Penicillin AllergyPhase 3NCT06303128
Penicillin Allergy Delabeling After a One-Dose Versus Two-Dose Graded Direct Oral Challenge
A Phase 3 study testing Amoxicillin 250 MG, Amoxicillin 62.5mg and Amoxicillin 187.5mg in people with Penicillin Allergy, run by James Tarbox, MD at 1 site in United States.
Trial summary
The goal of this clinical trial is to learn about dosing when testing to see if a penicillin allergy label can be removed from adults that had been labeled as "penicillin-allergic" previously. Read more about this study
- Who is it for?
- Ages 18 to 89 years
- Conditions the study is for
- Penicillin Allergy
- What is being tested?
- Amoxicillin 250 MG, Amoxicillin 62.5mg and Amoxicillin 187.5mg
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 380 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Feb 2024to Dec 2026
- Phase
- Phase 3
- 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 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Expresses interest in participating by calling or filling out information form on study website
- 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.
Who cannot join
- Penicillin allergy deemed to be more than "low-risk" per PEN-FAST (score ≥ 3 points)
- History of acute kidney injury (acute interstitial nephritis), severe liver impairment (drug- induced liver injury), serum sickness, or isolated drug fever attributed to a penicillin- based antibiotic
- Anaphylaxis for any reason in the last year
- Cognitive impairment where a collateral history could not be obtained and/or patient does not have capacity to consent for themselves
- Pregnant (self-reported)
- Any illness or condition that would increase the risk of participation in the study, per the evaluating clinician's judgment
Show all 11Show fewer
- Active treatment of or history of acute angle closure glaucoma
- On H1- or H2-blockers (i.e. diphenhydramine, hydroxyzine, chlorpheniramine, cetirizine, levocetirizine, loratadine, fexofenadine or famotidine, ranitidine, cimetidine, nizatidine, respectively) within 72 hours of initiating direct oral challenge (will be counseled to discontinue prior to testing)
- Actively receiving greater than stress dose steroid (hydrocortisone >50mg four times a day or steroid equivalent)
- Actively receiving any antibiotic
- Relative contraindication: Patients on beta blockers and angiotensin converting enzyme inhibitors (ACE inhibitors) will have an open dialog with the study team regarding the risks and benefits of testing a low-risk penicillin allergy patient. A joint decision will be made based on the patient's preference and the physician's comfort level.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Joshua A Peterson, MD contact
United States1 site, 1 recruiting
- Recruiting
Texas Tech University Health Sciences Center
Lubbock, Texas, 79430
Study Coordinator, 806-543-8994, clinicalresearch@ttuhsc.edu
Joshua A Peterson, MD, josh.peterson.587@gmail.com
About this study
The goal of this clinical trial is to learn about dosing when testing to see if a penicillin allergy label can be removed from adults that had been labeled as "penicillin-allergic" previously. The main question it aims to answer is:
- In penicillin-allergic patients that are at low risk of having an allergic reaction, is a one-dose oral challenge with amoxicillin (a penicillin-based antibiotic) as safe and effective as a two-dose oral challenge?
Participants will, after being identified as having a low-risk penicillin allergy, be administered oral amoxicillin in a controlled setting and then monitored for an allergic reaction. Researchers will compare participants that took one dose of amoxicillin to participants that took two doses of amoxicillin (a small dose and then a larger dose) to see if either group was more likely to develop an allergic reaction.
Read the detailed description
Anywhere from 5-15% of patients have a reported penicillin allergy listed in their medical record. However, most patients with this listed allergy had reactions with characteristics that would qualify their penicillin allergy as low-risk of having a subsequent serious reaction (when considering initial reaction symptoms, time since initial reaction and if treatment was required). Of patients with penicillin allergy listed, it has been demonstrated that >90% can tolerate penicillin after further evaluation, indicating a significant number of patients with an unnecessary penicillin allergy label.
Penicillin allergy delabeling is a practice commonly performed by allergists to test patients for safe removal of penicillin allergy from their medical records. The protocol of penicillin allergy delabeling has historically consisted of a skin test, followed by a two-step graded direct oral challenge, in which patients are given a smaller, then larger, oral dose of amoxicillin, a penicillin-containing medication. The patient is monitored closely throughout the process for reaction to penicillin and, if necessary, treatment is given for management of reaction symptoms. This method, though functional, takes time and resources to delabel patients.
As our understanding of penicillin drug allergy evolves, it may be possible to reduce the number of steps (and therefore resources) necessary to safely remove penicillin allergy labels. New data suggests that skin testing may not be a necessary step in penicillin allergy delabeling in a subset of low-risk patients. It has also been demonstrated in several studies that a single-dose direct oral challenge (rather than a two-step graded dose) is safe. A recent pilot study also showed that penicillin allergy delabeling can be safely performed in a primary care setting without the direct supervision of an allergist.
Per the authors' literature review, no prospective studies have directly compared the safety and efficacy of a single-dose versus a two-dose graded direct oral challenge. We propose a non-inferiority study in which patients classified as having a low-risk penicillin allergy are randomized into two groups and then receive either a single-dose or the traditional two-dose graded direct oral challenge to be able to evaluate these two treatment protocols in a side-by-side fashion. The results will contribute to our understanding of if a single-dose direct oral challenge can be safely used in place of the traditional two-dose graded direct oral challenge, thus reducing barriers for implementation in a primary care setting.
Patients with penicillin allergy that express interest through publicly posted recruitment materials will be screened to determine if they meet criteria for a "low-risk" allergy through the PEN-FAST screening tool, a recently developed, externally validated penicillin allergy risk assessment calculator. Those that meet the low-risk criteria and other eligibility criteria will be scheduled for an outpatient delabeling appointment. Participants will be randomly assigned in a double-blinded manner to receive either a two-dose graded direct oral challenge (DOC) with amoxicillin or a one-dose DOC placebo, followed by amoxicillin. Each group will receive the same cumulative dose of amoxicillin by the end of the challenge. Participants assigned to the two-dose graded DOC will be administered 62.5mg amoxicillin (25% of the full dose), followed by 187.5mg amoxicillin. Patients assigned to the one-dose DOC will be administered a placebo (Syrpalta or similar, a syrup used in drug compounding), followed by 250mg amoxicillin.
Doses will be given 30 minutes apart from one another. Both groups will be observed for a minimum of 1 hour after administration of the final dose of amoxicillin. Vital signs will be taken immediately before starting the trial, 30 minutes after administration of the first dose, and 60 minutes after administration of the second dose. If patients develop a reaction at any point in the trial, they will be treated according to the type and severity of their symptoms in an appropriate and standardized manner.
As both single-dose and graded two-dose challenges have been used in clinical practice to remove penicillin allergy labels in the past, if no reaction occurs, patients can have their penicillin allergy removed from their chart. Patients will be contacted around 5 days after the challenge to evaluate for any delayed reactions. If, at the 5-day phone call, patients have not had any other reactions suspected to be related to amoxicillin, their penicillin allergy label will be removed at that time. Patients will also be contacted around 6 months after the DOC to evaluate for any reactions to antibiotics received since successful delabeling. The two groups will then be compared to determine if the one-dose challenge is noninferior to the standard graded two-dose challenge (based upon the rate of successful delabeling without adverse reactions).
Currently, this study is approved as a single-site study only.
- Conditions
- Penicillin Allergy
- Being tested
- Amoxicillin 250 MG, Placebo, Amoxicillin 62.5mg, Amoxicillin 187.5mg
- Keywords
- low-risk allergy, amoxicillin, drug allergy, direct oral challenge
- Medical subject headings
- Drug Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Amoxicillin 250 MGDrug
Also called One-dose group
Liquid amoxicillin 250mg PO
PlaceboDrug
Also called Liquid placebo (Syrpalta or similar) for one-dose group
Given prior to amoxicillin 250mg in one-dose group
Amoxicillin 62.5mgDrug
Also called Two-dose group, dose 1 of 2
Given first in two-dose group, liquid amoxicillin 62.5mg PO
Amoxicillin 187.5mgDrug
Also called Two-dose group, dose 2 of 2
Given second in two-dose group, liquid amoxicillin 187.5mg PO
| Study group | Role | What they receive |
|---|---|---|
| One-dose group | Experimental | Patients assigned to this group will receive a liquid placebo followed by full-dose liquid amoxicillin 250mg PO thirty minutes later. Receives: Drug: Amoxicillin 250 MG; Drug: Placebo |
| Graded, two-dose group | Active comparator | 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. Receives: Drug: Amoxicillin 62.5mg; Drug: Amoxicillin 187.5mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of successfully "delabeled" subjects in one-dose versus two-dose groups
Percentage of subjects that successfully complete either the one-dose or graded two-dose direct oral challenge with amoxicillin without adverse reactions during the challenge, as determined by no reaction reported at first follow up phone call.
Measured: 5 days (at time of first follow up phone call)
Secondary outcomes (4)
Analysis of adverse reactions
Percentage of subjects that report adverse reactions during direct oral challenge and at 5-day follow-up phone call, including type of reaction, timing, severity, treatment required (if any), and classification of degree of causality.
Measured: 2 hours (during direct oral challenge) and 5 days (at time of first follow up phone call)
Analysis of medical and allergic history
For further stratification of primary outcome, other medical and allergic history items including: reported penicillin allergy label, history of cephalosporin allergy, PEN-FAST score, time (in years) since index reaction, time (in hours) between administration of medication and index reaction, treatment required for index reaction, antibiotics tolerated since index reaction, history of other atopic conditions, and use of beta blockers/ACE inhibitors.
Measured: Reported at time of direct oral challenge
Validation of penicillin allergy delabeling
Data from 6-month follow up phone call including: percentage of successfully delabeled patients able to tolerate penicillin-derived antibiotics since DOC and any associated reactions, percentage of patients confident in taking a penicillin derivative should it be required in the future.
Measured: 6 months
Analysis of demographic data
For further stratification of primary outcome, demographic data, including age, gender, race/ethnicity, urban vs. rural and other measures of socioeconomic status. This will allow us to analyze differences in reaction rates between different groups, as well as psychological differences between groups when considering patient confidence in their allergy label being removed.
Measured: Reported at time of direct oral challenge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2024
- Study start3 Feb 2024
- Primary completionJul 2026 (estimated)
- Study completionDec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Penicillin AllergyStudies of the same condition, open and under way.
- 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 3
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- \- Low-risk penicillin allergic patients ("low-risk" determined by a PEN-FAST score of 2 or less) will be recruited. Clinically stable patients will be randomly assigned in a double-blinded manner to receive either a one-dose or graded two-dose direct oral challenge with amoxicillin in an outpatient setting. Those assigned to receive one dose of amoxicillin will receive a placebo in place of a second dose of amoxicillin. Both groups will receive the same cumulative dose of amoxicillin (250mg) by the end of the trial. Baseline vital signs will be obtained and tracked throughout the trial. Patients will also be monitored for development of signs of allergic reactions during the trial, with administration of appropriate treatment should the need arise.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 380 participants (estimated)
Sponsor and investigators
- Lead sponsor
- James Tarbox, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Texas Tech University Health Sciences Center
- Responsible party
- Sponsor-investigator, James Tarbox, MD, Texas Tech University Health Sciences Center
- Investigators
- James A Tarbox, MD, Principal investigator, Texas Tech University Health Sciences Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06303128
- Sponsor's protocol ID
- IRB-FY2024-61
- Status last verified
- Apr 2025
- First submitted
- 4 Mar 2024
- Last updated
- 1 May 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in the article that is planned to be published, after deidentification.
Publications
Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019 Jan 12;393(10167):183-198. doi: 10.1016/S0140-6736(18)32218-9. Epub 2018 Dec 14.
PubMed 30558872Trubiano JA, Vogrin S, Chua KYL, Bourke J, Yun J, Douglas A, Stone CA, Yu R, Groenendijk L, Holmes NE, Phillips EJ. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020 May 1;180(5):745-752. doi: 10.1001/jamainternmed.2020.0403.
PubMed 32176248Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, Bernstein JA, Chu DK, Ellis AK, Golden DBK, Greenhawt MJ, Horner CC, Ledford D, Lieberman JA, Oppenheimer J, Rank MA, Shaker MS, Stukus DR, Wallace D, Wang J; Chief Editor(s):; Khan DA, Golden DBK, Shaker M, Stukus DR; Workgroup Contributors:; Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA; Joint Task Force on Practice Parameters Reviewers:; Bernstein JA, Chu DK, Ellis AK, Golden DBK, Greenhawt MJ, Horner CC, Ledford D, Lieberman JA, Oppenheimer J, Rank MA, Shaker MS, Stukus DR, Wallace D, Wang J. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022 Dec;150(6):1333-1393. doi: 10.1016/j.jaci.2022.08.028. Epub 2022 Sep 17. No abstract available.
PubMed 36122788Iammatteo M, Lezmi G, Confino-Cohen R, Tucker M, Ben-Shoshan M, Caubet JC. Direct Challenges for the Evaluation of Beta-Lactam Allergy: Evidence and Conditions for Not Performing Skin Testing. J Allergy Clin Immunol Pract. 2021 Aug;9(8):2947-2956. doi: 10.1016/j.jaip.2021.04.073.
PubMed 34366093Iammatteo M, Alvarez Arango S, Ferastraoaru D, Akbar N, Lee AY, Cohen HW, Jerschow E. Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing. J Allergy Clin Immunol Pract. 2019 Jan;7(1):236-243. doi: 10.1016/j.jaip.2018.05.008. Epub 2018 May 23.
PubMed 29802906Copaescu AM, Vogrin S, James F, Chua KYL, Rose MT, De Luca J, Waldron J, Awad A, Godsell J, Mitri E, Lambros B, Douglas A, Youcef Khoudja R, Isabwe GAC, Genest G, Fein M, Radojicic C, Collier A, Lugar P, Stone C, Ben-Shoshan M, Turner NA, Holmes NE, Phillips EJ, Trubiano JA. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023 Sep 1;183(9):944-952. doi: 10.1001/jamainternmed.2023.2986.
PubMed 37459086Wang LA, Patel K, Kuruvilla ME, Shih J. Direct amoxicillin challenge without preliminary skin testing for pediatric patients with penicillin allergy labels. Ann Allergy Asthma Immunol. 2020 Aug;125(2):226-228. doi: 10.1016/j.anai.2020.05.004. Epub 2020 May 11. No abstract available.
PubMed 32407949Lin L, Nagtegaal JE, Buijtels PCAM, Jong E. Antimicrobial stewardship intervention: optimizing antibiotic treatment in hospitalized patients with reported antibiotic allergy. J Hosp Infect. 2020 Feb;104(2):137-143. doi: 10.1016/j.jhin.2019.10.007. Epub 2019 Oct 13.
PubMed 31618608Trubiano JA, Smibert O, Douglas A, Devchand M, Lambros B, Holmes NE, Chua KY, Phillips EJ, Slavin MA. The Safety and Efficacy of an Oral Penicillin Challenge Program in Cancer Patients: A Multicenter Pilot Study. Open Forum Infect Dis. 2018 Nov 17;5(12):ofy306. doi: 10.1093/ofid/ofy306. eCollection 2018 Dec.
PubMed 30547046Chua KYL, Vogrin S, Bury S, Douglas A, Holmes NE, Tan N, Brusco NK, Hall R, Lambros B, Lean J, Stevenson W, Devchand M, Garrett K, Thursky K, Grayson ML, Slavin MA, Phillips EJ, Trubiano JA. The Penicillin Allergy Delabeling Program: A Multicenter Whole-of-Hospital Health Services Intervention and Comparative Effectiveness Study. Clin Infect Dis. 2021 Aug 2;73(3):487-496. doi: 10.1093/cid/ciaa653.
PubMed 32756983Tucker MH, Lomas CM, Ramchandar N, Waldram JD. Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits. J Allergy Clin Immunol Pract. 2017 May-Jun;5(3):813-815. doi: 10.1016/j.jaip.2017.01.023. Epub 2017 Mar 21. No abstract available.
PubMed 28341170Kuruvilla M, Shih J, Patel K, Scanlon N. Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy. Allergy Asthma Proc. 2019 Jan 1;40(1):57-61. doi: 10.2500/aap.2019.40.4184.
PubMed 30582497Chow TG, Patel G, Mohammed M, Johnson D, Khan DA. Delabeling penicillin allergy in a pediatric primary care clinic. Ann Allergy Asthma Immunol. 2023 May;130(5):667-669. doi: 10.1016/j.anai.2023.01.034. Epub 2023 Feb 2. No abstract available.
PubMed 36738783Livirya S, Pithie A, Chua I, Hamilton N, Doogue M, Isenman H. Oral amoxicillin challenge for low-risk penicillin allergic patients. Intern Med J. 2022 Feb;52(2):295-300. doi: 10.1111/imj.14978. Epub 2022 Jan 12.
PubMed 32672891
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Penicillin Allergy Delabeling After a One-Dose Versus Two-Dose Graded Direct Oral Challenge
- ClinicalTrials.gov ID
- NCT06303128
- Acronym / sponsor ID
- IRB-FY2024-61
- Conditions
- Penicillin Allergy
- Keywords
- low-risk allergy, amoxicillin, drug allergy, direct oral challenge
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 380 participants (estimated)
- Lead sponsor
- James Tarbox, MDUniversity, hospital or other
- Collaborators
- Texas Tech University Health Sciences Center
- Study start
- 3 Feb 2024 (actual)
- Primary completion
- Jul 2026 (estimated)
- Study completion
- Dec 2026 (estimated)
- First posted
- 12 Mar 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.
The goal of this clinical trial is to learn about dosing when testing to see if a penicillin allergy label can be removed from adults that had been labeled as "penicillin-allergic" previously. The main question it aims to answer is:
- In penicillin-allergic patients that are at low risk of having an allergic reaction, is a one-dose oral challenge with amoxicillin (a penicillin-based antibiotic) as safe and effective as a two-dose oral challenge?
Participants will, after being identified as having a low-risk penicillin allergy, be administered oral amoxicillin in a controlled setting and then monitored for an allergic reaction. Researchers will compare participants that took one dose of amoxicillin to participants that took two doses of amoxicillin (a small dose and then a larger dose) to see if either group was more likely to develop an allergic reaction.
Detailed description
Anywhere from 5-15% of patients have a reported penicillin allergy listed in their medical record. However, most patients with this listed allergy had reactions with characteristics that would qualify their penicillin allergy as low-risk of having a subsequent serious reaction (when considering initial reaction symptoms, time since initial reaction and if treatment was required). Of patients with penicillin allergy listed, it has been demonstrated that >90% can tolerate penicillin after further evaluation, indicating a significant number of patients with an unnecessary penicillin allergy label.
Penicillin allergy delabeling is a practice commonly performed by allergists to test patients for safe removal of penicillin allergy from their medical records. The protocol of penicillin allergy delabeling has historically consisted of a skin test, followed by a two-step graded direct oral challenge, in which patients are given a smaller, then larger, oral dose of amoxicillin, a penicillin-containing medication. The patient is monitored closely throughout the process for reaction to penicillin and, if necessary, treatment is given for management of reaction symptoms. This method, though functional, takes time and resources to delabel patients.
As our understanding of penicillin drug allergy evolves, it may be possible to reduce the number of steps (and therefore resources) necessary to safely remove penicillin allergy labels. New data suggests that skin testing may not be a necessary step in penicillin allergy delabeling in a subset of low-risk patients. It has also been demonstrated in several studies that a single-dose direct oral challenge (rather than a two-step graded dose) is safe. A recent pilot study also showed that penicillin allergy delabeling can be safely performed in a primary care setting without the direct supervision of an allergist.
Per the authors' literature review, no prospective studies have directly compared the safety and efficacy of a single-dose versus a two-dose graded direct oral challenge. We propose a non-inferiority study in which patients classified as having a low-risk penicillin allergy are randomized into two groups and then receive either a single-dose or the traditional two-dose graded direct oral challenge to be able to evaluate these two treatment protocols in a side-by-side fashion. The results will contribute to our understanding of if a single-dose direct oral challenge can be safely used in place of the traditional two-dose graded direct oral challenge, thus reducing barriers for implementation in a primary care setting.
Patients with penicillin allergy that express interest through publicly posted recruitment materials will be screened to determine if they meet criteria for a "low-risk" allergy through the PEN-FAST screening tool, a recently developed, externally validated penicillin allergy risk assessment calculator. Those that meet the low-risk criteria and other eligibility criteria will be scheduled for an outpatient delabeling appointment. Participants will be randomly assigned in a double-blinded manner to receive either a two-dose graded direct oral challenge (DOC) with amoxicillin or a one-dose DOC placebo, followed by amoxicillin. Each group will receive the same cumulative dose of amoxicillin by the end of the challenge. Participants assigned to the two-dose graded DOC will be administered 62.5mg amoxicillin (25% of the full dose), followed by 187.5mg amoxicillin. Patients assigned to the one-dose DOC will be administered a placebo (Syrpalta or similar, a syrup used in drug compounding), followed by 250mg amoxicillin.
Doses will be given 30 minutes apart from one another. Both groups will be observed for a minimum of 1 hour after administration of the final dose of amoxicillin. Vital signs will be taken immediately before starting the trial, 30 minutes after administration of the first dose, and 60 minutes after administration of the second dose. If patients develop a reaction at any point in the trial, they will be treated according to the type and severity of their symptoms in an appropriate and standardized manner.
As both single-dose and graded two-dose challenges have been used in clinical practice to remove penicillin allergy labels in the past, if no reaction occurs, patients can have their penicillin allergy removed from their chart. Patients will be contacted around 5 days after the challenge to evaluate for any delayed reactions. If, at the 5-day phone call, patients have not had any other reactions suspected to be related to amoxicillin, their penicillin allergy label will be removed at that time. Patients will also be contacted around 6 months after the DOC to evaluate for any reactions to antibiotics received since successful delabeling. The two groups will then be compared to determine if the one-dose challenge is noninferior to the standard graded two-dose challenge (based upon the rate of successful delabeling without adverse reactions).
Currently, this study is approved as a single-site study only.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- - Low-risk penicillin allergic patients ("low-risk" determined by a PEN-FAST score of 2 or less) will be recruited. Clinically stable patients will be randomly assigned in a double-blinded manner to receive either a one-dose or graded two-dose direct oral challenge with amoxicillin in an outpatient setting. Those assigned to receive one dose of amoxicillin will receive a placebo in place of a second dose of amoxicillin. Both groups will receive the same cumulative dose of amoxicillin (250mg) by the end of the trial. Baseline vital signs will be obtained and tracked throughout the trial. Patients will also be monitored for development of signs of allergic reactions during the trial, with administration of appropriate treatment should the need arise.
| Arm | Type | Receives |
|---|---|---|
| One-dose group | Experimental | Drug: Amoxicillin 250 MG, Drug: PlaceboPatients assigned to this group will receive a liquid placebo followed by full-dose liquid amoxicillin 250mg PO thirty minutes later. |
| Graded, two-dose group | Active comparator | Drug: Amoxicillin 62.5mg, Drug: Amoxicillin 187.5mgPatients 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. |
Who may qualify
- Ages
- 18 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Expresses interest in participating by calling or filling out information form on study website
- 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.
Key exclusion criteria (11 listed)
- Penicillin allergy deemed to be more than "low-risk" per PEN-FAST (score ≥ 3 points)
- History of acute kidney injury (acute interstitial nephritis), severe liver impairment (drug- induced liver injury), serum sickness, or isolated drug fever attributed to a penicillin- based antibiotic
- Anaphylaxis for any reason in the last year
- Cognitive impairment where a collateral history could not be obtained and/or patient does not have capacity to consent for themselves
- Pregnant (self-reported)
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 |
|---|---|---|
| Amoxicillin 250 MGAlso: One-dose groupLiquid amoxicillin 250mg PO | Drug | One-dose group |
| PlaceboAlso: Liquid placebo (Syrpalta or similar) for one-dose groupGiven prior to amoxicillin 250mg in one-dose group | Drug | One-dose group |
| Amoxicillin 62.5mgAlso: Two-dose group, dose 1 of 2Given first in two-dose group, liquid amoxicillin 62.5mg PO | Drug | Graded, two-dose group |
| Amoxicillin 187.5mgAlso: Two-dose group, dose 2 of 2Given second in two-dose group, liquid amoxicillin 187.5mg PO | Drug | Graded, two-dose group |
Primary outcome
Proportion of successfully "delabeled" subjects in one-dose versus two-dose groups
Time frame: 5 days (at time of first follow up phone call)
Percentage of subjects that successfully complete either the one-dose or graded two-dose direct oral challenge with amoxicillin without adverse reactions during the challenge, as determined by no reaction reported at first follow up phone call.
4 secondary outcomes
Analysis of adverse reactions
Time frame: 2 hours (during direct oral challenge) and 5 days (at time of first follow up phone call)
Analysis of medical and allergic history
Time frame: Reported at time of direct oral challenge
Validation of penicillin allergy delabeling
Time frame: 6 months
Analysis of demographic data
Time frame: Reported at time of direct oral challenge
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 1 May 2025.
- Background: PubMed 30558872Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019 Jan 12;393(10167):183-198. doi: 10.1016/S0140-6736(18)32218-9. Epub 2018 Dec 14.
- Background: PubMed 32176248Trubiano JA, Vogrin S, Chua KYL, Bourke J, Yun J, Douglas A, Stone CA, Yu R, Groenendijk L, Holmes NE, Phillips EJ. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020 May 1;180(5):745-752. doi: 10.1001/jamainternmed.2020.0403.
- Background: PubMed 36122788Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, Bernstein JA, Chu DK, Ellis AK, Golden DBK, Greenhawt MJ, Horner CC, Ledford D, Lieberman JA, Oppenheimer J, Rank MA, Shaker MS, Stukus DR, Wallace D, Wang J; Chief Editor(s):; Khan DA, Golden DBK, Shaker M, Stukus DR; Workgroup Contributors:; Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA; Joint Task Force on Practice Parameters Reviewers:; Bernstein JA, Chu DK, Ellis AK, Golden DBK, Greenhawt MJ, Horner CC, Ledford D, Lieberman JA, Oppenheimer J, Rank MA, Shaker MS, Stukus DR, Wallace D, Wang J. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022 Dec;150(6):1333-1393. doi: 10.1016/j.jaci.2022.08.028. Epub 2022 Sep 17. No abstract available.
- Background: PubMed 34366093Iammatteo M, Lezmi G, Confino-Cohen R, Tucker M, Ben-Shoshan M, Caubet JC. Direct Challenges for the Evaluation of Beta-Lactam Allergy: Evidence and Conditions for Not Performing Skin Testing. J Allergy Clin Immunol Pract. 2021 Aug;9(8):2947-2956. doi: 10.1016/j.jaip.2021.04.073.
- Background: PubMed 29802906Iammatteo M, Alvarez Arango S, Ferastraoaru D, Akbar N, Lee AY, Cohen HW, Jerschow E. Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing. J Allergy Clin Immunol Pract. 2019 Jan;7(1):236-243. doi: 10.1016/j.jaip.2018.05.008. Epub 2018 May 23.
- Background: PubMed 37459086Copaescu AM, Vogrin S, James F, Chua KYL, Rose MT, De Luca J, Waldron J, Awad A, Godsell J, Mitri E, Lambros B, Douglas A, Youcef Khoudja R, Isabwe GAC, Genest G, Fein M, Radojicic C, Collier A, Lugar P, Stone C, Ben-Shoshan M, Turner NA, Holmes NE, Phillips EJ, Trubiano JA. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023 Sep 1;183(9):944-952. doi: 10.1001/jamainternmed.2023.2986.
- Background: PubMed 32407949Wang LA, Patel K, Kuruvilla ME, Shih J. Direct amoxicillin challenge without preliminary skin testing for pediatric patients with penicillin allergy labels. Ann Allergy Asthma Immunol. 2020 Aug;125(2):226-228. doi: 10.1016/j.anai.2020.05.004. Epub 2020 May 11. No abstract available.
- Background: PubMed 31618608Lin L, Nagtegaal JE, Buijtels PCAM, Jong E. Antimicrobial stewardship intervention: optimizing antibiotic treatment in hospitalized patients with reported antibiotic allergy. J Hosp Infect. 2020 Feb;104(2):137-143. doi: 10.1016/j.jhin.2019.10.007. Epub 2019 Oct 13.
- Background: PubMed 30547046Trubiano JA, Smibert O, Douglas A, Devchand M, Lambros B, Holmes NE, Chua KY, Phillips EJ, Slavin MA. The Safety and Efficacy of an Oral Penicillin Challenge Program in Cancer Patients: A Multicenter Pilot Study. Open Forum Infect Dis. 2018 Nov 17;5(12):ofy306. doi: 10.1093/ofid/ofy306. eCollection 2018 Dec.
- Background: PubMed 32756983Chua KYL, Vogrin S, Bury S, Douglas A, Holmes NE, Tan N, Brusco NK, Hall R, Lambros B, Lean J, Stevenson W, Devchand M, Garrett K, Thursky K, Grayson ML, Slavin MA, Phillips EJ, Trubiano JA. The Penicillin Allergy Delabeling Program: A Multicenter Whole-of-Hospital Health Services Intervention and Comparative Effectiveness Study. Clin Infect Dis. 2021 Aug 2;73(3):487-496. doi: 10.1093/cid/ciaa653.
- Background: PubMed 28341170Tucker MH, Lomas CM, Ramchandar N, Waldram JD. Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits. J Allergy Clin Immunol Pract. 2017 May-Jun;5(3):813-815. doi: 10.1016/j.jaip.2017.01.023. Epub 2017 Mar 21. No abstract available.
- Background: PubMed 30582497Kuruvilla M, Shih J, Patel K, Scanlon N. Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy. Allergy Asthma Proc. 2019 Jan 1;40(1):57-61. doi: 10.2500/aap.2019.40.4184.
- Recruiting WebsiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in the article that is planned to be published, after deidentification.
Related trials for Penicillin Allergy
Not yet recruiting
Multimodal Stewardship Programme to Improve Antibiotic Prescribing for Children With Lower Respiratory Tract Infections
Bronchitis, Acute, Community-acquired Pneumonia
RecruitingPhase 2
Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
Drug Allergy, Cephalosporin Allergy
RecruitingPhase 4
Allergy Delabeling in Antibiotic Stewardship - Intervention
Beta Lactam Allergy, Hematologic Malignancy
Enrolling by invitationObservational study
Allergy Delabeling in Antibiotic Stewardship - Evaluations
Beta Lactam Allergy in Patients With a Hematologic Malignancy
RecruitingObservational study
Provocation After Nurse-Directed Assessment (PANDA) Study
Drug Allergy, Penicillin Allergy
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.
Joshua A Peterson, MD contact
James A Tarbox, MD principal investigator
Texas Tech University Health Sciences Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Amoxicillin 250 MG, Amoxicillin 62.5mg and Amoxicillin 187.5mg in people with Penicillin Allergy, run by James Tarbox, MD at 1 site 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 2 inclusion and 11 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 1 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 Study Coordinator (806-543-8994, clinicalresearch@ttuhsc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of successfully "delabeled" subjects in one-dose versus two-dose groups (time frame: 5 days (at time of first follow up phone call)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06303128, which also lists 14 linked publications.
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 1 May 2025.