Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Intracerebral Haemorrhage (ICH)
• Intervention / Treatment: Drug: telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 1600
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ruth Freed; Phone Number: +61 2 8052 4522; Email: rfreed@georgeinstitute.org.au
• Study Contact Backup: Name: Natalie Espinosa; Phone Number: +61 2 8052 4561; Email: nespinosa@georgeinstitute.org.au

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Active, not recruiting
      • Liverpool Hospital
    • Port Macquarie, New South Wales, Australia, 2444
      • Active, not recruiting
      • Port Macquarie Base Hospital
    • Sydney, New South Wales, Australia, 2050
      • Completed
      • Royal Prince Alfred Hospital
  • Queensland
    • Birtinya, Queensland, Australia, 4575
      • Active, not recruiting
      • Sunshine Coast University Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Active, not recruiting
      • Princess Alexandra Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Completed
      • Royal Melbourne Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Active, not recruiting
      • Fiona Stanley Hospital
• Brazil
  • Botucatu, Brazil
    • Active, not recruiting
    • Hospital das Clínicas de Botucatu
  • Curitiba, Brazil
    • Active, not recruiting
    • Instituto Flumignano de Medicina
  • Fortaleza, Brazil
    • Active, not recruiting
    • Hospital Geral de Fortaleza
  • Joinville, Brazil
    • Active, not recruiting
    • Clínica Neurológica e Neurocirurgica de Joinville
  • Porto Alegre, Brazil
    • Active, not recruiting
    • Hospital das Clínicas de Porto Alegre
  • Porto Alegre, Brazil
    • Active, not recruiting
    • Hospital Moinhos de Vento
  • Ribeirão Preto, Brazil
    • Active, not recruiting
    • Hospital das Clínicas de Ribeirão Preto
  • Rio Prêto, Brazil
    • Active, not recruiting
    • Hospital de Base São José do Rio Preto
  • Salvador, Brazil
    • Active, not recruiting
    • Hospital da Bahia
  • São Paulo, Brazil
    • Active, not recruiting
    • Irmandade da Santa Casa de Misericórdia de Matão
  • São Paulo, Brazil
    • Active, not recruiting
    • Universidade Federal de São Paulo
• Georgia
  • Tbilisi, Georgia, 0112
    • Active, not recruiting
    • LTD Pineo Medical Ecosystem
  • Tbilisi, Georgia, 0141
    • Active, not recruiting
    • The First University Clinic of Tbilisi State Medical University
  • Tbilisi, Georgia, 0179
    • Active, not recruiting
    • LTD S. Khechinashvili University Hospital
  • Tbilisi, Georgia, 0144
    • Active, not recruiting
    • LTD Urgent Neurological Clinic "Neurology"
• Malaysia
  • Hulu Langat, Malaysia
    • Completed
    • University Kebangsaan Malaysia Medical Centre
  • Kota Kinabalu, Malaysia
    • Completed
    • Hospital Queen Elizabeth
  • Kubang Kerian, Malaysia
    • Completed
    • Hospital Universiti Sains Malaysia
  • Kuching, Malaysia
    • Completed
    • Sarawak General Hospital
  • Pulau Pinang, Malaysia
    • Completed
    • Hospital Seberang Jaya
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Completed
    • Academic Medical Center
  • Arnhem, Netherlands, 6815 AD
    • Completed
    • Rijnstate Hospital
  • Heerlen, Netherlands, 6419 PC
    • Active, not recruiting
    • Zuyderland Medical Centre
  • Maastricht, Netherlands
    • Active, not recruiting
    • Maastricht University Medical Center
  • Nijmegen, Netherlands, 6525 GC
    • Active, not recruiting
    • Radboud University Medical Center
  • Utrecht, Netherlands
    • Completed
    • University Medical Centre, Utrecht
• Nigeria
  • Ibadan, Nigeria
    • Active, not recruiting
    • University College Hospital Ibadan
  • Ilorin, Nigeria
    • Active, not recruiting
    • University of Ilorin
  • Jos, Nigeria
    • Completed
    • Jos University Teaching Hospital
  • Lagos, Nigeria
    • Completed
    • Lagos University Teaching Hospital, Lagos
  • Zaria, Nigeria
    • Active, not recruiting
    • Ahmadu Bello University Teaching Hospital
• Singapore
  • Singapore, Singapore
    • Completed
    • National University Hospital
• Sri Lanka
  • Colombo, Sri Lanka
    • Recruiting
    • National Hospital of Sri Lanka
    • Principal Investigator: Bimsara Senanayake
    • Contact: Sonali Liyanagamage; Email: sonali@remediumone.com
  • Colombo, Sri Lanka
    • Active, not recruiting
    • Colombo North Teaching Hospital
  • Colombo, Sri Lanka
    • Active, not recruiting
    • Kalubowila (Colombo South) Teaching Hospital
  • Galle, Sri Lanka
    • Recruiting
    • Karapitiya Teaching Hospital
    • Contact: Charika Rajinee; Email: charika@remediumone.com
    • Principal Investigator: Damith Liyanage
  • Gampaha, Sri Lanka, 11000
    • Active, not recruiting
    • Gampaha District General Hospital
  • Jaffna, Sri Lanka, 40000
    • Recruiting
    • Jaffna Teaching Hospital
    • Principal Investigator: Ajantha Keshavaraj
  • Kandy, Sri Lanka, 20000
    • Active, not recruiting
    • Kandy Teaching Hospital
  • Kurunegala, Sri Lanka
    • Recruiting
    • Teaching Hospital Kurunegala
    • Contact: Jayani Sumanapala; Email: jayani@remediumone.com
    • Principal Investigator: Dilum Palliyeguruge
  • Nugegoda, Sri Lanka
    • Active, not recruiting
    • Sri Jayewardenepura General Hospital
  • Peradeniya, Sri Lanka
    • Active, not recruiting
    • Peradeniya Teaching Hospital
  • Ragama, Sri Lanka, 11010
    • Recruiting
    • Ragama Teaching Hospital
    • Contact: Prathishka Nelushani; Email: prathishka@remediumone.com
    • Principal Investigator: Dharshana Wijegunasinghe
• Switzerland
  • Zürich, Switzerland
    • Completed
    • University Hospital Zurich
• Taiwan
  • Chiayi City, Taiwan
    • Completed
    • Chiayi Chang Gung Memorial Hospital
  • Kaohsiung, Taiwan, 833
    • Completed
    • Kaohsiung Chang Gung Memorial Hospital
  • Keelung, Taiwan, 204
    • Completed
    • Keelung Chang Gung Memorial Hospital
  • Taoyuan, Taiwan, 333
    • Completed
    • Linkou Chang Gung Memorial Hospital
• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SB
    • Active, not recruiting
    • Royal Infirmary Edinburgh
  • Exeter, United Kingdom, EX2 5DW
    • Active, not recruiting
    • Royal Devon & Exeter Hospital
  • Glasgow, United Kingdom, G51 4TF
    • Active, not recruiting
    • Queen Elizabeth University Hospital
  • Kirkcaldy, United Kingdom, KY2 5AH
    • Active, not recruiting
    • Victoria Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Active, not recruiting
    • Nottingham City Hospital
  • Salford, United Kingdom, M6 8HD
    • Active, not recruiting
    • Salford Royal Hospital
  • Sheffield, United Kingdom, S10 2JF
    • Active, not recruiting
    • Royal Hallamshire Hospital
  • Stoke-on-Trent, United Kingdom, T4 6QG
    • Active, not recruiting
    • Royal Stoke University Hospital
  • Swansea, United Kingdom, SA6 6NL
    • Active, not recruiting
    • Morriston Hospital
• Vietnam
  • Hanoi, Vietnam
    • Completed
    • Military Central Hospital 108

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults (≥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 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 or 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)

Exclusion Criteria for MRI (as applies)

• Any MRI contraindication (e.g. metallic implants, claustrophobia, etc) or participant refusal.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matched placebo	Drug: Placebo; 1 pill taken orally once daily for average of 72 months
Experimental: Triple Pill (active treatment); telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg;	Drug: telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg; 1 pill taken orally once daily for average of 72 months; Other Names: Triple Pill

What is the study measuring?

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) 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.	Average of 6 years
Depression	According to standard cut-point scores on the PHQ-9	Average of 6 years
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.	Average of 6 years
Medication Adherence	Self-reported measures, pill counts	Average of 6 years
Safety in terms of Serious Adverse Events (SAEs)	SAEs	Average of 6 years
Tolerability in terms of Adverse Events of Special Interest (AESIs)	AESIs: Headache, Syncope/collapse, Falls, Pedal oedema/ankle swelling, Hypo/hyperkalaemia, Hyponatraemia	Average of 6 years

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: The University of New South Wales
• Investigators: Principal Investigator: Craig Anderson, The George Institute

Publications and helpful links

General Publications

• Li L, Poon MTC, Samarasekera NE, Perry LA, Moullaali TJ, Rodrigues MA, Loan JJM, Stephen J, Lerpiniere C, Tuna MA, Gutnikov SA, Kuker W, Silver LE, Al-Shahi Salman R, Rothwell PM. Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies. Lancet Neurol. 2021 Jun;20(6):437-447. doi: 10.1016/S1474-4422(21)00075-2. Erratum In: Lancet Neurol. 2021 Jun 9;:

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2017
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: March 2, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (Estimated): March 4, 2016

Study Record Updates

• Last Update Posted (Estimated): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Stroke; Blood Pressure (BP)
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; 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-1103886

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: 2 years after publication of main results
• IPD Sharing Access Criteria: Bone fide researchers submit protocol to the Research Office of The George Institute for Global Health
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No