ANZCTR - Registration

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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]

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

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.

Participants will complete study dosing log and return study bottle to trial pharmacy to monitor adherence to protocol

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]

Positive oral challenge (immune mediated reaction) within 7 days post first test dose

Timepoint [1]

Day 1, 5 and 7 post-treatment commencement

Secondary outcome [1]

Positive oral challenge (immune mediated reaction) within 14 days post first test dose

Timepoint [1]

Day 1, 5, 7 and 14 post-treatment commencement

Secondary outcome [2]

Time to positive oral challenge

Timepoint [2]

Day 1, Day 5, Day 7, Day 14 post-treatment commencement

Secondary outcome [3]

Quality of life

Timepoint [3]

Day 0 and Day 90 post-treatment commencement

Secondary outcome [4]

[Safety Outcomes] Proportion of participants with immediate severe adverse reaction (anaphylaxis or death)

Timepoint [4]

Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement

Secondary outcome [5]

[Safety Outcomes] Proportion of participants with delayed adverse reaction (severe cutaneous adverse reaction)

Timepoint [5]

Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement

Secondary outcome [6]

[Safety Outcomes] Proportion of participants with non-immune mediated adverse event

Timepoint [6]

Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement

Secondary outcome [7]

[Safety Outcomes] Proportion of participants with RegiSCAR score of greater than or equal to 2

Timepoint [7]

Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement

Secondary outcome [8]

[Safety Outcomes] Proportion of participants with grade 3 or 4 adverse reactions as defined by World Allergy Organisation

Timepoint [8]

Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement

Secondary outcome [9]

[Safety Outcomes] Proportion of participants with any cutaneous adverse reactions

Timepoint [9]

Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement

Secondary outcome [10]

[Exploratory efficacy outcomes] Proportion of participants with c. difficile infection at 30-day, 90-day, 120-day follow up

Timepoint [10]

day 30, 90 and day 120 post-treatment commencement

Secondary outcome [11]

[Exploratory efficacy outcomes] Multidrug resistant infection at 30-day, 90-day, 120-day follow up as per protocol definitions

Timepoint [11]

day 30, 90 and day 120 post-treatment commencement

Secondary outcome [12]

[Exploratory efficacy outcomes] Multidrug resistant colonisation at 30-day, 90-day, 120-day follow-up

Timepoint [12]

day 30, day 90 and day 120 post-treatment commencement

Secondary outcome [13]

[Cost effectiveness outcome] Cost effectiveness analysis of prolonged vs single dose oral challenge

Timepoint [13]

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]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [3]

Royal Melbourne Hospital - Royal Park campus - Parkville

Recruitment hospital [4]

St George Private Hospital - Kogarah

Recruitment hospital [5]

Royal North Shore Hospital - St Leonards

Recruitment hospital [6]

Royal Brisbane & Womens Hospital - Herston

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3000 - Melbourne

Recruitment postcode(s) [3]

3052 - Parkville

Recruitment postcode(s) [4]

2217 - Kogarah

Recruitment postcode(s) [5]

2065 - St Leonards

Recruitment postcode(s) [6]

4029 - Herston

Recruitment outside Australia

Country [1]

Canada

State/province [1]

Country [2]

South Africa

State/province [2]

Country [3]

Denmark

State/province [3]

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Address [1]

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Submitted, not yet approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

https://www.austin.org.au/Office-for-Research/

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

09/08/2024

Approval date [1]

Ethics approval number [1]

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

Prof Jason Trubiano

Address

Austin Health, 145 Studley Road Heidelberg, VIC 3084

Country

Australia

Phone

+61 394966676

Fax

Email

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

Email

jason.trubiano@austin.org.au

Contact person for scientific queries

Name

Jason Trubiano

Address

Austin Health, 145 Studley Road Heidelberg, VIC 3084

Country

Australia

Phone

+61 394966676

Fax

Email

jason.trubiano@austin.org.au

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.