Amoxicillin Challenge for Penicillin Allergy

Overseen By KaKa L Adams, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: James Tarbox, MD

Must not be taking: Antihistamines, Steroids, Antibiotics

Disqualifiers: High-risk penicillin allergy, Anaphylaxis, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

380 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a single dose of amoxicillin (an antibiotic) is as safe and effective as two doses for individuals labeled as penicillin-allergic but at low risk for a serious reaction. Participants will receive either one full dose or a graded two-dose of the antibiotic in a controlled setting to monitor for allergic reactions. This trial suits those who believe they have a penicillin allergy but have not experienced severe reactions previously. As a Phase 3 trial, it represents the final step before FDA approval, providing participants an opportunity to contribute to significant research that could alter treatment guidelines.

Will I have to stop taking my current medications?

The trial requires you to stop taking H1- or H2-blockers (like diphenhydramine or famotidine) 72 hours before the test and any antibiotics you are currently taking. If you are on beta blockers or ACE inhibitors, you will discuss with the study team to decide if you should continue them.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that amoxicillin is generally safe for most people. The FDA has approved it as a common antibiotic for many uses. Many individuals who believe they are allergic to penicillin can actually take it without issues. Studies indicate that 80% to 90% of those who once thought they were allergic can tolerate penicillins. Less than 1% are truly allergic when evaluated by doctors.

However, severe reactions can occur in those with a true penicillin allergy. To ensure safety, this trial includes only individuals at low risk of a reaction. Participants will receive close monitoring while taking the medication. This controlled setting helps quickly identify any issues. Overall, amoxicillin is well-tolerated by most, especially those identified as low-risk. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about this trial because it explores a potentially groundbreaking way to address penicillin allergies. Unlike traditional approaches that avoid penicillin-based antibiotics altogether, this trial uses amoxicillin in a graded, two-dose method and a one-dose challenge. The aim is to determine if patients who believe they are allergic can actually tolerate penicillin, potentially expanding treatment options. This approach could help patients access more effective antibiotics and reduce reliance on broader-spectrum alternatives, which often have more side effects and contribute to antibiotic resistance.

What evidence suggests that this trial's treatments could be effective for penicillin allergy?

Research has shown that taking amoxicillin directly can safely help many people determine if they are truly allergic to penicillin. In this trial, participants will join one of two groups to test for penicillin allergies. One group will receive a graded, two-dose regimen of amoxicillin, gradually increasing the dose, which studies have shown to be a safe and reliable method. The other group will receive a single full dose of amoxicillin following a placebo. These findings suggest that taking one or two doses of amoxicillin can effectively confirm a penicillin allergy, allowing for accurate updates to medical records. ^{6 7 8 9 10}

Who Is on the Research Team?

James A Tarbox, MD

Principal Investigator

Texas Tech University Health Sciences Center

Are You a Good Fit for This Trial?

This trial is for adults previously labeled as 'penicillin-allergic' but are considered low-risk for an actual allergic reaction. They will be given amoxicillin to see if their allergy label can be safely removed.

Inclusion Criteria

Reports an allergy to one of the following medications: penicillin VK, penicillin G, amoxicillin, ampicillin, dicloxacillin, flucloxacillin, nafcillin, oxacillin, amoxicillin-clavulanate, ampicillin-sulbactam. Subjects with an unspecified penicillin allergy are also eligible to participate.

I have shown interest in the study by contacting or filling out a form.

Exclusion Criteria

I use beta blockers or ACE inhibitors and will discuss penicillin allergy testing with my doctor.

Pregnant (self-reported)

Penicillin allergy deemed to be more than 'low-risk' per PEN-FAST (score ≥ 3 points)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Direct Oral Challenge

Participants receive either a one-dose or two-dose graded direct oral challenge with amoxicillin to test for penicillin allergy delabeling

1 day

1 visit (in-person)

Immediate Follow-up

Participants are monitored for immediate allergic reactions for at least 1 hour after the final dose of amoxicillin

2 hours

1 visit (in-person)

Short-term Follow-up

Participants are contacted 5 days after the challenge to evaluate for any delayed reactions

5 days

1 phone call

Long-term Follow-up

Participants are contacted 6 months after the challenge to evaluate for any reactions to antibiotics received since successful delabeling

6 months

1 phone call

What Are the Treatments Tested in This Trial?

Interventions

• Amoxicillin

Trial Overview The study tests whether a single dose of oral amoxicillin is as safe and effective in delabeling penicillin allergy as a two-dose challenge, with participants monitored for any allergic reactions.

How Is the Trial Designed?

Group I: One-dose group Experimental Treatment 2 Interventions

Patients assigned to this group will receive a liquid placebo followed by full-dose liquid amoxicillin 250mg PO thirty minutes later.

Group II: Graded, two-dose group Active Control 2 Interventions

Patients assigned to this group will receive liquid amoxicillin (25% of 250mg dose), followed by liquid amoxicillin 187.5mg PO (75% of 250mg dose) thirty minutes later.

Amoxicillin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections
• Ear, nose and throat infections

Approved in United States as Amoxicillin for:

• Infections of the ear, nose, throat, genitourinary tract, skin and skin structure, and lower respiratory tract

Approved in Canada as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections

Who Is Running the Clinical Trial?

James Tarbox, MD

Lead Sponsor

Trials

1

Recruited

380+

Texas Tech University Health Sciences Center

Collaborator

Trials

107

Recruited

11,500+

Published Research Related to This Trial

Many patients labeled with a penicillin allergy do not actually have a confirmed allergy, which can lead to unnecessary avoidance of penicillins and other related antibiotics.

Understanding the characteristics that differentiate low-risk from high-risk patients for true penicillin allergy is crucial for proper assessment and management of antibiotic treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penicillin allergy-getting the label right. [2017]

Out of 288 subjects with a history of penicillin allergy, 22% were confirmed to be allergic through a combination of skin tests, IgE measurements, and direct challenge tests, highlighting the importance of comprehensive testing for accurate diagnosis.

The study revealed that relying solely on benzyl or phenoxymethyl-penicillin tests would have missed 31% of the confirmed allergic cases, indicating that side chain-specific diagnostic tests are crucial for identifying true penicillin allergies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allergy to penicillin with good tolerance to other penicillins; study of the incidence in subjects allergic to beta-lactams. Blanca, M., Vega, JM., Garcia, J., et al.[2019]

A case study of a woman who developed allergic reactions to amoxicillin-clavulanic acid after previously tolerating it well suggests that sensitization can occur even after prior exposure without issues.

Testing revealed that while she had undetectable IgE levels to several beta-lactam antibiotics, she developed specific IgE to penicillin V later, indicating a unique sensitization to the combination of amoxicillin and clavulanic acid rather than cross-reactivity with other beta-lactams.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective sensitization to clavulanic acid and penicillin V. González de Olano, D., Losada, PA., Caballer, Bde L., et al.[2013]

Penicillin, particularly amoxicillin, is a common cause of allergic reactions and anaphylaxis, with adverse events occurring in 1% to 10% of cases, and up to 10% of these can be life-threatening, especially in patients without prior allergy history.

The case of a 5-year-old girl who experienced a severe allergic reaction to amoxicillin highlights the importance of recognizing and managing penicillin hypersensitivity, especially in pediatric dental settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reaction to amoxicillin: a case report. da Fonseca, MA.[2013]

In a study of 247 children and adolescents with suspected allergies to penicillin, amoxicillin, and cephalosporins, only 34% were confirmed to have IgE-mediated reactions through skin testing and oral challenges, indicating that many diagnosed allergies may not be true allergies.

The study found that after negative skin tests, 163 patients safely received beta-lactam antibiotics, with only 1.8% experiencing mild adverse reactions, highlighting the importance of skin testing to accurately identify patients who can tolerate these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin testing and oral challenge. Pichichero, ME., Pichichero, DM.[2019]

Most reported penicillin allergies are not clinically significant, and skin testing can safely confirm or refute true IgE-mediated allergies, allowing for the safe use of penicillin in many patients.

There is minimal cross-reactivity between penicillins and other beta-lactam antibiotics, meaning that cephalosporins and other alternatives can be safely used even in patients with a confirmed penicillin allergy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penicillin and beta-lactam allergy: epidemiology and diagnosis. Macy, E.[2022]

Despite the low likelihood of true penicillin allergy in patients with a documented history, a case study of a 74-year-old woman revealed that rechallenging with amoxicillin/clavulanate led to an allergic reaction, highlighting the potential risks involved in such protocols.

This case underscores the importance of careful assessment and monitoring when considering rechallenge protocols for patients with a long-standing history of penicillin allergy, even when the risk of reactivity is thought to be low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penicillin allergy that persisted after 66 years: case report. Anukam, E., Zhu, J.[2023]

Proper evaluation of penicillin allergy, through skin testing and assessment of previous reactions, is essential for determining whether patients should receive alternative antibiotics or undergo desensitization, especially since penicillin is often the only effective treatment for certain infections.

The review highlights that penicillin allergy can complicate treatment options, particularly with cephalosporins, and emphasizes the need for more research on cross-reactivity and hypersensitivity between these antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A perspective on penicillin allergy. Lin, RY.[2022]

In a study of 50 adults with a penicillin allergy label, 76% were eligible for a direct oral amoxicillin challenge, and none experienced immediate or delayed hypersensitivity reactions, indicating the safety of this approach.

The study found that 48% of participants had their penicillin allergy label removed after the challenge, supporting the efficacy of direct oral challenges in de-labeling patients who are not truly allergic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy. Kuruvilla, M., Shih, J., Patel, K., et al.[2019]

Skin tests commonly used to identify penicillin allergies may not effectively detect allergies to specific beta-lactam antibiotics, as shown in six patients who had anaphylactic reactions to amoxicillin but tolerated other beta-lactams.

Four out of the six patients tested positive for amoxicillin skin tests, highlighting the need for more comprehensive allergy testing to ensure patient safety when prescribing beta-lactam antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allergy to amoxicillin in patients who tolerated benzylpenicillin, aztreonam, and ceftazidime. Martin, JA., Igea, JM., Fraj, J., et al.[2019]

A study reviewing 325 patient charts found that adjusting electronic medical record alerting rules for β-lactam antibiotics resulted in no cases of anaphylaxis (0%) among patients who received these medications after being documented as allergic to penicillins.

The new alerting rules, which only flagged similar side chain antibiotics, effectively reduced unnecessary alerts for prescribers while maintaining patient safety, although some patients did experience non-anaphylactic delayed reactions like rashes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

β-lactam exposure outcome among patients with a documented allergy to penicillins post-implementation of a new electronic medical record system and alerting rules. Buffone, B., Lin, YC., Grant, J.[2022]

In a study of 99 patients at low risk for amoxicillin allergy, 97% successfully underwent an oral provocation challenge (OPC) without any serious reactions, demonstrating the safety of this procedure in primary care settings.

The study suggests that implementing OPC for penicillin allergies in primary care could help correct false allergy labels, potentially improving patient access to effective antibiotics and reducing healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amoxicillin oral provocation challenge in a primary care clinic: a descriptive analysis. Gateman, DP., Rumble, JE., Protudjer, JLP., et al.[2021]

Citations

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Direct Amoxicillin Challenges for Penicillin Allergy Through ... Fifty-two (85%) reported a cutaneous-only index reaction to a penicillin, and 18 (30%) reported a reaction within 1 hour of penicillin dose at ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03757052

Amoxicillin Challenge for Penicillin Allergy Diagnosis The objective of this study is to demonstrate the safety, efficiency, and validity of direct, two-step graded oral challenge with amoxicillin for the evaluation ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10789979/

Oral amoxicillin challenges for low-risk penicillin-allergic ... We retrospectively reviewed the records of 136 veterans with a penicillin allergy label during a quality improvement initiative.

4. jamanetwork.com jamanetwork.com/journals/jamainternalmedicine/fullarticle/2806976

Efficacy of a Clinical Decision Rule to Enable Direct Oral ... Direct oral penicillin challenge is a safe and effective procedure that may facilitate the removal of a larger number of penicillin allergy labels.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2213219819304945

Comparing Direct Challenge to Penicillin Skin Testing for ... A total of 159 patients were randomized to DC (49.7%) or PST (50.3%). PST result was negative in 70 of 80 (87.5%) patients. All 70 patients had a negative ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/050813s009lbl.pdf

MOXATAG® (amoxicillin extended-release tablets) There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2015/050813s003lbl.pdf

MOXATAG® (amoxicillin extended-release) Tablets There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK482250/

Amoxicillin - StatPearls - NCBI Bookshelf - NIH Amoxicillin is a widely utilized beta-lactam antimicrobial drug approved by the US Food and Drug Administration (FDA) for use in the primary care setting.

9. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK459320/

Penicillin Allergy - StatPearls - NCBI Bookshelf 80% to 90% of people once considered allergic are ultimately able to tolerate penicillins resulting in the decreased need for broad-spectrum antibiotics.

10. cdc.gov cdc.gov/antibiotic-use/hcp/clinical-signs/index.html

Clinical Features of Penicillin Allergy 10% of U.S. patients reported having a penicillin allergy. When evaluated by clinicians, less than 1% of those patients were truly allergic.