ANZCTR - Registration

Registration number

ACTRN12623000484640

Ethics application status

Approved

Date submitted

30/04/2023

Date registered

12/05/2023

Date last updated

13/04/2025

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 type 2 hybrid effectiveness-implementation cohort study evaluating the safety and impact of direct oral challenge in patients with a low risk penicillin allergy and an Audit and Feedback and education implementation strategy in participating health services.

Secondary ID [1]

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

Antibiotic Allergy

Condition category

Condition code

Inflammatory and Immune System

Allergies

Intervention/exposure

Study type

Observational

Description of intervention(s) / exposure

EFFECTIVENESS: 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.

IMPLEMENTATION: At a minimum of three months following site activation and administration of the digital penicillin allergy toolkit, iNAAN clinicians and health services will receive bimonthly digitally delivered A&F (‘Health Service Report’) detailing local effectiveness and implementation outcomes of penicillin allergy assessment and delabeling. Additional optional education sessions will be facilitated by the study team and will be open to all investigators and stakeholders at participating health services throughout the study period.

Intervention code [1]

Not applicable

Comparator / control treatment

EFFECTIVENESS: 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. These patients retain their penicillin allergy label.

IMPLEMENTATION: Following health service activation, no A&F will be provided to clinicians or health services for a period of at least three months, after which bimonthly A&F will be then delivered as per the implementation intervention.

Control group

Active

Outcomes

Primary outcome [1]

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]

Upon study completion

Primary outcome [2]

Implementation Outcome: Adoption: To determine the adoption (i.e. uptake) of the digital penicillin allergy toolkit (NAAN App) by: a. Number of 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 enroled 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]

Adoption of the digital penicillin allergy toolkit (NAAN App) will be measured as the change in number of NAAN App users at each site from baseline to 6-months post activation.

Secondary outcome [1]

Effectiveness outcome: 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]

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]

Effectiveness outcome: 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]

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]

Effectiveness outcome: 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]

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]

Effectiveness outcome: 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]

Upon study completion.

Secondary outcome [5]

Effectiveness outcome: 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]

Upon study completion.

Secondary outcome [6]

Implementation Outcome: 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]

Individual health services receive bimonthly reports with individual implementation outcome measures. Total iNAAN implementation outcomes will be assessed upon study completion.

Secondary outcome [7]

Implementation Outcome: 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 [7]

Individual health services receive bimonthly reports with individual implementation outcome measures. Total iNAAN implementation outcomes will be assessed upon study completion.

Secondary outcome [8]

Implementation Outcome: Sustainability - To determine the adoption digital penicillin allergy toolkit (NAAN App) and how this is sustained or become routine clinical practice over time. Measured by the number of by of digital penicillin allergy toolkit (NAAN App) users over a period baseline to 6 months and then to 12 months, incorporating growth and attrition. Quantitative data will be drawn from the iNAAN database.

Timepoint [8]

Individual health services receive bimonthly reports with individual implementation outcome measures. Sustainability will be measured over a period of from baseline to 6 months and then to 12 months. Total iNAAN implementation outcomes will be assessed upon study completion.

Secondary outcome [9]

Effectiveness outcome: The proportion (n,%) of patients that utilise a narrow-spectrum beta-lactam antibiotic pre- and post- direct oral penicillin challenge. Narrow-specturm beta-lactam antibiotics include: phenoxymethylpenicillin, benzylpenicillin, flucloxacillin, dicloxacillin, ampicillin or amoxicillin. This data will be drawn from the patient medical records and study database.

Timepoint [9]

Narrow-spectrum beta-lactam use pre- allergy assessment +/- penicillin direct oral challenge will be identified during the index admission. Narrow-spectrum beta-lactam use post- allergy assessment +/- penicillin direct oral challenge will be identified up to 90 days post-discharge from hospital.

Secondary outcome [10]

Effectiveness outcome: The proportion (n,%) of patients that utilise a highest priority critically important antimicrobial (HPCIA)* as per published definitions pre- and post- direct oral penicillin challenge. This data will be drawn from the patient medical records and study database. *Highest priority critically important antimicrobial (HPCIA): 3rd and 4th generation cephalosporins, fluoroquinolones, polymixins, phosphonic acid derivatives (WHO List of Medical Important Antimicrobials: a risk management tool for mitigating antimicrobial resistance due to non-human use published by the World Health Organization, 2024. Available from: https://cdn.who.int/media/docs/default-source/gcp/who-mia-list-2024-lv.pdf)

Timepoint [10]

Highest priority critically important antimicrobial (HPCIA)* use pre- allergy assessment +/- penicillin direct oral challenge will be identified during the index admission. HPCIA use post- allergy assessment +/- penicillin direct oral challenge will be identified up to 90 days post-discharge from hospital.

Secondary outcome [11]

Effectiveness outcome: The proportion (n,%) of patients that utilise a World Health Organization (WHO) AWaRe ‘Watch’ or ‘Reserve’ antibiotic as per published definitions* pre- and post- direct oral penicillin challenge. This data will be drawn from the patient medical records and study database. *World Health Organization AWaRe ‘Watch’ or ‘Reserve’ antibiotic: Per defined list in WHO Access, Watch, Reserve (AWaRe) classification of antibiotics for evaluation and monitoring of use, published by the World Health Organization, 2021. Available from: https://iris.who.int/handle/10665/345555

Timepoint [11]

World Health Organization (WHO) AWaRe ‘Watch’ or ‘Reserve’ antibiotic use pre- allergy assessment +/- penicillin direct oral challenge will be identified during the index admission. World Health Organization (WHO) AWaRe ‘Watch’ or ‘Reserve’ antibiotic use post- allergy assessment +/- penicillin direct oral challenge will be identified up to 90 days post-discharge from hospital.

Secondary outcome [12]

Implementation Outcome: 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 [12]

Individual health services receive bimonthly reports with individual implementation outcome measures. Total iNAAN implementation outcomes will be assessed upon study completion.

Secondary outcome [13]

Implementation Outcome: Feasibility: To determine the extent to which the digital penicillin allergy toolkit (NAAN App) can be used within a given context, including by multi-disciplinary clinicians and within various types of health services and countries.

Timepoint [13]

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

Statistical methods / analysis

Effectiveness evaluation including target trial emulation (TTE) -
An analysis of the effectiveness outcomes relating to (i) delabeling, including safety of penicillin DOC led by multi-disciplinary clinicians, (ii) antibiotic utilisation pre- and post- penicillin allergy assessment +/- DOC and (iii) economic costs will be performed.
Baseline characteristics will be described using median with interquartile range and frequency with percentage. The primary effectiveness outcome will be presented as count and percentage of all participants who underwent penicillin DOC with 95% confidence intervals.
In participants with complete data, a target trial emulation causative analysis will be performed to evaluate the impact of penicillin DOC on antibiotic prescribing in patients with a pre-defined low-risk penicillin allergy. The target trial specification and emulation, including inclusion and exclusion criteria, intervention (DOC) and control (assessment only) groups, and estimand of interest, was designed prior to study completion. The statistical analysis will mimic per-protocol analysis of target trial using inverse probability of treatment weighting approach. Baseline confounders will be selected with the help of direct acrylic graphs and balancing approach (entropy balancing) will be used to generate the weights. Generalized linear model with binomial family, log link and robust variance estimator will be used to assess the antibiotic utilization between those delabeled via DOC and those not delabeled. Results will be expressed as risk ratios with 95% confidence intervals. This analysis will be performed separately for each antibiotic group. Antibiotic utilisation will be defined as the number of participants receiving at least one dose of antibiotic of interest.

Health economic evaluation -
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.

Implementation evaluation -
The implementation strategy will use a mixed methods evaluation, balancing in-depth qualitative data with quantitative data from participating sites. Qualitative data, obtained via focus groups utilising semi-structured interview questions, will be thematically analysed to identify barriers and facilitators to behaviour change throughout the audit and feedback implementation strategy. This analysis will be examined using an appropriate theoretical framework including the Theoretical Framework of Acceptability, Theoretical Domains Framework and the Framework of Implementability to refine the intervention and/or strategy. Constructs from the Consolidated Framework for Implementation Research, such as staffing profile of sites, will be used to explore contextual influences. The effect of the implementation strategy on each of the implementation outcomes, collected on a bimonthly or six-monthly basis, will be evaluated using interrupted time series (ordinary least square methods). This method enables comparison to the time period without the implementation strategy as well as comparison over time, while taking into account the autocorrelation and seasonal effects.

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

1429

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [3]

Albury Wodonga Health - Albury campus - Albury

Recruitment hospital [4]

Bendigo Health Care Group - Bendigo Hospital - Bendigo

Recruitment hospital [5]

St George Hospital - Kogarah

Recruitment hospital [6]

Royal North Shore Hospital - St Leonards

Recruitment hospital [7]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [8]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [9]

Royal Perth Hospital - Perth

Recruitment hospital [10]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [11]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [12]

Eastern Health - Box Hill

Recruitment hospital [13]

Redcliffe Hospital - Redcliffe

Recruitment hospital [14]

Gold Coast Hospital - Southport

Recruitment hospital [15]

Lismore Base Hospital - Lismore

Recruitment hospital [16]

Westmead Hospital - Westmead

Recruitment hospital [17]

Armadale Kelmscott Memorial Hospital - Armadale

Recruitment hospital [18]

Campbelltown Hospital - Campbelltown

Recruitment hospital [19]

Sunshine Coast University Hospital - Birtinya

Recruitment hospital [20]

East Grampians Health Service - Ararat - Ararat

Recruitment hospital [21]

Mildura Base Hospital - Mildura

Recruitment hospital [22]

Ballarat Health Services - Queen Elizabeth Centre - Ballarat

Recruitment hospital [23]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [24]

Launceston General Hospital - Launceston

Recruitment hospital [25]

The Alfred - Melbourne

Recruitment hospital [26]

Latrobe Regional Hospital - Traralgon

Recruitment hospital [27]

Western Hospital - Footscray - Footscray

Recruitment hospital [28]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [29]

Ipswich Hospital - Ipswich

Recruitment hospital [30]

St John of God Hospital, Subiaco - Subiaco

Recruitment hospital [31]

Central Gippsland Health Service (Sale) - Sale

Recruitment hospital [32]

Northeast Health Wangaratta - Wangaratta

Recruitment hospital [33]

Orange Health Service - Orange

Recruitment hospital [34]

Royal Melbourne Hospital - City campus - Parkville

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3000 - Melbourne

Recruitment postcode(s) [3]

2640 - Albury

Recruitment postcode(s) [4]

3550 - Bendigo

Recruitment postcode(s) [5]

2217 - Kogarah

Recruitment postcode(s) [6]

2065 - St Leonards

Recruitment postcode(s) [7]

3220 - Geelong

Recruitment postcode(s) [8]

3168 - Clayton

Recruitment postcode(s) [9]

6000 - Perth

Recruitment postcode(s) [10]

5000 - Adelaide

Recruitment postcode(s) [11]

6150 - Murdoch

Recruitment postcode(s) [12]

3128 - Box Hill

Recruitment postcode(s) [13]

4020 - Redcliffe

Recruitment postcode(s) [14]

4215 - Southport

Recruitment postcode(s) [15]

2480 - Lismore

Recruitment postcode(s) [16]

2145 - Westmead

Recruitment postcode(s) [17]

6112 - Armadale

Recruitment postcode(s) [18]

2560 - Campbelltown

Recruitment postcode(s) [19]

4575 - Birtinya

Recruitment postcode(s) [20]

3377 - Ararat

Recruitment postcode(s) [21]

3500 - Mildura

Recruitment postcode(s) [22]

3350 - Ballarat

Recruitment postcode(s) [23]

2050 - Camperdown

Recruitment postcode(s) [24]

7250 - Launceston

Recruitment postcode(s) [25]

3844 - Traralgon

Recruitment postcode(s) [26]

3011 - Footscray

Recruitment postcode(s) [27]

4029 - Herston

Recruitment postcode(s) [28]

4305 - Ipswich

Recruitment postcode(s) [29]

6008 - Subiaco

Recruitment postcode(s) [30]

3850 - Sale

Recruitment postcode(s) [31]

3677 - Wangaratta

Recruitment postcode(s) [32]

2800 - Orange

Recruitment postcode(s) [33]

3050 - Parkville

Recruitment outside Australia

Country [1]

South Africa

State/province [1]

Western Cape

Country [2]

Canada

State/province [2]

Montreal

Country [3]

Malaysia

State/province [3]

Selangor

Country [4]

Hong Kong

State/province [4]

Southern District

Country [5]

United States of America

State/province [5]

North Carolina

Country [6]

United States of America

State/province [6]

Tennessee

Country [7]

United Kingdom

State/province [7]

Greater London

Country [8]

United Kingdom

State/province [8]

Cornwall

Country [9]

New Zealand

State/province [9]

Auckland Region

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee (HREC)

Ethics committee address [1]

145 Studley Road
Heidelberg
VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/08/2021

Approval date [1]

13/12/2021

Ethics approval number [1]

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

Public notes

Contacts

Principal investigator

Name

Prof Jason Trubiano

Address

Austin Health 145 Studley Road Heidelberg VIC 3084

Country

Australia

Phone

+61 3 9496 6676

Email

[email protected]

Contact person for public queries

Name

Jason Trubiano

Address

Austin Health 145 Studley Road Heidelberg VIC 3084

Country

Australia

Phone

+61 3 9496 6676

Email

[email protected]

Contact person for scientific queries

Name

Jason Trubiano

Address

Austin Health 145 Studley Road Heidelberg VIC 3084

Country

Australia

Phone

+61 3 9496 6676

Email

[email protected]

Trial Review

Documents added manually

Documents added automatically