Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000484640
Ethics application status
Approved
Date submitted
30/04/2023
Date registered
12/05/2023
Date last updated
16/01/2024
Date data sharing statement initially provided
12/05/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
An audit of penicillin allergy assessment and outcomes of oral penicillin test-dose challenge in hospitalised patients with a low risk penicillin allergy.
Scientific title
International Network of Antibiotic Allergy Nations (iNAAN) - A prospective cohort study and audit of a clinical health services program to evaluate the safety and impact of direct oral challenge and delabelling in hospitalised patients with a low risk penicillin allergy in participating health services.
Secondary ID [1] 309551 0
Nil known.
Universal Trial Number (UTN)
U1111-1291-9756
Trial acronym
iNAAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Penicillin Allergy 329841 0
Antibiotic Allergy 329842 0
Condition category
Condition code
Inflammatory and Immune System 326751 326751 0 0
Allergies

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
90
Target follow-up type
Days
Description of intervention(s) / exposure
National (pre-dominantly Australian) and International prospective cohort study/registry and audit of health services' routine/standard of care antibiotic allergy assessment and direct oral penicillin challenge and delabelling programs.
Hospitalised participants with a penicillin allergy will be identified by site investigators. Patients with a penicillin allergy will undergo formal antibiotic allergy assessment using validated antibiotic allergy assessment tools and/or according to local health service antibiotic allergy protocols. Patients identified as having a low-risk penicillin allergy, according to the validated antibiotic allergy assessment tools, will be offered a direct oral penicillin challenge, which, if negative, will enable delabelling of the penicillin allergy.
Patient demographic data (age, sex, ethnicity), medical co-morbidities, antibiotic allergy phenotype and penicillin oral challenge data (if performed) will be collected by the secure National Antibiotic Allergy Network (NAAN) smart-phone app with secure upload to the iNAAN REDCap database, hosted by BioGrid. The NAAN smart-phone app is accessible only by participating health service study teams. Data is entered into the NAAN smart-phone app by multi-disciplinary clinicians (Medical, Nursing, Pharmacy) who are part of the site project team. Additional data, including hospital admission data, antibiotic usage pre- and post- antibiotic allergy testing and antibiotic adverse events may also be entered into the REDCap database for up to 90 days post discharge.
Intervention code [1] 325978 0
Not applicable
Comparator / control treatment
Patients who undergo an antibiotic allergy assessment without proceeding to direct oral penicillin challenge due to, for example, high risk allergy phenotype, medical instability, patient refusal or any other reason.
Control group
Active

Outcomes
Primary outcome [1] 334606 0
Effectiveness outcome: The proportion (n, %) of patients discovered with a low-risk penicillin allergy label that are delabelled following penicillin direct oral challenge. This data will be drawn from the study database.
Timepoint [1] 334606 0
Upon study completion
Primary outcome [2] 337116 0
Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Adoption: To determine the adoption (i.e. uptake) of the intervention by:
a. Number of digital penicillin allergy toolkit (NAAN App) users within participating sites
b. Discipline-specific uptake of the NAAN App within and across participating sites
c. Individual health service enrolment - by jurisdiction (Australia) and country
d. Number of countries with a participating health service
Adoption will be measured as participating health services enrol in the iNAAN study. Data pertaining to the number of investigators, number and health profession of NAAN App users within the health service, and health service enrolment across Australian jurisdictions and countries will be entered into the iNAAN database.
Timepoint [2] 337116 0
Primary outcome [3] 337117 0
Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Adoption: To determine the adoption (i.e. uptake) of the intervention by:
a. Number of digital penicillin allergy toolkit (NAAN App) users within participating sites
b. Discipline-specific uptake of the NAAN App within and across participating sites
c. Individual health service enrolment - by jurisdiction (Australia) and country
d. Number of countries with a participating health service
Adoption will be measured as participating health services enrol in the iNAAN study. Data pertaining to the number of investigators, number and health profession of NAAN App users within the health service, and health service enrolment across Australian jurisdictions and countries will be entered into the iNAAN database.
Timepoint [3] 337117 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Primary outcome [4] 337118 0
Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

2. Fidelity: To determine the fidelity of the individual site penicillin direct oral challenge activity to the audited health service site-specific penicillin allergy delabelling protocol.
Participating iNAAN health service provide their health service approved penicillin direct oral challenge protocol at the point of study enrolment. Specific metrics within the protocol (oral challenge drug, dose, single vs split dose challenge, single vs prolonged challenge) are matched against individual health service penicillin direct oral challenge activity that is entered into the iNAAN database. Fidelity (% adherence to health service delabelling protocol) is provided as a feedback measure to participating iNAAN sites.
Timepoint [4] 337118 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Primary outcome [5] 337119 0
Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

2. Fidelity: To determine the fidelity of the individual site penicillin direct oral challenge activity to the audited health service site-specific penicillin allergy delabelling protocol.
Participating iNAAN health service provide their health service approved penicillin direct oral challenge protocol at the point of study enrolment. Specific metrics within the protocol (oral challenge drug, dose, single vs split dose challenge, single vs prolonged challenge) are matched against individual health service penicillin direct oral challenge activity that is entered into the iNAAN database. Fidelity (% adherence to health service delabelling protocol) is provided as a feedback measure to participating iNAAN sites.
Timepoint [5] 337119 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Secondary outcome [1] 421388 0
The proportion (n,%) of patients that utilise a penicillin antibiotic pre- and post- direct oral penicillin challenge. This data will be drawn from the patient medical records and study database.
Timepoint [1] 421388 0
Penicillin use pre- allergy assessment +/- penicillin direct oral challenge will be identified during the index admission.
Penicillin use post- allergy assessment +/- penicillin direct oral challenge will be identified up to 90 days post-discharge from hospital.
Secondary outcome [2] 421389 0
The proportion (n,%) of patients that utilize an appropriate antibiotic pre- and post- antibiotic allergy assessment +/- direct oral penicillin challenge. This information will be drawn from the patient medical records and study database.
Timepoint [2] 421389 0
Appropriate antibiotic use pre- allergy assessment +/- penicillin direct oral challenge will be identified during the index admission.
Appropriate antibiotic use post- allergy assessment +/- penicillin direct oral challenge will be identified up to 90 days post-discharge from hospital.
Secondary outcome [3] 421390 0
The proportion (n,%) of patients that utilise a restricted antibiotic pre- and post- antibiotic allergy assessment +/- direct oral penicillin challenge. This information will be drawn from the patient medical records and study database.
Restricted antibiotics are defined as: cefepime, ceftazidime, ceftriaxone, ciprofloxacin, clindamycin, meropenem, moxifloxacin, piperacillin/tazobactam, teicoplanin, tobramycin and vancomycin
Timepoint [3] 421390 0
Restricted antibiotic use pre- allergy assessment +/- penicillin direct oral challenge will be identified during the index admission.
Restricted antibiotic use post- allergy assessment +/- penicillin direct oral challenge will be identified up to 90 days post-discharge from hospital.
Secondary outcome [4] 421391 0
The median hospital length of stay (LOS) (days), for patients who have their penicillin allergy delabelled following antibiotic allergy assessment and direct oral penicillin challenge compared with the median hospital LOS (days) for patients who have a high-risk penicillin allergy label and who are not delabelled. This information will be drawn from the patient medical records and study database.
Timepoint [4] 421391 0
Upon study completion.
Secondary outcome [5] 421392 0
The cost-effectiveness of health service programs designed to assess antibiotic allergy and offer direct oral challenge to hospitalised inpatients. This information will be drawn from the study database - an economic analysis of staff resourcing, antibiotic costs pre- / post- antibiotic allergy assessment +/- direct oral challenge and hospital LOS.
Timepoint [5] 421392 0
Upon study completion.
Secondary outcome [6] 430770 0
Primary Outcome - Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Adherence: To determine the proportion of patients with an antibiotic allergy (n, %) who meet the National Safety and Quality Health Service (NSQHS) standards for antibiotic allergy assessment and documentation in the medical record (i.e. adherence), stratified for site (Australia only).
The NSQHS standards stipulate that when a patient has a documented antibiotic allergy, the implicated drug, date, nature and severity of the reaction must be documented in the medical record. iNAAN participating sites enter the number and proportion of required metrics for patient antibiotic allergy documentation into the iNAAN database. The resulting health service audit and feedback report enables participating iNAAN sites to demonstrate their health service adherence to NSQHS standards.
Timepoint [6] 430770 0
Secondary outcome [7] 430771 0
Primary Outcome - Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Adherence: To determine the proportion of patients with an antibiotic allergy (n, %) who meet the National Safety and Quality Health Service (NSQHS) standards for antibiotic allergy assessment and documentation in the medical record (i.e. adherence), stratified for site (Australia only).
The NSQHS standards stipulate that when a patient has a documented antibiotic allergy, the implicated drug, date, nature and severity of the reaction must be documented in the medical record. iNAAN participating sites enter the number and proportion of required metrics for patient antibiotic allergy documentation into the iNAAN database. The resulting health service audit and feedback report enables participating iNAAN sites to demonstrate their health service adherence to NSQHS standards.
Timepoint [7] 430771 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Secondary outcome [8] 430772 0
Primary Outcome - Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Acceptability: To determine the perception amongst participating hospital clinicians that the penicillin allergy toolkit is acceptable.
A NAAN app usability survey, utilising a 5-point Likert scale, will trigger beginning 6 months post site activation, on a 6-monthly basis, to NAAN app users. The survey is designed to assess opinions and acceptability of the NAAN app with the embedded penicillin allergy toolkit and to enable an avenue to provide feedback. The survey will be delivered via the NAAN app and data will be collected and stored in the existing iNAAN database.
Timepoint [8] 430772 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Secondary outcome [9] 430773 0
Primary Outcome - Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Acceptability: To determine the perception amongst participating hospital clinicians that the penicillin allergy toolkit is acceptable.
A NAAN app usability survey, utilising a 5-point Likert scale, will trigger beginning 6 months post site activation, on a 6-monthly basis, to NAAN app users. The survey is designed to assess opinions and acceptability of the NAAN app with the embedded penicillin allergy toolkit and to enable an avenue to provide feedback. The survey will be delivered via the NAAN app and data will be collected and stored in the existing iNAAN database.
Timepoint [9] 430773 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Secondary outcome [10] 430774 0
Primary Outcome - Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Sustainability: Individual health services receive reports detailing the numbers of penicillin allergy assessments and penicillin direct oral challenges performed over time.
Timepoint [10] 430774 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.
Secondary outcome [11] 430775 0
Primary Outcome - Implementation Outcome(s): To assess the effects of a digitally delivered audit and feedback strategy in implementing a penicillin allergy toolkit in participating health services. Individual health service reports will be provided to participating iNAAN sites on a bimonthly frequency against a range of implementation measures.

Sustainability: Individual health services receive reports detailing the numbers of penicillin allergy assessments and penicillin direct oral challenges performed over time.
Timepoint [11] 430775 0
Individual health services receive bimonthly reports with individual implementation outcome measures.
Total iNAAN implementation outcomes will be assessed upon study completion.

Eligibility
Key inclusion criteria
Hospitalised inpatients reporting a penicillin allergy.
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients without a penicillin allergy label

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
An analysis of the impacts of the program on named objectives relating to (i) de-labelling, (ii) antibiotic utilization and (iii) model costs will be performed.

Baseline characteristics will be presented using median with interquartile range and frequency with percentage.
The propensity score (PS) model estimating the probability of having a penicillin allergy and being de-labelled after oral challenge/direct de-labelling will be fitted using logistic regression with numerous baseline variables.
The balance between groups in all baseline characteristics will be estimated using standardised differences (absolute values below 0.1).
Average treatment effect in the treated group will be estimated using propensity score matching of participants who were delabelled with those who did not undergo direct oral challenge/direct-de-labelling or the inverse probability treatment weighted propensity score (IPTWS) approach will be undertaken with those who received treatment being weighted as 1, while those untreated being weighted as PS/(1-PS).
Conditional logistic regression and negative binomial regression (for matched samples and unconditional for IPTWs) will be used to evaluate antibiotic evaluation and healthcare outcomes. p < 0.05 (two-sided) will be deemed statistically significant.

Comparative effectiveness of oral challenge will be evaluated using propensity score analysis.
Antibiotic utilisation (penicillin, restricted antibiotic usage, narrow spectrum penicillin and narrow spectrum beta-lactam utilization (unit of analysis -antibiotic courses)) and healthcare outcomes (LOS, readmission, days of IV therapy) will be compared between intervention group (penicillin allergy that underwent oral challenge or direct de-labelling) and control group (penicillin allergy that did not undergo protocolised oral challenge or direct de-labelling) by either propensity score matching or inverse probability treatment weighted propensity score to evaluate the average treatment effect in the treated.

The mean cost difference will be determined between the control group and the intervention group using independent t-tests to report significance. Incremental cost-effectiveness ratios (ICERs) will be determined for the control group and the intervention group based on a ratio between the incremental difference in cost per patient de-labelled. Confidence intervals around the individual ICERs will be calculated using bootstrapping methods (5,000 repetitions), the difference in the number of patients de-labelled and total cost. Confidence ellipses will be generated via the individual ICERs.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
9/11/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
4000
Accrual to date
953
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 24620 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 24622 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 24623 0
Albury Wodonga Health - Albury campus - Albury
Recruitment hospital [4] 24624 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [5] 24625 0
St George Hospital - Kogarah
Recruitment hospital [6] 24626 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [7] 26029 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [8] 26030 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [9] 26031 0
Royal Perth Hospital - Perth
Recruitment hospital [10] 26032 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [11] 26033 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [12] 26034 0
Eastern Health - Box Hill
Recruitment hospital [13] 26035 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [14] 26036 0
Gold Coast Hospital - Southport
Recruitment hospital [15] 26037 0
Lismore Base Hospital - Lismore
Recruitment hospital [16] 26038 0
Westmead Hospital - Westmead
Recruitment hospital [17] 26039 0
Armadale Kelmscott Memorial Hospital - Armadale
Recruitment hospital [18] 26040 0
Campbelltown Hospital - Campbelltown
Recruitment postcode(s) [1] 40237 0
2065 - St Leonards
Recruitment postcode(s) [2] 41885 0
2145 - Westmead
Recruitment postcode(s) [3] 40236 0
2217 - Kogarah
Recruitment postcode(s) [4] 41884 0
2480 - Lismore
Recruitment postcode(s) [5] 41887 0
2560 - Campbelltown
Recruitment postcode(s) [6] 40234 0
2640 - Albury
Recruitment postcode(s) [7] 40233 0
3000 - Melbourne
Recruitment postcode(s) [8] 40231 0
3084 - Heidelberg
Recruitment postcode(s) [9] 41881 0
3128 - Box Hill
Recruitment postcode(s) [10] 41877 0
3168 - Clayton
Recruitment postcode(s) [11] 41876 0
3220 - Geelong
Recruitment postcode(s) [12] 40235 0
3550 - Bendigo
Recruitment postcode(s) [13] 41882 0
4020 - Redcliffe
Recruitment postcode(s) [14] 41883 0
4215 - Southport
Recruitment postcode(s) [15] 41879 0
5000 - Adelaide
Recruitment postcode(s) [16] 41878 0
6000 - Perth
Recruitment postcode(s) [17] 41886 0
6112 - Armadale
Recruitment postcode(s) [18] 41880 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 25419 0
South Africa
State/province [1] 25419 0
Capetown
Country [2] 26083 0
Canada
State/province [2] 26083 0
Montreal

Funding & Sponsors
Funding source category [1] 313743 0
Hospital
Name [1] 313743 0
Austin Health
Country [1] 313743 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 315560 0
None
Name [1] 315560 0
Address [1] 315560 0
Country [1] 315560 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312915 0
Austin Health Human Research Ethics Committee (HREC)
Ethics committee address [1] 312915 0
145 Studley Road
Heidelberg
VIC 3084
Ethics committee country [1] 312915 0
Australia
Date submitted for ethics approval [1] 312915 0
26/08/2021
Approval date [1] 312915 0
13/12/2021
Ethics approval number [1] 312915 0
78719-Austin2021

Summary
Brief summary
More than two million Australians report an antibiotic or penicillin allergy. Patients’ reports are not always accurate, which may lead to them receiving second-line antibiotic therapies. It has been found that 85% of reported allergies are false and can be removed by testing: in fact, more than 95% of low-risk penicillin allergies. The International Network of Antibiotic Allergy Nations (iNAAN) is a health services program that seeks to improve access to direct oral penicillin challenge for Australian patients. This will reduce the burden and cost of antibiotic allergies in healthcare. At present, many of the patients carrying an antibiotic allergy label remain undiscovered with 50% of these patients not having access to vital testing. We seek to prospectively audit this clinical program to assess safety and the impact on reducing the burden of penicillin allergy in hospitalized patients and the subsequent effects on antibiotic prescribing and patient outcomes.
Trial website
https://antibioticallergy.org.au/naan
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126318 0
Prof Jason Trubiano
Address 126318 0
Austin Health
145 Studley Road
Heidelberg VIC 3084
Country 126318 0
Australia
Phone 126318 0
+61 3 9496 6676
Fax 126318 0
Email 126318 0
jason.trubiano@austin.org.au
Contact person for public queries
Name 126319 0
Prof Jason Trubiano
Address 126319 0
Austin Health
145 Studley Road
Heidelberg VIC 3084
Country 126319 0
Australia
Phone 126319 0
+61 3 9496 6676
Fax 126319 0
Email 126319 0
jason.trubiano@austin.org.au
Contact person for scientific queries
Name 126320 0
Prof Jason Trubiano
Address 126320 0
Austin Health
145 Studley Road
Heidelberg VIC 3084
Country 126320 0
Australia
Phone 126320 0
+61 3 9496 6676
Fax 126320 0
Email 126320 0
jason.trubiano@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to potentially sensitive nature of patient data this will not be publically presented


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19014Ethical approval    385815-(Uploaded-30-04-2023-22-21-11)-Study-related document.pdf



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