ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12613000349741

Ethics application status

Approved

Date submitted

28/03/2013

Date registered

2/04/2013

Date last updated

5/07/2018

Type of registration

Retrospectively registered

Titles & IDs

Public title

AspiriN To Inhibit SEPSIS (ANTISEPSIS) trial

Scientific title

The AspiriN To Inhibit SEPSIS (ANTISEPSIS) trial; an ASPirin in Preventing Events in the Elderly, (ASPREE) Substudy to measure the benefit of low dose aspirin in the prevention of severe sepsis in the elderly.

Secondary ID [1]

NIL

Universal Trial Number (UTN)

U1111-1141-1933

Trial acronym

ANTISEPSIS

Linked study record

Health condition

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

sepsis

Condition category

Condition code

Infection

Studies of infection and infectious agents

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Aspirin 100mg taken orally once daily. The study drugs, aspirin or placebo, will be taken for a minimum of 5 years and maximum of 7 years according to the timing of entry to study in the enrollment period.

One “Study Drug Accountability” Log will be provided for each study participant. These Drug Accountability Logs record the drug dispensed to the participant and drug returned from the participant.
The Study Drug Accountability log will record, at minimum, the following information:
Date dispensed (initials of dispenser)
Date of medication return (initialed by research staff)
Number of tablets returned
Date of medication destruction

Intervention code [1]

Prevention

Comparator / control treatment

Enteric coated un-scored white tablet with identical appearance to aspirin. Study medications are provided by Bayer HealthCare. The enteric coating will ensure that both active and placebo medication have an identical taste. One placebo tablet is taken daily and will be taken for a minimum of 5 years and maximum of 7 years according to the timing of entry to study in the enrollment period.

Control group

Placebo

Outcomes

Primary outcome [1]

mortality due to sepsis

Timepoint [1]

Intention to treat; on treatment/placebo. The primary outcome will be measured at the end of the study as multiple events may be recorded in study participants.

Secondary outcome [1]

admission to ICU for sepsis

Timepoint [1]

Intention to treat; on treatment/placebo. The secondary outcomes will be measured at the end of the study as multiple events may be recorded in study participants.

Secondary outcome [2]

admission to hospital for sepsis

Timepoint [2]

Intention to treat; on treatment/placebo. The secondary outcomes will be measured at the end of the study as multiple events may be recorded in study participants.

Eligibility

Key inclusion criteria

AS PER ASPREE STUDY
Non-institutionalised
Willing and able to provide informed consent, and willing to accept the study
requirements
Physically capable of regularly attending his/her family physician.
Without major cardiovascular disease, dementia or other exclusion criteria, as
listed below.

Minimum age

70 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

AS PER ASPREE STUDY
A history of a diagnosed cardiovascular event defined as MI, heart failure, peripheral arterial disease, angina pectoris, stroke, transient ischemic attack, >50% carotid stenosis or previous carotid endarterectomy or stenting, coronary artery angioplasty or stenting, coronary artery bypass grafting, or abdominal aortic aneurysm.
A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer or obstructive airways disease.
A current or recurrent condition with a high risk of major bleeding, e.g. cerebral aneurysm or cerebral AV malformation, any bleeding diathesis, gastrointestinal malignancy, recent peptic ulcer, liver disease, oesophageal varicosities, uremia, aortic aneurysm or any other condition known to be associated with a high risk of serious bleeding.
Anaemia, i.e. haemoglobin level below the normal value for the gender of the participant (males: 13g/L, females: 11.5 g/L).
Absolute contraindication or allergy to aspirin.
Current participation in a clinical trial.
Current continuous use of aspirin or other anti-platelet drug or anticoagulant.
Participants with previous use may enter the trial, provided they have been off the medication for 3 months. (Concurrent use of a NSAID is not an exclusion criterion but subjects are requested to take their trial medication 30 minutes prior to other medications.)
A systolic blood pressure 180 mmHg and or a diastolic blood pressure 105mmHg
A history of a clinical diagnosis of diabetes (glucose 7.0 mmol/L (fasting) or 11.1 mmol/L (non fasting) )
A history of dementia or a Modified Mini-Mental State Examination (3MS) score 77 as measured at Visit 1: Lifestyle Profile and Screening.
An inability to perform independently, or more than ‘A little difficulty’ reported in performing, any one of the 6 Katz ADLs.
Pill-taking compliance outside the range of 80-120% during the placebo run-in phase.

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Following the completion of the randomisation
process by the RN / research assistant, a study medication number will be provided. All staff remain blinded to treatment allocation through the randomisation procedure. The RN or research assistant is required to immediately confirm the study medication number through the Interactive Voice
Response System / web portal system.

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

Computer-generated medication numbers will be provided to trial sites through the IVRS or the web portal. The randomisation list will be generated by an independent statistician. This arrangement will ensure that the randomisation code remains inaccessible to all study staff and senior investigators.

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

Single group

Other design features

Phase

Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

We will analyse our three end-points (primary endpoint, sepsis death: secondary endpoints; severe infection episodes and ICU admission due to sepsis) without Bonferroni correction using a survival time method and the proportional hazards assumption (which will be tested). We will adjust for a number of covariates including; diabetes, age at recruitment, malignancy, alcohol intake and smoking or chronic lung disease. This will allow for any imbalance of baseline variables and therefore increase the efficiency of the analysis. We will also perform an unadjusted log-rank test on the final results.

Available data in ICU patients show that there is an effect size on mortality from sepsis of the order of 40 to 80% associated with patients treated with aspirin prior to ICU admission. Using a hazard ratio of 0.63 to examine the sample size required to power our ANTISEPSIS study for the outcome of sepsis-related mortality is a conservative approach. The ASPREE trial will observe approximately 47500 patient years in each of the aspirin and non-aspirin group from Australian and US participants. Overall, the ASPREE study rate of death is estimated as being 17.6 per 1000 participant year. Approximately 4.75 years average follow-up time per participant will be available in an analysis of time to death. If we assume that 20% of the deaths in ASPREE participants will be contributed to by sepsis, this provides an event rate for the primary endpoint of ANTISEPSIS of 3.5 per 1000 participant years. With a minimum of 16,000 Australian ASPREE participants, 4.75 years average follow-up (accounting for expected drop-out), and an event rate of 3.5 per 1000 participant year, we would expect a total of 133 primary endpoint events (deaths) in the control group. With this number of sepsis-related deaths, we would have 80% power to detect a hazard ratio of 0.77 for aspirin users vs. non-users. If only 15% of ASPREE deaths are contributed to by sepsis, we would instead expect 100 primary end point events in the control group and still have 80% power to detect a hazard ratio of 0.74. Finally, if only 10% of ASPREE deaths are contributed to by sepsis, we would expect 66 ANTISEPSIS primary endpoint events in the control group and have 80% power to detect a hazard ratio of 0.68. In all of these scenarios, the ANTISEPSIS study is powered to detect an effect less than that measured in our study of sepsis mortality where the hazard ratio for mortality associated with aspirin administration was 0.63. The two secondary endpoints, admission to hospital for sepsis and admission to ICU for sepsis are more common than death due to sepsis, so they will also be adequately powered by the ASPREE sample.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

10/01/2011

Actual

10/01/2011

Date of last participant enrolment

Anticipated

21/12/2018

Actual

12/06/2017

Date of last data collection

Anticipated

Actual

29/06/2018

Sample size

Target

17000

Accrual to date

Final

17000

Recruitment in Australia

Recruitment state(s)

ACT,NSW,SA,TAS,VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Government body

Name

National Health and Medical Research Council

Address

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country

Australia

Secondary sponsor category [1]

Government body

Name [1]

National Institute on Aging

Address [1]

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892

Country [1]

United States of America

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Universtiy Human Research Ethics Commitee

Ethics committee address [1]

Monash Research Office
Building 3d
Monash University
Victoria 3800

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

19/03/2013

Approval date [1]

05/07/2018

Ethics approval number [1]

CF13/466 - 2013000204

Summary

Brief summary

The ANTISEPSIS study will investigate whether the low doses of aspirin being trialled in the randomised controlled ASPREE study work to reduce the severity of infection in the patients who have been taking aspirin. There are numerous pieces of information from test tube and laboratory animal studies that show us that low dose aspirin helps to reduce inflammation which contributes to the disease caused by severe infection. If we can show that low dose aspirin safely reduces the severity of infection in elderly patients we will be able to recommend that it should be taken in all patients who are not at high risk of side effects of this drug.

We hypothesise that severe outcomes relating to sepsis in the elderly may be prevented by daily low-dose aspirin. We have the opportunity to test this hypothesis through a substudy of the ASPirin in Preventing Events in the Elderly (ASPREE) trial. ASPREE is a major, Australian/US randomised controlled primary prevention trial of low dose aspirin in the elderly. Our aims are to use the ASPREE randomised controlled trial (RCT) framework and extend data collection relating to sepsis events in its participants to assess our primary endpoint:
reduction of deaths contributed to by sepsis in participants receiving aspirin versus placebo.
We will also conduct an analysis of two secondary endpoints:
reduction of severe infection episodes requiring hospital admissions 
reduction of ICU admissions among patients hospitalised for severe sepsis 
The ASPREE study, which will provide a sufficient sample size to assess our primary outcome, represents an ideal chance to assess the impact of aspirin on outcomes of sepsis in the trial population of elderly participants.

Trial website

Trial related presentations / publications

Public notes

Participant recruitment in the ASPREE trial of which ANTISEPSIS is a substudy began in 2011. ASPREE HREC approval included use of participant data for substudies such as ANTISEPSIS. For completeness, specific ethics approval for ANTISEPSIS was granted by the Monash University HREC: Monash University HREC approval 9 April 2013 CF13/466 - 2013000204. This postdated HREC approval for the, parent, ASPREE trial. This is the reason why first enrolment of patients into the ANTISEPSIS trial predated its HREC approval.

Contacts

Principal investigator

Name

Prof Damon Eisen

Address

Townsville Hospital and Health Service
100 Angus Smith Drive, QLD, 4814

Country

Australia

Phone

61 7 47813892

Fax

61 7 4433 2459

damon.eisen@jcu.edu.au

Contact person for public queries

Name

damon eisen

Address

Townsville Hospital and Health Service
100 Angus Smith Drive, QLD, 4814

Country

Australia

Phone

61 7 47813892

Fax

61 7 4433 1271

damon.eisen@jcu.edu.au

Contact person for scientific queries

Name

damon eisen

Address

Townsville Hospital and Health Service
100 Angus Smith Drive, QLD, 4814

Country

Australia

Phone

+61 7 4433 2459

Fax

61 7 4433 1271

damon.eisen@jcu.edu.au

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	Sepsis-associated thrombocytopenia.	2016	https://dx.doi.org/10.1016/j.thromres.2016.02.022
Dimensions AI	Association of prior antiplatelet agents with mortality in sepsis patients	2016	https://doi.org/10.1007/s00134-016-4230-x
Embase	AspiriN To Inhibit SEPSIS (ANTISEPSIS) randomised controlled trial protocol.	2017	https://dx.doi.org/10.1136/bmjopen-2016-013636
Embase	Platelets in Host Defense: Experimental and Clinical Insights.	2019	https://dx.doi.org/10.1016/j.it.2019.08.004
Dimensions AI	Platelets Are Critical Key Players in Sepsis	2019	https://doi.org/10.3390/ijms20143494
Embase	Current understanding and future implications of sepsis-induced thrombocytopenia.	2021	https://dx.doi.org/10.1111/ejh.13549
Embase	Effect of aspirin on deaths associated with sepsis in healthy older people (ANTISEPSIS): a randomised, double-blind, placebo-controlled primary prevention trial.	2021	https://dx.doi.org/10.1016/S2213-2600%2820%2930411-2

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

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Documents added manually

Documents added automatically