Clinical trial NCT02699645: Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial
Official title: Triple Therapy Prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT), Substudies: MRI, Cognitive
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Intracerebral Haemorrhage (ICH)
Hypertension
Keywords: Blood Pressure (BP)
Stroke
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: The University of New South Wales
First posted: 2016-03-04
Enrollment: 1600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Recurrent Stroke
timeFrame: Average of 6 years
Secondary outcomes:
measure: Recurrent ICH
timeFrame: Average of 6 years
measure: Ischaemic Stroke
timeFrame: Average of 6 years
measure: Fatal or disabling stroke
timeFrame: Average of 6 years
measure: Mortality
timeFrame: Average of 6 years
measure: MACE
timeFrame: Average of 6 years
measure: Physical function
timeFrame: Average of 6 years
measure: Change in SBP
timeFrame: Average of 6 years
measure: HRQoL according to the EQ-5D-3L
timeFrame: Average of 6 years
measure: Cognitive Impairment
timeFrame: Average of 6 years
measure: Cognitive Impairment Supplement
timeFrame: Average of 6 years
measure: Depression
timeFrame: Average of 6 years
measure: Cerebral small vessel disease
timeFrame: Average of 6 years
measure: Medication Adherence
timeFrame: Average of 6 years
measure: Safety in terms of Serious Adverse Events (SAEs)
timeFrame: Average of 6 years
measure: Tolerability in terms of Adverse Events of Special Interest (AESIs)
timeFrame: Average of 6 years
Other outcomes:
Locations:
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Botucatu
country: Brazil
facility: Hospital das Clínicas de Botucatu
city: Curitiba
country: Brazil
facility: Instituto Flumignano de Medicina
city: Fortaleza
country: Brazil
facility: Hospital Geral de Fortaleza
city: Joinville
country: Brazil
facility: Clínica Neurológica e Neurocirurgica de Joinville
city: Porto Alegre
country: Brazil
facility: Hospital das Clínicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas de Ribeirão Preto
city: Rio Prêto
country: Brazil
facility: Hospital de Base São José do Rio Preto
city: Salvador
country: Brazil
facility: Hospital da Bahia
city: São Paulo
country: Brazil
facility: Irmandade da Santa Casa de Misericórdia de Matão
city: São Paulo
country: Brazil
facility: Universidade Federal de São Paulo
city: Tbilisi
country: Georgia
facility: LTD Pineo Medical Ecosystem
city: Tbilisi
country: Georgia
facility: The First University Clinic of Tbilisi State Medical University
city: Tbilisi
country: Georgia
facility: LTD Urgent Neurological Clinic "Neurology"
city: Tbilisi
country: Georgia
facility: LTD S. Khechinashvili University Hospital
city: Hulu Langat
country: Malaysia
facility: University Kebangsaan Malaysia Medical Centre
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth
city: Kubang Kerian
country: Malaysia
facility: Hospital Universiti Sains Malaysia
city: Kuching
country: Malaysia
facility: Sarawak General Hospital
city: Pulau Pinang
country: Malaysia
facility: Hospital Seberang Jaya
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Heerlen
country: Netherlands
facility: Zuyderland Medical Centre
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Utrecht
country: Netherlands
facility: University Medical Centre, Utrecht
city: Ibadan
country: Nigeria
facility: University College Hospital Ibadan
city: Ilorin
country: Nigeria
facility: University of Ilorin
city: Jos
country: Nigeria
facility: Jos University Teaching Hospital
city: Lagos
country: Nigeria
facility: Lagos University Teaching Hospital, Lagos
city: Zaria
country: Nigeria
facility: Ahmadu Bello University Teaching Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Colombo
country: Sri Lanka
facility: Colombo North Teaching Hospital
city: Colombo
country: Sri Lanka
facility: Kalubowila (Colombo South) Teaching Hospital
city: Colombo
country: Sri Lanka
facility: National Hospital of Sri Lanka
city: Galle
country: Sri Lanka
facility: Karapitiya Teaching Hospital
city: Gampaha
country: Sri Lanka
facility: Gampaha District General Hospital
city: Jaffna
country: Sri Lanka
facility: Jaffna Teaching Hospital
city: Kandy
country: Sri Lanka
facility: Kandy Teaching Hospital
city: Kurunegala
country: Sri Lanka
facility: Teaching Hospital Kurunegala
city: Nugegoda
country: Sri Lanka
facility: Sri Jayewardenepura General Hospital
city: Peradeniya
country: Sri Lanka
facility: Peradeniya Teaching Hospital
city: Ragama
country: Sri Lanka
facility: Ragama Teaching Hospital
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: Chiayi City
country: Taiwan
facility: Chiayi Chang Gung Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Keelung
country: Taiwan
facility: Keelung Chang Gung Memorial Hospital
city: Taoyuan
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary Edinburgh
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Swansea
country: United Kingdom
facility: Morriston Hospital
city: Hanoi
country: Vietnam
facility: Military Central Hospital 108
Study officials:
affiliation: The George Institute
name: Craig Anderson
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.