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Trial registered on ANZCTR

Registration number

ACTRN12620001295932

Ethics application status

Approved

Date submitted

1/10/2020

Date registered

30/11/2020

Date last updated

22/08/2022

Date data sharing statement initially provided

30/11/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

Streamlining antibiotic allergy testing for elective surgery patients using smartphone based apps

Scientific title

PeRiopErative Penicillin/Cephalosporin AlleRgy TEsting - A phase II feasibility/safety randomised control trial to empower anaesthetists to risk stratify and de-label antibiotic allergy labels in the perioperative period using digital health solutions.

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

U1111-1258-1711

Trial acronym

PREPARE

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Penicillin Allergy

Cephalosporin Allergy

Antibiotic Allergy

Condition category

Condition code

Inflammatory and Immune System

Allergies

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Pre-operative risk stratification and de-labelling of antibiotic allergy labels:

Aim: Develop and implement a point of care, smartphone app based beta-lactam allergy de-labelling tool in perioperative medicine and assess the safety and feasibility of this intervention.

Materials:
Risk stratification of antibiotic allergy labels via a custom built smartphone app, based on a validated assessment tool. To be used by anaesthetists during pre-operative assessment.

Procedure:
Participants in pre-operative assessment clinic (PAC) with penicillin or cephalosporin allergy will be randomised to either the intervention arm or control arm. Those randomised to intervention arm will go on to be risk-stratified. Risk stratification is carried out by clinical staff within the PAC during a routine 20min consultation via the use of a smartphone application containing the validated Antibiotic Allergy Assessment Tool. Pre-operative assessment occurs between 1 week and 1 day prior to surgery.

Participants identified as having a 'low-risk' penicillin or cephalosporin allergy label will go on to be challenged with an oral dose of penicillin VK, amoxicillin or cefalexin and observed for 1 hour post. This challenge occurs on the same day, directly after risk stratification occurs.

Delivered by who and where:
Risk-stratification will be completed by anaesthetic specialist in pre-operative assessment outpatient clinic. Participants who go on to challenge will also be challenged with a dose of antibiotic and observed within the same outpatient clinic.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Participants randomised to the control arm will go on to receive standard of care and will be referred for allergy testing via the normal hospital based pathways. Standard of care in this context includes use of alternative antibiotics on the day of surgery and/or referral for further allergy testing post-surgery. This referral occurs on discharge from hospital.

Control group

Active

Outcomes

Primary outcome [1]

Feasibility of recruitment/intervention delivery:
a) Feasibility of intervention delivery defined as the proportion of patients randomised to the intervention arm who had the intervention delivered as per protocol
- Determined by audit of clinical notes
b) Feasibility of recruitment defined as the proportion of patients consenting to participation in the study as per protocol from eligible patients.
- Determined by audit of clinical notes

Timepoint [1]

On the day of pre-operative assessment

Primary outcome [2]

Safety:
a) The proportion of patients with a penicillin allergy who experience an antibiotic associated adverse event and/or severe adverse drug reaction.
- Occurrence of adverse events will be determined from medical records

Timepoint [2]

Assessed at two main time points:
a) On the day of pre-operative assessment and/or challenge
b) At the time of surgery and in the post-surgical period

Secondary outcome [1]

Beta-lactam utilization in perioperative period (n, %). This would be assessed by examining patient medical records.

Timepoint [1]

At time of surgery (up to 72 hours post surgery)

Secondary outcome [2]

Surgical operating times (minutes). This would be assessed by examining patient medical records.

Timepoint [2]

At time of surgery

Secondary outcome [3]

Proportion of patients (n, %) with a beta-lactam allergy that develop a surgical site infection up to 90 days post surgery.

Timepoint [3]

Assessed at 30 days and 90 days post surgery.

Secondary outcome [4]

Proportion of patients with a beta-lactam allergy that utilize any beta-lactam in surgical prophylaxis. This will be assessed via telephone follow up at 30 and 90 days.

Timepoint [4]

Assessed at time of surgery, with surgical prophylaxis defined as antibiotic given 30min to 1hr prior to surgical incision.

Secondary outcome [5]

Proportion of patients with a beta-lactam allergy that develop an acute kidney injury in the 72 hours post surgery. This will be collected via data-linkage to medical records.

Timepoint [5]

Assessed within 72hours after surgery, done by chart review.

Secondary outcome [6]

Median time from antibiotic administration to surgical incision (mins). This will be collected via data-linkage to medical records.

Timepoint [6]

Assessed at time of surgery

Secondary outcome [7]

Proportion of patients with a beta-lactam allergy with a non-elective admission to the ICU unit in the 72 hours post surgery. This will be collected via data-linkage to medical records.

Timepoint [7]

Assessed within preoperative period up to 72hours post surgery

Secondary outcome [8]

Median length-of-stay. This will be collected via data-linkage to medical records.

Timepoint [8]

On discharge from hospital, identified via chart review at the 30 day post-surgical time point

Secondary outcome [9]

Inpatient mortality. This will be collected via data-linkage to medical records.

Timepoint [9]

Defined as death during inpatient stay post surgery.

Secondary outcome [10]

Proportion of patients with a beta-lactam allergy that utilize an appropriate antibiotic for surgical prophylaxis (defined by NAPs definitions). This will be collected via data-linkage to medical records.

Timepoint [10]

Assessed at time of surgery, with surgical prophylaxis defined as antibiotic given 30min to 1hr prior to surgical incision.

Secondary outcome [11]

Proportion of patients with a beta-lactam allergy that utilize an appropriate antibiotic in the perioperative period (72 hours post surgery) [defined by NAPs definitions]. This will be collected via data-linkage to medical records.

Timepoint [11]

At time of surgery, up to 72hours post surgery.

Eligibility

Key inclusion criteria

Patients aged 18 years and above that are reviewed in the perioperative assessment clinic under the care of a surgerical unit, having a reported penicillin or cephalosporin allergy label, and will require intravenous antibiotic therapy in planned perioperative care.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Inpatients
Patients aged < 18 years
Patients currently receiving beta-lactam antibiotic therapy
Previous referral or assessment by a specialist for beta-lactam allergy
Under the current care of an Allergy/Immunology specialist
Require non-beta-lactam antibiotics for an infection or colonization with an organism resistant to beta-lactam (eg MRSA, ESBL producing gram negatives)
Emergency or trauma surgery
Contraindication for oral penicillin provocation
• Patients receiving more than 10mg of prednisolone or
equivalent daily
• Patients receiving antihistamine therapies
• Patients with a history of drug-associated anaphylaxis or idiopathic urticaria/anaphylaxis

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation is not concealed

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomisation via computer program

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people administering the treatment/s

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Safety

Statistical methods / analysis

The sample size calculations for this feasibility and safety study is based on the precision of
the estimates for the feasibility outcomes.

Feasibility considerations: We would like to be able to estimate the proportion of patients
randomized in the intervention arm to actually receive the intervention as per protocol with
sufficient precision. Recruiting 49 patients in the intervention arm of the study would provide
the precision (half-width of the 95% confidence interval) of 8% to estimate the underlying
proportion of patients treated per protocol to be 85% as per the definition provided earlier in
this protocol.

Safety considerations: We would like to be able to estimate the proportion of patients
experiencing adverse events casually related to the study in the intervention arm with sufficient precision. Recruiting 73 patients in the intervention arm of the study would provide the precision (half-width of the 95% confidence interval) of 5% to estimate the underlying proportion of patients experiencing any adverse event (See - serious adverse event or antibiotic associated adverse event definitions) to the study to be 5%.

Assuming 1:1 randomization between two study arms, we would randomize 150 patients
(sample size calculation to assessed safety requires 73 in each arm [146 total], total
randomized rounded to 150 total). in total, providing sufficient precision for both feasibility and
safety outcomes.

This sample size is feasible, as we assume that 9% of all screened patients will report a
penicillin allergy as per national data, thus requiring us to screen up to 1750 patients. This
will be achieved by 4 centres each contributing approximately 40 patients out of their general
480 patient per year cohort.

Feasibility of intervention delivery and feasibility of recruitment will be reported as proportions
with respective 95% confidence intervals. The proportions of patients with a penicillin allergy
who experience an antibiotic associated adverse event and/or severe adverse drug reaction
as per protocol definitions will be reported by group with respective 95% confidence intervals
and compared using modified Poisson regression model with robust standard error estimation. Corresponding effect size will be reported as risk ratio with respective 95% confidence interval.

Secondary outcomes will be reported by group and compared using appropriate regression
models. Details of statistical analysis will be documented in a separate Statistical Analysis
Plan (SAP) that will be developed and finalized prior to the study database lock.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

14/12/2020

Actual

4/02/2021

Date of last participant enrolment

Anticipated

31/01/2023

Actual

Date of last data collection

Anticipated

31/03/2023

Actual

Sample size

Target

150

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [2]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [3]

The Alfred - Melbourne

Recruitment postcode(s) [1]

3050 - Parkville

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

3004 - Melbourne

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

MERCK SHARP & DOHME

Address [1]

Building A, Level 1, 26 Talavera Rd
Macquarie Park NSW

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Rd
Heidelberg VIC 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

145 Studley Rd
PO Box 5555
Heidelberg VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/04/2018

Approval date [1]

28/01/2020

Ethics approval number [1]

Summary

Brief summary

Antibiotic adverse drug reactions (ADRs), commonly known as "allergies", are a major burden on patients and hospitals. Currently, up to one in four Australian and American patients admitted to hospital will report an antibiotic "allergy" (so-called antibiotic allergy “labels” [AAL]), many of which limit appropriate antibiotic usage. In many instances, patients may undergo challenge with the antibiotic due to incorrect allergy reporting and recording. The nature of a patient’s antibiotic allergy and what antibiotics should be avoided are a common source of confusion for both doctors and patients alike. Penicillin allergy labels in the perioperative space have been associated with inferior patient (e.g. increased rates of periprosthetic infection), hospital (e.g. increased surgical time), and prescribing outcomes (e.g. vancomycin > cefazolin utilization), and conversely in observational and non-controlled studies penicillin allergy “de-labelling” has been associated with improved utilization of beta-lactams and patient outcomes. Further, whilst direct oral penicillin challenge has increasing observational evidence for safety and efficacy, it has not been applied to the perioperative assessment of orthopaedic patients reporting a penicillin allergy. 

This project is a collaboration between Austin Health, Alfred Health and Royal Melbourne Hospital. The PREPARE study is a feasibility and safety randomized control trial examining feasibility and safety of enhanced antibiotic allergy assessment and penicillin allergy testing in the perioperative setting in surgical patients planned for elective surgery.  The PREPARE study will examine the utility of decision support (via smartphone app) utilizing a validated Antibiotic Allergy Assessment Tool9 for patients reporting a penicillin allergy in the perioperative arena in identifying those patients appropriate for a direct oral penicillin challenge in the perioperative clinic. PREPARE hopes to provide a useful point of care toolkit to improve clinician antibiotic allergy knowledge, antibiotic prescribing and medication safety, subsequently benefiting patients, clinicians and hospital networks.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Jason Trubiano

Address

Department of Infectious Diseases
Austin Health
145 Studley Rd
Heidelberg VIC 3084

Country

Australia

Phone

+61394966676

Fax

jason.trubiano@austin.org.au

Contact person for public queries

Name

Joseph De luca

Address

Department of Infectious Diseases
Austin Health
145 Studley Rd
Heidelberg VIC 3084

Country

Australia

Phone

+61394966676

Fax

joseph.deluca@austin.org.au

Contact person for scientific queries

Name

Joseph De luca

Address

Department of Infectious Diseases
Austin Health
145 Studley Rd
Heidelberg VIC 3084

Country

Australia

Phone

+61394966676

Fax

joseph.deluca@austin.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	Study protocol for PREPARE: a phase II feasibility/safety randomised controlled trial on PeRiopErative Penicillin AlleRgy TEsting	2023	https://doi.org/10.1136/bmjopen-2022-067653

N.B. These documents automatically identified may not have been verified by the study sponsor.

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