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Trial registered on ANZCTR


Registration number
ACTRN12618001677291
Ethics application status
Approved
Date submitted
9/10/2018
Date registered
11/10/2018
Date last updated
29/01/2019
Date data sharing statement initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT) Cognitive Sub-Study: Effectiveness of intensive long-term blood pressure lowering treatment, provided by a Triple Pill strategy, for slowing memory decline as measured by Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with a history of acute stroke due to intracerebral haemorrhage.
Scientific title
A Sub-Study of an investigator initiated and conducted, multicentre, international, double-blinded, placebo-controlled, parallel-group, randomised controlled trial (TRIDENT) to determine the effect of more intensive long-term blood pressure control, provided by a fixed low-dose combination blood pressure lowering pill (“Triple Pill”) strategy on top of standard of care, for slowing memory decline as measured by Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with a history of acute stroke due to intracerebral haemorrhage (ICH).
Secondary ID [1] 295631 0
None
Universal Trial Number (UTN)
Trial acronym
TRIDENT Cognitive
Linked study record
This study is a sub-study of ACTRN12616000327482 Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT). Participants must be enrolled and participating in TRIDENT to be eligible for this sub-study

Health condition
Health condition(s) or problem(s) studied:
Stroke caused by Intracerebral Haemorrhage (ICH) 308963 0
Hypertension 308964 0
Cognitive Decline 308965 0
Dementia 310007 0
Condition category
Condition code
Stroke 307861 307861 0 0
Haemorrhagic
Cardiovascular 307863 307863 0 0
Hypertension
Neurological 307864 307864 0 0
Dementias

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
TRIDENT:
Triple Pill (active treatment) - telmisartan 20mg, amlodipine 2.5mg and indapamide 1.25mg; taken orally, once daily for 36 months. Medication adherence and accountability is monitored through self-reports of doses missed and pill counts at every visit until end of treatment (Visits 3-9).

Cognitive Sub-study:
All participants who are involved in the start-up phase of the main study will be invited to participate in the Cognitive Sub-study. Consenting participants will undergo cognitive assessments using CANTAB, a well-validated cognitive assessment battery administered via iPad. This involves three computer-based assessment tasks:
• Paired Associates Learning (PAL)
• Rapid Visual Information Processing (RVP)
• Multitask Test (MTT)
Assessments will be carried out at baseline (6 months post-randomisation period), 18 months and 36 months.

Participants recruited from Sydney-based TRIDENT sites will also be offered the opportunity to undergo additional cognitive assessments at the BMC, University of Sydney using a battery of gold standard, paper-and-pencil neuropsychological tests at baseline (6 months post-randomisation), 18 months and 36 months. These tests may also be conducted at other TRIDENT centres with involvement of a trained neuropsychologist. The gold-standard assessments include:
• Trails A – assessing processing speed
• Trails B – assessing executive functioning
• Rey Auditory Verbal Learning Test (RAVLT) – assessing verbal learning and memory
• Delis-Kaplan Executive Functioning System (D-KEFS) “Stroop” Colour-Word Interference Test – assessing executive functioning
• Controlled Oral Word Association Test (COWAT) – assessing language
• Test of Premorbid Functioning (TOPF) – assessing pre-morbid intelligence for descriptive purposes
Intervention code [1] 301947 0
Diagnosis / Prognosis
Comparator / control treatment
TRIDENT: Placebo - commonly used excipients (to be determined) received via blinded study capsules
Control group
Placebo

Outcomes
Primary outcome [1] 306839 0
Memory as measured by the CANTAB PAL subtest. Raw scores and z-scores will be used. Change scores on the CANTAB PAL will be computed between baseline, 18 and 36 months (primary endpoint).
Timepoint [1] 306839 0
36 months
Secondary outcome [1] 349886 0
Change scores will be computed for CANTAB RVP between baseline, 18 and 36 months
Timepoint [1] 349886 0
36 months
Secondary outcome [2] 352751 0
Change scores will be computed for CANTAB MTT between baseline, 18 and 36 months
Timepoint [2] 352751 0
36 months
Secondary outcome [3] 352752 0
Change scores will be computed for gold-standard neuropsychological assessment (Trails A & B, D-KEFS Colour-Word Interference Test, RAVLT, COWAT and TOPF) between baseline, 18 and 36 months
Timepoint [3] 352752 0
36 months
Secondary outcome [4] 352753 0
Diagnosis of all-cause dementia as determined by consensus of three blinded adjudicators based on established criteria following collection of data of the 3-year study period
Timepoint [4] 352753 0
36 months

Eligibility
Key inclusion criteria
1. Eligible for, randomised and continuing in the TRIDENT Main Study
2. Must be able to attend the site conducting the cognitive assessments. In Sydney, this will either be at the same site as where TRIDENT study is conducted or at the BMC, University of Sydney, Camperdown.
3. Ability and willingness to undergo neuropsychological testing (i.e. have no major visual, auditory or motor impairments)
4. Language spoken compatible with CANTAB administration (i.e. CANTAB will be administered in the local language(s) of the country in question. E.g. in Australia, the CANTAB will only be administered in English).
5. Provision of written informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Study medication has been permanently stopped prior to or at the 6-month visit of the TRIDENT main study
2. Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) score of 3.3 or higher
3. Cognitive performance indicative of dementia at 6-month TRIDENT main study visit defined by Montreal Cognitive Assessment (MoCA) score less than 24.
4. Evidence of rapid deterioration suggestive of dementia by decline of 3 points in MoCA assessments between randomisation and the 6-month study visits in the TRIDENT main study

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Prior trials of dementia prevention targeting BP have achieved effect sizes of 0.3 to 0.4, We have therefore powered the Cognitive Sub-Study to detect at least a 0.3 SD relative difference in memory outcomes attributable to an expected greater than or equal to 7 mmHg SBP difference between groups (e.g. from an average baseline of 145 to 137 mmHg [placebo] vs. 130 mmHg [Triple Pill]). In the field of dementia prevention, even small effect size benefits are likely to confer public health benefits. The mean CANTAB PAL score is estimated to be 14.85 (SD = 6.5) at baseline (based on healthy control data and research showing that 75% of dementia-free ICH patients will exhibit mild cognitive decline of <1 SD). Given the natural slope of decline, performance is estimated to be 17.45 in the controls after two years. A sample of N=403 patients will provide 80% power (alpha=0.05) to detect a >0.3 SD effect size difference between groups (17.45 vs. 15.5, SD = 6.5), assuming equal group participation. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS), also coordinated by the TGI, was associated with a 14% attrition over a 4-year period. Our calculations thus assume a modest 15% dropout for the 2-year follow-up.

The intention-to-treat principle will be applied in the analysis. The primary endpoint of change on the CANTAB PAL will be summarised by means (SD) or medians (interquartile range [IQR]). The effect of treatment will preferably be tested by a Wilcoxon test. If the data is not skewed, general linear mixed models will be used to describe the change on CANTAB PAL over time and assess the effect of BP-lowering treatment.

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)
NSW
Recruitment hospital [1] 11492 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 23514 0
2170 - Liverpool
Recruitment outside Australia
Country [1] 20897 0
Netherlands
State/province [1] 20897 0
Country [2] 20898 0
Singapore
State/province [2] 20898 0

Funding & Sponsors
Funding source category [1] 297352 0
Charities/Societies/Foundations
Name [1] 297352 0
The National Heart Foundation of Australia (NHFA)
Address [1] 297352 0
Unit 1, Level 1, 17-23 Townshend Street, Phillip ACT, 2606
Country [1] 297352 0
Australia
Funding source category [2] 300214 0
Government body
Name [2] 300214 0
NHMRC
Address [2] 300214 0
Levels 4-6 Medical Foundation Building, 92-94 Parramatta Rd, Camperdown NSW, 2050
Country [2] 300214 0
Australia
Primary sponsor type
Other
Name
The George Institute
Address
83-117 Missenden Rd, Level 10, King George V Building, Camperdown, Postcode: 2050
Country
Australia
Secondary sponsor category [1] 296327 0
University
Name [1] 296327 0
Brain and Mind Centre, University of Sydney
Address [1] 296327 0
94 Mallett St, Camperdown NSW 2050
Country [1] 296327 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298448 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 298448 0
Royal Prince Alfred Hospital
Missenden Road, CAMPERDOWN, NSW, 2050
Ethics committee country [1] 298448 0
Australia
Date submitted for ethics approval [1] 298448 0
23/04/2018
Approval date [1] 298448 0
24/04/2018
Ethics approval number [1] 298448 0
HERC\EXECOR\18-04

Summary
Brief summary
Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial or ‘TRIDENT’, is investigating the effectiveness of more intensive blood pressure-lowering treatment to prevent recurrent stroke. As part of the TRIDENT study, we are inviting participants to the TRIDENT Cognitive Sub-study to assess the effectiveness of the TRIDENT blood pressure-lowering study treatment on cognition as assessed by neuropsychological tests. ‘Cognition’ is a term referring to memory and other thinking skills. These processes include speed of thinking, finding words, visual skills and problem-solving. Neuropsychological tests, also referred to as ‘cognitive assessments’ assess these mental processes.

Cerebral small vessel disease (CSVD) is a disease process in the brain involving small blood vessels. CSVD is common in people who have had a stroke caused by intracerebral haemorrhage (ICH) (large bleed in the brain). CSVD has been shown to be associated with dementia, memory problems, balance disturbances and other neurological conditions such as Parkinson’s disease.

CSVD is also known to be more common in people with high blood pressure or hypertension. There is uncertainty, however, if lowering blood pressure slows the progression of cognitive decline associated with CSVD. The purpose of this study is to investigate the effect of intensive blood pressure-lowering treatment on cognitive decline measured by specific neuropsychological tests.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77126 0
Prof Craig Anderson
Address 77126 0
The George Institute for Global Health, Australia
Level 10, King George V Building, 83-117 Missenden Rd, Camperdown NSW 2050
Country 77126 0
Australia
Phone 77126 0
+61 2 8052 4521
Fax 77126 0
Email 77126 0
canderson@georgeinstitute.org.au
Contact person for public queries
Name 77127 0
Ms Ruth Freed
Address 77127 0
The George Institute for Global Health, Australia
Level 10, King George V Building, 83-117 Missenden Rd, Camperdown NSW 2050
Country 77127 0
Australia
Phone 77127 0
+61 2 8052 4522
Fax 77127 0
Email 77127 0
rfreed@georgeinstitute.org.au
Contact person for scientific queries
Name 77128 0
Prof Craig Anderson
Address 77128 0
The George Institute for Global Health, Australia
Level 10, King George V Building, 83-117 Missenden Rd, Camperdown NSW 2050
Country 77128 0
Australia
Phone 77128 0
+61 2 8052 4521
Fax 77128 0
Email 77128 0
canderson@georgeinstitute.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
privacy laws
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable