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Trial registered on ANZCTR


Registration number
ACTRN12619000029190
Ethics application status
Approved
Date submitted
19/12/2018
Date registered
11/01/2019
Date last updated
13/12/2019
Date data sharing statement initially provided
11/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Safely Preventing Errors and Complications due to Inappropriate Allergy Labelling: The SPECIAL Study - The Adult Arm.
Scientific title
Safely Preventing Errors and Complications due to Inappropriate Allergy Labelling in Adults with a self-reported drug allergy using a drug challenge to confirm or refute allergy label: The SPECIAL Study - Adult Arm
Secondary ID [1] 296891 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SPECIAL ADULT ARM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Antibiotic allergy 310832 0
Condition category
Condition code
Inflammatory and Immune System 309508 309508 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Based on their allergy history, patients (N=768) will be randomised to receive a drug challenge (oral or IV) +/- skin testing (ARM 1), OR receive usual standard of in-patient care (control group, ARM 2). After discharge, both groups will be followed up for one year to record use of antibiotics, clinical events and the need for medical care. At the end of this period, patients who had been randomised to the control group will be offered the drug provocation testing following specialist assessment.
The antibiotic allergy testing will be either an oral or intravenous challenge, with or without skin testing to be carried out in the hospital (inpatient) setting, under specialist guidance, where emergency equipment and medications are accessible and potential anaphylaxis can be treated. Management algorithms and the need for determination of a pre-test probability of IgE-mediated antibiotic allergy will be assessed against the clinical history of the patient. Skin testing will be carried out once in patients with a history that is suggestive of an IgE-mediated skin reaction (estimated to be approximately 40% of patients recruited).
Skin Testing (Skin prick test and intradermal): The skin testing procedure for each participant will be carried out by a trained and qualified nurse. The Australasian Society of Clinical Immunology and Allergy (ASCIA) Manual for skin prick testing for the diagnosis of allergic disease: A manual for practitioners (March, 2016) describes the standard methodology for skin prick testing, and these recommendations will be followed. Departmental guidelines for routine clinical intradermal testing will be followed. Generally the most convenient and frequently used sites for skin testing are either the volar surface of the forearm, the outer upper arm or the back.
The antibiotic challenge for people with a beta-lactam allergy label and history suggestive of an IgE mediated reaction, will involve the skin prick test followed by an intradermal skin test against the minor and major determinant of penicillins, benzylpenicillin, amoxicillin, ampicillin and the culprit antibiotic if different, followed by a two-dose oral antibiotic challenge. We will challenge with the culprit antibiotic, if it is known, and for patients with an unspecified penicillin allergy we will use amoxicillin. For the assessment of other antibiotic types (sulphonamides, macrolides or quinolones) no skin testing will be performed as it is less validated for these antibiotics, and 2-stage oral challenges will be performed instead. The hospital pharmacy (ies) will provide the solutions for skin testing. On the designated testing day, the study nurse will carry out the skin testing and/or oral provocation or IV challenge according to the medication orders from the study doctor whcih will be documented on the patient’s PBS Hospital Medication Chart.
If an IV challenge is proposed the study doctor will cannulate the patient and administer the intravenous doses. In cases of unspecified ‘penicillin’ or ‘beta-lactam’ allergy, participants will be assessed with an amoxicillin challenge (a commonly used penicillin-antibiotic in the community). Oral challenges will be performed in 2-stages (10% followed by the rest of the dose); IV challenges will be performed as 3-dose challenges (1%, 10%, followed by the rest of the dose). The study nurse will record observations for 20-30 minutes following the challenge, thereafter ward nurses will be responsible for recording patient observations for a further two hours after administration of the last dose of the challenge. Drug reactions will be managed following hospital protocols for managing anaphylaxis.
Post-discharge the patient will be contacted by the study nurse who will assess whether there is any delayed reaction or sequelae to the drug provocation. Thereafter, participants from both arms, will be followed up for one year by a clinical member of the research team who will ask them a series of questions concerning their clinical history since the last data collection. Questions will include: use of antibiotics, infections (including microbiological findings), GP and other primary care provider visits, readmission rates after discharge, presentation to ED, referrals and attendance at the Immunology/Allergy clinic.
Intervention code [1] 313168 0
Diagnosis / Prognosis
Comparator / control treatment
The control group (Arm 2) will not receive the in-patient antibiotic allergy testing but will be followed up post-discharge at 3-month intervals in an identical manner to that of Arm 1. Questions will include: use of antibiotics, infections (including microbiological findings), GP and other primary care provider visits, readmission to hospital, presentation to ED, referrals and attendance at the Immunology/Allergy clinic. At the end of the study follow-up period of one year, they will attend a specialist appointment in the outpatient Immunology/Allergy clinic and, following assessment, offered the antibiotic provocation testing to confirm or refute the allergy label.
Control group
Active

Outcomes
Primary outcome [1] 318621 0
Six-month hospital readmission rate as assessed by data from hospital admission records.
Timepoint [1] 318621 0
Six-months following antibiotic allergy testing to one year later.
Primary outcome [2] 318622 0
Number of days spent in hospital (length of stay) as assessed by data from hospital admission records.
Timepoint [2] 318622 0
Six-months following antibiotic allergy testing to one year later.
Primary outcome [3] 318623 0
Economic viability.

Assessed by costs associated with in-patient testing accessed from Hospital Finance Departments.
Assessed by costs associated with prescriptions for antibiotics, morbidity from infections, GP and pathology services. Sources will be PBS and Medicare Schedules.
Timepoint [3] 318623 0
Six-months following antibiotic allergy testing to one year later.
Secondary outcome [1] 355040 0
Antibiotic options available as assessed from patient records following clinical assessment and information given by participant during the follow-up phase of the study.
Timepoint [1] 355040 0
Assessed from the day of challenge, every three months up to one year after the testing date.

Eligibility
Key inclusion criteria
Patients (male or female), 16 years and above, presenting as medical or surgical inpatients with a self-reported allergy to beta lactam and/or sulphonamide antibiotics. Clinical examination will determine whether the patient with a disease state, for example a chronic medical condition, is well enough to undergo allergy testing. Any acute condition that necessitated admission will be resolved before allergy testing.

Self-reported Antibiotic Allergy Label (AAL)
Allergy to any beta-lactam, or allergy to any beta lactam and/or an allergy to one of the following: sulphonamide, macrolide or quinolone antibiotic
Reported reaction to an intravenous or oral antibiotic
Age >16 years
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants unable to give written informed consent
A history of severe cutaneous adverse reactions
Type II-IV reactions according to the ASCIA Criteria: 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, Drug-induced liver injury (DILI).
Participants with clinically established intolerances or allergy to an antibiotic.
Females who are pregnant
Antihistamine intake within 2 days prior to the scheduled challenge (including medications whose primary use is not as antihistamine but which are known to interact with histamine receptors). Daily antihistamine intake required for management of chronic disease, e.g. chronic idiopathic urticaria.
Immunosuppressive treatment at the time of testing
Patients on beta-blocker medication
A relevant medical contraindication to testing

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed and allocation will involve contacting the holder of the allocation schedule who will be at the central administration site.
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
Participants are randomised to ARM 1 and receive the intervention or ARM 2 who receive usual care. Follow-up observations on use of medical care, antibiotics and clinical events such as infections will be done on both groups.
Phase
Not Applicable
Type of endpoint/s
Safety/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, whether patients are admitted to the Intensive Care Unit (ICU) or die within the one-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 delabelling 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 participant age, gender, site location, whether the participant was on antibiotics and medical specialty. 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. Statistical monitoring of the data completeness, data variance, and risk-appropriate endpoint rates will be undertaken for all participant data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/02/2019
Actual
23/07/2019
Date of last participant enrolment
Anticipated
31/12/2020
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
768
Accrual to date
18
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 12760 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 12761 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 25189 0
6009 - Nedlands
Recruitment postcode(s) [2] 25190 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 301463 0
Government body
Name [1] 301463 0
Government of Western Australia, Department of Health
Country [1] 301463 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Hospital Ave,
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 301154 0
Individual
Name [1] 301154 0
Prof Michaela Lucas
Address [1] 301154 0
Sir Charles Gairdner Hospital
Department of Immunology
Hospital Ave,
Nedlands
WA 6009
Country [1] 301154 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302197 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 302197 0
Ethics committee country [1] 302197 0
Australia
Date submitted for ethics approval [1] 302197 0
04/07/2018
Approval date [1] 302197 0
18/12/2018
Ethics approval number [1] 302197 0
RGS0000000844

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89446 0
Prof Michaela Lucas
Address 89446 0
Immunology Department
Sir Charles Gairdner Hospital
Verdun Street Nedlands, WA 6009
Country 89446 0
Australia
Phone 89446 0
+61 08 63834311
Fax 89446 0
Email 89446 0
Michaela.Lucas@health.wa.gov.au
Contact person for public queries
Name 89447 0
Michaela Lucas
Address 89447 0
Immunology Department
Sir Charles Gairdner Hospital
Verdun Street Nedlands, WA 6009
Country 89447 0
Australia
Phone 89447 0
+61 08 63834311
Fax 89447 0
Email 89447 0
Michaela.Lucas@health.wa.gov.au
Contact person for scientific queries
Name 89448 0
Michaela Lucas
Address 89448 0
Immunology Department
Sir Charles Gairdner Hospital
Verdun Street Nedlands, WA 6009
Country 89448 0
Australia
Phone 89448 0
+61 08 63834311
Fax 89448 0
Email 89448 0
Michaela.Lucas@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The individual participant data will contain medical information.


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.