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Trial registered on ANZCTR


Registration number
ACTRN12623001242617
Ethics application status
Approved
Date submitted
10/07/2023
Date registered
30/11/2023
Date last updated
14/01/2024
Date data sharing statement initially provided
30/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
PROlonged versus Single dose in PEnicillin oral Challenge Testing
Scientific title
PROlonged versus Single dose in PEnicillin oral Challenge Testing in adult with reported penicillin allergy: A pilot randomized placebo-cOntrolled tRial - The PROSPECTOR Study
Secondary ID [1] 310080 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PROSPECTOR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Allergies 330629 0
Adverse drug reaction 330630 0
Penicillin allergy 330631 0
Delayed hypersensitivity 330632 0
Condition category
Condition code
Inflammatory and Immune System 327459 327459 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Amoxicillin 500mg (oral capsule) twice daily for 5 days
Intervention code [1] 326481 0
Diagnosis / Prognosis
Comparator / control treatment
5 day placebo (in microcrystalline cellulose capsule) oral challenge (twice daily dosing).
Control group
Placebo

Outcomes
Primary outcome [1] 335318 0
Compliance with the intervention (number and percentage of participants taking at least 80% of the doses) as assessed during patient review as per protocol.
Timepoint [1] 335318 0
day 1, day 5 and day 14 post-treatment commencement
Primary outcome [2] 335319 0
Need for unblinding (number and percentage of participants being intentionally or unintentionally unblinded) will be assessed during patient review as per protocol
Timepoint [2] 335319 0
up to 90 days post-treatment commencement
Primary outcome [3] 336683 0
% participants consenting to participate in the study per protocol from eligible patients [Recruitment to eligibility ratio], determined by audit of clinical notes.
Timepoint [3] 336683 0
before randomization
Secondary outcome [1] 423940 0
Recruitment rate per site (number of participants recruited / month) as assessed by investigators determined using the subject enrolment log
Timepoint [1] 423940 0
Assessed on monthly basis per site up to 12 months post-study commencement
Secondary outcome [2] 423941 0
Proportion of participants randomized to the intervention arm from recruited patient (randomization to recruitment ratio) will be assessed as per protocol determined using the subject randomization log
Timepoint [2] 423941 0
up to 90 days post treatment commencement
Secondary outcome [3] 423942 0
Proportion of participants that withdrew from the study will be assessed during patient review as per protocol determined using the participant withdrawal log
Timepoint [3] 423942 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [4] 423943 0
Proportion of participants who were lost to follow-up at each time point will be assessed during patient review as per protocol
Timepoint [4] 423943 0
up to 3 months post-treatment commencement
Secondary outcome [5] 423944 0
Proportion of participants with missing data for each efficacy outcome will be assessed by investigators determined by audit of study database
Timepoint [5] 423944 0
up to 3 months post-treatment commencement
Secondary outcome [6] 428453 0
Proportion of participants per each type of protocol violation (protocol compliance) will be assessed during patient review as per protocol
Timepoint [6] 428453 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [7] 428454 0
Proportion of participants with Severe adverse reaction - anaphylaxis/death will be assessed during patient review as per protocol
Timepoint [7] 428454 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [8] 428456 0
Proportion of participants with immune mediated adverse reaction or severe drug reaction as per protocol definitions (stratified by antibiotic associated vs non-antibiotic associated) will be assessed during patient review as per protocol
Timepoint [8] 428456 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [9] 428457 0
Proportion of participants with non-immune mediated adverse event (stratified by antibiotic associated vs non-antibiotic associated) will be assessed during patient review as per protocol
Timepoint [9] 428457 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [10] 428458 0
Proportion of participants with any cutaneous adverse reaction as assessed during patient review as per protocol
Timepoint [10] 428458 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [11] 428459 0
Proportion of participants with positive oral challenge (i.e. immune mediated reaction) will be assessed during patient review using a standardized questionnaire as per protocol
Timepoint [11] 428459 0
day 1, day 5 and day 14 post-treatment commencement
Secondary outcome [12] 428460 0
Proportion of participants with c. difficile infection assessed will be by study-specific 30 and 90 day follow up questionnaire
Timepoint [12] 428460 0
day 30 and 90 post-treatment commencement
Secondary outcome [13] 428461 0
Proportion of participants with multidrug resistant infection will be assessed by study-specific 30 and 90 day follow up questionnaire
Timepoint [13] 428461 0
Day 30 and 90 post-treatment commencement
Secondary outcome [14] 428462 0
Assessment of cost effectiveness of placebo vs open label trial will be assessed using cost effectiveness health economic analysis determined by resource use and costs from hospital medical records
Timepoint [14] 428462 0
up to 90 days post-treatment commencement

Eligibility
Key inclusion criteria
1. Adult patients referred to the outpatient allergy clinic or inpatient allergy service for a penicillin allergy history (i.e. amoxicillin or penicillin unspecified)

2. Adult patients with an immune-mediated penicillin allergy history with either delayed phenotype (> 2 hours post dose) or unknown timing

3. Tolerated first dose of an oral penicillin challenge

4. Being challenged to the implicated penicillin. In setting of unknown penicillin, challenge either to penicillin VK or amoxicillin

5. Willing and able to give consent

6. Willing and able to undergo telehealth or in clinic review post challenge
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient age is < 18 years;

2. Any other illness that, in the investigator’s judgement, will substantially increase the risk associated with subject’s participation in this study

3. Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis to beta-lactam

4. Inpatients receiving concurrent beta-lactam antibiotic therapy

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)
Randomization will be performed by the pharmacy dispensing team via REDCap just prior to the intervention. The allocation sequence will be concealed until the time of the randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block design randomisation will be used, stratified by the hospital site and setting (inpatient vs outpatient). While block design might result in larger treatment imbalances, such design is preferred to overcome logistical difficulties.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Results will be presented according to CONSORT guidelines for feasibility studies {Eldridge, 2016 #1960}.
Patient characteristics and penicillin allergy history will be presented by arm using median (interquartile range) for continuous variables and count (percentage) for categorical variables.
Binary outcomes will be presented as count and percentage with 95% exact confidence intervals. All outcomes (where feasible) will be presented as overall, by study arm and by setting. Exploratory efficacy outcomes will also be presented as absolute (risk difference) and relative difference (risk ratio) with 95% confidence intervals. No statistical tests will be performed. Amount and pattern of missing data will be explored.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
11/12/2023
Actual
20/12/2023
Date of last participant enrolment
Anticipated
2/09/2024
Actual
Date of last data collection
Anticipated
6/12/2024
Actual
Sample size
Target
120
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 25088 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 25089 0
St George Hospital - Kogarah
Recruitment hospital [3] 25090 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 25791 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 40757 0
3084 - Banyule
Recruitment postcode(s) [2] 40758 0
3084 - Heidelberg
Recruitment postcode(s) [3] 40759 0
2217 - Kogarah
Recruitment postcode(s) [4] 40760 0
3000 - Melbourne
Recruitment postcode(s) [5] 41617 0
4029 - Herston
Recruitment outside Australia
Country [1] 25627 0
South Africa
State/province [1] 25627 0
Capetown
Country [2] 25628 0
Canada
State/province [2] 25628 0
Quebec
Country [3] 25945 0
Denmark
State/province [3] 25945 0

Funding & Sponsors
Funding source category [1] 314245 0
Hospital
Name [1] 314245 0
Austin Health
Country [1] 314245 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road Heidelberg, VIC 3084
Country
Australia
Secondary sponsor category [1] 316178 0
None
Name [1] 316178 0
Address [1] 316178 0
Country [1] 316178 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313363 0
Austin Health
Ethics committee address [1] 313363 0
145 Studley Road Heidelberg, VIC 3084
Ethics committee country [1] 313363 0
Australia
Date submitted for ethics approval [1] 313363 0
01/08/2023
Approval date [1] 313363 0
30/10/2023
Ethics approval number [1] 313363 0

Summary
Brief summary
Penicillin allergies are a major burden on patients and health care worldwide. Currently, up to 1 in 4 hospitalised patients admitted to hospital will report an antibiotic allergy, which limits appropriate antibiotic use and leads to poorer health outcomes. In some instances, patients can be given a single or multiple test dose of an antibiotic to determine if a patient is truly allergic. This study will inform whether research to determine if a multiple dose challenge (5-days) elicits more true penicillin allergy than a single dose challenge is feasible.

The current Drug Allergy Practice Parameters recommend “against the routine use of multiple-day challenges in the evaluation of penicillin allergy”, providing a “strong recommendation” but with ” low certainty of evidence”. In Europe, a mixture of observational and retrospective studies has suggested that extended challenges ranging from 3 to 10 days may be superior to single dose challenges at excluding delayed immune reactions, however the reported prevalence of delayed reactions is highly variable (5-12% of patients) and many were reliant on patient self-reporting. This is converse to the North American experience where delayed prolonged challenges have been associated with low rates of delayed reactions (0-1.8%). Whilst a study of children demonstrated that delayed reactions may occur <7 days following a single challenge. Therefore, whilst oral challenge is the well-defined gold standard for penicillin allegro-immunological investigation, limited controlled evidence is available regarding the safety and efficacy of single dose versus prolonged oral challenge.

Blinded randomized placebo-controlled trials have not been previously used in any drug allergy trials. The aim of this double blinded placebo controlled pilot randomised control trial is to evaluate the feasibility of placebo controlled trial and safety of oral penicillin challenge (5-day) versus single dose challenge penicillin challenge (followed by 5 day placebo) for evaluation of immune-mediated penicillin allergy in the inpatient and outpatient setting to inform the design of a definitive trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127890 0
Prof Jason Trubiano
Address 127890 0
Austin Health, 145 Studley Road Heidelberg, VIC 3084
Country 127890 0
Australia
Phone 127890 0
+61433303415
Fax 127890 0
Email 127890 0
[email protected]
Contact person for public queries
Name 127891 0
Jason Trubiano
Address 127891 0
Austin Health, 145 Studley Road Heidelberg, VIC 3084
Country 127891 0
Australia
Phone 127891 0
+61 394966676
Fax 127891 0
Email 127891 0
[email protected]
Contact person for scientific queries
Name 127892 0
Jason Trubiano
Address 127892 0
Austin Health, 145 Studley Road Heidelberg, VIC 3084
Country 127892 0
Australia
Phone 127892 0
+61433303415
Fax 127892 0
Email 127892 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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
No additional documents have been identified.