Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000327482
Ethics application status
Approved
Date submitted
7/03/2016
Date registered
11/03/2016
Date last updated
22/04/2024
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): Effect of intensive blood pressure lowering treatment provided by a Triple Pill strategy on the time to first occurence of recurrent stroke in patients with a history of acute stroke due to intracerebral haemorrhage.
Scientific title
An investigator initiated and conducted, multicentre, international, double-blinded, placebo-controlled, parallel-group, randomised controlled trial to determine the effect of more intensive blood pressure control provided by a fixed low-dose combination blood pressure lowering pill (“Triple Pill”) strategy on top of standard of care, on the on time to first occurrence of recurrent stroke in patients with a history of acute stroke due to intracerebral haemorrhage (TRIDENT).
Secondary ID [1] 288692 0
None
Secondary ID [2] 296230 0
ClinicalTrials.gov Identifier: NCT02699645
Universal Trial Number (UTN)
Trial acronym
TRIDENT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke caused by Intracerebral Haemorrhage (ICH) 297906 0
Hypertension 297963 0
Condition category
Condition code
Stroke 298073 298073 0 0
Haemorrhagic
Cardiovascular 298123 298123 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Triple Pill (active treatment) - telmisartan 20mg, amlodipine 2.5mg and indapamide 1.25mg; taken orally, once daily until end of study.
The study is event-driven, with the average follow-up treatment period for participants being 3 years. The study will end after the required number of primary endpoints have been reported.
Medication adherence and accountability is monitored through self-reports of doses missed and pill counts at every visit until end of treatment.
Intervention code [1] 294117 0
Treatment: Drugs
Comparator / control treatment
Placebo - commonly used excipients received via blinded pills.
Control group
Placebo

Outcomes
Primary outcome [1] 297589 0
The time to first occurrence of recurrent stroke, whether ischaemic or haemorrhagic, assessed by patient and/or clinical report verified by medical documentation of stroke symptoms and imaging.
Timepoint [1] 297589 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [1] 321515 0
Recurrent ICH, assessed by patient and/or clinical report verified by medical documentation of stroke symptoms and imaging
Timepoint [1] 321515 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [2] 321623 0
Ischaemic Stroke, assessed by patient and/or clinical report verified by medical documentation of stroke symptoms and imaging.
Timepoint [2] 321623 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [3] 321624 0
Fatal or disabling stroke, assessed by patient and/or clinical report verified by medical documentation of stroke symptoms and imaging.
Timepoint [3] 321624 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [4] 321625 0
Mortality, assessed by review of medical records
Timepoint [4] 321625 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [5] 321626 0
Occurrence of MACE (major adverse CV events - CV death, non-fatal myocardial infarction, or non-fatal stroke), assessed by patient report verified by medical records and investigations
Timepoint [5] 321626 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [6] 321627 0
Physical function assessed by Modified Rankin Scale (mRS) assessed during follow up clinic visits
Timepoint [6] 321627 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [7] 321628 0
Change in systolic blood pressure (BP) assessed by sphygmomanometer during follow up clinic visits
Timepoint [7] 321628 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [8] 321629 0
Health-related Quality of Life (HRQoL) according to the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) assessed during follow up clinic visits
Timepoint [8] 321629 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [9] 321630 0
Clinically significant cognitive impairment, overall defined by standard cut-points on the MoCA
and supplemented with the BMET together with assessments of functional impairment related to cognition defined by QDRS score and short form IQCODE, which will also allow subtyping of ‘probable’ or ‘definite’ dementia or mild cognitive impairment according to standard diagnostic criteria.
Timepoint [9] 321630 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [10] 321631 0
Medical adherence assessed by self-reported measures and pill counts
Timepoint [10] 321631 0
Reviewed 6-monthly; participant follow-up, 6 years
Secondary outcome [11] 434334 0
Depression, according to standard cut-point scores on the PHQ-9.
Timepoint [11] 434334 0
Secondary outcome [12] 434335 0
Depression, according to standard cut-point scores on the PHQ-9.
Timepoint [12] 434335 0
Penultimate visit
Secondary outcome [13] 434336 0
Cerebral small vessel disease defined by various standard markers on routine MRI, measured by
individual components and overall CSVD burden. The primary measure of CSVD is FLAIR WMH
volume.
Timepoint [13] 434336 0
Penultimate visit
Secondary outcome [14] 434337 0
Cerebral small vessel disease defined by various standard markers on routine MRI, measured by
individual components and overall CSVD burden. The primary measure of CSVD is FLAIR WMH
volume.
Timepoint [14] 434337 0
At penultimate visit

Eligibility
Key inclusion criteria
• Adults (greater than or equal to 18 years) with a history of primary ICH that is confirmed by imaging (copy of the brain imaging report to be uploaded to the database, labelled with participant identification (ID) and with personal identifiers removed)
• Clinically stable, as judged by investigator
• Average of two resting SBP levels measured 5 minutes apart in the range 130-160mmHg recorded in a seated position (National Heart Foundation of Australia [NHF] Guidelines). (Patients with higher SBP can be included if considered by attending clinician that management is consistent with local standards of clinical practice)
• Geographical proximity to the recruiting hospital and/or follow-up medical clinic site to allow ready access for in-person clinic visits during follow-up
• No clear contraindication to any of the study treatments
• Provision of written informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Taking an ACE-I that cannot be switched to any of the following alternatives
o telmisartan 20 or 40mg, amlodipine 2.5 or 5mg, indapamide 1.25mg, or
o an equivalent class (ARB, CCB or thiazide [TZ]-like diuretic), or
o a beta-blocker (BB)
• Contraindication to any of the study medications, in the context of currently prescribed BP-lowering medication

Exclusion Criteria for MRI (as applies)
• Any MRI contraindication (e.g. metallic implants, claustrophobia, etc) or participant refusal
• Unable to complete the study procedures and/or follow-up
• Females of child-bearing age and capability, who are pregnant or breast-feeding, or those of child-bearing age and capability who are not using adequate birth control
• Significant hyperkalaemia and/or hyponatremia, in the opinion of the responsible physician
• Estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2
• Severe hepatic impairment (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3x the upper limit of normal [ULN])
• Any other condition that in the opinion of the responsible physician investigator renders the patient unsuitable for the study (e.g. severe disability [i.e. simplified modified Rankin Scale (smRS) of 4-5] or significant memory or behavioural disorder)

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2016
Actual
7/09/2017
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1800
Accrual to date
1601
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 10267 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 10268 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [3] 10270 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [4] 12060 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [5] 14100 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [6] 15451 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 21934 0
2170 - Liverpool
Recruitment postcode(s) [2] 21935 0
2444 - Port Macquarie
Recruitment postcode(s) [3] 21937 0
4575 - Birtinya
Recruitment postcode(s) [4] 24217 0
3050 - Parkville
Recruitment postcode(s) [5] 26891 0
6150 - Murdoch
Recruitment postcode(s) [6] 28801 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 7647 0
United Kingdom
State/province [1] 7647 0
Edinburgh, Nottingham, Kirkcaldy, Exeter, Glasgow, Stoke-on-Trent, Sheffield, Salford
Country [2] 7649 0
Brazil
State/province [2] 7649 0
Porto Alegre, Ribeirão Preto, Vila Clementino, Botucatu, Joinville, São José do Rio Preto, Fortaleza, Brasília, Curitiba
Country [3] 7651 0
Sri Lanka
State/province [3] 7651 0
Colombo, Nugegoda, Kurunegala, Peradeniya, Kandy, Ragama, Dehiwala, Jaffna, Galle, Gampaha
Country [4] 9238 0
Netherlands
State/province [4] 9238 0
Nijmegen, Maastricht, Heerlen
Country [5] 21646 0
Nigeria
State/province [5] 21646 0
Ilorin, Shika Zaria, Ibadan
Country [6] 21647 0
Georgia
State/province [6] 21647 0
Tbilisi

Funding & Sponsors
Funding source category [1] 293056 0
Government body
Name [1] 293056 0
National Health and Medical Research Council
Country [1] 293056 0
Australia
Primary sponsor type
Other
Name
The George Institute for Global Health
Address
Level 10 King George V Building, 83-117 Missenden Road, Camperdown, NSW 2050
Country
Australia
Secondary sponsor category [1] 291835 0
None
Name [1] 291835 0
Address [1] 291835 0
Country [1] 291835 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294564 0
Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Hospital (RPAH) Zone)
Ethics committee address [1] 294564 0
Royal Prince Alfred Hospital
Missenden Road, CAMPERDOWN, NSW, 2050
Ethics committee country [1] 294564 0
Australia
Date submitted for ethics approval [1] 294564 0
07/03/2016
Approval date [1] 294564 0
30/06/2016
Ethics approval number [1] 294564 0
16/RPAH/100

Summary
Brief summary
Acute intracerebral haemorrhage (ICH) is the most serious and least treatable form of stroke, accounting for at least 10% of the 20 million new strokes (including 50,000+ Australians) that occur in the world each year. Survivors of ICH are at high risk of recurrent ICH and other serious cardiovascular events. While there is strong evidence that this risk can be reduced by lowering the BP of patients after ICH, such as from the PROGRESS trial undertaken by several of the applicants, many patients with ICH do not receive blood pressure lowering and if they do, receive treatment so that their BP is inadequately controlled.

The aim of this study is to demonstrate the superiority of a combination of fixed low-dose generic BP lowering agents as a “Triple Pill” strategy on top of standard of care for the prevention of recurrent stroke in patients with a history of ICH and high normal or low grade hypertension in a large-scale, international, double-blind, placebo-controlled, randomised controlled trial.
Trial website
www.tridentstudy.org
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64150 0
Prof Craig Anderson
Address 64150 0
The George Institute for Global Health, Level 18, International Tower 3, 300 Barangaroo Avenue, Sydney, New South Wales 2000, Australia
Country 64150 0
Australia
Phone 64150 0
+61 2 9993 4521
Fax 64150 0
Email 64150 0
[email protected]
Contact person for public queries
Name 64151 0
Ms Ruth Freed
Address 64151 0
The George Institute for Global Health, Level 18, International Tower 3, 300 Barangaroo Avenue, Sydney, New South Wales 2000, Australia
Country 64151 0
Australia
Phone 64151 0
+61 2 9993 4522
Fax 64151 0
Email 64151 0
[email protected]
Contact person for scientific queries
Name 64152 0
Prof Craig Anderson
Address 64152 0
The George Institute for Global Health, Level 18, International Tower 3, 300 Barangaroo Avenue, Sydney, New South Wales 2000, Australia
Country 64152 0
Australia
Phone 64152 0
+61 2 9993 4521
Fax 64152 0
Email 64152 0
[email protected]

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


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
SourceTitleYear of PublicationDOI
EmbaseTriple Therapy Prevention of Recurrent Intracerebral Disease Events Trial: Rationale, design and progress.2022https://dx.doi.org/10.1177/17474930211068671
N.B. These documents automatically identified may not have been verified by the study sponsor.