Trial Review

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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] 282203 0
NIL
Universal Trial Number (UTN)
U1111-1141-1933
Trial acronym
ANTISEPSIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
sepsis
 288722 0
Condition category
Condition code
Infection 289076 289076 0 0
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] 286818 0
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] 289185 0
mortality due to sepsis
Timepoint [1] 289185 0
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] 301972 0
admission to ICU for sepsis
Timepoint [1] 301972 0
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] 301973 0
admission to hospital for sepsis
Timepoint [2] 301973 0
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] 286965 0
Government body
Name [1] 286965 0
National Health and Medical Research Council
Country [1] 286965 0
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] 285756 0
Government body
Name [1] 285756 0
National Institute on Aging
Address [1] 285756 0
Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
Country [1] 285756 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289014 0
Monash Universtiy Human Research Ethics Commitee
Ethics committee address [1] 289014 0
Monash Research Office
Building 3d
Monash University
Victoria 3800
Ethics committee country [1] 289014 0
Australia
Date submitted for ethics approval [1] 289014 0
19/03/2013
Approval date [1] 289014 0
05/07/2018
Ethics approval number [1] 289014 0
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 38818 0
Prof Damon Eisen
Address 38818 0
Townsville Hospital and Health Service
100 Angus Smith Drive, QLD, 4814
Country 38818 0
Australia
Phone 38818 0
61 7 47813892
Fax 38818 0
61 7 4433 2459
Email 38818 0
damon.eisen@jcu.edu.au
Contact person for public queries
Name 38819 0
Prof damon eisen
Address 38819 0
Townsville Hospital and Health Service
100 Angus Smith Drive, QLD, 4814
Country 38819 0
Australia
Phone 38819 0
61 7 47813892
Fax 38819 0
61 7 4433 1271
Email 38819 0
damon.eisen@jcu.edu.au
Contact person for scientific queries
Name 38820 0
Prof damon eisen
Address 38820 0
Townsville Hospital and Health Service
100 Angus Smith Drive, QLD, 4814
Country 38820 0
Australia
Phone 38820 0
+61 7 4433 2459
Fax 38820 0
61 7 4433 1271
Email 38820 0
damon.eisen@jcu.edu.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