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Trial registered on ANZCTR


Registration number
ACTRN12616001377426
Ethics application status
Approved
Date submitted
31/08/2016
Date registered
5/10/2016
Date last updated
5/10/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
The Mechanisms of Aspirin Therapy in Sepsis [MATHS] trial
Scientific title
The Mechanisms of Aspirin Therapy in Sepsis [MATHS] trial
Secondary ID [1] 290065 0
None
Universal Trial Number (UTN)
Trial acronym
MATHS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
sepsis 300126 0
Condition category
Condition code
Inflammatory and Immune System 300004 300004 0 0
Other inflammatory or immune system disorders
Infection 300149 300149 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Aspirin 100mg administered orally as single dose at time of randomization and at 24 hrs OR
Aspirin 300mg administered orally as single dose at time of randomization and at 24 hrs

Both will be administered to septic patients that are in ICU at the time therefore adherence will not be an issue. If patients are intubated doses will be administered via NG tube.
Intervention code [1] 295791 0
Treatment: Drugs
Comparator / control treatment
The control group will consist of septic patients not treated with aspirin
Control group
Active

Outcomes
Primary outcome [1] 299492 0
Measurement of the effect of low-dose aspirin on immunological pathways caused by ATL. Will be assessed using blood tests and subsequent assays on expression patterns of the above molecule taken at below specified timepoints.
Timepoint [1] 299492 0
Baseline, at 1 hour, at 4 hours, at 8 hours, at 24 hours, and at 48 hours post intervention
Primary outcome [2] 299641 0
Measurement of the effect of low-dose aspirin on immunological pathways caused by NF-kB. Will be assessed using blood tests and subsequent assays on expression patterns of the above molecule taken at below specified timepoints.
Timepoint [2] 299641 0
Baseline, at 1 hour, at 4 hours, at 8 hours, at 24 hours, and at 48 hours post intervention
Secondary outcome [1] 327325 0
Exploratory assessment of trends in clinical outcomes shown by sequential organ failure assessment (SOFA) score reductions in treated compared with control populations.
Timepoint [1] 327325 0
At 24 and 48 hours post intervention
Secondary outcome [2] 327326 0
Comparison of safety as measured by new onset bleeding or renal injury. Will be assessed using clinical examination, blood tests, scoring systems such as APACHE II, and imaging methods where appropriate.
Timepoint [2] 327326 0
At 24 and 48 hours post intervention
Secondary outcome [3] 327723 0
Inflammatory markers, such as platelet activation indices and immune cellular markers will be assessed using blood samples and subsequent assays including flow cytometry.
Timepoint [3] 327723 0
At baseline, at 1 hour, at 4 hours, at 24 hours, and at 48 hours post intervention.
Secondary outcome [4] 328172 0
ATL and deterioration in SOFA scores – exact tests for comparisons of categorical outcomes
Timepoint [4] 328172 0
At 24 and 48 hours
Secondary outcome [5] 328173 0
ATL and deterioration in APACHE II scores – log ranked tests for non-parametric data
Timepoint [5] 328173 0
At 24 and 48 hours
Secondary outcome [6] 328174 0
ATL levels and mortality. Using ordinal logistic regression for multivariable analysis.
Timepoint [6] 328174 0
24 and 48 hours
Secondary outcome [7] 328175 0
ATL levels and length of stay in ICU. Using ordinal logistic regression for multivariable analysis.
Timepoint [7] 328175 0
At 24 and 48 hours

Eligibility
Key inclusion criteria
Sepsis according to Sepsis-3 consensus definition
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Regular aspirin for myocardial ischaemia.
Aspirin/NSAID in last 7 days
Hypersensitivity to aspirin/NSAIDs
Platelet count <100,000 x10^9/L
Active bleeding (trauma, gastrointestinal, or intracranial)
Life expectancy less than 24 hours

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)
Sealed opaque envelopes in a locked office
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A list of random numbers will be generated by a computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Pharmacodynamics
Statistical methods / analysis
This study has been adequately powered to detect a difference in baseline versus Day2 ATL concentrations in the control versus aspirin group. Baseline normal ATL concentrations and population standard deviation ATL concentrations used to determine sample size are derived from a randomised clinical trial of low doses of aspirin that showed a baseline concentration of ATL of 2.45ng/mL (std 0.96 ng/ml) with no significant change over time in healthy subjects not taking aspirin. We assume that regardless of any change that occurs in the setting of sepsis, the combined aspirin groups will have ATL concentrations at least 0.6 mg/ml higher than the control group. This being the case, we require a sample size of 45 participants per group to have 80% power to reject the null hypothesis - change in ATL concentrations of cases is identical to the change in ATL levels of controls- with a P-value of 0.05. The proposed sample size calculations used the most conservative available estimate for effect of low dose aspirin on ATL in human subjects. Blister studies, that reflect the effect of aspirin in the setting of inflammation, show an increase of ATL in the aspirin group of around 80% at 24 hours. We powered the study on the assumption that the effect of aspirin would be an increase of 25% in ATL. Measurements of SOFA and APACHE II scores at T0 with follow up SOFA at T24 and T48 will be made for comparison between groups using student-t tests and log ranked tests. Exploratory analyses, such as the correlation between ATL levels at 24 hours, and change in SOFA scores/mortality/length of stay in ICU, will involve exact tests for comparisons of categorical outcomes (SOFA), log ranked tests for non-parametric data (APACHE II) and ordinal logistic regression for multivariable analysis.

Recruitment
Recruitment status
Not yet recruiting
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)
QLD
Recruitment hospital [1] 6585 0
The Townsville Hospital - Douglas
Recruitment postcode(s) [1] 14192 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 294429 0
Hospital
Name [1] 294429 0
Townsville Hospital and Health Service
Address [1] 294429 0
100 Angus Smith Dr, Douglas QLD 4814
Country [1] 294429 0
Australia
Primary sponsor type
Hospital
Name
Townsville Hospital and Health Service
Address
100 Angus Smith Dr, Douglas QLD 4814
Country
Australia
Secondary sponsor category [1] 293282 0
None
Name [1] 293282 0
Address [1] 293282 0
Country [1] 293282 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295871 0
Townsville Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 295871 0
Human Research Ethics Committee

Townsville Hospital and Health Service
Townsville Hospital
100 Angus smith drive, douglas, QLD, 4814
Ethics committee country [1] 295871 0
Australia
Date submitted for ethics approval [1] 295871 0
11/07/2016
Approval date [1] 295871 0
30/08/2016
Ethics approval number [1] 295871 0
HREC/16/QTHS/160

Summary
Brief summary
Background: Despite the high burden of mortality of sepsis, there are no clearly effective strategies to suppress the underlying inflammatory response. Studies have suggested that low-dose aspirin - a cost-effective and safe medication - has a potential role in the prevention and treatment of sepsis. This trial aims to measure the effects of low-dose aspirin on target inflammatory markers; activation of NF-KB, increases in aspirin triggered lipoxins (ATLs) pathway, platelet activation indices, immune cellular markers and the rate of organ dysfunction in septic patients.

Method:
The MATHS trial is a single-centre, randomised, open label, phase II trial. One hundred and thirty-five septic patients (Sepsis-3 definition) will be randomised to one of three treatment groups: aspirin 100mg, aspirin 300mg both given daily for two days or no treatment. Blood samples will be taken at regular set intervals and assays will be performed to quantify the inflammatory response via NF-KB activation, expression of aspirin triggered lipoxins (ATLs) and various other inflammatory markers. Initial SOFA and APACHE II scores will be calculated, with repeat SOFA scores at 24 and 48 hours. Exploratory analyses, such as the correlation between ATL levels at 24 hours, and deterioration in SOFA scores/mortality/length of stay in ICU, will involve exact tests for comparisons of categorical outcomes (SOFA), log ranked tests for non-parametric data (APACHE II) and ordinal logistic regression for multivariable analysis.

Conclusions:
The results of this this trial could add further evidence to support the use of low-dose aspirin in sepsis.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1079 1079 0 0

Contacts
Principal investigator
Name 68666 0
Prof Damon Eisen
Address 68666 0
Townsville Hospital and Health Service
Clinical School IMB 52, The Townsville Hospital
100 Angus Smith Drive, Douglas, QLD, 4814
Country 68666 0
Australia
Phone 68666 0
+61 7 4433 2459
Fax 68666 0
Email 68666 0
Damon.Eisen@health.qld.gov.au
Contact person for public queries
Name 68667 0
Prof Damon Eisen
Address 68667 0
Director of Clinical Research
The Townsville Hospital
100 Angus Smith Drive, Douglas, QLD, 4814
Country 68667 0
Australia
Phone 68667 0
+61 7 4433 2459
Fax 68667 0
Email 68667 0
Damon.Eisen@health.qld.gov.au
Contact person for scientific queries
Name 68668 0
Prof Damon Eisen
Address 68668 0
Townsville Hospital and Health Service
Clinical School IMB 52, The Townsville Hospital
100 Angus Smith Drive, Douglas, QLD, 4814
Country 68668 0
Australia
Phone 68668 0
+61 7 4433 2459
Fax 68668 0
Email 68668 0
Damon.Eisen@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
No Results