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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 acute stroke due to intracerebral hemorrhage. -

SLCTR Registration Number

SLCTR/2017/030


Date of Registration

19 Sep 2017

The date of last modification

Sep 19, 2017



Application Summary


Scientific Title of Trial

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 acute stroke due to intracerebral hemorrhage.


Public Title of Trial

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 occurrence of recurrent stroke in patients with a history of acute stroke due to intracerebral haemorrhage.


Disease of Health Condition(s) Studied

Stroke caused by Intracerebral Hemorrhage (ICH), Hypertension


Scientific Acronym

TRIDENT


Public Acronym

TRIDENT


Brief title

Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial(TRIDENT)


Universal Trail Number

None


Any other number(s) assigned to the trial and issuing authority

NCT02699645 (ClinicalTrials.gov), ANZCTR: 12616000327482 (Australian New Zealand Clinical Trials Registry)


Trial Details


What is the research question being addressed?

Can the superiority of a combination of fixed low-dose generic blood pressure lowering agents as a “Triple Pill” strategy on top of standard of care prevent recurrent stroke in patients with a history of ICH and high normal or low-grade hypertension?


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Double blinded


Control

Placebo


Assignment

Parallel


Purpose

Prevention


Intervention(s) planned

  1. Study sites • National Hospital of Sri Lanka • Sri Jayewardenepura General Hospital • Colombo North Teaching Hospital, Ragama • Kurunegala Teaching Hospital • Peradeniya Teaching Hospital

  2. Method of randomization: via a secure web-based internet system. The randomization ratio will be 1:1, and will be stratified to ensure balance in prognostic factors: country of recruitment, age (<65 vs. >65 years) and average of 2 recorded baseline systolic BP measurements (<140 vs >140mmHg).

  3. The double-blind period will be preceded by a single-blind (participants will remain blind), active run-in phase to ensure tolerability and adherence of the regimen. This will last a minimum of 2 weeks and may be extended for a further 2 weeks if the first period was interrupted, problematic or another reason (maximum 4 weeks run-in phase)

  4. All randomized participants will receive study medication for an average of three years.

  5. Interventions Experimental arm: Triple Pill (active treatment) telmisartan 20mg, amlodipine 2.5mg, and indapamide 1.25mg. 1 capsule taken orally once daily for 36 months

  6. Placebo Comparator: Placebo Received via blinded study capsules. 1 capsule taken orally once daily for 36 months


Inclusion criteria

  1. Male and female adults (>18 years) with a history of up to 6 months after symptom onset of primary ICH that is confirmed by imaging (copy of the brain imaging report to be submitted to the Central Coordinating Centre (CCC) labelled with study ID and with personal identifiers removed)

  2. Clinically stable, as judged by investigator

  3. Two resting systolic blood pressure (SBP) levels measured 5 minutes apart in the range 130-160mmHg recorded in a seated position (Patients with higher SBP can be included if considered by attending clinician that management is consistent with local standards of clinical practice)

  4. 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

  5. Provision of written informed consent


Exclusion criteria

  1. Taking an ACE-I that cannot be switched to any of the following alternatives: • telmisartan 20 or 40mg, amlodipine 2.5 or 5mg, indapamide 1.25 or 2.5mg, or • an equivalent class (ARB, CCB or thiazide-like diuretic), or • a beta-blocker

  2. Contraindication to any of the study medications, in the context of currently prescribed lowering medication

  3. Unlikely/unable to complete the study procedures and/or follow-up

  4. Females of child bearing age and capability, who are pregnant or breast-feeding, or those not Using adequate birth control



Primary outcome(s)

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.


Primary outcome(s) - Time of assessment(s)

6 monthly from commencement for a total of 3 years


Secondary outcome

  1. Recurrent ICH, ischaemic stroke, fatal or disabling stroke, mortality
  2. MACE (major adverse cardiovascular [CV] events of CV death, non-fatal myocardial infarction, or non-fatal stroke)
  3. Health-related quality of life (HRQoL) using the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D)
  4. Physical function (simplified modified Rankin scale [smRS]),
  5. Cognitive impairment, defined by standard cut-points on the Montreal Cognitive Assessments (MoCA), and supplemented by the Brief Memory and Executive Test.

Secondary outcome(s) - Time of assessment(s)

  1. Recurrent ICH, ischaemic stroke, fatal or disabling stroke, mortality
  2. MACE (major adverse cardiovascular [CV] events of CV death, non-fatal myocardial infarction, or non-fatal stroke)
  3. Health-related quality of life (HRQoL) using the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D)
  4. Physical function (simplified modified Rankin scale [smRS]),
  5. Cognitive impairment, defined by standard cut-points on the Montreal Cognitive Assessments (MoCA), and supplemented by the Brief Memory and Executive Test.


Target number/sample size

500 subjects from Sri Lanka (250 in each arm)


Countries of recruitment

Australia, Japan, Netherlands, Sri Lanka, Taiwan, Province of China, United Kingdom


Anticipated start date

2017-09-25


Anticipated end date

2023-08-01


Recruitment status

Pending


State of ethics review approval

Approved by the Ethics Review Committee, Faculty of Medicine, University of Kelaniya on 14 Mar 2017 (P/112/03/2017)


Funding source

National Health and Medical Research Council (NHMRC) of Australia (Grant number: APP1103886)



Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Dr Bimsara Senanayake
Consultant Neurologist
National Hospital of Sri Lanka Colombo 10

94773046096

bimsaras@sltnet.lk

Contact Person for Public Queries

Dr Bimsara Senanayake
Consultant Neurologist
National Hospital of Sri Lanka Colombo 10

94773046096



Primary study sponsor/organization

The George Institute for Global Health

The University of Sydney Level 10, King George V Building, 83-117 Missenden Rd Camperdown NSW 2050 Australia
+61 2 8052 4500
+61 2 8052 4501
TRIDENT@georgeinsitute.org.au

Secondary study sponsor (If any)

None