ANZCTR - Registration

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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]

None

Universal Trial Number (UTN)

U1111-1261-2578

Trial acronym

ICARUS

Linked study record

Health condition

Health condition(s) or problem(s) studied:

sepsis

Condition category

Condition code

Emergency medicine

Resuscitation

Infection

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]

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]

Systolic blood pressure obtained from the patient's medical records

Timepoint [1]

24 hours after randomization

Secondary outcome [1]

Number of patients enrolled in the study each month (feasibility outcome). Data will be obtained from the study database

Timepoint [1]

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]

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]

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]

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]

4 hours post randomisation

Secondary outcome [4]

Total fluid in mL (either crystalloid or albumin) administered within 72 hours, obtained from the patient's medical record

Timepoint [4]

72 hours after randomisation

Secondary outcome [5]

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]

72 hours after randomisation.

Secondary outcome [6]

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]

72 hours after randomisation

Secondary outcome [7]

Intensive care unit admission, obtained from the hospital administrative database (HBCIS)

Timepoint [7]

During the index presentation

Secondary outcome [8]

Hospital length of stay (in days) assessed using the hospital administrative database (HBCIS)

Timepoint [8]

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?

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]

Royal Brisbane & Womens Hospital - Herston

Recruitment postcode(s) [1]

4029 - Herston

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Emergency Medicine Foundation

Address [1]

Suite 1b, Terraces, 19 Lang Parade Milton QLD 4064

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal Brisbane and Women's Hospital

Address

Butterfield Street, Herston, QLD, 4029

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Brisbane and Women's Hospital Human Research Ethics Committee

Ethics committee address [1]

Royal Brisbane and Women's Hospital, Butterfield Street, Herston, QLD, 4029

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

27/10/2020

Approval date [1]

07/12/2020

Ethics approval number [1]

Summary

Brief summary

Global estimates suggest that approximately 5 million people die from infection each year. Research into improved management and treatment for patients with infection is essential for reducing such mortality. Individuals who present to the Emergency Department with severe infections are treated with fluids in the vein to maintain optimal blood volume, keep the heart working properly, and keep tissues well oxygenated. There are a number of fluids that Emergency Physicians can provide to patients, including crystalloids (water-based fluids that include salts and other water-soluble molecules), and albumin (a fluid manufactured from human plasma). Any of these fluids can be used by Emergency physicians, but crystalloids are most commonly used in standard care. There is some initial evidence that albumin may result in better outcomes for patients with severe infections, but further quality trials are required to validate these initial studies. 

Within this study, we will randomise patients with severe infection to receive either albumin or crystalloids while they are in the Emergency Department. The aim is to determine whether albumin improves the patient’s blood pressure, reduces the amount of fluid they need to receive, reduces organ failure, and reduces the need for intensive care admission.. The results of the study will provide emergency doctors with important information about how to best treat patients with infections and potentially reduce the number of deaths. The primary hypothesis is that In patients presenting to the Emergency Department with presumed infection, usual care plus intervention with 400mL 20% albumin IV over 4 hours compared to usual treatment without albumin results in higher systolic blood pressure at 24 hours.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Julian Williams

Address

Emergency and Trauma Centre
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD, 4029

Country

Australia

Phone

+61 7 3646 7901

Fax

julian.williams@health.qld.gov.au

Contact person for public queries

Name

Julian Williams

Address

Emergency and Trauma Centre
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD, 4029

Country

Australia

Phone

+61 7 3646 7901

Fax

julian.williams@health.qld.gov.au

Contact person for scientific queries

Name

Julian Williams

Address

Emergency and Trauma Centre
Royal Brisbane and Women's Hospital
Butterfield Street
Herston, QLD, 4029

Country

Australia

Phone

+61 7 3646 7901

Fax

julian.williams@health.qld.gov.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.	Type	Email
9765	Informed consent form	jaimi.greenslade@health.qld.gov.au
9766	Ethical approval	jaimi.greenslade@health.qld.gov.au
9767	Analytic code	jaimi.greenslade@health.qld.gov.au
9768	Study protocol	jaimi.greenslade@health.qld.gov.au
9769	Statistical analysis plan	jaimi.greenslade@health.qld.gov.au

Results publications and other study-related documents

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No additional documents have been identified.

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