated from this project will be made available as soon as possible, and no later than the time of publication or the end of the funding period, whichever comes first. The duration of preservation and sharing of the data will be a minimum of 5 years after the funding period.
Access criteria: Access to the data will be shared under controlled-access conditions as required by the policies of NIH/NIAID and the Mass General Brigham (MGB), which will serve as the sIRB. In accordance with HIPAA, scientific data derived from humans will be protected through de-identification, removal of information that may be used to infer the identity and shared under controlled-access conditions as required by NIH/NIAID and MGB institutional policy.
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Started May 2025 (actual). Primary completion is estimated for Jul 2028, 37 months after the start.
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