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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] 285546 0
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 293363 0
Condition category
Condition code
Inflammatory and Immune System 293641 293641 0 0
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] 290493 0
Treatment: Drugs
Comparator / control treatment
Placebo tablet (microcellulose tablet) administered twice daily.
Control group
Placebo

Outcomes
Primary outcome [1] 293458 0
Serum concentration of interleukin 6 (IL-6)
Timepoint [1] 293458 0
48 hours after randomisation
Secondary outcome [1] 311083 0
Duration of invasive mechanical ventilation.
Timepoint [1] 311083 0
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] 311084 0
Mortality - hospital
Timepoint [2] 311084 0
Assessed at time when participant is discharged from hospital
Secondary outcome [3] 311085 0
Mortality - intensive care
Timepoint [3] 311085 0
Assessed at time when participant is discharged from the intensive care unit.
Secondary outcome [4] 311086 0
Length of stay - hospital
Timepoint [4] 311086 0
Hospital admission duration in days
Secondary outcome [5] 311087 0
length of stay - intensive care unit
Timepoint [5] 311087 0
Intensive care unit admission duration in days
Secondary outcome [6] 311088 0
Bleeding - requiring the need for red blood cell transfusion
Timepoint [6] 311088 0
Bleeding requiring the need for red blood cell transfusion while the participant in admitted to the intensive care unit
Secondary outcome [7] 311089 0
Renal replacement therapy - need for renal replacement therapy
Timepoint [7] 311089 0
Renal replacement therapy while the participant in admitted to the intensive care unit.
Secondary outcome [8] 311090 0
Surival status (alive or dead)
Timepoint [8] 311090 0
28-days following enrolment.
Secondary outcome [9] 311091 0
Changes in serum creatinine from baseline to highest value
Timepoint [9] 311091 0
While participant is admitted to the intensive care unit
Secondary outcome [10] 311092 0
Recruitment rate
Timepoint [10] 311092 0
Per month from the commencement of participant screening until the end of the study (Up to 12 months).
Secondary outcome [11] 311093 0
Screened to enrolled participant ratio
Timepoint [11] 311093 0
Per month from the commencement of participant screening until the end of the study (Up to 12 months).
Secondary outcome [12] 311094 0
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] 311094 0
Monthly reporting until the end of the study (up to 12 months)
Secondary outcome [13] 311095 0
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] 311095 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 3084 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 3085 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [3] 3086 0
Western Hospital - Footscray
Recruitment hospital [4] 10912 0
Bankstown-Lidcombe Hospital - Bankstown
Recruitment postcode(s) [1] 8842 0
3084 - Heidelberg
Recruitment postcode(s) [2] 8843 0
3220 - Geelong
Recruitment postcode(s) [3] 8844 0
3011 - Footscray
Recruitment postcode(s) [4] 22674 0
2200 - Bankstown

Funding & Sponsors
Funding source category [1] 290151 0
Hospital
Name [1] 290151 0
Austin Health - Anaesthesia Intensive Care Trust Fund
Address [1] 290151 0
Austin Hospital
Department of Intensive Care
145 Studley Road
Heidelberg VIC 3084
Country [1] 290151 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg
Victoria 3094
Country
Australia
Secondary sponsor category [1] 288861 0
Individual
Name [1] 288861 0
Professor Rinaldo Bellomo
Address [1] 288861 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country [1] 288861 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291861 0
Austin Health
Ethics committee address [1] 291861 0
145 Studley Road
Heidelberg
Victoria 3084
Ethics committee country [1] 291861 0
Australia
Date submitted for ethics approval [1] 291861 0
29/04/2014
Approval date [1] 291861 0
15/10/2014
Ethics approval number [1] 291861 0
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

Contacts
Principal investigator
Name 52294 0
Prof Rinaldo Bellomo
Address 52294 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 52294 0
Australia
Phone 52294 0
+61 3 9496 5992
Fax 52294 0
+61 3 9496 3932
Email 52294 0
rinaldo.bellomo@austin.org.au
Contact person for public queries
Name 52295 0
Prof Rinaldo Bellomo
Address 52295 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 52295 0
Australia
Phone 52295 0
+61 3 9496 5992
Fax 52295 0
+61 3 9496 3932
Email 52295 0
rinaldo.bellomo@austin.org.au
Contact person for scientific queries
Name 52296 0
Prof Rinaldo Bellomo
Address 52296 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 52296 0
Australia
Phone 52296 0
+61 3 9496 5992
Fax 52296 0
+61 3 9496 3932
Email 52296 0
rinaldo.bellomo@austin.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary