EPICS-Pilot: European Blood Pressure Intensive Control After Stroke

Sponsor

University College Dublin (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04647292

Collaborator

St Vincent's University Hospital, Ireland (Other), Cork University Hospital (Other), Tallaght University Hospital (Other), University of Limerick (Other), University of Calgary (Other), Universitaire Ziekenhuizen Leuven (Other), Attikon Hospital (Other), Hospital Universitario La Paz (Other), HRB Stroke Trials Network Ireland (Other), National University of Ireland, Galway, Ireland (Other), Mater Misericordiae University Hospital (Other), University of Oslo (Other), Newcastle University (Other), University Hospital Waterford (Other)

122

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Stroke is the third most common cause of death worldwide and the leading cause of disability. High blood pressure is an important risk factor for stroke. Lowering a person's blood pressure reduces the risk of future stroke or heart attack. However, the optimal target blood pressure after a person suffers a stroke is not known. This is a study designed to establish the feasibility of a larger clinical trial, the aim of which will be to find out if greater blood pressure lowering is safe and effective for patients who suffer a stroke.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke Transient Ischemic Attack	Drug: anti-hypertensive	Phase 2

Detailed Description

Background:

Stroke is the third leading cause of global death, the leading cause of acquired disability and contributes substantially to dementia, cognitive decline, and healthcare costs. Global epidemiological studies such as INTERSTROKE and the Global Burden of Disease study estimated that hypertension is the leading modifiable risk factor for stroke, with a population attributable risk of approximately 50%. Recurrent vascular events (stroke, coronary events, vascular death) cause significant morbidity in ischaemic stroke survivors, affecting approximately 30% at 5 years. Blood-pressure reduction is a proven, inexpensive strategy to prevent stroke with benefits widely-generalizable in developed and developing countries. No randomised trials have demonstrated the efficacy and safety of SBP reduction to prevent secondary vascular events after ischaemic stroke to levels of about 120mmHg compared with 130-139mmHg. Consequently, most guidelines recommend reduction of systolic blood pressure (SBP) less than 140mmHg.

Aim:

The aim is to conduct an initial pilot randomised trial in Ireland and 7 leading European centres involved in the European Stroke Organisation Trials Alliance. This feasibility study will assess key design aspects and establish trial governance, data management, and procedures in preparation for a larger definitive trial.

Methods:

Design: Prospective, open-label, blinded endpoint assessed (PROBE) randomised, parallel-group pilot trial, comparing safety, efficacy, and other feasibility measures of two target SBP goals (intervention 115-125 mmHg, control 130-139 mmHg).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

122 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

European Blood Pressure Intensive Control After Stroke - Pilot Trial

Anticipated Study Start Date :

Jun 1, 2021

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Target systolic blood pressure 115-125 mmHg Recommended target SBP 115-125 millimetres of mercury (mmHg).	Drug: anti-hypertensive The recommended target SBP will be 115-125 mmHg in the intervention arm. A medication algorithm based on the SPRINT trial protocol will be provided. The final choice and dose of antihypertensive treatment(s) will be at the discretion of the treating clinicians. If no contra-indications, indapamide or other thiazide diuretic and/or angiotensin-converting enzyme (ACE) inhibitor (perindopril or other) will be encouraged as initial therapy, with long-acting calcium-channel antagonists (eg.amlodipine) encouraged as third-line therapy. At scheduled face-to-face or remote follow-up, patients will have their home blood pressure monitoring diary reviewed by the study team. If SBP is out of the allocated target range, a prescription to titrate (up or down) antihypertensive medication will be given to the patient.
Active Comparator: Target systolic blood pressure 130-139 mmHg Target SBP 130-139 mmHg (per American Stroke Association, European Stroke Organisation guidelines).	Drug: anti-hypertensive The recommended target SBP will be 115-125 mmHg in the intervention arm. A medication algorithm based on the SPRINT trial protocol will be provided. The final choice and dose of antihypertensive treatment(s) will be at the discretion of the treating clinicians. If no contra-indications, indapamide or other thiazide diuretic and/or angiotensin-converting enzyme (ACE) inhibitor (perindopril or other) will be encouraged as initial therapy, with long-acting calcium-channel antagonists (eg.amlodipine) encouraged as third-line therapy. At scheduled face-to-face or remote follow-up, patients will have their home blood pressure monitoring diary reviewed by the study team. If SBP is out of the allocated target range, a prescription to titrate (up or down) antihypertensive medication will be given to the patient.

Arm

Intervention/Treatment

Experimental: Target systolic blood pressure 115-125 mmHg

Recommended target SBP 115-125 millimetres of mercury (mmHg).

Drug: anti-hypertensive

The recommended target SBP will be 115-125 mmHg in the intervention arm. A medication algorithm based on the SPRINT trial protocol will be provided. The final choice and dose of antihypertensive treatment(s) will be at the discretion of the treating clinicians. If no contra-indications, indapamide or other thiazide diuretic and/or angiotensin-converting enzyme (ACE) inhibitor (perindopril or other) will be encouraged as initial therapy, with long-acting calcium-channel antagonists (eg.amlodipine) encouraged as third-line therapy. At scheduled face-to-face or remote follow-up, patients will have their home blood pressure monitoring diary reviewed by the study team. If SBP is out of the allocated target range, a prescription to titrate (up or down) antihypertensive medication will be given to the patient.

Active Comparator: Target systolic blood pressure 130-139 mmHg

Target SBP 130-139 mmHg (per American Stroke Association, European Stroke Organisation guidelines).

Drug: anti-hypertensive

Outcome Measures

Primary Outcome Measures

Difference in achieved SBP [18 months (or end of trial visit)]
The difference in mean SBP in the intensive versus control groups, at 18 months (or end-of-trial visit)

Secondary Outcome Measures

Time to first composite major vascular event [18 months (or end of trial visit)]
Defined as recurrent stroke, myocardial infarction, cardiac arrest, and to each component of the composite, stratified as fatal, non-fatal and total.
Proportions of patients assigned to target goals successfully reaching target [18 months (or end of trial visit)]
All-cause death [18 months (or end of trial visit)]
Time to all-cause death
Number of dose-titrations required [18 months (or end of trial visit)]
Time in target range [18 months (or end of trial visit)]
Proportion of SBP measures in the assigned target during trial participation
Loss to follow-up [18 months (or end of trial visit)]
Number of participants lost to follow-up in both treatment arms
Time taken to reach target range [18 months (or end of trial visit)]
Change in cognition [18 months (or end of trial visit)]
Change in Montreal cognitive assessment score (range 0-30) at last follow-up compared with baseline score. A lower score indicates greater cognitive impairment.
Quality of life score [18 months (or end of trial visit)]
Change in EQ5D-5L score (5 domains assessed with scores of 1-5 ranking the severity of impairment, with higher scores indicating poorer quality of life) at last follow-up compared with baseline
Difference in mean achieved diastolic blood pressure (DBP) between groups [18 months (or end of trial visit)]
Change in SBP and DBP from baseline to end-of-trial [18 months (or end of trial visit)]
Time required per follow up visit [18 months (or end of trial visit)]
Feasibility of remote BP titration [18 months (or end of trial visit)]
Qualitative feedback from patients on their views relating to the feasibility of home blood pressure monitoring and remote dose titration will be sought. This design feature will be carefully examined in the pilot, before incorporation into the main trial.
Disability in intensive-SBP and guideline-based SBP target patients assessed by modified Rankin score (shift analysis and proportion with no, mild, or moderate disability, Rankin score 0-3) [18 months (or end of trial visit)]
Proportion of participants with disability. The modified Rankin scale is graded from 0-6, with 0 indicating no disability and 6 indicating death.
Number of adverse events, serious adverse events, and suspected unexpected serious adverse reactions (SUSARs) [18 months (or end of trial visit)]
Difference in proportion of patients with adverse events, serious adverse events and SUSARS
Number of pre-specified adverse events [18 months (or end of trial visit)]
Qualitative patient feedback obtained via workshops and questionnaires [18 months (or end of trial visit)]
Total, direct and indirect (eg. via lost income to study participants or family members) costs associated with face-to-face visits for study participants will be quantified [18 months (or end of trial visit)]

Other Outcome Measures

Number of patients who do not complete the study due to tolerability or other issues [18 months (or end of trial visit)]
Patients who are not retained in the study will give an insight into anticipated retention in the Phase 3 trial and sample size considerations.
Ability of sites to rapidly identify eligible patients from clinics and stroke units [18 months (or end of trial visit)]
The inclusion of prevalent cases already attending stroke clinics or discharged from stroke units within the last year is an important design feature, aimed to rapidly accrue patients into the trial and thus to maximise the duration of follow-up within the terms allowed by funders. This outcome will be judged on the basis of qualitative feedback from participating sites.
Feasibility of home blood pressure (BP) measures and diary entries [18 months (or end of trial visit)]
This outcome will be judged on the basis of qualitative feedback from participants and the the proportions of participants adhering to the use of home blood pressure diaries.
Feasibility of remote (phone/video) visits [18 months (or end of trial visit)]
The feasibility of remote (phone/video) visits will be assessed by the proportion of patients adhering to participation in remote visit consultations

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥40
Ischaemic stroke, proven by imaging (including transient ischaemic attack with imaging evidence of acute brain ischaemia
Living at home and independent (walking without the aid of another person, but may have some help for daily activities - equivalent to Rankin score 3 or less)
SBP≥130mmHg at entry (average of 2 measures, seated, after resting alone in office for 5 minutes)
Qualifying Stroke/TIA between 7 days and 1 year of randomization
Glomerular filtration rate (eGFR) greater than or equal to 50 ml/min/m2
Medically-stable and capable of participating in a randomised trial, including home BP measures, in the opinion of the study physician
Willing to provide informed consent (no surrogate consent will apply)

Exclusion Criteria:

Stroke/TIA due to cardio-embolism or other defined causes (eg. dissection, endocarditis, other specified)
Severe stenosis of large cranio-cervical artery (>70% stenosis of cervical carotid, vertebral, or Circle of Willis artery)
Medical history of primary intracerebral haemorrhage (asymptomatic cerebral microbleeds detected on brain MRI are not excluded)
SBP <110mmHg after 3 minutes of standing or other contra-indication to intensive SBP lowering in opinion of treating clinician* (eg. syncope or pre-syncope, recurrent falls)
Unlikely to comply with study procedures (home BP measures, follow-up visits) due to severe or fatal co-morbid illness (eg. dementia, active malignancy, severe frailty) or other factor (eg. inability to travel)
Women of child-bearing potential