Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT) Cognitive Sub-Study (TRIDENT COG)

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).

Study Overview

• Status: Terminated
• Conditions: Hypertension; Cerebral Small Vessel Diseases; Dementia, Vascular; Stroke Hemorrhagic; Cognitive Decline; Intracerebral Hemorrhage
• Intervention / Treatment: Drug: telmisartan 20mg + amlodipine 2.5mg +indapamide 1.25mg; Drug: Placebo oral capsule

Detailed Description

Cognitive decline and dementia in ICH is high due to the common underlying vasculopathy of cerebral small vessel disease (CSVD). However, in general, detailed cognitive outcomes in ICH have been neglected, possibly due to the high mortality rate of ICH (up to 60% within the first year).

Blood pressure (BP) management in those with ICH has been suboptimal. Most hypertensive patients need more than two medications. Combination therapy may improve adherence and BP reduction and reduce cardiovascular (CV) event rates. In the main TRIDENT study, it is hypothesised that a fixed low-dose triple combination BP-lowering agent, termed the 'Triple Pill' will prevent recurrent stroke. The Triple Pill is composed of a single capsule containing either a combination of telmisartan 20 mg, amlodipine 2.5 mg and indapamide 1.25 mg, or placebo.

In addition to achieving optimal BP control, the Triple Pill also has the capacity to slow cognitive decline and dementia in ICH survivors. Research shows that elevated BP is associated with Alzheimer's disease and vascular dementia, even after accounting for prior stroke or transient ischaemic attack, and large scale prospective studies have shown a 50% reduction in dementia when BP is managed appropriately

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • Sydney, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Netherlands
  • Nijmegen, Netherlands, 6525 GC
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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 3.313 or higher
3. Cognitive performance indicative of dementia at 6-month TRIDENT main study visit defined by Montreal Cognitive Assessment (MoCA) score less than 2414.
4. Evidence of rapid deterioration suggestive of dementia by decline of 3 points in MoCA assessments between randomisation and the 6-month study visit in the TRIDENT main study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Triple Pill (Active Treatment); Main Study: Fixed low-dose combination BP-lowering pill ("Triple Pill") telmisartan 20mg + amlodipine 2.5mg + indapamide 1.25mg Sub-Study: single-arm	Drug: telmisartan 20mg + amlodipine 2.5mg +indapamide 1.25mg; 1 capsule taken orally once daily for 36 months; Other Names: Triple Pill
Placebo Comparator: Placebo; Main Study: Matched placebo, received via blinded study capsules Sub-Study: single-arm	Drug: Placebo oral capsule; 1 capsule taken orally once daily for 36 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Memory as measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (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).	Baseline, 18 and 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change scores will be computed for CANTAB Rapid Visual Information Processing (RVP)	Change scores will be computed for CANTAB RVP between baseline, 18 and 36 months	Baseline, 18 and 36 months
Change scores will be computed for CANTAB Multi-tasking Test (MTT)	Change scores will be computed for CANTAB MTT between baseline, 18 and 36 months	Baseline, 18 and 36 months
Change scores will be computed for gold-standard neuropsychological assessments	Change scores will be computed for gold-standard neuropsychological assessment between baseline, 18 and 36 months	Baseline, 18 and 36 months
Diagnosis of all-cause dementia	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	36 months

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: University of Sydney
• Investigators: Principal Investigator: Prof Craig Anderson, The George Institute; Principal Investigator: Prof Sharon Naismith, University of Sydney

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2020
• Primary Completion (Actual): February 3, 2021
• Study Completion (Actual): February 3, 2021

Study Registration Dates

• First Submitted: December 6, 2018
• First Submitted That Met QC Criteria: December 19, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): April 1, 2021
• Last Update Submitted That Met QC Criteria: March 29, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: TRIDENT
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Dementia; Cognition Disorders; Stroke; Intracranial Arterial Diseases; Intracranial Hemorrhages; Intracranial Arteriosclerosis; Leukoencephalopathies; Hemorrhage; Cognitive Dysfunction; Cerebral Hemorrhage; Dementia, Vascular; Hemorrhagic Stroke; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Amlodipine; Telmisartan; Indapamide
• Other Study ID Numbers: TRIDENT COG

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No