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Trial registered on ANZCTR


Registration number
ACTRN12618000788279
Ethics application status
Approved
Date submitted
22/03/2018
Date registered
9/05/2018
Date last updated
11/09/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Safely Preventing Errors and Complications in children due to Inappropriate Allergy Labelling by undergoing antibiotic allergy testing in order to confirm or de-label the antibiotic allergy label.
Scientific title
Safely Preventing Errors and Complications in children aged 6 months to 16 years due to Inappropriate Antibiotic Allergy Labelling by safely completing an antibiotic provocation challenge to confirm or deny the label.
(The SPECIAL Study – The Paediatric Arm)
Secondary ID [1] 294426 0
None
Universal Trial Number (UTN)
Trial acronym
SPECIAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Antibiotic Allergy 307173 0
Condition category
Condition code
Inflammatory and Immune System 306289 306289 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Paediatric study subjects will be randomised to receive outpatient de-labelling/verification assessment after referral to the study team (Group 1P) or usual care, which does not include antibiotic allergy label assessment (Group 2P).
In detail, the patients in Group 1P will participate in the assessment arm of the study with the objective of the unequivocal clarification of antibiotic allergy status. Clinical history taking will be completed allowing a detailed de-labelling plan to be formulated (type of assessment, type of antibiotic and route e.g. oral or intravenous).
All participants will be challenged to the culprit antibiotic to which they report an antibiotic allergy to.
Oral provocation challenge (where applicable) for paediatric study subjects, will be performed as a 2-stage oral provocation challenge (1/10 dose followed by 90% of the recommended dose calculated based on weight and age) or a 3-stage intravenous provocation challenge (1/100 dose followed by 1/10, followed by the remainder of the daily single dose calculated based on weight and age). An intravenous provocation challenge will only be performed in those subjects where the culprit antibiotic is known to be an intravenous antibiotic; based on our preliminary data the rate of intravenous antibiotic allergy is approximately 2% for children and 30% for adults. Doses will be given 30 minutes apart with a 1-hour observation of the patient to follow. On the testing challenge day, an experienced Immunology consultant will be present at each site in addition to the emergency response team within the hospital. In cases of unspecified ‘penicillin’ or ‘beta-lactam’ allergy patients, they will be challenged against amoxicillin (a commonly used penicillin-antibiotic in the community). Paediatric challenges will be performed in the hospital outpatient/day-stay setting. Management of reactions (including anaphylaxis) will be available at all challenge areas. If the patient does not react they will be given a five day course of the culprit/testing antibiotic to take home, together with an information sheet detailing signs of delayed reaction, how to manage them and who to contact if such a reaction occurs. All participants will receive multiple follow up calls while on the 5 day course of antibiotics to ensure compliance with taking the medication and in case of any reactions.
Intervention code [1] 300721 0
Diagnosis / Prognosis
Comparator / control treatment
Group 2P will undergo no antibiotic allergy testing/challenge. They will simply be followed up for normal care.
Control group
Active

Outcomes
Primary outcome [1] 305292 0
Choices of antibiotics available to participants after they have been de-labelled of their antibiotic allergy.

Assessed by follow up phone calls which will include a detailed history of all medical events, appointments, antibiotic prescriptions and hospital admissions,
Timepoint [1] 305292 0
Assessed from the day of challenge up to 2 years.
Primary outcome [2] 305423 0
Number of visits to the GP for participants who have been successfully de-labelled of their antibiotic allergy compared to participants who's allergy has been confirmed.

Assessed by follow up phone calls which will include a detailed history of all medical events, appointments, antibiotic prescriptions and hospital admissions,
Timepoint [2] 305423 0
Assessed from the day of challenge up to 2 years.
Primary outcome [3] 305424 0
To assess if length of stay in hospitals is affected by de-labelling or confirming an antibiotic allergy.

Assessed by follow up phone calls which will include a detailed history of all medical events, appointments, antibiotic prescriptions and hospital admissions,
Timepoint [3] 305424 0
Assessed from the day of challenge up to 2 years.
Secondary outcome [1] 344755 0
To assess if this antibiotic allergy de-labelling approach is cost effective.

Net cost-effectiveness will compare costs of intervention and savings due to reduced resource demand due to health outcomes (benefits) as detailed in the primary outcomes (including choices of antibiotics available to participant, number of visits to GPs, lenght of stay of any hospital admissions). Information on costs will be drawn from standard government sources.
Timepoint [1] 344755 0
Assessed from the day of challenge up to 2 years.
Secondary outcome [2] 345772 0
To assess if there is a difference in hospital readmission rates in participants who have been de-labelled from their antibiotic allergy compared to those that have had confirmation of their antibiotic allergy.

Assessed by follow up phone calls which will include a detailed history of all medical events, appointments, antibiotic prescriptions and hospital admissions,
Timepoint [2] 345772 0
Time of challenge to 2 years after.

Eligibility
Key inclusion criteria
Children and young adults, male or female, aged 6 months to 16 years of age (inclusive) who have a self-reported antibiotic allergy who are willing and available for the 2 year follow up in Western Australia.
Minimum age
6 Months
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Females who are pregnant (Pregnancy tests will be offered to sexually active females and can be performed on the day of challenge)
>Families with the inability to give informed consent based on language barriers
>Severe cutaneous adverse reactions
>Type II-IV allergies (Serum sickness, Stevens-Johnson Syndrome (SJS), Toxic epidermal necrolysis (TEN), Acute interstitial nephritis (AIN), Drug rash eosinophilia syndrome (DRESS), Acute generalised Exanthematous Pustulosis (AGEP), Haemolytic anaemia)

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)
Study allocation will remain concealed in an opaque envelope until patient is enrolled.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated block-randomisation will be performed for the study.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Initially, differences between those that remain labelled and those de-labelled in the utilisation of antibiotics in the community, type and cause of infections in the community (including microbiological findings, especially infections with multi-resistant bacteria), GP and other primary care provider visits, presentations to ED, details about hospital admissions in regards to length of stay, intensive care admissions, readmission rates after discharge, details of antibiotics use in hospital, infection rates, type and cause of infections (including microbiological findings), referrals to allergy clinics and mortality will be assessed using chi-squared tests whilst differences in the time to readmission will be examined using Kaplan Meier curves and log rank tests and length of stay outcomes will be analysed compared using Mann-Whitney non-parametric tests.
Subsequently, supporting analyses using binary logistic regression will be used to analyse the effect of antibiotic allergy de-labelling on whether patients are readmitted to hospital (adults and children), whether patients are admitted to the Intensive Care Unit (ICU) or die within the two-year follow-up, whether patients suffered an infection or were referred to an allergy clinic and whether patients are prescribed specific antibiotics (event=Yes for all analyses). Odds ratios, 95% confidence intervals and P-values will be calculated.
Cox proportional hazards regression for competing risks will be used to analyse the effect of antibiotic allergy de-labelling on the time to readmission (event=readmission), where death will be treated as a competing risk. Cumulative incidence curves will be generated and hazard ratios, 95% confidence intervals and P-values will be calculated.
Linear regression will be used to analyse the effect of antibiotic allergy de-labelling on the number of days spent in hospital (excluding initial admission). Appropriate transformations will be performed to ensure model assumptions are met. Coefficient estimates standard error of the estimates and P-values will be calculated.
Multivariate analysis will be conducted for all above models to adjust for possible confounding variables such as patient age, gender, site location, whether the patient was on antibiotics and medical speciality. For all multivariate analyses, model selection will be conducted where variables significant at the 5% level will be retained for the final models. Data will be analysed using the R environment for statistical computing 17.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10449 0
Perth Children's Hospital - Nedlands
Recruitment hospital [2] 10450 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 22158 0
6009 - Nedlands
Recruitment postcode(s) [2] 22159 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 299057 0
Charities/Societies/Foundations
Name [1] 299057 0
Perth Children's Hospital Foundation
Address [1] 299057 0
15 Hospital Ave,
Nedlands
WA 6009
Country [1] 299057 0
Australia
Primary sponsor type
Hospital
Name
Perth Children's Hospital
Address
15 Hospital Ave,
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 298292 0
Individual
Name [1] 298292 0
A/Prof Michaela Lucas
Address [1] 298292 0
Department of Immunology,
Perth Children's Hospital,
15 Hospital Ave,
Nedlands
WA 6009
Country [1] 298292 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299990 0
Children and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 299990 0
Princess Margaret Hospital
Roberts Road
Subiaco
WA 6008
Ethics committee country [1] 299990 0
Australia
Date submitted for ethics approval [1] 299990 0
20/06/2017
Approval date [1] 299990 0
19/12/2017
Ethics approval number [1] 299990 0
RGS0000000401

Summary
Brief summary
A fifth of Australian hospital patients self-report an allergy to antibiotics (“antibiotic allergy label”, AAL) which interferes with their optimal clinical care.
There is strong evidence that unverified antibiotic allergy labelling is a substantial and growing public health problem resulting in:
• Significant adverse patient outcomes
• Increased health economic burden
• Suboptimal choice of antibiotic, leading to the overuse of broad spectrum antibiotics and the emergence of microbial antibiotic resistance.
International studies suggest that the majority (>90%) of subjects with AAL can safely use antibiotics without restrictions following a clinical assessment (“de-labelling”). Thus, unverified AAL is mostly inaccurate and its associated negative consequences are potentially avoidable. There is currently no effective clinical strategy developed that addresses the high national incidence of AAL in Australia.
This study aims to develop a new model of care for paediatric patients with current AAL and to improve management of antibiotic therapy in our hospitals and community.
A large randomised prospective study design allows for the analysis of key clinical outcomes for all study participants, with regards to details about GP and hospital visits, infection history, subsequent antibiotics usage and mortality, and compares patients which have been actively de-labelled against those receiving current standard care.
This project will also calculate the true health economic cost impact of de-labelling patients at a population level, compared to standard clinical care.
We hypothesise that a systematic approach to antibiotic allergy de-labelling patients with AAL will lead to a national improvement in clinical care characterised by both better long-term health outcomes and cost savings to the health budget.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82186 0
A/Prof Michaela Lucas
Address 82186 0
Department of Immunology
Perth Children's Hospital
15 Hospital Ave,
Nedlands
WA 6009
Country 82186 0
Australia
Phone 82186 0
+61466553256
Fax 82186 0
Email 82186 0
michaela.lucas@health.wa.gov.au
Contact person for public queries
Name 82187 0
A/Prof Michaela Lucas
Address 82187 0
Department of Immunology
Perth Children's Hospital
15 Hospital Ave,
Nedlands
WA 6009
Country 82187 0
Australia
Phone 82187 0
+61466553256
Fax 82187 0
Email 82187 0
michaela.lucas@health.wa.gov.au
Contact person for scientific queries
Name 82188 0
A/Prof Michaela Lucas
Address 82188 0
Department of Immunology
Perth Children's Hospital
15 Hospital Ave,
Nedlands
WA 6009
Country 82188 0
Australia
Phone 82188 0
+61466553256
Fax 82188 0
Email 82188 0
michaela.lucas@health.wa.gov.au

No data has been provided for results reporting
Summary results
Not applicable