Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000036819
Ethics application status
Approved
Date submitted
16/11/2020
Date registered
18/01/2021
Date last updated
28/01/2024
Date data sharing statement initially provided
18/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparing albumin and saline for treatment of patients with severe infection in the Emergency Department: A randomised trial
Scientific title
Intervention with concentrated albumin for resuscitation of undifferentiated sepsis: A randomised controlled trial
Secondary ID [1] 302803 0
None
Universal Trial Number (UTN)
U1111-1261-2578
Trial acronym
ICARUS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
sepsis 319765 0
Condition category
Condition code
Emergency medicine 317700 317700 0 0
Resuscitation
Infection 317996 317996 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention group will receive 20% human serum albumin, infused intravenously at 100mL/hr over 4 hours, concurrently with standard crystalloid-based fluid therapy as deemed appropriate by the treating emergency team. Adherence to the intervention will be monitored using the patient medication chart.

Crystalloid fluid therapies will be administered to patients in both study arms according to evidence-based guidelines such as those disseminated by the Surviving Sepsis Campaign. Modern guidelines advocate discrete bolus fluid therapy (most clinicians utilise volumes of 500mL) with frequent reassessment, clinical examination and evaluation of available physiologic variables (heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output, and others, as available) as well as other non-invasive or invasive monitoring, as available.

Both crystalloid and albumin will be administered while the patient is in the Emergency Department. This time period is on average 4-6 hours. Crystalloid and albumin may also be provided throughout the hospital stay as required for standard care at the discretion of inpatient treating teams.

Intervention code [1] 319083 0
Treatment: Drugs
Comparator / control treatment
The standard care group will receive crystalloid solutions as required in accordance with standard care, and no albumin. The type of crystalloid fluid administered will be at the discretion of the treating clinician. Crystalloid fluid therapies will be administered to patients in both study arms according to evidence-based guidelines such as those disseminated by the Surviving Sepsis Campaign. Modern guidelines advocate discrete bolus fluid therapy (most clinicians utilise volumes of 500mL intravenously) with frequent reassessment, clinical examination and evaluation of available physiologic variables (heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output, and others, as available) as well as other non-invasive or invasive monitoring, as available.

Crystalloid will be administered while the patient is in the Emergency Department. This time period is on average 4-6 hours. Crystalloid may also be provided throughout the hospital stay as required standard care at the discretion of inpatient treating teams.
Control group
Active

Outcomes
Primary outcome [1] 325740 0
Systolic blood pressure obtained from the patient's medical records
Timepoint [1] 325740 0
24 hours after randomization
Secondary outcome [1] 388943 0
Number of patients enrolled in the study each month (feasibility outcome). Data will be obtained from the study database
Timepoint [1] 388943 0
The number of patients enrolled each month will be counted over the study period. This outcome will be monitored over the 12 month study period.
Secondary outcome [2] 388944 0
The proportion of patients who are eligible for this study (i.e., meet all inclusion criteria and no exclusion criteria) who are enrolled in the study (feasibility outcome). Data will be obtained from the study database
Timepoint [2] 388944 0
The proportion of patients enrolled will be assessed at the end of the study. This outcome will be assessed at the end of the 12 month study period
Secondary outcome [3] 388945 0
Protocol compliance, namely what proportion of patients were provided 20% albumin, infused at 100ml/hr over 4 hours. (Feasibility outcome) Data will be obtained from the patient's medical record.
Timepoint [3] 388945 0
4 hours post randomisation
Secondary outcome [4] 388946 0
Total fluid in mL (either crystalloid or albumin) administered within 72 hours, obtained from the patient's medical record
Timepoint [4] 388946 0
72 hours after randomisation
Secondary outcome [5] 388948 0
Requirement for vasoactive agents, defined as the use of noradrenaline, adrenaline, dobutamine or vasopressin. This outcome will be assessed using the patient's medical record
Timepoint [5] 388948 0
72 hours after randomisation.
Secondary outcome [6] 388949 0
Organ dysfunction, measured using the total sequential organ failure assessment (SOFA) score, modified for use in the emergency department. This score incorporates five components (respiratory, coagulation, liver, cardiovascular, and renal components), each scored 0 to 4. These scores are added up to create the total SOFA with higher scores indicating more severe organ dysfunction.
Timepoint [6] 388949 0
72 hours after randomisation
Secondary outcome [7] 388950 0
Intensive care unit admission, obtained from the hospital administrative database (HBCIS)
Timepoint [7] 388950 0
During the index presentation
Secondary outcome [8] 388951 0
Hospital length of stay (in days) assessed using the hospital administrative database (HBCIS)
Timepoint [8] 388951 0
During the index admission

Eligibility
Key inclusion criteria
Adult Emergency Department patients. >=18 years of age with:
1a) Systolic blood pressure (SBP) <90mmHg within 8 hours of triage OR
1b) Lactate < 4 mmol/L

AND

2) Proven or presumed infection. Patients with presumed infection will be those where the treating senior treating emergency physician deems infection the most likely cause for the patient presentation
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Jehovah’s Witness
2) Known adverse reaction to albumin administration
3) Terminal state - death seems imminent and inevitable
4) Pathological conditions in which albumin administration is clinically indicated (hepatic cirrhosis with ascites, intestinal malabsorption syndrome, nephrotic syndrome)
5) Acute congestive heart failure
6) Acute head injury
7) Inter-hospital transfer
8) Prior enrolment in the trial within the past 90 days

Patients must be enrolled as soon as possible, and within one hour of meeting inclusion criteria.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involves contacting the holder of the allocation schedule who is off-site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomisation sequence will be generated using R software. Permuted block randomisation with variable block sizes will be used
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
We anticipate enrolling 400 patients over a 2 year period. With a SD of 10 mm Hg for systolic blood pressure (SBP), a sample size of 200 provides >90% power to detect a mean difference of 5 mm Hg in SBP. This difference was deemed to be clinically significant.

The primary analyses will be conducted on an intention-to-treat basis. If the number of missing data are small (<5%) and random, missing data will be removed from the analyses. If there are more substantial missing data or data are not missing at random, analyses will be conducted in two ways 1) missing data removed from the analyses, and 2) missing data imputed using multiple imputation. The flow of patients through the study will be displayed in a CONSORT diagram that includes the number (%) of trial participants who meet the inclusion criteria, the number excluded, the number randomised, and the number analysed for the primary outcome.

A description of baseline characteristics of trial participants will be presented by treatment group. Discrete data will be presented as number and % of treatment group. Continuous data will either be presented as mean (standard deviation, SD) or median (interquartile range, IQR).

Data for the primary outcome (SBP at 24 hours) will be reported by treatment group as either mean (SD) or median (IQR). Our previous research has shown that SBP is relatively normally distributed in this cohort. As such, a t-test will compare SBP across the treatment groups and the difference between group means with 95% confidence interval of the difference will be reported. Mann-Whitney U may instead be utilised if the data do not meet the assumptions of the t-test. We also will compare SBP at 24 hours across treatment groups after adjustment for baseline SBP. The difference in adjusted SBP will be calculated using generalized estimating equations with the 95% CI calculated using a cluster bootstrap or cluster sandwich covariance estimator to correct the independence model for within subject correlation.


The secondary feasibility outcomes (number of patients enrolled each month, proportion of eligible patients enrolled and protocol compliance) will be reported as descriptive statistics. These outcomes will be reported for the overall study and by treatment group.

The secondary clinical and health services outcomes will also be reported by treatment group using standard descriptive statistics. For continuous data, such as total fluid administered at 72 hours, fluid balance at 72 hours, duration of vasopressors, total SOFA, and hospital length of stay, the difference between group means or group medians will be calculated with 95% confidence intervals of the difference. For categorical data, such as administration of vasopressors and ICU admission, the risk difference and risk ratio will be reported with 95% confidence intervals of the difference.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/01/2021
Actual
19/01/2021
Date of last participant enrolment
Anticipated
31/12/2022
Actual
31/08/2023
Date of last data collection
Anticipated
Actual
4/09/2023
Sample size
Target
400
Accrual to date
Final
463
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18035 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 32011 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 307230 0
Charities/Societies/Foundations
Name [1] 307230 0
Emergency Medicine Foundation
Country [1] 307230 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane and Women's Hospital
Address
Butterfield Street, Herston, QLD, 4029
Country
Australia
Secondary sponsor category [1] 307835 0
None
Name [1] 307835 0
Address [1] 307835 0
Country [1] 307835 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307326 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 307326 0
Ethics committee country [1] 307326 0
Australia
Date submitted for ethics approval [1] 307326 0
27/10/2020
Approval date [1] 307326 0
07/12/2020
Ethics approval number [1] 307326 0

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

Contacts
Principal investigator
Name 106842 0
Dr Julian Williams
Address 106842 0
Emergency and Trauma Centre
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD, 4029
Country 106842 0
Australia
Phone 106842 0
+61 7 3646 7901
Fax 106842 0
Email 106842 0
[email protected]
Contact person for public queries
Name 106843 0
Julian Williams
Address 106843 0
Emergency and Trauma Centre
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD, 4029
Country 106843 0
Australia
Phone 106843 0
+61 7 3646 7901
Fax 106843 0
Email 106843 0
[email protected]
Contact person for scientific queries
Name 106844 0
Julian Williams
Address 106844 0
Emergency and Trauma Centre
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD, 4029
Country 106844 0
Australia
Phone 106844 0
+61 7 3646 7901
Fax 106844 0
Email 106844 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Private health information can not be routinely shared due to privacy legislation and hospital policy. However, individuals may contact the principal investigator for information about applying to the hospital for the data.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9765Informed consent form  [email protected]
9766Ethical approval  [email protected]
9767Analytic code  [email protected]
9768Study protocol  [email protected]
9769Statistical analysis plan  [email protected]



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.