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

• Register: EUCTR
• Last refreshed on: 18 August 2020
• Main ID: EUCTR2016-003724-23-GB
• Date of registration: 15/05/2018
• Prospective Registration: No
• Primary sponsor: The George Institute for Global Health, University of New South Wales
• Public title: Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT)
• Scientific title: Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT) - TRIDENT
• Date of first enrolment: 20/10/2017
• Target sample size: 1500
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003724-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Brazil, Canada, China, India, Japan, Korea, Republic of, Malaysia, Netherlands, New Zealand, Nigeria, Pakistan, Philippines, Singapore, Sri Lanka, Switzerland, Taiwan, United Kingdom, Vietnam

Contacts

• Name: Salman
• Affiliation: University of Edinburgh

• Name: Salman
• Affiliation: University of Edinburgh

Key inclusion & exclusion criteria

Inclusion criteria:
1. Adults (=18 years) up to 12 months after symptom onset of stroke due to primary intracerebral haemorrhage (ICH) confirmed by brain imaging.
2. Clinically stable, as judged by investigator
3. Two resting systolic BP (SBP) levels, measured 5 minutes apart in the range 130-160mmHg recorded in a seated position. (Patients with higher SBP can be included if it is 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.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
1. Taking an ACE inhibitor antihypertensive drug that cannot be switched to any of the following alternatives:
o telmisartan 20 or 40mg, amlodipine 2.5 or 5mg, indapamide 1.25 or 2.5mg, or
o an equivalent class (angiotensin receptor blocker, calcium channel blocker, or thiazide-like diuretic), or
o a beta-blocker
2. Contraindication to any of the study medications, in the context of currently prescribed BP 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 contraception
6. Significant hyperkalaemia and/or hyponatremia, in the opinion of the responsible physician
7.Estimated glomerular filtration rate (eGFR) <30 mL/min ?
8. Severe hepatic impairment (ALT or AST >3x the upper limit of normal [ULN])
9. Any condition that in the opinion of the responsible physician or investigator that renders the patient unsuitable for the study (e.g. severe disability (ie modified Rankin Scale [mRS] score of 4-5] or significant memory or behavioural disorder or hyperkalaemia and/or hyponatremia, defined by local lab criteria)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with a history of acute stroke due to Intracranial Haemorrhage with mild to moderately high blood pressure.
MedDRA version: 21.1 Level: PT Classification code 10019016 Term: Haemorrhagic stroke System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: Triple Capsule (telmisartan + amlodipine + indapamide)
Pharmaceutical Form: Capsule
INN or Proposed INN: Temisartan
CAS Number: 144701-48-4
Other descriptive name: Telmisartan
Concentration unit: mg milligram(s)
Concentration number: 20mg-
INN or Proposed INN: Amlodipine
CAS Number: 111470-99-6
Other descriptive name: Amlodipine Besylate
Concentration unit: mg milligram(s)
Concentration number: 2.5mg-
INN or Proposed INN: Indapamide
CAS Number: 26807-65-8
Concentration unit: mg milligram(s)
Concentration number: 1.25-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: The primary outcome will be analysed using a survival analysis technique performed with a Cox proportional hazards model for its occurrence over the follow-up period.

Main Objective: Does a strategy of giving a 'triple pill' (using 3 low-dose licensed blood pressure (BP) lowering drugs in one pill) to patients with a history of ICH with mild to moderately high BP (defined as =130 mmHg) reduce the risk of stroke recurrence?

Primary end point(s): The primary outcome is the time to first occurrence of recurrent stroke, whether ischaemic or haemorrhagic.

The outcomes for the start-up (vanguard) phase are:
1. Efficacy: difference in SBP between groups at 6 months
2. Tolerability at 6 months:
a. difference between groups in potentially related side-effects (syncope/collapse, falls, pedal/ankle oedema, hyperkalaemia, hypokalaemia, hyponatraemia)
b. difference between groups in participant withdrawals from treatment
3. Safety: difference between groups in the frequency of SAEs
4. Medication adherence: differences in self-reported measures, pill counts

Secondary Objective: The study has two phases. The objective of the first 'vanguard' phase of the study including 500 participants will establish whether the Triple Pill plan is effective in lowering BP, well tolerated and the protocol can be followed. These will be assessed at 6 months then followed by the expansion phase to recruit the remaining 1000 participants to assess clinical outcomes.

Secondary outcomes: Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke); health-related quality of life (HRQoL); physical function; cognitive impairment defined by standard cutpoints on the Montreal Cognitive Assessment (MOCA) and other tests; depression from the EQ5D-5L (EuroQol); and all-cause mortality.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Analyses will be specified in a full published statistical analysis plan.

Secondary end point(s): The stroke related secondary outcomes are:
1. Recurrent ICH
2. Ischaemic stroke
3. Fatal or disabling stroke
4. Mortality
5. MACE (major adverse CV events - CV death, non-fatal myocardial infarction, or non-fatal stroke)
6. Physical function assessed by smRS (Appendix 19.3)
7. Change in SBP
8. HRQoL according to the EQ-5D (Appendix 19.4)
9. Cognitive impairment, overall defined by standard cut-points on the MoCA (Appendix 19.5), and supplemented with d the Brief Memory and Executive Test (Appendix 19.6)
10. Medical adherence: Self-reported measures, pill counts, Morisky scale (Appendix 19.7)

Secondary ID(s)

2016-003724-23-NL

NCT02699645

12616000327482

GI-AU-NMH-2016-01

Source(s) of Monetary Support

National Health and Medical Research Council

Ethics review

Status: Approved
Approval date: 20/10/2017
Contact: