ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000051842

Ethics application status

Approved

Date submitted

4/11/2020

Date registered

20/01/2021

Date last updated

21/01/2024

Date data sharing statement initially provided

20/01/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

The safety and feasibility of an oral test-dose challenge to assess low-risk penicillin allergy in critically ill hospital patients.

Scientific title

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial

Secondary ID [1]

NONE

Universal Trial Number (UTN)

U1111-1260-7632

Trial acronym

ORACLE

Linked study record

Health condition

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

Penicillin allergy

Antibiotic-associated adverse events

Condition category

Condition code

Inflammatory and Immune System

Allergies

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

A 12-month study period is anticipated.
The intervention is 250mg of oral amoxicillin* (capsule or liquid via enteral route, including nasogastric, with mode of enteral administration at the discretion of the treating clinician) following baseline observations being performed (i.e. temperature, heart rate, blood pressure, respiratory rate, skin check). The amoxicillin test doses will be charted by the study clinician following approval by the treating ICU clinician and admitting unit (review of baseline observations) and administered via bedside nursing staff, with dosing directly observed by bedside nursing staff. Patients in the intervention arm will have the same observations performed by the beside nursing staff at +30, +60, +90 and +120 minutes post oral provocation. If at any stage an antibiotic associated adverse event is noted the treating and study clinicians will be informed and treatment of the adverse event will be at the discretion of the treating clinician. If patients are randomised to the intervention arm they will also undergo a repeat single-dose oral amoxicillin (250mg) provocation at least 48 hours post initial provocation, if they remain an inpatient. The repeat challenge is to ensure that a false negative oral provocation secondary to critical illness did not occur with the first challenge. Patients will be reviewed post each provocation at 24 hours and 5 days, and at 90 days post randomisation [in person if inpatient or alternatively via phone if discharged] for any serious or antibiotic-associated adverse events.

Intervention code [1]

Early detection / Screening

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

Routine management as per local hospital intensive care protocols, without oral penicillin provocation. Patients in the control arm will have observations performed by the beside nursing staff at +30, +60, +90 and +120 minutes post randomisation. Patients will be reviewed at 24 hours and 5 days post-randomisation, 24 hours and 5 days post discharge and 90 days post randomization for any serious or antibiotic-associated adverse events.

Control group

Active

Outcomes

Primary outcome [1]

Proportion of patients assessed that are eligible for intervention (i.e. randomisation) as per protocol [Eligibility to screened ratio]

This data will be drawn from the study database.

Timepoint [1]

Upon study completion.

Primary outcome [2]

Feasibility of recruitment defined as the proportion of patients consenting to participation in the study as per protocol from eligible patients. [Recruitment to eligibility ratio].

This data will be drawn from the study database.

Timepoint [2]

Upon study completion

Primary outcome [3]

Safety: The proportion of patients with a penicillin allergy who experience an antibiotic associated immune mediated adverse event OR severe adverse drug reaction as per protocol definitions.

Possible adverse events and drug reactions include, skin rash or swelling, unexplained fever, respiratory distress, haemodynamic compromise, cytopoenia, renal impairment, hepatic impairment, gastrointestinal symptoms (e.g. nausea or vomiting), mild neurological reactions (e.g. headache and mood disturbance) and severe neurological reactions (e.g. seizure or psychosis).

Adverse events and drug reactions will be identified through clinical examination by investigators (during post-randomisation clinical review), treating physician reporting, participant self-reporting and participant medical record review at the time of hospital discharge.

Timepoint [3]

+30, +60, +90 and +120 minutes post oral provocation
24 hours post oral provocation
5 days post oral provocation

Secondary outcome [1]

Protocol compliance

This data will be drawn from the study database and patient medical records.

Timepoint [1]

Day 90 post randomisation

Secondary outcome [2]

Feasibility of intervention delivery defined as the proportion of patients randomised to the intervention arm who had the intervention delivered as per protocol. [Intervention to recruitment ratio]

This data will be drawn from the study database and patient medical records.

Timepoint [2]

Upon study completion

Eligibility

Key inclusion criteria

1. A low or moderate penicillin allergy phenotype with a PEN-FAST score < 3
2. Are expected to stay in the ICU at least 24 hours from time of initial assessment

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Patient age is < 18 years
2. Pregnancy
3. DNR (do not resuscitate) DNI (do not intubate) orders
4. Death is deemed imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
5. Any other illness that, in the investigator’s judgement, will substantially increase the risk associated with subject’s participation in this study
6. Patients with known history of drug-associated anaphylaxis
7. Patients with idiopathic urticaria/anaphylaxis or mastocytosis
8. Patients where the allergy history was not able to be confirmed with patient or substitute decision maker
9. Patients on antihistamine therapy (excluding ranitidine)
10. Patients on adrenaline or noradrenaline therapy in last 4 hours
11. Patients receiving more than stress dose steroids (i.e. > 50mg QID hydrocortisone [or steroid equivalent])
12. High ventilator requirement if intubated (any of the following)
i. Any mode other than spontaneous
ii. Peak end expiratory pressure (PEEP) >5cm H2O
iii. FiO2 >40%

Study design

Purpose of the study

Diagnosis

Allocation to intervention

Randomised controlled trial

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

Sealed opaque envelopes

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

Permuted block randomisation

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

SAMPLE SIZE ESTIMATION & JUSTIFICATION
This is a pilot feasibility and safety study and it is designed to allow subsequent power calculation for future trials as well as feasibility. As the primary outcome of the study is proportion of patients with their penicillin allergy de-labelled following randomization, we believe that a study of 80 patients would provide sufficient exposure to the study protocol to achieve a sufficiently preliminary assessment of effect of oral penicillin provocation. Forty will be allocated to oral penicillin provocation and the other forty to the standard of care arm.
POWER CALCULATIONS
This sample size is feasible, as we assume that 9% of all screened patients will report a penicillin allergy as per national data (Trubiano. J, Chen. C, Cheng, A, et al. 2016) and in an observational study in the Austin Health ICU (Moran. R, Devchand. M, Churilov. L, et al. 2019) 200 patients would be expected to be eligible in an 12 month study period. Assuming a 50% recruitment and 85% actually receive the intervention post randomization, this would generate a projected total sample size of 85 patients.
Assuming 1:1 randomization between two study arms, this will provide sufficient precision for both feasibility and safety outcomes.
STATISTICAL METHODS TO BE UNDERTAKEN
Data analysis will be performed on an intention-to-treat basis as well as per protocol. Summary statistics will be used to describe the clinical data and presented as mean ± SD, median with interquartile range (IQR) or percentages as appropriate.
Feasibility and safety outcomes will be reported as percentage with 95% confidence intervals. Logistic regression will be used to compare antibiotic utilization and mortality between groups. Results will be reported as odds ratios with 95% confidence intervals. Negative binomial regression will be used for comparison of length of stay (reported as incidence rate ratio with 95% CI). Level of statistical significance will be set at 0.05 or less. Results will be reported according to CONSORT guidelines.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

1/02/2021

Actual

20/03/2021

Date of last participant enrolment

Anticipated

1/06/2023

Actual

1/11/2023

Date of last data collection

Anticipated

30/01/2024

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [3]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [4]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [5]

The Alfred - Melbourne

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3000 - Melbourne

Recruitment postcode(s) [3]

3050 - Parkville

Recruitment postcode(s) [4]

3168 - Clayton

Recruitment postcode(s) [5]

3004 - Melbourne

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Hospital

Address [1]

145 Studley Road
Heidelberg, 3084
Victoria

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Road
Heidelberg, 3084
Victoria

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]

L8 Harold Stokes Building,

145 Studley Road, Heidelberg

PO Box 5555, Victoria, 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

29/04/2020

Ethics approval number [1]

HREC/59438/Austin-2020

Summary

Brief summary

Penicillin allergies are a major burden on patients and hospitals. Currently, up to 1 in 4 Australian patients admitted to hospital will report an antibiotic allergy, many of which limit appropriate antibiotic usage and lead to inferior health outcomes. In many instances, patients will report what is considered a “low-risk” penicillin allergy and are appropriate for a penicillin re-challenge (i.e. a simple test dose) to determine if they are still allergic. We have developed assessment tools and a protocol for performing this test dose which has been safe and effective in over 98% of Austin inpatients. However, at present the safety and efficacy of performing oral penicillin re-challenge in the intensive care unit (ICU) setting is unknown, despite significant potential benefits to patients. This study will determine if penicillin oral re-challenge can be feasibly and safely performed in a small number of ICU patients to allow for future studies to examine the potential benefits of such testing in a larger group of patients.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Morgan Rose

Address

Infectious Diseases Department
Level 7, Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 9496 6676

Fax

morgan.rose2@austin.org.au

Contact person for public queries

Name

Morgan Rose

Address

Infectious Diseases Department
Level 7, Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 9496 6676

Fax

morgan.rose2@austin.org.au

Contact person for scientific queries

Name

Morgan Rose

Address

Infectious Diseases Department
Level 7, Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 9496 6676

Fax

morgan.rose2@austin.org.au

Data sharing statement

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

Yes

What data in particular will be shared?

Individual participant data underlying published results only, after de-identification

When will data be available (start and end dates)?

Immediately following publication, no end date determined

Available to whom?

Case-by-case basis at the discretion of the primary sponsor

Available for what types of analyses?

Any purpose

How or where can data be obtained?

Access subject to approval by investigator

A/Prof Jason Trubiano
Department of Infectious Diseases/ Centre for Antibiotic Allergy and Research
Level 7 Harold Stokes Building
145 Studley Road, Heidelberg
PO Box 5555, Victoria, 3084
jason.trubiano@austin.org.au

What supporting documents are/will be available?

Doc. No.	Type	Attachment
9615	Ethical approval	379735-(Uploaded-03-12-2020-14-53-29)-Study-related document.pdf
9617	Study protocol	379735-(Uploaded-04-11-2020-12-45-21)-Study-related document.docx
9955	Informed consent form	379735-(Uploaded-03-12-2020-14-54-52)-Study-related document.doc

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
Embase	Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot randomised controlled trial.	2023	https://dx.doi.org/10.1186/s40814-023-01337-8

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

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