Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000704998
Ethics application status
Approved
Date submitted
20/05/2020
Date registered
29/06/2020
Date last updated
4/08/2023
Date data sharing statement initially provided
29/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
PREDICTive value of aggressive risk factor modification on the occurrence of major cardiovascular events in patients with embolic STROKE: PREDICT-STROKE
Scientific title
PREDICTive value of aggressive risk factor modification on the occurrence of major cardiovascular events in patients with embolic STROKE: PREDICT-STROKE
Secondary ID [1] 300806 0
Nil
Universal Trial Number (UTN)
Trial acronym
PREDICT-STROKE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial fibrillation 316687 0
Stroke 318023 0
Condition category
Condition code
Cardiovascular 314933 314933 0 0
Other cardiovascular diseases
Stroke 315863 315863 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study intervention to be evaluated is aggressive risk factor modification. Risk factors including obesity, hypertension, dyslipidaemia, glucose intolerance/diabetes, obstructive sleep apnoea, physical activity levels, alcohol, and tobacco use will be systematically evaluated in each participant. Each of the relevant risk factors for that given individual is then targeted aggressively.

Risk factor modification will be performed in a multidisciplinary clinic with appointments and contact frequency adjusted according to individual needs. These range from 3-monthly formal appointments to weekly contact by phone or email.

Participants will receive regular consultation from a doctor or nurse, with or without exercise physiologist input regarding risk factor modification via intensification of management and treatment for hypertension, dyslipidaemia, diabetes/glucose intolerance, obstructive sleep apnoea, overweight or obesity, physical activity levels, smoking and alcohol consumption. At each appointment, goals will be set in order to achieve optimisation of cardiovascular risk factors. Medications will be increased where required, meal plans and exercise regimes will be modified accordingly. Face-to-face interview and/or telephone/video calls will involve an initial assessment and follow-up appointments of 30-60 minutes. Anticoagulation according to standard indications for any atrial fibrillation detected will be prescribed utilising the appropriate oral anticoagulation agent. A structured, motivational, and goal-directed program will be used for weight reduction within scheduled sessions, with encouragement to keep an accurate food and physical activity diary and blood pressure record. Measurements of weight, blood pressure and results from any appropriate re- assessment of tests such as serum cholesterol or glucose will be evaluated at each visit. Participants will be encouraged to utilise support counselling and schedule more frequent reviews as required. In participants with a body mass index (BMI) greater than or equal to 27kg/m2, a meal plan and behaviour modification will be utilised initially for weight reduction. The initial goal is to reduce body weight by 10%.

Participants will be encouraged to increase their exercise habits progressively until they reach an initial weekly target volume of at least 150 minutes, with a view to increasing to a final target of 250 minutes. The aim is moderate intensity aerobic exercise (for example brisk walking or other), ideally with some strength work sessions (for example home-based body-weight-based exercises), tailored to individual physical activity/exercise preference patterns.
Where progress is not satisfactory, accredited exercise physiologist input will be sought. Any exercise prescription will be initiated according to baseline exercise testing and physical activity profile. Adherence to treatment strategies will be assessed at each visit via comparison of prescribed diet, exercise and medication changes with exercise and food diary. Goals will be set at each visit with intensification of the follow up schedule if progress has not been achieved.
Intervention code [1] 317135 0
Lifestyle
Intervention code [2] 317136 0
Treatment: Other
Intervention code [3] 317137 0
Behaviour
Comparator / control treatment
Participants who are randomised to the control arm will receive standard medical therapy left to the discretion of their treating physician. Standard medical therapy for stroke as per current national and international guidelines includes antiplatelet therapy (aspirin 50 to 325mg/day alone, or aspirin combined with clopidogrel monotherapy), statin therapy and treatment of co-morbidities. Usual post-stroke or post-TIA care also includes advice regarding health nutrition and exercise guidelines from the treating neurology team. Control arm participants will receive this usual care, with any additional follow-up (for example smoking cessation counselling) to take place through existing referral networks at the discretion of the referring physicians. Completion of a diet and activity diary will not be requested, and no specific risk factor clinic appointments will be scheduled for control group participants.
Control group
Active

Outcomes
Primary outcome [1] 323244 0
A composite of major adverse cardiovascular events defined as recurrent stroke, asymptomatic cerebral embolism, any acute coronary syndrome, or vascular death, assessed by participant medical records and self-report assessment.
Timepoint [1] 323244 0
24 months
Secondary outcome [1] 381281 0
Change in quality of life assessed by the SF-36 questionnaire.
Timepoint [1] 381281 0
6, 12 and 24 months.
Secondary outcome [2] 381282 0
All-cause mortality assessed through medical records cross-referenced with family contact. Death certificate retrieval
Timepoint [2] 381282 0
24 months.
Secondary outcome [3] 381283 0
Cardiovascular mortality assessed through medical records cross-referenced with family contact. Death certificate retrieval. Classified according to Hinkle-Thaler criteria, including: cardiac arrhythmic, cardiac non-arrhythmic, and vascular non-cardiac causes.
Timepoint [3] 381283 0
24 months.
Secondary outcome [4] 381285 0
Asymptomatic cerebral embolism as assessed by MRI brain
Timepoint [4] 381285 0
24 months.
Secondary outcome [5] 381286 0
Atrial fibrillation burden assessed by implantable loop recorder where implanted (after ESUS), or holter monitoring and surface ECG where no loop recorder is implanted
Timepoint [5] 381286 0
24 months.
Secondary outcome [6] 381287 0
All-cause hospitalisation as assessed through medical records cross-referenced with data linkage
Timepoint [6] 381287 0
24 months.
Secondary outcome [7] 381435 0
Cardiovascular hospitalisation as assessed through medical records cross-referenced with data linkage. This includes hospitalisation for: Arrhythmic events (AF, atrial arrhythmias, sustained ventricular tachycardia, cardiac arrest) confirmed on ECG; Embolic complications (ischemic stroke, Transient Ischaemic Attack, peripheral, pulmonary or systemic embolism) confirmed by a neurologist based on computerized tomography or Magnetic Resonance Imaging; Major bleeding (drop in Haemoglobin level by >2 g/L, or requiring blood transfusion); Heart failure (independent of left ventricular ejection fraction, preferably confirmed by biomarker assessment using NT-pro-BNP); Acute coronary syndrome (STEMI/NSTEMI or unstable angina pectoris) documented on ECG as well as/or assessed in blood levels of key biochemical markers.
Timepoint [7] 381435 0
24 months
Secondary outcome [8] 406759 0
Clinical stroke recurrence assessed via medical history obtained from participants and hospitalisation history for stroke with adjudicated radiological confirmation on magnetic resonance imaging (MRI).
Timepoint [8] 406759 0
24 months.
Secondary outcome [9] 406760 0
Transient Ischaemic Attack via medical history obtained from participants and hospitalisation history with neurologist adjudication and confirmation of no new causative lesion on magnetic resonance imaging (MRI).
Timepoint [9] 406760 0
24 months.

Eligibility
Key inclusion criteria
• At least 18 years old
• Embolic Stroke or TIA
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Age > 85 years
• Pregnancy or planned pregnancy within the next 24 months
• Unable to undergo MRI scan
• Major Surgery <6 months
• Valvular Disease Needing Intervention
• LVEF equal to or less than 35%
• Active Malignancy
• Autoimmune or Systemic Inflammation
• Specific Stroke Mechanisms: Patent Foramen Ovale, Vessel Dissection, Subacute Bacterial Endocarditis
• Severe Renal Dysfunction (defined as dialysis, prior or planned transplant, Cr >2.26 mg/dl or > 200 µmol/L)
• Severe Liver Dysfunction (Cirrhosis or Bilirubin > 2 x Normal or AST/ALT/ALP > 3x Normal)
• Malabsorption Disorders
• Institutional Living
• Inability to Attend Appointments
• Inability to Provide Informed Consent

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised using a computer-generated web-based randomisation schedule. Randomisation will be stratified by trial centre using randomly permuted blocks of sizes 2 and 4.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Not Applicable
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculation for this trial is based on the composite primary endpoint of major adverse cardiovascular events (MACE). The following assumptions were considered: (1) 24-month minimum follow- up; (2) 27 % annual risk of composite endpoint (6% for recurrent stroke, 15% for asymptomatic cerebral embolism, 6% for any acute coronary syndrome or vascular death); (3) 25% reduction in MACE recurrence with our planned intervention compared to the standard care group; (4) 15% attrition rate (loss- to-follow-up or withdrawal of consent); (5) 1:1 allocation ratio.

The study will require 1240 participants (620 in each arm) with a = 0.05 and an 80% power. Considering the 15% attrition rate, the recruitment aim is for a total of 1460 participants (730 in each arm). Statistical analysis will be performed by a senior statistician with experience in managing clinical trial data. Analyses will be conducted under the intention to treat principle. Logistic regression will be used to calculate hazard ratios for the composite primary end point. Time to event data will be analysed using the Kaplan-Meier method with comparison between-groups using Log-Rank statistics with two degrees of freedom. Pre-specified subgroup analysis will be performed using Cox-proportional hazards regression specifically for participants with a diagnosis of ESUS.

Two formal interim analyses for the composite primary endpoint will be performed after 1/3rd and 2/3rds of total participants have been recruited and have completed full trial follow-up of at least 2 years. Stopping rules have been planned according to the method of O’Brien and Fleming. The formal stopping criteria to reject the null hypothesis of no difference between treatment groups at two interim analyses are, respectively, p-values <0.0005, 0.014, and p < 0.045 for the final analysis of the primary outcome.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/02/2021
Actual
17/02/2021
Date of last participant enrolment
Anticipated
10/01/2024
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1460
Accrual to date
131
Final
Recruitment in Australia
Recruitment state(s)
ACT,SA,VIC
Recruitment hospital [1] 16132 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 16133 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [3] 16134 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [4] 16135 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [5] 16136 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [6] 16138 0
The Canberra Hospital - Garran
Recruitment hospital [7] 21833 0
Calvary Wakefield Hospital - Adelaide
Recruitment hospital [8] 21834 0
Ashford Community Hospital - Ashford
Recruitment hospital [9] 21835 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment postcode(s) [1] 29660 0
5000 - Adelaide
Recruitment postcode(s) [2] 29661 0
5011 - Woodville
Recruitment postcode(s) [3] 29662 0
5042 - Bedford Park
Recruitment postcode(s) [4] 29663 0
3052 - Parkville
Recruitment postcode(s) [5] 29664 0
3084 - Heidelberg
Recruitment postcode(s) [6] 29666 0
2605 - Garran
Recruitment postcode(s) [7] 36890 0
5000 - Adelaide
Recruitment postcode(s) [8] 36891 0
5035 - Ashford
Recruitment postcode(s) [9] 36892 0
5112 - Elizabeth Vale

Funding & Sponsors
Funding source category [1] 305262 0
University
Name [1] 305262 0
University of Adelaide
Country [1] 305262 0
Australia
Primary sponsor type
University
Name
Centre for Heart Rhythm Disorders, University of Adelaide
Address
North Terrace, Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 305623 0
None
Name [1] 305623 0
Address [1] 305623 0
Country [1] 305623 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305605 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 305605 0
Ethics committee country [1] 305605 0
Australia
Date submitted for ethics approval [1] 305605 0
11/05/2020
Approval date [1] 305605 0
07/07/2020
Ethics approval number [1] 305605 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100934 0
Prof Prashanthan Sanders
Address 100934 0
Centre for Heart Rhythm Disorders
University of Adelaide/Royal Adelaide Hospital
Port Road, Adelaide, SA, 5000
Country 100934 0
Australia
Phone 100934 0
+61 08 8313 9000
Fax 100934 0
Email 100934 0
prash.sanders@adelaide.edu.au
Contact person for public queries
Name 100935 0
John Fitzgerald
Address 100935 0
Centre for Heart Rhythm Disorders
University of Adelaide/Royal Adelaide Hospital
Port Road, Adelaide, SA, 5000
Country 100935 0
Australia
Phone 100935 0
+61 08 8313 9000
Fax 100935 0
Email 100935 0
john.fitzgerald@adelaide.edu.au
Contact person for scientific queries
Name 100936 0
John Fitzgerald
Address 100936 0
Centre for Heart Rhythm Disorders
University of Adelaide/Royal Adelaide Hospital
Port Road, Adelaide, SA, 5000
Country 100936 0
Australia
Phone 100936 0
+61 08 8313 9000
Fax 100936 0
Email 100936 0
john.fitzgerald@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.