The Effect of Providing Stratification of Low Risk Penicillin Allergies on Penicillin Allergy Label Removal
Phase: NA
Conditions: Penicillin Allergy
Sponsor: Vanderbilt University Medical Center

Revision Date: April 26, 2022  
 
 
 
 
 
 
 
 
 
The Effect of Providing Stratification of Low 
Risk Penicillin Allergies on Penicillin Allergy 
Label Removal 
 
 
Cosby Stone, Jr. MD, MPH 
Mentor: Elizabeth Phillips, MD 
Vanderbilt University Division of Allergy, 
Pulmonary and Critical Care Medicine 
1161 21st Ave so T-1218, MCN 
Nashville, TN 37215 
cosby.a.stone@vumc.org 
elizabeth.j.phillips@vanderbilt.edu 
 
 
NCT03702270 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Revision Date: April 26, 2022  
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Follow-up and Record Retention 
 
 

Revision Date: April 26, 2022  
 
1.0 
Background 
 
Up to 20% of the US population carries a label of penicillin allergy, the most commonly 
reported medication allergy.  However, in the presence of appropriate skin and oral 
challenge testing in current practice only 4% or less of these allergy labels can be 
verified as accurate. Because most patients reporting allergy to penicillin aren't actually 
allergic their reported allergy leads to unnecessary avoidance of penicillins, treatment 
with less effective 2nd and 3rd line antibiotics with more side effects, and worsened 
outcomes.  At Vanderbilt, in current practice, only 13.4% of patients ever get their 
penicillin allergy label removed, despite up to 96% being potentially able to tolerate a 
penicillin safely.  
 
When asked about their history of penicillin allergy, most patients report symptoms that 
are considered low-risk by specialists in allergy.  Low-risk penicillin allergies are routinely 
challenged by allergy doctors with test dose challenges, meaning a small dose of 
amoxicillin is given and the patient is observed.  Patients who tolerate the medication 
during observation have their allergy label to penicillin removed from the chart. Test 
dose challenges are known to be safe in low-risk patients and are recommended as a 
tool in penicillin allergy evaluation by the American Academy of Asthma, Allergy and 
Immunology. Unfortunately, test dose challenges are not performed as a part of routine 
practice outside of the field of allergy due to most physicians being unfamiliar with the 
features of low-risk penicillin allergy and the procedure of performing a test dose 
challenge.   
 
Therefore, we developed a risk stratification tool validated on the outcomes of penicillin 
allergy testing in the Vanderbilt Drug Allergy Clinic that can help physicians to identify 
low-risk penicillin allergy patients who would successfully tolerate a test dose challenge.   
 
Our objective is to increase the familiarity with penicillin allergy history taking among 
physicians, and the rate at which low-risk penicillin allergies are tested and removed in 
current practice.  
 
We plan to perform a stepped wedge cluster randomized trial of this best practices 
intervention to provide risk stratification and test dose amoxicillin challenges in patients 
who are at low risk of having an ongoing penicillin allergy, using our internally validated 
risk stratification tool.  
 
We anticipate that this study will provide evidence that our approach is an effective 
strategy by which to implement current guidelines recommending the use of allergy 
evaluations and test dose challenges in hospitalized patients with low risk penicillin 
allergy. We anticipate that the current study will lead to further studies in specialized 
populations with a more frequent need for antibiotics, such as transplant patients, 
cancer patients, and immune deficient patients.   
 
Improvements in the management of penicillin allergy will provide significant direct and 
indirect benefits to patients, society, and the healthcare system. 
 
 

Revision Date: April 26, 2022  
 
2.0 
Rationale and Specific Aims: 
 
Currently it is estimated that at least 25 million people in the United States are labeled as 
penicillin allergic although less than 1.5 million of these are truly allergic.  Although 
combined skin testing and oral challenge is an evidence-based de-labeling strategy the 
high burden of penicillin allergy labels means these services are available only through 
specialty allergy practices. There is therefore a need to provide evidence for alternative 
penicillin de-labeling strategies such as direct oral challenge. Previous studies have 
utilized quasi-experimental designs. Test dose challenges are currently recommended 
as a strategy for removal of low risk drug allergies, but the current experience is limited 
to single arm observational studies and evidence-based strategies for identifying low risk 
patients are lacking.  Our objective is to demonstrate the benefit of providing risk 
stratification in removing penicillin allergy labels for low risk penicillin allergy patients in a 
randomized controlled trial. 
 
Health literacy is the capacity of an individual to obtain and understand health 
information and services to make appropriate health decisions, and could play a role in a 
patient's decision to undergo testing for a penicillin allergy. We propose to use the 
Health Literacy Screening (HEALS) Database to determine if there is a difference in 
health literacy 1) between low-risk penicillin allergy patients who agree to versus refuse 
an amoxicillin challenge and 2) among low-risk challenge accepted, low-risk challenge 
refused, and higher-risk history patients. This information will help us determine if we 
need to adapt our communication strategies with patients approached for penicillin 
allergy label removal to be more accessible for patients with low or limited health 
literacy. 
 
We therefore aim to establish the safety, effectiveness, and impact of single dose 
oral challenge as a testing strategy to remove the label of low-risk penicillin 
allergy. 
 
3.0 
Inclusion/Exclusion Criteria 
 
• 
Inclusion Criteria:  
 
o For Pilot Study: VUMC patients age 18 or older with a penicillin allergy 
reported in their chart and are medically stable, currently admitted to ICU.  
 
o For the RCT:  VUMC patients age 18 or older with a penicillin allergy 
reported in their chart, and are medically stable, currently admitted to 
stepdown unit or regular floor bed.   
 
• 
Exclusion Criteria: Patients with a penicillin allergy reported in their chart, but 
who are currently medically unstable.  Patients who are pregnant.  
 
4.0 
Enrollment/Randomization 
 
Patients with penicillin allergy listed in their chart and admitted to a medical unit 
qualifying for intervention or control group during the study period will be enrolled in the 
study to the respective group that their unit is assigned to, with waiver of 
consent/authorization. 

Revision Date: April 26, 2022  
 
 
An initial pilot study will be performed in the medical ICU to demonstrate safety in a 
setting with the highest level of acute nursing and skilled support.   
 
During the trial, randomization will occur using a stepped wedge cluster randomized 
controlled trial design.  Medical units at VUMC will assigned to clusters. A single cluster 
will be selected for intervention at the outset of the trial.  Subsequent additional clusters 
will first contribute to the control group, and be selected to randomly cross over to the 
intervention group at regular 1-month intervals.  
 
Randomization by medical unit with a stepped inclusion of additional medical units over 
time is the most equitable way of providing the study intervention, which we expect will 
provide a significant benefit compared to standard of care.  
 
As penicillin allergy is a diagnosis that can affect people across differing age, sex, 
race/ethnicity backgrounds, we fully expect that patients will receive equitable inclusion 
due to the randomized nature of our study. 
 
 
5.0 
Study Procedures 
 
Pilot Study: The teams caring for eligible penicillin allergic patients admitted to the ICU 
will be provided with the study intervention, as described below.  
 
Control Arm: The current standard of care in hospitalized patients with reported 
penicillin allergy is to do nothing, versus direct challenge with amoxicillin when an 
allergy history is perceived to be sufficiently low risk, versus obtaining an allergy 
consultation for help with management, at the discretion of the primary team.  Hence, 
no intervention will be provided.   
 
Intervention Arm: The intervention will provide access to a best-practices alert 
containing a penicillin allergy risk stratification tool and an oral amoxicillin test dose 
challenge orderset for patients who stratify as low risk.  The risk stratification tool has 
been demonstrated retrospectively to have a >99% (95% CI 96.4,99.9) negative 
predictive value for the presence of penicillin allergy in those who stratify as low risk. 
Test dose challenges are a recommended part of routine practice in patients who report 
allergy but have symptoms that are low risk for true or ongoing allergy. 
 
Scenario: For patients who qualify for intervention in a unit randomized to intervention, 
the following best practice alert or a similar alert will be provided to the rounding 
physician.   
 
“Did you know that 96-99% of patients of patients labeled as allergic to penicillin can 
safely tolerate these drugs?  Use our tool to determine if your patient is low risk (<1% 
likely to have a positive allergy skin test) and can be considered for a potential challenge 
with amoxicillin to remove this allergy label. (Link to tool).”   
 

Revision Date: April 26, 2022  
 
The embedded link will provide an online risk stratification tool that will allow treating 
physicians to assess if their patient is low risk.  For patients who stratify as low risk, 
information on oral challenges with amoxicillin and the name of an order set that 
contains the necessary elements for an oral challenge with amoxicillin will be provided 
(250mg amoxicillin PO x 1 dose, epinephrine at bedside, vital signs at baseline and q 30 
minutes x 2.)  For patients whose penicillin allergies stratify as higher or highest risk, 
information will be provided on the management of these penicillin allergies, with or 
without consultation from the allergy service.  Treatment decisions on whether to 
act on the provided information will be made by the treating physician and 
the patient. 
 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
Data and Safety Monitoring: Given there are minor potential risks to participants in the 
proposed trial with waiver of consent, it will  be performed with monitoring and review 
by Vanderbilt University Medical Center IRB and under the guidance of the Vanderbilt 
Institute for Clinical and Translational Research. We propose to implement an 
overseeing data and safety monitoring plan that includes the appointment of Dr. Todd 
Rice, MD as an independent data safety monitor.  
 
Investigator Training and Involvement: 
1) 
All investigators, research coordinators, and other staff will complete and 
maintain training in the protection of human research subjects. 
2) 
All persons accessing trial data, will in addition to the above, complete 
appropriate institutional training. 
3) 
The physician leader at Vanderbilt (Dr. Stone), will be available to treating 
physicians who might implement the best practice alert in order to provide additional 
information about the study, including risks, benefits and alternatives, and to answer 
questions as needed. 
4) 
All investigators and staff involved with patient care will remain updated on 
issues related to patient rights and safety through educational programs and updates 
provided by the institutions. 
 
Data Handling/Confidentiality 
1) 
Training outlined above addresses issues of confidentiality in research. 
2) 
All patients will be assigned a study number and de-identified upon entering the 
study. A master list linking the patient identifying information such as the electronic 
health record and de-identified study identification will be kept under double-lock and 
key at each site with an access log required for when the list is accessed. A computer 
that is password-protected and behind a restricted, locked office door will also be 
acceptable.  
3) 
All patient records for the research study will be maintained on the HIPAA-
compliant server where the completed case report forms are kept or similarly on the 
HIPAA-compliant cloud server for photographs. To ensure accuracy, data will be checked 
and reviewed by research staff. Audits of the data will be done by the Vanderbilt 
Coordinating Center to ensure quality and completion of the forms.  

Revision Date: April 26, 2022  
 
4) 
Only de-identified data will be electronically transmitted and this will be done 
using institutional encryption procedures. 
 
Adverse Events 
1) 
Exclusion criteria include patients who are currently medically unstable and 
unable to receive study procedures, or patients whose primary care is received outside 
of Vanderbilt University Medical Center. We know that by restricting inclusion to patients 
who receive the majority of their care at Vanderbilt that this will enable better long term 
monitoring of adverse events via the EHR.  
2) 
All adverse events will be discussed with and evaluated by a physician 
investigator as soon as the subject or study personnel report them. 
3) 
Adverse events including SAEs upon initial amoxicillin challenge or upon 
subsequent administration of penicillin class drugs in patients whose penicillin allergy 
label has been removed, or any unanticipated problems will be appropriately reported to 
the IRB, safety monitor, and NIAID. In addition to the IRB review of adverse events 
outlined above, the PIs will meet at least quarterly with staff to discuss any problems 
that arise that could compromise patient safety. Meetings will be held more frequently to 
quickly rectify problems if they arise. When necessary, the IRB will be consulted for 
further guidance. This is particularly true for reactions, which, in their most severe 
forms, threaten life or function.  A serious AE (SAE) or serious adverse drug experience 
(SADE) is any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening. 'Life-threatening" refers to an event in which the subject is at 
risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe (ICH E6). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/ incapacity (as per reporter's opinion) 
• 
Is a congenital anomaly/birth defect 
• 
Is another medically important condition.  Important medical conditions that may 
not result in death, be life-threatening or require hospitalization may be considered as 
SAEs or SADEs when, based upon appropriate medical judgment, they may jeopardize 
the subject or may require intervention to prevent one of the outcomes listed in the 
definition above. Examples of such events relevant to this trial are urticaria, 
angioedema, respiratory distress, prolonged nausea or vomiting after direct provocation 
testing with amoxicillin that might be the prelude to anaphylactic shock. [Code of 
Federal Regulations Title 21, Volume 5, 21CFR312.32, revised April 1, 2006]. 
4) 
The PI, staff, and the research coordinators (or qualified persons providing 
coverage) will be available 24 hours each day to participants and other investigators, 
should an emergency arise. 
5) 
The Vanderbilt Coordinating Center will submit an annual safety and adverse 
event report to the NIAID program official and the Vanderbilt IRB. 
 
 
7.0 
Study Withdrawal/Discontinuation 
 
Participants will contribute data to the study under conditions of waiver of 
consent/assent, as our intervention is an improvement upon best practices that poses 
minimal to low additional risk to participants compared to standard of care.  Treatment 

Revision Date: April 26, 2022  
 
decisions on whether to act on the provided information will be made by the 
treating physician and the patient. 
 
Patients who seek to have their data removed from the study can do so at any time by 
contacting the study team.  
 
8.0 
Statistical Considerations 
 
Statistical Analysis Plan: Our primary endpoint will be the percentage of patients who 
had their penicillin allergy label removed prior to discharge, comparing those who 
received intervention versus controls.  We will also assess the number of patients who 
underwent oral challenge with amoxicillin in both arms.  We will assess these outcomes 
using intention-to-treat analysis, using an adjusted logistic regression model.    
 
Power and Sample Size Considerations: With no intervention, we assume 0.5% of 
patients have their penicillin allergy label intentionally removed or receive a test dose 
challenge during current practice in a six month period based upon preliminary data at 
Vanderbilt.  We can power our study to detect a clinically meaningful difference of 20 
additional penicillin-allergic patients per 100 having their penicillin allergy label removed 
using our intervention. Preliminary data suggest that around 100 patients per month are 
admitted and discharged from the 8N medical unit, and that 15-20% of all patients 
admitted at Vanderbilt have a penicillin allergy listed in their chart. Hence, approximately 
15-20 penicillin allergic patients would be eligible for inclusion in the intervention group 
per month.  
 
Assuming pessimistically that a minimum of 10% of patients randomized to intervention 
will have their physician engage with the tool, leading to an allergy label removed, and 
that 0.1% of patients in the control group will have a penicillin allergy label removed 
during current practice, 1:1 allocation of participants, an alpha of 0.05, power of 0.8 and 
a two-sided test of proportions, we will need a minimum of 35 patients per group (70 
total) to detect a minimally clinically meaningful 20% increase in penicillin allergy label 
removals or amoxicillin challenges.  Much smaller sample sizes will be needed to see 
effects if higher engagement and utilization is observed. 
 

Revision Date: April 26, 2022  
 
 
 
 
Our study will be intentionally overpowered for the primary outcome of penicillin allergy 
label removal, in order to try and capture the effect of this intervention upon secondary 
outcomes of 1) Frequency of risk stratification tool usage by physicians, 2) Any reported 
adverse events associated with oral challenge, 3) Communication about penicillin allergy 
label removal in the discharge summary. 4) longer term assessment of durability of label 
removal (at 3-18 months following label removal) 5) antibiotic utilization and use and 
tolerance of penicillins following label removal at 3- 18 months. In addition, we will add 
the amended baseline demographic of health literacy. 
 
9.0 
Privacy/Confidentiality Issues 
 
All data collected from patient medical records or through the risk stratification tool will 
be kept in a REDCap database which can only be accessed by key study personnel who 
have been given access and have a login and password. Identifiable information will not 
be linked or shared to data collected. All identifiable information will be stored in a study 
binder in a locked cabinet or within RedCAP. Only the PI and KSP on the study will have 
access to this information. Upon discontinuation of the study, the database will be 
purged of identifiers and kept within the HIPAA compliant RedCAP system. Therefore, 
we perceive the risks to privacy to be minimal. 
 
We have developed our penicillin allergy risk stratification tool into a secure online 
questionnaire with data collecting ability within the RedCAP system, such that it can now 
serve as both an interactive educational tool for physicians and also collect data. This 

Revision Date: April 26, 2022  
 
tool and others to be developed will be utilized by KSP during retrospective chart review, 
as a means for collecting relevant data related to risk stratification and validating the 
instruments. 
 
The only identifier collected by the current RedCAP risk stratification tool itself is the 
medical record number, to allow linkage with other data that will be collected in a 
separate, secure RedCAP database. A copy of the RedCAP risk stratification 
questionnaire is attached separately in file PenicillinAllergyRiskStratific.pdf. 
 
The anticipated benefits to patients are much larger. Access to the information will allow 
us to determine the effectiveness of our proposed intervention compared to current 
practice in a pragmatic, patient-oriented, real world setting.  Removal of unnecessary 
penicillin allergy labels, in turn, has impacts on major patient impacts as described on 
previous pages of this application.   
 
Health literacy data are collected and entered into the EHR routinely by nurses as adult 
patients are admitted to Vanderbilt University Hospital. The Effective Health 
Communication Core maintains an IRB-approved data repository (#150406, PI: 
Kripalani) of the health literacy screening data (HEALS Database) collected during 
routine clinical care. The PI will provide the HEALS coordinator, added as KSP to this 
study, with a list of MRNs of the participants enrolled in this study via a HIPPA-compliant 
secure file transfer. The HEALS coordinator will then provide the PI with health literacy 
data for only the patients enrolled in this study, via a HIPPA-compliant secure file 
transfer. The health literacy data will be stored in a REDCap database which can only be 
accessed by key study personnel who have been given access and have a login and 
password. 
 
10.0 Follow-up and Record Retention 
 
Study Duration will be 30 months total, with 12 months in which intervention will be 
provided and 18 months of follow up.  
 
All data will be de-identified prior to any analyses and data sharing. Data from the study 
will eventually be published but no identifiers will be mentioned as they will be kept 
separate once the collection of data is complete. Only authorized study personnel will 
have access to this information. PHI will no longer be accessed upon closure of the 
study, at which point any patient identifiers in the database will be deidentified. 
 
Paper versions of any data will be destroyed upon completion of the study.   
 
Electronic data will be stored indefinitely in a secured server using the RedCAP system.