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Trial registered on ANZCTR


Registration number
ACTRN12624001107516p
Ethics application status
Submitted, not yet approved
Date submitted
5/08/2024
Date registered
13/09/2024
Date last updated
13/09/2024
Date data sharing statement initially provided
13/09/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
PROlonged versus Single dose in PEnicillin oral Challenge Testing-2
Scientific title
PROlonged versus Single dose in PEnicillin oral Challenge Testing double-blind parallel randomized placebo cOntrolled tRial – PROSPECTOR-2 Study: Evaluating the efficacy of prolonged oral penicillin challenge over single dose oral penicillin challenge to ascertain true penicillin allergy
Secondary ID [1] 312619 0
None
Universal Trial Number (UTN)
Trial acronym
PROSPECTOR-2
Linked study record
This study is a follow up study to: ACTRN12623001242617

Health condition
Health condition(s) or problem(s) studied:
allergies 334552 0
adverse drug reaction 334553 0
Penicillin allergy 334554 0
Delayed hypersensitivity 334555 0
Condition category
Condition code
Inflammatory and Immune System 331160 331160 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Amoxicillin 500mg (oral capsule) twice daily for 5 days.

Participants will complete study dosing log and return study bottle to trial pharmacy to monitor adherence to protocol
Intervention code [1] 329130 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] 338921 0
Positive oral challenge (immune mediated reaction) within 7 days post first test dose
Timepoint [1] 338921 0
Day 1, 5 and 7 post-treatment commencement
Secondary outcome [1] 437909 0
Positive oral challenge (immune mediated reaction) within 14 days post first test dose
Timepoint [1] 437909 0
Day 1, 5, 7 and 14 post-treatment commencement
Secondary outcome [2] 437911 0
Time to positive oral challenge
Timepoint [2] 437911 0
Day 1, Day 5, Day 7, Day 14 post-treatment commencement
Secondary outcome [3] 437912 0
Quality of life
Timepoint [3] 437912 0
Day 0 and Day 90 post-treatment commencement
Secondary outcome [4] 437913 0
[Safety Outcomes] Proportion of participants with immediate severe adverse reaction (anaphylaxis or death)
Timepoint [4] 437913 0
Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
Secondary outcome [5] 437914 0
[Safety Outcomes] Proportion of participants with delayed adverse reaction (severe cutaneous adverse reaction)
Timepoint [5] 437914 0
Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
Secondary outcome [6] 437915 0
[Safety Outcomes] Proportion of participants with non-immune mediated adverse event
Timepoint [6] 437915 0
Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
Secondary outcome [7] 437916 0
[Safety Outcomes] Proportion of participants with RegiSCAR score of greater than or equal to 2
Timepoint [7] 437916 0
Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
Secondary outcome [8] 437917 0
[Safety Outcomes] Proportion of participants with grade 3 or 4 adverse reactions as defined by World Allergy Organisation
Timepoint [8] 437917 0
Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
Secondary outcome [9] 437918 0
[Safety Outcomes] Proportion of participants with any cutaneous adverse reactions
Timepoint [9] 437918 0
Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
Secondary outcome [10] 437919 0
[Exploratory efficacy outcomes] Proportion of participants with c. difficile infection at 30-day, 90-day, 120-day follow up
Timepoint [10] 437919 0
day 30, 90 and day 120 post-treatment commencement
Secondary outcome [11] 437920 0
[Exploratory efficacy outcomes] Multidrug resistant infection at 30-day, 90-day, 120-day follow up as per protocol definitions
Timepoint [11] 437920 0
day 30, 90 and day 120 post-treatment commencement
Secondary outcome [12] 437921 0
[Exploratory efficacy outcomes] Multidrug resistant colonisation at 30-day, 90-day, 120-day follow-up
Timepoint [12] 437921 0
day 30, day 90 and day 120 post-treatment commencement
Secondary outcome [13] 437946 0
[Cost effectiveness outcome] Cost effectiveness analysis of prolonged vs single dose oral challenge
Timepoint [13] 437946 0
up to 120 days post-treatment commencement

Eligibility
Key inclusion criteria
1. Adult patients referred to the inpatient or outpatient allergy services for a suspected penicillin allergy with an immune-related allergy history of delayed (> 6 hours after first dose of drug administration) or unknown timing, who tolerate first single-dose of an oral amoxicillin challenge.

2. Willing and able to give consent and undergo telehealth/telephone review
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 concurrently receiving or likely to receive a beta-lactam antibiotic therapy during the 14-day study period.

5. Concurrent use of antihistamines and systemic steroid therapy (i.e. > 10mg daily)

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).
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
Phase 3
Type of endpoint/s
Safety
Statistical methods / analysis
Results will be presented according to CONSORT guidelines (Schulz, KF, et al, Ann Intern Med, 2010)

Patient characteristics and penicillin allergy history will be presented by arm using median (interquartile range) for continuous variables and count (percentage) for categorical variables.

Primary analysis will be on intention-to-treat basis. Generalized linear model with binomial family will be used to calculate risk difference (identity link) and risk ratio (log link) between intervention and control. Results will be presented with two-sided 95% confidence intervals. Models will be adjusted for stratification variables (clinical site and setting).

Subgroup analysis will be performed by an inclusion of interaction term between subgroup and arm.

Primary analysis will be also performed in per-protocol population.

Time to adverse reaction will be evaluated using Kaplan-Meier method and Cox proportions hazards regression.

Detailed statistical analysis plan will be prepared and published prior to study completion.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/11/2024
Actual
Date of last participant enrolment
Anticipated
27/11/2026
Actual
Date of last data collection
Anticipated
26/03/2027
Actual
Sample size
Target
830
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 26856 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 26857 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 26859 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [4] 26860 0
St George Private Hospital - Kogarah
Recruitment hospital [5] 26861 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [6] 26862 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 42917 0
3084 - Heidelberg
Recruitment postcode(s) [2] 42918 0
3000 - Melbourne
Recruitment postcode(s) [3] 42920 0
3052 - Parkville
Recruitment postcode(s) [4] 42921 0
2217 - Kogarah
Recruitment postcode(s) [5] 42922 0
2065 - St Leonards
Recruitment postcode(s) [6] 42923 0
4029 - Herston
Recruitment outside Australia
Country [1] 26460 0
Canada
State/province [1] 26460 0
Country [2] 26461 0
South Africa
State/province [2] 26461 0
Country [3] 26462 0
Denmark
State/province [3] 26462 0

Funding & Sponsors
Funding source category [1] 317050 0
Hospital
Name [1] 317050 0
Austin Health
Country [1] 317050 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
Country
Australia
Secondary sponsor category [1] 319297 0
None
Name [1] 319297 0
Address [1] 319297 0
Country [1] 319297 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315803 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 315803 0
https://www.austin.org.au/Office-for-Research/
Ethics committee country [1] 315803 0
Australia
Date submitted for ethics approval [1] 315803 0
09/08/2024
Approval date [1] 315803 0
Ethics approval number [1] 315803 0

Summary
Brief summary
Penicillin allergies are highly prevalent in the healthcare setting and are associated with second-line inferior antibiotics being prescribed. An incorrect penicillin allergy label leads to increased risk of resistant organisms, side effects from second-line antibiotics as well as increased medical costs. The gold standard for penicillin allergy testing is an oral challenge – either direct or following skin testing. What remains unknown is if a single dose is sufficient to determine if the patient has a delayed or unknown timing immune mediated penicillin allergy or if a prolonged oral challenge (5 days or more) is required. The PROSPECTOR pilot trial demonstrated the feasibility and safety of a placebo-controlled trial of single dose penicillin challenge versus prolonged challenge (5-day).

PROSPECTOR2 continues from the PROSECTOR pilot trial (ACTRN12623001242617) to assess the superiority of prolonged oral challenge versus single dose challenge for identifying immune-mediated penicillin allergy.

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”. The European guidelines reviewed the literature of over 6484 patients, demonstrating a 2.3% positive rate following the initial challenge and 5.5% during the varied prolonged challenges. They concluded there is no consensus on a preferred procedure and could not provide a recommendation for or against prolonged challenge. 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. In a recent retrospective single centre Danish experience of 3,179 low-risk patients, 2.6% were positive on day 1 of challenge and 7.2% on days 3-10. This is in contrast 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 less than 7 days following a single challenge. Therefore, whilst oral challenge is the well-defined gold standard for penicillin allergo-immunological investigation, limited controlled evidence is available regarding the efficacy of single dose versus prolonged oral challenge.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 135850 0
Prof Jason Trubiano
Address 135850 0
Austin Health, 145 Studley Road Heidelberg, VIC 3084
Country 135850 0
Australia
Phone 135850 0
+61 394966676
Fax 135850 0
Email 135850 0
[email protected]
Contact person for public queries
Name 135851 0
Jason Trubiano
Address 135851 0
Austin Health, 145 Studley Road Heidelberg, VIC 3084
Country 135851 0
Australia
Phone 135851 0
+61 394966676
Fax 135851 0
Email 135851 0
[email protected]
Contact person for scientific queries
Name 135852 0
Jason Trubiano
Address 135852 0
Austin Health, 145 Studley Road Heidelberg, VIC 3084
Country 135852 0
Australia
Phone 135852 0
+61 394966676
Fax 135852 0
Email 135852 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.