ANZCTR - Registration

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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]

Nil known

Universal Trial Number (UTN)

Trial acronym

PROSPECTOR

Linked study record

Health condition

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

Allergies

Adverse drug reaction

Penicillin allergy

Delayed hypersensitivity

Condition category

Condition code

Inflammatory and Immune System

Allergies

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Amoxicillin 500mg (oral capsule) twice daily for 5 days

Intervention code [1]

Diagnosis / Prognosis

Comparator / control treatment

5 day placebo (in microcrystalline cellulose capsule) oral challenge (twice daily dosing).

Control group

Placebo

Outcomes

Primary outcome [1]

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]

day 1, day 5 and day 14 post-treatment commencement

Primary outcome [2]

Need for unblinding (number and percentage of participants being intentionally or unintentionally unblinded) will be assessed during patient review as per protocol

Timepoint [2]

up to 90 days post-treatment commencement

Primary outcome [3]

% participants consenting to participate in the study per protocol from eligible patients [Recruitment to eligibility ratio], determined by audit of clinical notes.

Timepoint [3]

before randomization

Secondary outcome [1]

Recruitment rate per site (number of participants recruited / month) as assessed by investigators determined using the subject enrolment log

Timepoint [1]

Assessed on monthly basis per site up to 12 months post-study commencement

Secondary outcome [2]

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]

up to 90 days post treatment commencement

Secondary outcome [3]

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]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [4]

Proportion of participants who were lost to follow-up at each time point will be assessed during patient review as per protocol

Timepoint [4]

up to 3 months post-treatment commencement

Secondary outcome [5]

Proportion of participants with missing data for each efficacy outcome will be assessed by investigators determined by audit of study database

Timepoint [5]

up to 3 months post-treatment commencement

Secondary outcome [6]

Proportion of participants per each type of protocol violation (protocol compliance) will be assessed during patient review as per protocol

Timepoint [6]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [7]

Proportion of participants with Severe adverse reaction - anaphylaxis/death will be assessed during patient review as per protocol

Timepoint [7]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [8]

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]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [9]

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]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [10]

Proportion of participants with any cutaneous adverse reaction as assessed during patient review as per protocol

Timepoint [10]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [11]

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]

day 1, day 5 and day 14 post-treatment commencement

Secondary outcome [12]

Proportion of participants with c. difficile infection assessed will be by study-specific 30 and 90 day follow up questionnaire

Timepoint [12]

day 30 and 90 post-treatment commencement

Secondary outcome [13]

Proportion of participants with multidrug resistant infection will be assessed by study-specific 30 and 90 day follow up questionnaire

Timepoint [13]

Day 30 and 90 post-treatment commencement

Secondary outcome [14]

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]

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?

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

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

St George Hospital - Kogarah

Recruitment hospital [3]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [4]

Royal Brisbane & Womens Hospital - Herston

Recruitment postcode(s) [1]

3084 - Banyule

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

2217 - Kogarah

Recruitment postcode(s) [4]

3000 - Melbourne

Recruitment postcode(s) [5]

4029 - Herston

Recruitment outside Australia

Country [1]

South Africa

State/province [1]

Capetown

Country [2]

Canada

State/province [2]

Quebec

Country [3]

Denmark

State/province [3]

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Address [1]

145 Studley Road Heidelberg, VIC 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Road 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

Ethics committee address [1]

145 Studley Road Heidelberg, VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/08/2023

Approval date [1]

30/10/2023

Ethics approval number [1]

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

Prof Jason Trubiano

Address

Austin Health, 145 Studley Road Heidelberg, VIC 3084

Country

Australia

Phone

+61433303415

Fax

jason.trubiano@austin.org.au

Contact person for public queries

Name

Jason Trubiano

Address

Austin Health, 145 Studley Road Heidelberg, VIC 3084

Country

Australia

Phone

+61 394966676

Fax

antibiotic.allergy@austin.org.au

Contact person for scientific queries

Name

Jason Trubiano

Address

Austin Health, 145 Studley Road Heidelberg, VIC 3084

Country

Australia

Phone

+61433303415

Fax

jason.trubiano@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?

Current supporting documents:

Updated to:

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
24411	Study protocol					386208-(Uploaded-19-12-2024-08-50-25)-26122022 FORM - PROTOCOL_PROSPECTOR_v7_clean.pdf

Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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