ANZCTR - Registration

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial registered on ANZCTR

Registration number

ACTRN12614001165673

Ethics application status

Approved

Date submitted

27/10/2014

Date registered

6/11/2014

Date last updated

17/05/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

A randomised, feasibility, safety and biological efficacy placebo-controlled trial of aspirin in intensive care unit (ICU) patients with the systemic inflammatory syndrome

Scientific title

A randomised, feasibility, safety and biological efficacy placebo-controlled trial of aspirin in intensive care unit (ICU) patients with the systemic inflammatory syndrome

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

Trial acronym

PROTECTIN

Linked study record

Health condition

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

Systemic inflammatory response syndrome

Condition category

Condition code

Inflammatory and Immune System

Other inflammatory or immune system disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Aspirin (100 mg twice daily) in the form of a soluble tablet given orally or by nasogastric tube from the time of enrollment following admission to the intensive care unit until discharge from the intensive care unit. Adherence with study protocol will be determined by the number of times the tablet was due to be administered compared with actually administered to the patient.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo tablet (microcellulose tablet) administered twice daily.

Control group

Placebo

Outcomes

Primary outcome [1]

Serum concentration of interleukin 6 (IL-6)

Timepoint [1]

48 hours after randomisation

Secondary outcome [1]

Duration of invasive mechanical ventilation.

Timepoint [1]

Invasive mechanical ventilation is defined as positive pressure ventilation via an endotracheal tube, nasotracheal tube or tracheostomy. Invasive mechanical ventilation is defined as being stopped only when invasive mechanical ventilation is discontinued for more than 24 hours.

Secondary outcome [2]

Mortality - hospital

Timepoint [2]

Assessed at time when participant is discharged from hospital

Secondary outcome [3]

Mortality - intensive care

Timepoint [3]

Assessed at time when participant is discharged from the intensive care unit.

Secondary outcome [4]

Length of stay - hospital

Timepoint [4]

Hospital admission duration in days

Secondary outcome [5]

length of stay - intensive care unit

Timepoint [5]

Intensive care unit admission duration in days

Secondary outcome [6]

Bleeding - requiring the need for red blood cell transfusion

Timepoint [6]

Bleeding requiring the need for red blood cell transfusion while the participant in admitted to the intensive care unit

Secondary outcome [7]

Renal replacement therapy - need for renal replacement therapy

Timepoint [7]

Renal replacement therapy while the participant in admitted to the intensive care unit.

Secondary outcome [8]

Surival status (alive or dead)

Timepoint [8]

28-days following enrolment.

Secondary outcome [9]

Changes in serum creatinine from baseline to highest value

Timepoint [9]

While participant is admitted to the intensive care unit

Secondary outcome [10]

Recruitment rate

Timepoint [10]

Per month from the commencement of participant screening until the end of the study (Up to 12 months).

Secondary outcome [11]

Screened to enrolled participant ratio

Timepoint [11]

Per month from the commencement of participant screening until the end of the study (Up to 12 months).

Secondary outcome [12]

Reasons for failure to enrol eligible participants as a feasibility measure determined via assessing the reasons for participant exclusion based on the eligibility criteria.

Timepoint [12]

Monthly reporting until the end of the study (up to 12 months)

Secondary outcome [13]

In a nested cohort of forty participants the following inflammatory markers in the serum will be measured -
1. C-reactive protein
2. E-Selectin
3. IL-1 and IL-10
4. Resolvin D1
5. D-dimer levels
6. Thromboxane B2

Timepoint [13]

Baseline, at 24 h, 48 h and 72 h follwoing randomisation.

Eligibility

Key inclusion criteria

Two or more of the follow critieria for the systemic inflammatory response sydrome (SIRS):
a. Body temperature less than 36oC or greater than 38oC
b. Heart rate greater than 90 beats per minute
c. Tachypnea, with greater than 20 breaths per minute, or, an arterial partial pressure of carbon dioxide of less than 32 mmHg) or mechanically ventilated
d. Leukocytes less than 4000 cells/mm3 (4 x 109 cells/L) or greater than 12,000 cells/mm3 (12 x 109 cells/L) or the presence or greater than 10% immature neutrophils (band forms).

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Known allergic response to Aspirin
- Severe thrombocytopenia (<75,000/mm3)
- Pregnancy
- Limitations of medical therapy
- Intracranial haemorrhage
- Ongoing bleeding
- Any bleeding episode in the last 24 hours
- Age <18 years
- Surgery in the last 12 hours
- Recent (< 3 months) diagnosis of gastric or duodenal ulcer
- History of gastric or duodenal ulcer or upper gastrointestinal bleeding in the last 10 years
- Prolonged International normalized ratio (INR) >2
- Prolonged activated partial thromboplastin time (APTT>50 seconds)
- Any neurosurgery in the last 3 months
- Patient is already on Aspirin for a specific indication (such as recent myocardial infarction of less than 12 months, recent cardiac stenting of less than 12 months or recent transient ischaemic attack of less than 12 months)
- Death is expected within the next 24 hours
- Any cardiac surgery (Aspirin is routinely prescribed)

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)

Patients will undergo concealed random allocation to either Aspirin 100 mg twice daily or placebo.

Aspirin as 100 mg soluble tablets or placebo will be to be given orally or by nasogastric tube twice daily by the blinded bedside nurse.

Study drug will be given < 24 hours of fulfilling the criteria for randomization and will be continued until discharge from ICU or death or the development of a serious adverse event or the development of a contraindication to Aspirin

All other treatment will continue until the patient leaves the ICU or contraindications to aspirin therapy arise or death occurs or serious adverse events suspected to be secondary to aspirin develop.

Patients readmitted to ICU during the same hospital stay will not received any further doses of study drug.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation will be performed by the site investigator or research coordinator via sealed opaque envelopes, including permuted block randomisation at each site.

After meeting eligibility criteria and obtaining informed consent, patients will be randomised in a 1:1 ratio to receive either Aspirin at 100 mg twice daily or placebo.

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

Phase 2

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

It is expected that the 120 participants enrolled into this trial will be exposed to 500 days of treatment. With this sample size and duration of treatment exposure we believe that it will be adequate to determine the safety, feasibility and biological effect of markers of inflammation. The findings of this trial will then be used to power phase-II trials with patient-centred outcomes.

Independent senior statisticians at Monash University Department of Epidemiology and Preventive Medicine will perform data analysis on an intention-to-treat basis. Baseline and outcome variables will be compared using Chi-square tests for equal proportion, Student’s t-test for normally distributed outcomes and Wilcoxon rank-sum tests otherwise. Multivariate models adjusting for baseline imbalances and known covariates will be performed using logistic regression. A p-value of 0.05 will be considered to be statistically significant.

Recruitment

Recruitment status

Stopped early

Data analysis

Data collected is being analysed

Reason for early stopping/withdrawal

Other reasons/comments

Other reasons

Expiry date of study drug and placebo reached

Date of first participant enrolment

Anticipated

8/11/2014

Actual

18/03/2015

Date of last participant enrolment

Anticipated

29/12/2017

Actual

28/11/2017

Date of last data collection

Anticipated

Actual

2/03/2018

Sample size

Target

120

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [3]

Western Hospital - Footscray

Recruitment hospital [4]

Bankstown-Lidcombe Hospital - Bankstown

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3220 - Geelong

Recruitment postcode(s) [3]

3011 - Footscray

Recruitment postcode(s) [4]

2200 - Bankstown

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health - Anaesthesia Intensive Care Trust Fund

Address [1]

Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Road
Heidelberg
Victoria 3094

Country

Australia

Secondary sponsor category [1]

Individual

Name [1]

Professor Rinaldo Bellomo

Address [1]

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health

Ethics committee address [1]

145 Studley Road
Heidelberg
Victoria 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

29/04/2014

Approval date [1]

15/10/2014

Ethics approval number [1]

HREC/14/Austin/219

Summary

Brief summary

When patients suffer infections or have damaged organs they may develop an excessive inflammatory response called the systemic inflammatory syndrome (SIRS). This SIRS manifests as changes in heart rate, breathing, white cells release into blood, fever and carbon dioxide production. While a small amount of SIRS may be helpful for the healing process, uncontrolled SIRS may contribute to making intensive care unit (ICU) patients unwell, leading to a low blood pressure, organ failure, need for artificial life support and, in some cases prolonged time in ICU and hospital and even death. 

Finding safe, effective and inexpensive ways to decrease the severity of SIRS is an important goal of modern ICU medicine. Unfortunately, no medications have been shown to do this. Recently, however, a safe drug used by millions of people every day has been shown to have unexpected properties that might reduce the severity of SIRS. This drug is Aspirin. Every day, Aspirin is given to millions of patients at low dose because it protects from heart attacks and strokes through its ability to block clotting.  

Over the last three to four years, however, multiple studies in animals and observational studies in man have shown that low-dose Aspirin (as given to patients with heart attacks and strokes) also inhibits excessive inflammation. Aspirin does this by stimulating the production of newly discovered helpful molecules called resolvins, protectins and maresins. These molecules combat inflammation and help the body to recover. 

Observational studies have reported that SIRS patients treated with Aspirin were more likely to live than similar untreated patients.  In addition, patients who were on Aspirin before admission to ICU were similarly more likely to survive. On the other hand, it is also known that Aspirin therapy may increase the risk of bleeding, stomach inflammation and maybe even kidney impairment. How the risks and benefits of aspirin therapy balance each other in patients with SIRS is unknown because no controlled studies have been done so far. 

Because of this, we plan to conduct a pilot randomized controlled trial to study whether Aspirin treatment in patients with SIRS is safe, feasible, and shows preliminary evidence of beneficial effects.

The primary outcome is the concentration of a substance which indicates severe inflammation, called interleukin 6 (IL-6) in the blood 48 hours after randomisation.  We wish to test the hypothesis that Aspirin improves the resolution of high levels of IL-6.

If our findings support the feasibility, safety and possible benficial effect of aspirin when used in this way, we will be able to conduct larger studies to asses its benefits in terms of patient-centred outcomes.

Trial website

Trial related presentations / publications

Public notes

Attachments [1]

/AnzctrAttachments/367309-Ssa_Form_PROTECTIN Trial_AU562F715_April 2014_declarations signed.pdf

Attachments [2]

/AnzctrAttachments/367309-20160829 HREC14Austin219 Ethics Amendment Approval Letter.pdf (Ethics approval)

Contacts

Principal investigator

Name

Prof Rinaldo Bellomo

Address

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 9496 5992

Fax

+61 3 9496 3932

[email protected]

Contact person for public queries

Name

Rinaldo Bellomo

Address

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 9496 5992

Fax

+61 3 9496 3932

[email protected]

Contact person for scientific queries

Name

Rinaldo Bellomo

Address

Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61 3 9496 5992

Fax

+61 3 9496 3932

[email protected]

No information has been provided regarding IPD availability

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

Source	Title	Year of Publication	DOI
Embase	Cytokine and lipid metabolome effects of low-dose acetylsalicylic acid in critically ill patients with systemic inflammation: a pilot, feasibility, multicentre, randomised, placebo-controlled trial.	2020

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Registering a new trial?

Documents added manually

Documents added automatically