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Trial registered on ANZCTR


Registration number
ACTRN12618001387213
Ethics application status
Approved
Date submitted
31/07/2018
Date registered
17/08/2018
Date last updated
17/08/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomised double-blind placebo controlled trial of cardiovascular risk reduction during bereavement
Scientific title
A randomised double-blind placebo controlled trial of cardiovascular risk reduction during bereavement
Secondary ID [1] 295688 0
None
Universal Trial Number (UTN)
U1111-1218-3588
Trial acronym
CARBER 2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bereavement 309062 0
Cardiovascular Risk 309063 0
Condition category
Condition code
Mental Health 307946 307946 0 0
Other mental health disorders
Cardiovascular 307947 307947 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Active treatment: metoprolol 25mg and aspirin 100mg
Daily treatment for 6 weeks
Administered as one daily tablet each of metoprolol 25mg and aspirin 100mg or one tablet each of the corresponding placebos.
Adherence was monitored by drug table return.
Intervention code [1] 302006 0
Treatment: Drugs
Comparator / control treatment
Control treatment: 2 matched placebos.
Daily treatment for 6 weeks

The placebo treatment was microcellulose tablets
Control group
Placebo

Outcomes
Primary outcome [1] 306919 0
Average Heart Rate

For average heart rate assessment, we used a 24-hour ECG Holter monitor (Medtel Digital System), and the Medilog Optima system (Oxford Instruments Medical Systems Division) for analysis.
Timepoint [1] 306919 0
After 6 weeks of treatment
Primary outcome [2] 306920 0
Resting blood pressure

For blood pressure recordings, we used a UA 787 Digital monitor (Grade A/A). The study investigator obtained blood pressure measurements for eligibility (mean of 3 measurements). Then the subject was instructed in obtaining duplicate measurements at 3 time points (morning, afternoon and evening) over a 24-hour period during each assessment.
Timepoint [2] 306920 0
After 6 weeks of treatment
Primary outcome [3] 306921 0
von Willebrand Factor antigen

von Willebrand Factor antigen was assessed using the immunoturbidimetric method in plasma.

Reference: Buckley T, Morel-Kopp MC, Ward C, Bartrop R, McKinley S, Mihailidou AS, Spinaze M, Chen W, Tofler G. Inflammatory and thrombotic changes in early bereavement: a prospective evaluation. Eur J Cardiovasc Prev Rehab 2012;19:1145-52
Timepoint [3] 306921 0
After 6 weeks of treatment
Secondary outcome [1] 350108 0
Platelet-granulocyte aggregates
(note this was a primary outcome)

Platelet-granulocyte aggregates were measured using flow cytometry

Reference: Morel-Kopp MC, McLean L, Chen Q, Tofler GH, Tennant C, Maddison V, Ward CM. The association of depression with platelet activation: evidence for a treatment effect. J Thromb Haemost 2009;7:573-81.
Timepoint [1] 350108 0
After 6 weeks of treatment
Secondary outcome [2] 350109 0
Heart rate variability (SDNNi)
(note this was a primary outcome)

Standard deviation of the NN intervals index (SDNNi) was obtained from the 24-hour Holter tracings (Medtel Digital System), and the Medilog Optima system (Oxford Instruments Medical Systems Division) for analysis
Timepoint [2] 350109 0
After 6 weeks of treatment
Secondary outcome [3] 350110 0
Symptoms of Anxiety

Symptoms of anxiety were assessed using the Spielberg State-trait Anxiety Scale

Reference: Spielberger CD. Manual for the State-Trait Anxiety Inventory (STAI). PaloAlto, CA: Consulting Psychologists Press. 1983.
Timepoint [3] 350110 0
After 6 weeks of treatment
Secondary outcome [4] 350111 0
Grief reaction

Grief intensity was measured by the Core Bereavement Items Questionnaire, (CBI-17)

Reference: Burnett P, Middleton W, Raphael B, Martinek N. Measuring core bereavement phenomena. Psycholog Med 1997;27:49-57.


Timepoint [4] 350111 0
After 6 weeks of therapy
Secondary outcome [5] 350692 0
Symptoms of anger were assessed using the Spielberg State-trait Anger Scale

Spielberger CD. State-Trait Anger Expression Inventory (STAXI) manual. Tampa, FL: Psychological Assessment Resources, Inc.; 1988.
Timepoint [5] 350692 0
After 6 weeks of therapy
Secondary outcome [6] 350693 0
Symptoms of Depression using the CES-D Scale

Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Appl Psych Measurement 1977;1:385-401.
Timepoint [6] 350693 0
After 6 weeks of therapy
Secondary outcome [7] 350694 0
Symptoms of Anxiety

Symptoms of anxiety were assessed using the Spielberg State-trait Anxiety Scale

Reference: Spielberger CD. Manual for the State-Trait Anxiety Inventory (STAI). PaloAlto, CA: Consulting Psychologists Press. 1983.
Timepoint [7] 350694 0
6 months
Secondary outcome [8] 350695 0
Grief reaction

Grief intensity was measured by the Core Bereavement Items Questionnaire, (CBI-17)

Reference: Burnett P, Middleton W, Raphael B, Martinek N. Measuring core bereavement phenomena. Psycholog Med 1997;27:49-57.


Timepoint [8] 350695 0
6 months
Secondary outcome [9] 350696 0
Symptoms of anger were assessed using the Spielberg State-trait Anger Scale

Spielberger CD. State-Trait Anger Expression Inventory (STAXI) manual. Tampa, FL: Psychological Assessment Resources, Inc.; 1988.
Timepoint [9] 350696 0
6 months
Secondary outcome [10] 350697 0
Symptoms of Depression using the CES-D Scale

Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Appl Psych Measurement 1977;1:385-401.
Timepoint [10] 350697 0
6 months
Secondary outcome [11] 350698 0
Grief reaction

Grief intensity was measured by the Core Bereavement Items Questionnaire, (CBI-17)

Reference: Burnett P, Middleton W, Raphael B, Martinek N. Measuring core bereavement phenomena. Psycholog Med 1997;27:49-57.


Timepoint [11] 350698 0
3 years
Secondary outcome [12] 350699 0
Post-bereavement medical illness

Using study-specific questionnaire
Timepoint [12] 350699 0
3 years
Secondary outcome [13] 350700 0
Post-bereavement health care utilisation

Using study-specific questionnaire
Timepoint [13] 350700 0
3 years
Secondary outcome [14] 350764 0
Multiplate ASPI test with Arachidonic Acid Stimulation 0.5mM

Reference: Jámbor C, Weber CF, Gerhardt K, Dietrich W, Spannagl M, Heindl B, Zwissler B. Whole blood multiple electrode aggregometry is a reliable point-of-care test of aspirin-induced platelet dysfunction. Anesth Analg 2009;109:25-31.
Timepoint [14] 350764 0
6 weeks

Eligibility
Key inclusion criteria
Spouses, partners or parents of patients who die in hospital; intensive care units, wards, emergency rooms, or are dead on arrival
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Active malignancy or any severe illness, respiratory, heart, liver, renal failure, coagulopathy, thrombocytopenia, cognitive impairment, psychotic illness, immunosuppressive illness or taking immunosuppressive drugs, nursing home residents or cannot speak or read English. We will further exclude people taking beta blockers, heart rate lowering calcium channel blockers, aspirin or with resting systolic BP<120mmHg or heart rate <60bpm, or with contraindication to aspirin or beta blockers, including peptic ulcer, asthma, unstable diabetes mellitus, or known allergy to these drugs.
Withdrawal: Subjects will be withdrawn at the project investigator's discretion, including if it is considered that participatiing in the study is causing undue psychological distress, or at the subjects request.

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)
Allocation involved contacting the holder of the allocation schedule who was at the central administration site (in the research pharmacy).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
Randomised double blind placebo controlled
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The study will utilise two statistical comparisons
1. A comparison after 6 weeks of active versus placebo therapy (primary analysis)
2 A longitudinal evaluation in which the cardiovascular risk factors will be compared from baseline to 6 weeks of therapy and from this timepoint to 6 weeks following cessation of therapy.
Active and placebo results will be compared using standard non-paired testing. Comparison from baseline to after 6 weeks of treatment will be performed using paired testing. Psychosocial measures will also be evaluated from baseline to 6 months. A three year follow-up telephone call and questionnaire will evaluate post-bereavement medical illness, health care utilisation and psychosocial measures, and be compared between groups..
Questionnaire data will initially be collected in paper form and then entered into an ACCESS database. This database has already been established. Data will then be analysed using the SPSS statistical package.
Sample size calculations: With a sample size of 40 completed subjects per group (assuming 50 subjects enrolled) power calculations will be based on endpoints previously identified as elevated in bereaved subjects, and prior study of the effect of atenolol on hemodynamic measures. Differences between bereaved and non-bereaved were: resting systolic BP 8.8mmHg (SD 18): 24 hour heart rate 5bpm (SD 9),; vWF (SD 30); HRV 14.5 (SD 31.5); Anxiety score 24 (SD 14). Based on effects of atenolol in healthy subjects; systolic BP 8 (SD 8); heart rate 13 (SD 9); SDNN 23 (SD 35) our power to detect significant (p<0.05) differences in systolic BP 91%, heart rate 100%, SDNN 82%. Our power to detect significant vWF change is more limited 65% based on differences between bereaved and non-bereaved, and 40% based on prior effect of beta-blocker.

Recruitment
Recruitment status
Active, not 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)
NSW
Recruitment hospital [1] 11529 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 11530 0
Ryde Hospital - Eastwood
Recruitment hospital [3] 11531 0
Hornsby Ku-ring-gai Hospital - Hornsby
Recruitment hospital [4] 11532 0
Manly Hospital - Manly
Recruitment hospital [5] 11533 0
Mona Vale Hospital - Mona Vale
Recruitment postcode(s) [1] 23556 0
2065 - St Leonards
Recruitment postcode(s) [2] 23557 0
2122 - Eastwood
Recruitment postcode(s) [3] 23558 0
2077 - Hornsby
Recruitment postcode(s) [4] 23559 0
2095 - Manly
Recruitment postcode(s) [5] 23560 0
2103 - Mona Vale

Funding & Sponsors
Funding source category [1] 300271 0
Charities/Societies/Foundations
Name [1] 300271 0
Heart Research Australia
Address [1] 300271 0
Royal North Shore Hospital, Reserve Rd, 35, Westbourne St, St Leonards NSW 2065
Country [1] 300271 0
Australia
Primary sponsor type
Hospital
Name
Royal North Shore Hospital
Address
St Leonards, NSW 2065
Country
Australia
Secondary sponsor category [1] 299700 0
None
Name [1] 299700 0
Address [1] 299700 0
Country [1] 299700 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301087 0
The Northern Sydney Local Health District Human Research Ethics Committee (NSLHD HREC)
Ethics committee address [1] 301087 0
Kolling Building
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 301087 0
Australia
Date submitted for ethics approval [1] 301087 0
03/08/2010
Approval date [1] 301087 0
02/02/2011
Ethics approval number [1] 301087 0
1003-077M

Summary
Brief summary
The purpose of the present project is to investigate whether individuals in early bereavement can reduce cardiovascular risk by taking therapy (beta-blocker and aspirin)
Trial website
Trial related presentations / publications
American Heart Association National Conference 2016 (presentation)
Cardiac Society of Australia and New Zealand National Conference 2017 (presentation)
Public notes

Contacts
Principal investigator
Name 85838 0
Prof Geoffrey Tofler
Address 85838 0
Cardiology Department
Royal North Shore Hospital
St Leonards NSW 2065
Country 85838 0
Australia
Phone 85838 0
+61 2 94632509
Fax 85838 0
+61 2 94632079
Email 85838 0
Geoffrey.Tofler@health.nsw.gov.au
Contact person for public queries
Name 85839 0
Prof Geoffrey Tofler
Address 85839 0
Cardiology Department
Royal North Shore Hospital
St Leonards NSW 2065
Country 85839 0
Australia
Phone 85839 0
+61 2 94632509
Fax 85839 0
+61 2 94632079
Email 85839 0
Geoffrey.Tofler@health.nsw.gov.au
Contact person for scientific queries
Name 85840 0
Prof Geoffrey Tofler
Address 85840 0
Cardiology Department
Royal North Shore Hospital
St Leonards NSW 2065
Country 85840 0
Australia
Phone 85840 0
+61 2 94632509
Fax 85840 0
+61 2 94632079
Email 85840 0
Geoffrey.Tofler@health.nsw.gov.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