Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624001002572p
Ethics application status
Not yet submitted
Date submitted
1/08/2024
Date registered
16/08/2024
Date last updated
16/08/2024
Date data sharing statement initially provided
16/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Increasing Rate Infusion System (IRIS) for drug provocation challenges
Scientific title
Comparative risk of non-linear versus linear infusion systems as drug provocation challenges in adult patients with suspected perioperative hypersensitivity.
Secondary ID [1] 312665 0
IRIS
Universal Trial Number (UTN)
U1111-1311-4360
Trial acronym
IRIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Perioperative hypersensitivity 334642 0
Condition category
Condition code
Inflammatory and Immune System 331222 331222 0 0
Allergies
Anaesthesiology 331223 331223 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
IRIS Protocol (Intervention Group):

Overview: The IRIS (Infusion Rate Increasing System) protocol is an innovative approach designed to reduce the total dose administered at the time a hypersensitivity reaction is recognized. This protocol uses a non-linear, exponentially increasing infusion rate, which gradually introduces the drug at a slower rate initially and accelerates as the infusion progresses.
Dose: Patients in this group will also receive 10% of the therapeutic dose of the drug being tested.
Infusion Rate and Duration: The 10% dose will be administered over the same period of 22 minutes, but the infusion rate will start slowly and increase exponentially as the infusion progresses. The initial rate is much lower than in the constant infusion method, with the rate increasing progressively over the 22-minute period.
Rationale: The IRIS protocol is designed to align with the log-normal distribution of hypersensitivity thresholds observed in the population. By starting with a very low infusion rate, the protocol aims to detect hypersensitivity reactions at lower doses. This method seeks to minimize the amount of drug delivered during the latency period (the time between reaching the reaction threshold and the onset of symptoms).
IRIS is used to administer the drug provocation challenge, as a non-linear intravenous infusion of 10% of the therapeutic dose of the suspected allergen (most commonly cephazolin or a neuromuscular blocking agent) in 50mL of solution over 22 minutes. The protocol will be administered by a non-blinded researcher, but the patient and staff monitoring the patient and collecting data will be blinded.
Intervention code [1] 329193 0
Diagnosis / Prognosis
Intervention code [2] 329244 0
Treatment: Devices
Comparator / control treatment
Standard Constant Infusion Protocol (Control Group):

Overview: The standard constant infusion protocol is the current standard of care for drug provocation testing in perioperative settings. This method involves administering a fixed, constant rate infusion of the drug to the patient over a predetermined period of time.
Dose: Patients in this group will receive 10% of the therapeutic dose of the drug being tested.
Infusion Rate and Duration: The 10% dose will be administered as a constant infusion over a period of 22 minutes. The infusion rate remains steady throughout the duration of the test.
Rationale: The constant infusion method is designed to gradually introduce the drug to the patient in a controlled manner, allowing clinicians to monitor for signs of hypersensitivity. The dose is capped at 10% to minimize the risk of triggering a severe reaction while still allowing the detection of hypersensitivity.
Control group
Dose comparison

Outcomes
Primary outcome [1] 338998 0
Primary Outcome:

Total Dose Administered at Reaction Recognition:
The primary outcome of this study is the total dose of the drug administered at the time a hypersensitivity reaction is recognized.
Timepoint [1] 338998 0
Time of Reaction Recognition:
The primary timepoint is the exact moment when a hypersensitivity reaction is identified during the infusion. This timepoint varies for each participant, depending on when the reaction occurs during the 22-minute infusion period. The assessment is focused on capturing the dose administered at this specific time to compare outcomes between the two intervention groups.
Secondary outcome [1] 438209 0
Severity of Hypersensitivity Reaction:
The secondary outcomes include the severity of the hypersensitivity reaction, which is graded on a standardized scale.
Timepoint [1] 438209 0
Primary Timepoint:
Severity:
The severity will be assessed at the time the reaction is recognized and continues to be evaluated until the reaction subsides. The peak severity grade will be recorded as the primary data point for this outcome.
Secondary outcome [2] 438459 0
Duration of the reaction following the onset of symptoms.
Timepoint [2] 438459 0
Duration:
The duration of the reaction will be assessed from the time of reaction onset until all symptoms have resolved. The total time from symptom onset to resolution will be recorded, with ongoing monitoring ensuring accurate timing.

Eligibility
Key inclusion criteria
Key Inclusion Criteria:

Adult Patients:
Participants must be adults (18 years and older).
Referral for Drug Provocation Testing:
Patients must be referred for drug provocation testing (DPT) due to suspected perioperative drug hypersensitivity.
Negative or Inconclusive Prior Diagnostic Tests:
Participants should have undergone prior diagnostic tests (such as skin tests or basophil activation tests) that have returned negative or inconclusive results, indicating the need for further testing through DPT.
Capacity to Consent:
Participants must be able to provide informed consent, understanding the nature and potential risks of the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Key Exclusion Criteria:

Known Hypersensitivity to Tested Drug:
Patients with a confirmed hypersensitivity or allergy to the specific drug being tested will be excluded, as the study focuses on those with suspected false-negative results.
Severe Comorbidities:
Participants with severe comorbid conditions (such as uncontrolled cardiovascular disease, severe asthma, or other conditions that could increase the risk of participating in the study) will be excluded to ensure patient safety.
Pregnancy or Breastfeeding:
Pregnant or breastfeeding women will be excluded from the study due to the potential risks to the fetus or infant.
Recent Anaphylaxis:
Patients who have experienced a recent anaphylactic reaction (within the last 6 weeks) may be excluded to prevent potential complications related to residual sensitivity.
Inability to Comply with Study Protocol:
Patients who are unable to comply with the study protocol, including follow-up visits and procedures, will be excluded to ensure the integrity of the study data.

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 Concealment:

To ensure allocation concealment, the study will implement a robust randomization process where the allocation sequence is concealed from both the participants and the researchers involved in patient recruitment and treatment administration.

Process: The randomization sequence will be generated by an independent statistician using computer-generated random numbers. The allocation sequence will be securely stored and managed by a third party, separate from the clinical team conducting the trial.
Blinding: The allocation will be revealed only after the participant has been enrolled and baseline data has been collected. The participant’s group assignment will be kept in sealed, opaque envelopes, or managed through an automated system that ensures no access until the point of allocation.
Maintaining Concealment: All investigators, clinical staff, and participants will remain blinded to the allocation until the intervention has been assigned and administered, thus preventing any potential bias in treatment assignment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence Generation:

The sequence generation for randomization will be conducted using a rigorous and unbiased method to ensure equal and fair allocation of participants to each study arm.

Method: The randomization sequence will be created using a computerized random number generator, employing block randomization to ensure an even distribution of participants across the two groups (Control and IRIS Protocol).
Stratification: If necessary, stratification will be applied based on key variables (e.g., type of drug being tested or patient characteristics) to ensure that these variables are evenly distributed across the intervention and control groups.
Independence: The sequence generation process will be overseen by an independent statistician who is not involved in the recruitment, allocation, or data collection phases of the trial, ensuring the integrity and randomness of the allocation sequence.
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
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Primary Outcome: Total Dose Administered at Reaction Recognition

Descriptive Statistics:
The total dose administered at the time of reaction recognition will be summarized using descriptive statistics, including mean, median, standard deviation, interquartile range, and range for each group (control and IRIS protocol).
Comparative Analysis:
The primary outcome will be analyzed using the Mann-Whitney U test, a non-parametric test used for comparing differences between two independent groups. This test is chosen because the total dose administered is expected to be non-normally distributed.
If the data meets the assumptions of normality, an independent t-test may be used as an alternative. However, given the nature of the outcome, the Mann-Whitney U test is expected to be more appropriate.
Secondary Outcomes: Severity and Duration of Hypersensitivity Reactions

Severity:
Severity of the reaction will be assessed using a standardized grading scale (e.g., Grade 1 to Grade 4).
Severity scores, as ordinal data, will be analyzed using the Mann-Whitney U test to compare the distribution of severity grades between the two groups.
Duration:
The duration of hypersensitivity reactions will be recorded from the onset of symptoms until the resolution of all clinical signs.
If the duration data is normally distributed, an independent t-test will be used to compare the mean duration between the two groups.
If the duration data is not normally distributed, the Mann-Whitney U test will be applied instead.
Safety Analysis:

Adverse Events:
The occurrence and type of adverse events will be summarized descriptively, with the number and percentage of participants experiencing adverse events reported for each group.
Adverse events will be compared between the groups using chi-square tests or Fisher’s exact tests (depending on the expected cell counts) to determine if there is a significant difference in the incidence of adverse events between the two study arms.
Sample Size and Power Calculation:

Sample Size:
The sample size will be calculated based on the expected difference in the total dose administered between the control and IRIS groups, with the power to detect a clinically meaningful difference set at 80% and a significance level (alpha) of 0.05.
Power Analysis:
The power analysis will take into account the variability observed in pilot data or previous studies to ensure the study is adequately powered to detect differences in the primary and secondary outcomes.
Missing Data Handling:

Missing Data:
Missing data will be handled using appropriate statistical methods, such as multiple imputation or sensitivity analyses, to assess the impact of missing data on the study’s conclusions.
The extent and nature of any missing data will be reported, and analyses will be conducted both with and without imputed data to ensure robustness.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2025
Actual
Date of last participant enrolment
Anticipated
1/12/2026
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 26895 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 42955 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 317102 0
Hospital
Name [1] 317102 0
Sir Charles Gairdner Hospital
Country [1] 317102 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Country
Australia
Secondary sponsor category [1] 319359 0
None
Name [1] 319359 0
Address [1] 319359 0
Country [1] 319359 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 315851 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 315851 0
Ethics committee country [1] 315851 0
Australia
Date submitted for ethics approval [1] 315851 0
30/08/2024
Approval date [1] 315851 0
Ethics approval number [1] 315851 0

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

Contacts
Principal investigator
Name 135990 0
Dr Paul Sadleir
Address 135990 0
Sadleir Laboratories, PO Box 305, Cottesloe 6911, Western Australia
Country 135990 0
Australia
Phone 135990 0
+61 8 64573011
Fax 135990 0
Email 135990 0
paul.sadleir@uwa.edu.au
Contact person for public queries
Name 135991 0
Paul Sadleir
Address 135991 0
Sadleir Laboratories, PO Box 305, Cottesloe 6911, Western Australia
Country 135991 0
Australia
Phone 135991 0
+61 8 64573011
Fax 135991 0
Email 135991 0
paul.sadleir@uwa.edu.au
Contact person for scientific queries
Name 135992 0
Paul Sadleir
Address 135992 0
Sadleir Laboratories, PO Box 305, Cottesloe 6911, Western Australia
Country 135992 0
Australia
Phone 135992 0
+61 8 64573011
Fax 135992 0
Email 135992 0
paul.sadleir@uwa.edu.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.