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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
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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
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Secondary ID [1]
312619
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None
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Universal Trial Number (UTN)
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Trial acronym
PROSPECTOR-2
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Linked study record
This study is a follow up study to: ACTRN12623001242617
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Health condition
Health condition(s) or problem(s) studied:
allergies
334552
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adverse drug reaction
334553
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Penicillin allergy
334554
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Delayed hypersensitivity
334555
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Condition category
Condition code
Inflammatory and Immune System
331160
331160
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0
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Allergies
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Intervention/exposure
Study type
Interventional
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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
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Intervention code [1]
329130
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Diagnosis / Prognosis
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Comparator / control treatment
5 day placebo (in microcrystalline cellulose capsule) oral challenge (twice daily dosing).
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Control group
Placebo
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Outcomes
Primary outcome [1]
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Positive oral challenge (immune mediated reaction) within 7 days post first test dose
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Assessment method [1]
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Total number and % of participants with confirmed immune mediated reaction as adjudicated by independent blinded panel
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Timepoint [1]
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Day 1, 5 and 7 post-treatment commencement
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Secondary outcome [1]
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Positive oral challenge (immune mediated reaction) within 14 days post first test dose
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Assessment method [1]
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Total number and % of participants with confirmed immune mediated reactions post-first dose as adjudicated by independent blinded panel
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Timepoint [1]
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Day 1, 5, 7 and 14 post-treatment commencement
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Secondary outcome [2]
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Time to positive oral challenge
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Assessment method [2]
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) review by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [2]
437911
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Day 1, Day 5, Day 7, Day 14 post-treatment commencement
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Secondary outcome [3]
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Quality of life
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Assessment method [3]
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Drug Hypersensitivity Quality of Life Questionnaire (DrHy-Q)
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Timepoint [3]
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Day 0 and Day 90 post-treatment commencement
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Secondary outcome [4]
437913
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[Safety Outcomes] Proportion of participants with immediate severe adverse reaction (anaphylaxis or death)
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Assessment method [4]
437913
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) and email (Day 30) review by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [4]
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Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
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Secondary outcome [5]
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[Safety Outcomes] Proportion of participants with delayed adverse reaction (severe cutaneous adverse reaction)
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Assessment method [5]
437914
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) and email (Day 30) review by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events, including delayed severe cutaneous adverse reaction. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [5]
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Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
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Secondary outcome [6]
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[Safety Outcomes] Proportion of participants with non-immune mediated adverse event
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Assessment method [6]
437915
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) and email (Day 30) by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [6]
437915
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Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
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Secondary outcome [7]
437916
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[Safety Outcomes] Proportion of participants with RegiSCAR score of greater than or equal to 2
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Assessment method [7]
437916
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) and email (Day 30) review by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events, including assessment of RegiSCAR score if necessary. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [7]
437916
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Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
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Secondary outcome [8]
437917
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[Safety Outcomes] Proportion of participants with grade 3 or 4 adverse reactions as defined by World Allergy Organisation
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Assessment method [8]
437917
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) and email (Day 30) review by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events, including grade 3 or 4 adverse reactions as defined by World Allergy Organisation. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [8]
437917
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Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
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Secondary outcome [9]
437918
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[Safety Outcomes] Proportion of participants with any cutaneous adverse reactions
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Assessment method [9]
437918
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Follow up questionnaire by telephone/inpatient (day 1, 5, 7 and 14) and email (Day 30) review by the study investigator/research coordinator at a specified timepoint. The questionnaire is designed specifically for this study and will assess compliance to the study medication and if patient experience any adverse events, including any cutaneous adverse reactions. Independent panel will determine if the adverse event is immune-mediated and if it is related to the study intervention.
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Timepoint [9]
437918
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Day 1, Day 5, Day 7, Day 14 and Day 30 post-treatment commencement
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Secondary outcome [10]
437919
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[Exploratory efficacy outcomes] Proportion of participants with c. difficile infection at 30-day, 90-day, 120-day follow up
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Assessment method [10]
437919
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Proportion of participants with c.difficile infection will be assessed by study-specific day 30, day 90 and day 120 follow up questionnaire
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Timepoint [10]
437919
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day 30, 90 and day 120 post-treatment commencement
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Secondary outcome [11]
437920
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[Exploratory efficacy outcomes] Multidrug resistant infection at 30-day, 90-day, 120-day follow up as per protocol definitions
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Assessment method [11]
437920
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Proportion of participants with multidrug resistant infection will be assessed by study-specific day 30, day 90 and day 120 follow up questionnaire
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Timepoint [11]
437920
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day 30, 90 and day 120 post-treatment commencement
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Secondary outcome [12]
437921
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[Exploratory efficacy outcomes] Multidrug resistant colonisation at 30-day, 90-day, 120-day follow-up
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Assessment method [12]
437921
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Proportion of participants with multidrug resistant colonisation will be assessed by study-specific day 30, day 90 and day 120 follow up questionnaire
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Timepoint [12]
437921
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day 30, day 90 and day 120 post-treatment commencement
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Secondary outcome [13]
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[Cost effectiveness outcome] Cost effectiveness analysis of prolonged vs single dose oral challenge
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Assessment method [13]
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Cost effectiveness health economic analysis determined by resource use and costs from hospital medical records
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Timepoint [13]
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up to 120 days post-treatment commencement
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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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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)
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Study design
Purpose of the study
Diagnosis
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Allocation to intervention
Randomised controlled trial
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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.
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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).
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Masking / blinding
Blinded (masking used)
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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
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
Safety
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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.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
4/11/2024
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Actual
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Date of last participant enrolment
Anticipated
27/11/2026
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Actual
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Date of last data collection
Anticipated
26/03/2027
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Actual
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Sample size
Target
830
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
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Recruitment hospital [1]
26856
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Austin Health - Austin Hospital - Heidelberg
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Recruitment hospital [2]
26857
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [3]
26859
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Royal Melbourne Hospital - Royal Park campus - Parkville
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Recruitment hospital [4]
26860
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St George Private Hospital - Kogarah
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Recruitment hospital [5]
26861
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Royal North Shore Hospital - St Leonards
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Recruitment hospital [6]
26862
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Royal Brisbane & Womens Hospital - Herston
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Recruitment postcode(s) [1]
42917
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3084 - Heidelberg
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Recruitment postcode(s) [2]
42918
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3000 - Melbourne
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Recruitment postcode(s) [3]
42920
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3052 - Parkville
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Recruitment postcode(s) [4]
42921
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2217 - Kogarah
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Recruitment postcode(s) [5]
42922
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2065 - St Leonards
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Recruitment postcode(s) [6]
42923
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4029 - Herston
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Recruitment outside Australia
Country [1]
26460
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Canada
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State/province [1]
26460
0
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Country [2]
26461
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South Africa
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State/province [2]
26461
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Country [3]
26462
0
Denmark
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State/province [3]
26462
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Funding & Sponsors
Funding source category [1]
317050
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Hospital
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Name [1]
317050
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Austin Health
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Address [1]
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Country [1]
317050
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Australia
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Primary sponsor type
Hospital
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Name
Austin Health
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Address
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Country
Australia
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Secondary sponsor category [1]
319297
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None
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Name [1]
319297
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Address [1]
319297
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Country [1]
319297
0
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Ethics approval
Ethics application status
Submitted, not yet approved
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Ethics committee name [1]
315803
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Austin Health Human Research Ethics Committee
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Ethics committee address [1]
315803
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https://www.austin.org.au/Office-for-Research/
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Ethics committee country [1]
315803
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Australia
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Date submitted for ethics approval [1]
315803
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09/08/2024
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Approval date [1]
315803
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Ethics approval number [1]
315803
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Jason Trubiano
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Address
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Austin Health, 145 Studley Road Heidelberg, VIC 3084
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Country
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Australia
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Phone
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+61 394966676
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
135851
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Jason Trubiano
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Address
135851
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Austin Health, 145 Studley Road Heidelberg, VIC 3084
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Country
135851
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Australia
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Phone
135851
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+61 394966676
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Fax
135851
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Email
135851
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[email protected]
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Contact person for scientific queries
Name
135852
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Jason Trubiano
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Address
135852
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Austin Health, 145 Studley Road Heidelberg, VIC 3084
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Country
135852
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Australia
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Phone
135852
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+61 394966676
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Fax
135852
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Email
135852
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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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.
Download to PDF