E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with a history of acute stroke due to Intracranial Haemorrhage with mild to moderately high blood pressure. |
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E.1.1.1 | Medical condition in easily understood language |
Stroke due to a bleed in the brain with mild to moderately high blood pressure. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019016 |
E.1.2 | Term | Haemorrhagic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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? |
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E.2.2 | Secondary objectives of the trial |
The study has two phases. The objective of the first 'vanguard' phase of the study including 1,000 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 which assess the clinical outcomes in 4,200 participants.
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adults (≥18 years) up to 6 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.
4. No major contraindications to any of the study treatments.
5. Provision of written informed consent.
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E.4 | Principal exclusion criteria |
1. Taking an ACE inhibitor antihypertensive drug that cannot be switched to any of the following alternative medications:
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
5. Significant hyperkalaemia and/or hyponatriemia, in the opinion of the responsible physician.
6. Estimated glomerular filtration rate (eGRF) < 30 mL/min.
7. Severe hepatic impairment (ALT or AST > 3x the upper limit of normal).
8. Any other 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). |
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E.5 End points |
E.5.1 | 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 |
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E.5.1.1 | 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. |
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E.5.2 | 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 cardiovascular (CV) events - CV death, non-fatal myocardial infarction, or non-fatal stroke)
6. Physical function assessed by short modified Rankin Scale
7. Change in SBP
8. Health-related Quality of Life (HRQoL) according to the EQ-5D
9. Cognitive impairment, overall defined by standard cut-points on the MoCA
10. Medical adherence: Self-reported measures, pill counts |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Analyses will be specified in a full published statistical analysis plan. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Sri Lanka |
Brazil |
Japan |
New Zealand |
Taiwan |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit last follow up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |