Third Enhanced Control of Hypertension and Thrombectomy Stroke Domain Within ACT-GLOBAL Adaptive Platform Trial (ENCHANTED3/MT)

Third Enhanced Control of Hypertension and Thrombectomy Stroke Domain Within A Multi-faCtorial, mulTi-arm, Multi-staGe, Randomised, gLOBal Adaptive pLatform Trial for Stroke (ACT-GLOBAL_ENCHANTED3/MT)

Several clinical trials have produced variable conclusions regarding the effects of intensive blood pressure (BP) lowering in post-EVT acute ischaemic stroke (AIS) patients. Although two trials indicate harm from very intensive target-based treatment (SBP <130 mmHg), the others neutral effects in the SBP range 140-160 mmHg. The ENCHANTED3/MT domain of the ACT-GLOBAL platform trial aims to test different approaches to the treatment of elevated SBP in post-EVT AIS patients to find an optimal BP management strategy. ENCHANTED3/MT will randomize (1:1:1) up to 2,000 patients with SBP ≥150 mmHg post-EVT to conservative (no or minimal SBP reduction by 5-10mmHg or a target of 175-180mmHg if very-high baseline SBP [≥180mmHg]), moderate (SBP reduction by 10-20mmHg or a target of 160 ± 5, whichever is higher; no control if low-high baseline SBP [150-160mmHg]), or intensive (SBP reduction by 30-50mmHg or a target of 140±5 mmHg, whichever is higher) BP management.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke, Acute
• Intervention / Treatment: Other: Conservative SBP Control; Other: Moderate SBP Control; Other: Intensive SBP Control

Detailed Description

ACT-GLOBAL is an international, multi-factorial, multi-arm, multi-stage, randomized, adaptive platform trial designed to simultaneously evaluate multiple treatments that may improve outcomes in stroke. One domain is ENCHANTED3/MT aiming to compare three BP lowering management strategies in post-EVT AIS patients with elevated SBP determine the best approach to improve functional outcome.

Background and Rationale - Different reperfusion status may have different BP patterns. A U-shaped correlation between post-EVT BP and outcomes may exist for patients who underwent recanalisation post-EVT. In addition, different BP lowering strategy may have different safety profiles and may potentially impact differently with regards to the risk of ICH for patients with reperfusion therapy.

The controversial overall clinical effect seen in clinical trials, including ENCHANTED2/MT, OPTIMAL BP, BP TARGET, BEST II and ENCHANTED, does not resolve the question over the optimal BP control strategy following EVT. The evidence is insufficient to make sensible recommendations over the optimal BP management in this important clinical group. Thus, the Blood Pressure Domain (ENCHANTED3/MT) aims to test different treatment approaches to the control of elevated SBP post-EVT in AIS patients to find the optimal BP management that leads to improved functional status with reduced ICH and no other harms.

ENCHANTED3/MT will randomize (1:1:1) up to 2,000 patients with SBP ≥150 mmHg post-EVT to the following three BP lowering management strategies.

Primary outcome is modified Rankin scale (mRS) at 90 days analysed with utility-weighted mRS using a Bayesian hierarchical linear model. Adaptive analyses will be conducted 3-monthly with prespecified statistical triggers for superiority, inferiority and equivalence.

• Study Type: Interventional
• Enrollment (Estimated): 2000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Craig Anderson, PhD; Phone Number: +61 2 8052 4521; Email: canderson@georgeinstitute.org.au
• Study Contact Backup: Name: Xiaoying Chen, PhD; Phone Number: +61 2 8052 4549; Email: xchen@georgeinstitute.org.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2000
      • Recruiting
      • The George Institute for Global Health
      • Contact: Xiaoying Chen, PhD; Phone Number: +61 2 8052 4549; Email: xchen@georgeinstitute.org.au
      • Contact: Craig Anderson, MD, PhD; Phone Number: +61 2 8052 4521; Email: canderson@georgeinstitute.org.au
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 1N4
      • Recruiting
      • University of Calgary
      • Contact: Michael D Hill, MD
      • Contact: Carol C Kenney, RN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years;
2. Use of endovascular therapy (EVT) within 24 hours of symptom onset or last known well according to local guidelines;
3. Sustained high systolic blood pressure ≥150 mmHg (2 readings <10 mins apart) within 3 hours after completion of EVT.

Exclusion Criteria:

1.Any definite contraindications to BP lowering treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Conservative SBP Control	Other: Conservative SBP Control; No or minimal treatment; if there is a need to treat a patient with a very-high (>180 mmHg) baseline SBP, then the SBP reduction is 5-10mmHg or a target is 175-180 mmHg
Experimental: Moderate SBP Control	Other: Moderate SBP Control; If the patient has a very high (>180 mmHg) or moderate high (160-180 mmHg) baseline SBP, SBP reduction is 10-20mmHg or a target of160±5 mmHg, which is higher; patients with low-high (150-160 mmHg) baseline SBP will not be treated
Experimental: Intensive SBP Control	Other: Intensive SBP Control; SBP reduction by 30-50mmHg or a target of 140±5 mmHg, which is higher

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin scale	The mRS is a 7-outcome ordered categorical scale that assesses functional neurological status after stroke. It is not intended for use as a measure of historical functional status. It is well accepted as a standard outcome around the world in the stroke community, by patients and by regulatory authorities. The seven values and the clinical summary of the individual scores are summarized in the following: 0 = No symptoms; = No significant disability; able to carry out all usual activities; = Slight disability; can look after own affairs, but unable to carry out all previous activities; = Moderate disability; require some help; = Moderately severe disability; unable to attend to own bodily needs without assistance; = Severe disability; bedridden and requiring constant nursing care and attention; = Dead	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality refers to the state of being not alive.	90 days
Ordinal shift of 7 levels of modified Rankin scale	The modified Rankin scale (mRs) is an ordinal disability score of 7 categories (0 = no symptoms to 6 = dead). The distribution of mRs scores across its different strata in patients will be calculated.	90 days
National Institute of Health Stroke Scale (NIHSS) score	The NIHSS is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity. The scale includes measures of level of consciousness, extra ocular movements, motor and sensory tests, coordination, language, and speech evaluations. The NIHSS will be administered at Baseline prior to each domain randomisation (unless specified otherwise in specific domains) and Day 2. The NIHSS as part of standard of care treatment may be used if an assessment was not done by clinical trial personnel.	24-48 hours
Any intracranial haemorrhage (ICH)	Any ICH is defined as ICH of any type on brain imaging ≤2 days of treatment, identified by adjudicators.	2 days
Excellent functional neurological outcome	Excellent functional neurological outcome refers to mRS 0-1. The minimum mRS is 0 (no symptoms) while the maximum mRS is 6 (death). The higher the mRS score is the worse outcome is.	90 days
Independent functional neurological outcome	Independent functional neurological outcome refers to mRS 0-2. The minimum mRS is 0 (no symptoms) while the maximum mRS is 6 (death). The higher the mRS score is the worse outcome is.	90 days
Health Related Quality of Life	Health Related Quality of Life is based on EuroQol 5 Dimension 5 Level (EQ-5D-5L). The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a descriptive system that defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has five response categories corresponding to: no problems, slight, moderate, severe and extreme problems. The version of the instrument selected for the trial is interviewer administered either in-person, or by telemedicine or by telephone.	90 days
Symptomatic intracerebral haemorrhage (sICH)	Symptomatic ICH on follow-up imaging (up to 2 days from randomization) will be a reportable serious adverse event that is adjudicated centrally according to the standard approach of reporting symptomatic ICHs used in the Heidelberg classification.	2 days
Serious Adverse Event (SAE)	As defined by the WHO International Drug Monitoring Centre (1994), an SAE is any untoward medical occurrence that is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; be an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes previously listed.	4 days

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: Changhai Hospital; University of Calgary
• Investigators: Principal Investigator: Craig Anderson, PhD, The George Institute

Publications and helpful links

Helpful Links

• ACT-GLOBAL Master Protocol Registration

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2024
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: April 2, 2024
• First Submitted That Met QC Criteria: April 2, 2024
• First Posted (Actual): April 8, 2024

Study Record Updates

• Last Update Posted (Estimated): November 21, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Ischemic Stroke; Blood Pressure; Endovascular Therapy
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Ischemic Stroke; Stroke; Hypertension
• Other Study ID Numbers: ACT-GLOBAL_AIS_03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After this domain is completed, the archived de-identified limited dataset of randomized participants will be transmitted to and stored in the ACT-GLOBAL Data Repository, for use by researchers. Data can be shared after publication of the main results.
• IPD Sharing Time Frame: Data can be shared after publication of the main results.

IPD Sharing Access Criteria

Data can be shared after publication of the main results, based on approval of a submitted protocol to the Publication Committee. Data can be shared to bona fide researchers with experience in medical research, and with no conflict of interest that may potentially influence their interpretation of any analyses, and employed by a recognised academic institute, health service organisation, commercial research organisation of from the pharmaceutical industry. The data sharing will be only for analyses within the constraints of the consent under which the data were originally gathered consent.

Data sharing with industry will be according to relevant contracts with appropriate approvals from all stake holders.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No