Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial

Study Overview
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Brief Summary
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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 time to first occurrence of recurrent stroke in patients with a history of stroke due to intracerebral haemorrhage.

Detailed Description
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Intracerebral haemorrhage (ICH) is the most serious and least treatable form of stroke, accounting for at least 10% of the 20 million new strokes that occur globally 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 blood pressure (BP) of patients after ICH, many patients with ICH do not receive BP-lowering treatment long-term unless BP levels are particularly high, and many do not receive BP combination therapy. The aim of this study is to assess the safety and efficacy 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. The study is a large-scale, international, double-blind, placebo-controlled, randomised controlled trial.

Official Title
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Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT), Substudies: MRI, Cognitive

Conditions
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Intracerebral Haemorrhage (ICH), Hypertension

Intervention / Treatment
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* Drug: telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥18 years) with a history of up to 12 months after symptom onset 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 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 Exclusion Criteria: Taking an ACE-I that cannot be switched to any of the following alternatives: telmisartan 20 or 40mg, amlodipine 2.5 or 5mg, indapamide 1.25mg, or an equivalent class (ARB, CCB or thiazide [TZ]-like diuretic), or a BB Contraindication to any of the study medications, in the context of currently prescribed BP-lowering medication 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Triple Pill (active treatment)<br>telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg; | Drug: telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg<br>* 1 capsule taken orally once daily for average of 72 months<br>* Other names: Triple Pill;|
| Placebo Comparator: Placebo<br>received via blinded study capsules | Drug: Placebo<br>* 1 capsule taken orally once daily for average of 72 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrent Stroke | Time to first occurrence of recurrent stroke, whether ischaemic or haemorrhagic. | Average of 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrent ICH | Time to first occurrence of recurrent ICH | Average of 6 years | 
| Ischaemic Stroke | Time to first occurrence of ischaemic stroke | Average of 6 years | 
| Fatal or disabling stroke | Time to first occurrence of fatal or disabling stroke | Average of 6 years | 
| Mortality | Mortality | Average of 6 years | 
| MACE | Major adverse cardiovascular events - CV death, non-fatal MI or non-fatal stroke | Average of 6 years | 
| Physical function | Physical function as assessed by smRS | Average of 6 years | 
| Change in SBP | Change in SBP | Average of 6 years | 
| HRQoL according to the EQ-5D-3L | Health-related quality of life according to the European Quality of Life 5-Dimensional Assessment, 3-Level version | Average of 6 years | 
| Cognitive Impairment | Overall defined by standard cut-points on the Montreal Cognitive Assessment (MoCA) | Average of 6 years | 
| Cognitive Impairment Supplement | Overall defined by standard cut-points with Brief Memory and Executive Test (BMET) | Average of 6 years | 
| Medication Adherence | Self-reported measures, Pill counts | Average of 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood Pressure (BP), Stroke