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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
20/01/2021
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 penicillin provocation to assess low risk penicillin allergies in critically ill adults – A safety and feasibility study - ORACLE
Secondary ID [1] 301161 0
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 319611 0
Antibiotic-associated adverse events 319612 0
Condition category
Condition code
Inflammatory and Immune System 317552 317552 0 0
Allergies
Infection 317553 317553 0 0
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] 318977 0
Early detection / Screening
Intervention code [2] 319222 0
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] 325597 0
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] 325597 0
Upon study completion.
Primary outcome [2] 325598 0
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] 325598 0
Upon study completion
Primary outcome [3] 325599 0
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] 325599 0
+30, +60, +90 and +120 minutes post oral provocation
24 hours post oral provocation
5 days post oral provocation
Secondary outcome [1] 388495 0
Protocol compliance

This data will be drawn from the study database and patient medical records.
Timepoint [1] 388495 0
Day 90 post randomisation
Secondary outcome [2] 388496 0
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] 388496 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17950 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 31815 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 305604 0
Hospital
Name [1] 305604 0
Austin Hospital
Address [1] 305604 0
145 Studley Road
Heidelberg, 3084
Victoria
Country [1] 305604 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg, 3084
Victoria
Country
Australia
Secondary sponsor category [1] 307709 0
None
Name [1] 307709 0
Address [1] 307709 0
Country [1] 307709 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305902 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 305902 0
L8 Harold Stokes Building,

145 Studley Road, Heidelberg

PO Box 5555, Victoria, 3084
Ethics committee country [1] 305902 0
Australia
Date submitted for ethics approval [1] 305902 0
Approval date [1] 305902 0
29/04/2020
Ethics approval number [1] 305902 0
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 101998 0
Dr Morgan Rose
Address 101998 0
Infectious Diseases Department
Level 7, Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 101998 0
Australia
Phone 101998 0
+61 3 9496 6676
Fax 101998 0
Email 101998 0
morgan.rose2@austin.org.au
Contact person for public queries
Name 101999 0
Dr Morgan Rose
Address 101999 0
Infectious Diseases Department
Level 7, Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 101999 0
Australia
Phone 101999 0
+61 3 9496 6676
Fax 101999 0
Email 101999 0
morgan.rose2@austin.org.au
Contact person for scientific queries
Name 102000 0
Dr Morgan Rose
Address 102000 0
Infectious Diseases Department
Level 7, Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 102000 0
Australia
Phone 102000 0
+61 3 9496 6676
Fax 102000 0
Email 102000 0
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?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 9615 0
Ethical approval
Citation [1] 9615 0
Link [1] 9615 0
Email [1] 9615 0
Other [1] 9615 0
Type [2] 9617 0
Study protocol
Citation [2] 9617 0
Link [2] 9617 0
Email [2] 9617 0
Other [2] 9617 0
Type [3] 9955 0
Informed consent form
Citation [3] 9955 0
Link [3] 9955 0
Email [3] 9955 0
Other [3] 9955 0
Summary results
No Results