Penicillin De-labeling in the Pediatric Primary Care Setting
Phase: PHASE4
Conditions: Penicillin Allergy, Penicillin Reaction
Sponsor: University of Texas Southwestern Medical Center

Title: Penicillin De-Labeling in the Pediatric Primary Care Setting; Protocol  
NCT Number: 05010304 
IRB Approval Date: 11/29/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB STU-2021-0517 
 
PROTOCOL FORM / RESEARCH DESCRIPTION 
 
If an item does not apply to your research project, indicate that the question is "not applicable” – do not leave 
sections blank 
 
Click once on the highlighted entry in each box to provide your response.  Click the item number/letter or word, 
if hyperlinked, for detailed instructions for that question.  If your response requires inserting a table, picture, etc, you 
may need to first delete the box that surrounds the answer and then insert your table or other special document. 
 
 
1.  Purpose and objectives.           List the purpose and objectives: 
 
The goal of this project is to explore the feasibility of implementing a penicillin allergy 
delabeling protocol for low-risk pediatric patients in the primary care setting. Specifically, we 
seek to demonstrate risk-stratification of reported adverse reactions to penicillins and 
completion of direct amoxicillin challenge in low-risk subjects can be performed in the 
outpatient pediatric primary care setting.  
 
 
 
2.  Background. 
• 
Describe past experimental and/or clinical findings leading to the formulation of your study.   
• 
For research involving investigational drugs, describe the previously conducted animal and human 
studies.   
• 
For research that involves FDA approved drugs or devices, describe the FDA approved uses of this 
drug/device in relation to your protocol.   
• 
Attach a copy of the approved labeling as a product package insert or from the Physician’s Desk 
Reference.   
You may reference sponsor’s full protocol or grant application (section number and/or title) or if none, ensure 
background includes references. 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
a. 
Background 
Reported adverse drug reactions to penicillins are common; however, more than 90% of 
patients with a penicillin allergy label can safely tolerate penicillins (1, 2). Numerous adverse 

outcomes are associated with an unverified penicillin allergy, and elective evaluation for 
penicillin allergy has been recommended (1, 3, 4). 
 
There is a vast disparity between the number of patients with a penicillin allergy label and 
practicing allergists in the United States, with over 30 million penicillin-allergic labeled 
patients and less than 5000 practicing allergists (5, 6). With such a significant prevalence of 
labeled penicillin allergy, no single medical discipline can handle this burden alone; a 
coordinated effort across both primary care and subspecialists will be required to address 
this. As the majority of penicillin allergy labels occur in young childhood, pediatricians are 
uniquely situated to have a significant impact in reducing the long-term consequences of a 
penicillin allergy label through delabeling strategies (1, 5). Direct oral challenge in low-risk 
patients has been recommended as a delabeling strategy for this population (7-9). 
Cumulative studies have now evaluated the safety and efficacy of direct amoxicillin 
challenge in children with a penicillin-allergy label in over 1400 subjects (8-16); the majority 
of studies have taken place in the outpatient allergist setting. Across studies, positive 
challenge rates ranging from 0-13%. The largest study was a single center prospective 
study which defined low-risk allergy patients as an absence of severe cutaneous adverse 
reactions (SCARs); they reported on 818 patients and found a 6% positive challenge rate 
(8). Across the above studies, all reactions were mild and only required treatment with oral 
antihistamines, no epinephrine use was documented in any of these studies.  
  
While there is significant evidence for the safety and efficacy of direct penicillin challenge in 
the evaluation of penicillin allergy, this has not yet been widely implemented in the primary 
care setting. There have been two pilot studies exploring direct amoxicillin challenge in the 
pediatric primary care setting. The first was a retrospective study of 42 children in Australia 
who included children greater than 18 months old. They performed direct amoxicillin 
challenges after 3 months had elapsed from the index reaction. There was a 3% positive 
challenge rate and all reactions resolved with only oral diphenhydramine. The second was a 
prospective study that included 102 children in Ireland and there no positive challenges to 
amoxicillin challenge. This approach has not been studied in the United States. A recent 
survey of US-based pediatricians identified perceived barriers to implementing penicillin 
allergy evaluations into their routine care (17). Significant gaps in knowledge exist regarding 
the feasibility of this approach involving direct amoxicillin challenge procedures in low-risk 
patients in the pediatric primary care setting. 
 
1. 
Castells M, Khan DA, Phillips EJ. Penicillin Allergy. N Engl J Med. 2019;381(24):2338-
51. 
2. 
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of 
Penicillin Allergy: A Review. JAMA. 2019;321(2):188-99. 

3. 
Blumenthal KG, Shenoy ES. Is My Child Allergic to Penicillin? JAMA Pediatr. 
2019;173(7):708. 
4. 
Joint Task Force on Practice P, American Academy of Allergy A, Immunology, 
American College of Allergy A, Immunology, Joint Council of Allergy A, et al. Drug allergy: an 
updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-73. 
5. 
Staicu ML, Vyles D, Shenoy ES, Stone CA, Banks T, Alvarez KS, et al. Penicillin Allergy 
Delabeling: A Multidisciplinary Opportunity. J Allergy Clin Immunol Pract. 2020;8(9):2858-
68 e16. 
6. 
American Academy of Allergy Asthma and Immunology Report on the Allergy and 
Immunology Physician Workforce (1999-2009/10). Rensselaer, NY: The Center for Health 
Workforce Studies; 2012 [Available from: https://www.aaaai.org/Aaaai/media/ 
MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/2012-AI- Physician-
Workforce-Report.pdf. 
7. 
Vyles D, Antoon JW, Norton A, Stone CA, Jr., Trubiano J, Radowicz A, et al. Children 
with reported penicillin allergy: Public health impact and safety of delabeling. Ann Allergy 
Asthma Immunol. 2020;124(6):558-65. 
8. 
Mill C, Primeau MN, Medoff E, Lejtenyi C, O'Keefe A, Netchiporouk E, et al. 
Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the 
Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children. JAMA 
Pediatr. 2016;170(6):e160033. 
9. 
Vyles D, Chiu A, Routes J, Castells M, Phillips EJ, Visotcky A, et al. Oral amoxicillin 
challenges in low-risk children during a pediatric emergency department visit. J Allergy Clin 
Immunol Pract. 2020;8(3):1126-8 e1. 
10. 
Gateman DP, Rumble JE, Protudjer JLP, Kim H. Amoxicillin oral provocation 
challenge in a primary care clinic: a descriptive analysis. CMAJ Open. 2021;9(2):E394-E9. 
11. 
Allen HI, Vazquez-Ortiz M, Murphy AW, Moylett EM. De-labeling penicillin-allergic 
children in outpatients using telemedicine: Potential to replicate in primary care. J Allergy 
Clin Immunol Pract. 2020;8(5):1750-2. 
12. 
Mustafa SS, Conn K, Ramsey A. Comparing Direct Challenge to Penicillin Skin Testing 
for the Outpatient Evaluation of Penicillin Allergy: A Randomized Controlled Trial. J Allergy 
Clin Immunol Pract. 2019;7(7):2163-70. 
13. 
Moral L, Garde J, Toral T, Fuentes MJ, Marco N. Short protocol for the study of 
paediatric patients with suspected betalactam antibiotic hypersensitivity and low risk 
criteria. Allergol Immunopathol (Madr). 2011;39(6):337-41. 
14. 
Chambel M, Martins P, Silva I, Palma-Carlos S, Romeira AM, Leiria Pinto P. Drug 
provocation tests to betalactam antibiotics: experience in a paediatric setting. Allergol 
Immunopathol (Madr). 2010;38(6):300-6. 
15. 
Labrosse R, Paradis L, Lacombe-Barrios J, Samaan K, Graham F, Paradis J, et al. 
Efficacy and Safety of 5-Day Challenge for the Evaluation of Nonsevere Amoxicillin Allergy in 
Children. J Allergy Clin Immunol Pract. 2018;6(5):1673-80. 
16. 
Caubet JC, Kaiser L, Lemaitre B, Fellay B, Gervaix A, Eigenmann PA. The role of 
penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. 
J Allergy Clin Immunol. 2011;127(1):218-22. 

17. 
Cherk E, Morris K, Collins CA. Partnering with general pediatricians to delabel 
penicillin allergies in children. Ann Allergy Asthma Immunol. 2020. 
 
 
 
b. 
Current practice 
Currently there is no standard protocol in the Children’s Health pediatric primary care clinic for evaluation of 
penicillin-allergy labels. Most often, children with a penicillin allergy label are referred to the Children’s Health 
pediatric allergy clinic for evaluation of penicillin allergy regardless of their risk status based on the history of 
their index reaction to penicillin.  
 
 
3.  Study Design.  
Describe the study design (e.g., single/double blind, parallel, crossover, etc.)  Consider inserting a scheme to 
visually present the study design. 
 
This study is a prospective, descriptive, single arm study of a convenience sample of children 
from age 2-18 with a history of parent reported penicillin allergy who present to an outpatient 
pediatric clinic for a routine healthcare maintenance visit. 
 
 
4.  Research Plan / Description of the Research Methods:   
4.a.  Provide a comprehensive narrative describing the research methods.   
     1) Provide the order in which tests/procedures will be performed,  
     2) Provide the setting for these events and a description of the methods used to protect privacy during the 
study.   
     3) Provide the plan for data analysis (include as applicable the sample size calculation) 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
 
Patients will be recruited from the pediatric primary care clinic at the Children’s Health 
Specialty Center Dallas campus who are scheduled for a routine healthcare maintenance 
visit, have a penicillin allergy listed in the electronic medical record, and have consented to 
participate in research activities. Patient caregivers will receive a telephone call, where in a 
study member will introduce the topic of penicillin allergy and delabeling through direct 

amoxicillin challenge and obtain verbal consent to administer a risk-stratifying questionnaire 
evaluating the index reaction and their interest in proceeding with the amoxicillin challenge, 
including reasons for hesitancy and perceived barriers. Subjects with a history of reactions 
consistent with severe cutaneous adverse reactions will be excluded. The study member will 
review the oral amoxicillin challenge procedure and assess caregiver and patient’s interest in 
proceeding with oral amoxicillin challenge.  
 
Subjects who are classified as low-risk and are interested to proceed with direct amoxicillin 
challenge will be sent the consent form through the caregiver’s preference of encrypted email, 
mail, or patient portal MyChart for their review. Caregivers will be provided the option to sign 
the electronic consent form, using an encrypted, secure platform provided through UTSW 
(Docusign/REDCap), and if they choose this option, will be contacted via telephone to review 
the consent form and answer applicable questions. Alternatively, when presenting for their 
healthcare maintenance visit at the pediatric primary care clinic at the Children’s Health 
Specialty Center Dallas campus, the written consent form will be reviewed.. Patients will be 
screened for acute dermatitis or respiratory symptoms. Subjects with acute dermatitis or 
respiratory symptoms at time of evaluation will be excluded. A point of care urine pregnancy 
test will be performed on adolescent female subjects who have begun menstruation; subjects 
who have a positive pregnancy test or who are breastfeeding will be excluded. 
 
A single dose of amoxicillin 50 mg will be administered at the start of the healthcare 
maintenance visit. Subjects will be observed for 10 minutes and if no reaction, will be given a 
second 200 mg dose and observed for a further 50 minutes for immediate reactions, defined 
as onset of urticaria, angioedema, cough, wheezing, rhinitis, repetitive vomiting, diarrhea, 
protracted abdominal pain, or hypotension, and managed accordingly. This direct amoxicillin 
challenge testing is the recommended evaluation for low-risk patients, and the investigatory 
component of this study is if it can be performed in conjunction with a routine healthcare 
maintenance visit in the pediatric primary care setting. During this observation period, 
subjects will have their healthcare maintenance visit with the primary pediatric provider. 
Subjects who have a negative oral challenge will be provided documentation of their 
immediate tolerance of penicillin. Upon completion of challenge, a survey will be administered 
to families to assess the quality of their experience and identify areas for improvement. If 
immunizations are indicated per the CDC vaccination schedule, they will be administered 
after this 60-minute period of observation from the challenge. Subjects will be discharged with 
instructions to contact the pediatrician and study team for any delayed symptoms. We will 
also measure the duration of each subject’s time in the clinic from check in to check out. A 
follow up encounter will occur over the phone at 7-10 days after the date of oral challenge to 
assess for delayed reactions. At 1 year post-challenge, subjects’ penicillin allergy status will 
be assessed in the electronic medical record, and patients who have had penicillin allergy 
label added back to their allergy list will be contacted via telephone to assess reasons for the 

addition of the penicillin allergy label. Descriptive statistics will be used to describe the 
population completing amoxicillin challenge testing.  
 
 
 
4.b.  List of the study intervention(s) being tested or evaluated under this protocol 
 
N/A -  this study does not test or evaluate an intervention.    Skip to item 4.d. 
# 
Study intervention(s) being tested or evaluated under the protocol 
 
 
 
Add or delete rows as needed 
 
Affiliate 
 
Place a check next 
to institution(s) 
where the  
intervention will be 
performed 
Local Standard 
Practice?  
Indicate whether 
the intervention is 
considered 
acceptable 
practice locally for 
applicable 
institutions 
1 
Direct Amoxicillin challenge  
☐ UTSW 
☐ Yes 
☐ PHHS 
☐ Yes 
☒CMC 
☐ Yes 
☐THR 
☐ Yes 
☐TSRH 
☐ Yes 
☐ Other: _____ 
☐ Yes 
2 
Insert study intervention 2 here 
☐ UTSW 
☐ Yes 
☐ PHHS 
☐ Yes 
☐CMC 
☐ Yes 
☐THR 
☐ Yes 
☐TSRH 
☐ Yes 
☐ Other: _____ 
☐ Yes 
 

 
4.c.  Risk:Benefit Analysis of study interventions being tested or evaluated under this protocol 
For each study intervention identified in section 6b above, complete a risk:benefit analysis table. 
 
(Two tables are provided, copy & paste additional tables as needed or delete both tables if this study does not test 
an intervention) 
 
 

4.c. 
Study Intervention #1 
Direct Amoxicillin Challenge 
List each group exposed to this 
intervention on a separate line. 
(e.g., experimental, control, Arm A, Arm B, 
etc) 
Or state All Groups/Subjects 
For each group, list the benefits of this intervention.  (Benefits can be directly from 
the intervention or from a monitoring procedure likely to contribute to the subject’s 
well being).  If there are no benefits, state “none”. 
All groups/subjects 
One benefit will be the accurate diagnosis of current penicillin tolerance status. If 
penicillin tolerant, would have the benefit of using penicillin-based antibiotic 
treatment for future infections and diminishing the harms associated with a 
penicillin-allergy label which include prolonged hospital stays, increased surgical 
site infections, increased rates of Clostridium Difficile infections, and increased 
healthcare utilization costs when compared to patients without a penicillin allergy 
label. Another benefit includes increased access to evaluation, as this evaluation 
would be included within patients’ healthcare maintenance visit and not require a 
separate referral to an allergist with the associated barriers of time and cost with 
seeing another provider.  
 
 
If you are requesting a Waiver of Informed Consent, complete the table below. 
 
If you have a consent form, list the reasonably foreseeable risks in the consent form (and do not complete this section).   
 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
Do not delete frequency.  Frequency must be estimated because it will assist you with determining which adverse events will require 
prompt reporting.   
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 out of 100 subjects. 
• 
 
• 
 
 
Not serious 
Serious 
Less likely  
These risks are expected to occur in 5-
20 subjects or less out of 100 subjects. 
• 
 
• 
 
 
 
Serious 

Rare  
These risks are expected to occur in 
less than 5 subjects out of 100  
 
• 
 
 
4.c. 
Study Intervention #1 
Insert name used in 4.b. 
List each group exposed to this 
intervention on a separate line. 
(e.g., experimental, control, Arm A, Arm B, 
etc) 
Or state All Groups/Subjects 
For each group, list the benefits of this intervention.  (Benefits can be directly from 
the intervention or from a monitoring procedure likely to contribute to the subject’s 
well being).  If there are no benefits, state “none”. 
 
 
 
 
If you are requesting a Waiver of Informed Consent, complete the table below. 
 
If you have a consent form, list the reasonably foreseeable risks in the consent form (and do not complete this section).   
 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
Do not delete frequency.  Frequency must be estimated because it will assist you with determining which adverse events will require 
prompt reporting.   
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 out of 100 subjects. 
• 
 
• 
 
 
Not serious 
Serious 
Less likely  
These risks are expected to occur in 5-
20 subjects or less out of 100 subjects. 
• 
 
• 
 
 
 
Serious 
Rare  
These risks are expected to occur in 
less than 5 subjects out of 100  
 
• 
 
 

 
 

 

 
4.d. List ALL other research procedures or components not listed in table 4.b. 
        The combination of Tables 4b and 4d should account for all of the research 
procedures that will take place during this study. 
 
Consider grouping similar procedures under a single component (e.g., blood work, CT 
= safety assessments) 
 
 
 
# 
Research component 
• 
individual 
procedures 
 
example: 
Eligibility Assessments 
• 
History and 
physical 
• 
Questionnaire 
• 
Laboratory 
tests 
Add or delete rows as 
needed 
Column A 
Local Standard 
Practice Indicate the 
number of times each 
procedure will be 
performed as 
stipulated in the 
research plan that 
would be performed 
if the participant 
were not 
participating in the 
study. 
Column B 
Research Only  
Indicate the number of 
times each procedure will 
be performed solely for 
research purposes 
(meaning that the 
participant would not 
undergo the same number 
of procedures or would not 
undergo the procedure(s) 
at the same frequency if 
they were not participating 
in the study) 
Column D 
Risks 
If you are requesting a Waiver of 
Informed Consent, complete the 
table below. 
 
List the reasonably expected risks for each 
procedure or group of procedures under the 
following categories as appropriate: 
• Serious and likely; 
• Serious and less likely; 
• Serious and rare; 
• Not serious and likely; 
• Not serious and less likely 
1 
Eligibility Assessments 
 
 
 
 
Questionnaire assessing 
Index Reaction and 
hesitancy and barriers to 
pursuing challenge  
 
1 
Not Serious and Less Likely 
2 
Healthcare Maintenance 
Visit 
 
 
 
 
History and Physical 
1 
 
Not Serious and Less Likely 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
3 
Post-challenge 
Assessment 
 
 
 
 
Questionnaire assessing 
post-challenge status 
 
1 
Not Serious and Less Likely 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 

4 
Urine Pregnancy Test 
 
 1 
Not Serious and Less Likely 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
 
 
5.  Safety Precautions.  (Describe safeguards to address the serious risks listed above.) 
a.  Describe the procedures for protecting against or minimizing any potential risks for each of the more than 
minimal risk research procedures listed above. 
NA 
b. Where appropriate, discuss provisions for ensuring necessary medical or professional intervention in the 
event of adverse events, or unanticipated problems involving subjects. 
Risks of Protocol Specified Medications/Procedures 
- 
Adverse reactions to amoxicillin include headache, diarrhea, nausea, vomiting, rash, and allergic 
reactions. Allergic reactions range from mild to severe, and if a patient has an allergic reaction, he/she 
may need oral, IM, or IV medications. The site investigators for this trial are credentialed advanced 
health providers who are trained to recognize and manage systemic reactions. Treatment will be 
available within 60 seconds in the event of a reaction. Emergency medications as listed below will be 
available to treat any allergic reactions.  
- 
Treatment of individual acute allergic reactions during the conduct of the study may include 
antihistamines, epinephrine, -adrenergic agonists, oxygen. The risks of these common medications 
include the following 
o 
Antihistamines: drowsiness, dizziness, constipation, stomach upset, blurred vision, dry 
mouth/nose/throat 
o 
Epinephrine: tachycardia, palpitations, nervousness, sweating, nausea, vomiting, trouble 
breathing, headache, dizziness, anxiety, tremors, pale skin 
o 
-adrenergic agonists: nervousness, shaking, headache, dizziness 
o 
These risks will be minimized by appropriate dosing per guideline management of systemic 
allergic reactions. 
 
c.  Will the safeguards be different between/among groups?   
 
Yes 
 
 
No 
If yes, describe here 
 
  
 
X