A Multi-faCtorial, mulTi-arm, Multi-staGe, Randomised, gLOBal Adaptive pLatform Trial for Stroke (ACT-GLOBAL)

A Multi-faCtorial, mulTi-arm, Multi-staGe, Randomised, gLOBal Adaptive pLatform Trial for Stroke (ACT-GLOBAL)

Stroke is causing 6.6 million deaths and is a major cause of disability worldwide in 2019. There remains an urgent need for interventions that improve outcomes which can be implemented with wide applicability for stroke. ACT-GLOBAL is a multi-factorial, multi-arm, multi-stage, randomised, global adaptive platform trial for stroke, aiming to identify the treatment/s associated with the highest chance of improving outcome in stroke patients. In ACT-GLOBAL multiple questions will be evaluated simultaneously and sequentially as data accrues and can evaluate interactions between different treatment options.

Study Overview

• Status: Not yet recruiting
• Conditions: Stroke
• Intervention / Treatment: Drug: Standard-dose intravenous tenecteplase; Drug: Low-dose intravenous tenecteplase; Other: No intravenous tenecteplase; Other: Moderate Blood Pressure Control; Other: Intensive Blood Pressure Control; Other: Placebo; Drug: NoNO-42; Other: Conservative Blood Pressure Control

Detailed Description

Stroke is the second leading cause of death, worldwide. It is also the second largest cause of disability-adjusted-life-years (DALYs) lost after ischaemic heart disease in developing countries, and third largest contributor to DALYs in developed countries (after ischaemic heart disease, low back and neck pain). In 2019, the absolute numbers of new strokes (12.2 million), stroke-related deaths (6.6 million), and people living with stroke (101.5 million) had increased globally from 1990 (70%, 43%, and 85% increases, respectively).

Steady progress has been made in establishing specific management strategies for patients affected by, or at high-risk of, stroke. Unfortunately, only a few acute treatments have been proven to be beneficial: thrombolysis, endovascular thrombectomy, hemicraniectomy, stroke unit care, and aspirin. There is a continued need for interventions that improve outcomes which can be implemented with wide applicability for stroke.

ACT-GLOBAL is an investigator-initiated, multi-factorial, multi-arm, multi-stage, randomised, global adaptive platform trial for stroke, aiming to find the treatment/s associated with the highest chance of improving outcome after stroke. In ACT-GLOBAL multiple questions will be evaluated simultaneously and sequentially as data accrues and can evaluate interactions between different treatment options.

Frequent adaptive analyses are conducted to assess whether a given intervention is superior, inferior, or equivalent either within a domain or for specific populations within the domain. Where it is anticipated that interactions between interventions in different domains may be likely, the statistical models will allow evaluation of such interactions. Each intervention within a domain with prospectively defined and mutually exclusive strata (sub-groups) of participants will be evaluated within the strata, while information from one stratum may be used (via 'borrowing') to contribute to the analysis of the effect of that intervention in other strata. Specific interventions or subgroups within overall populations may be dropped or cease to enrol, based on pre-specified rules.

The adaptive design allows new interventions or domains or both to be introduced. A Response Adaptive Randomisation algorithm may be used to preferentially randomize participants to interventions that appear to be performing better in domains where applicable.

Unlike traditional trial designs which explicitly prohibit co-enrollment of patients into different trials or multiple therapies, or use a factorial design, the adaptive platform design allows investigators to replicate the real-world environment to estimate possible synergy, competitive interference, or safety profiles of complex treatment protocols.

• Study Type: Interventional
• Enrollment (Estimated): 20000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Xiaoying Chen, PhD; Phone Number: +61280524549; Email: xchen@georgeinstitute.org.au
• Study Contact Backup: Name: Bijoy Menon, MD, PhD; Phone Number: +14033381198; Email: docbijoymenon@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Platform Inclusion Criteria:

1. Age ≥18 years
2. Clinical diagnosis of stroke

Platform Exclusion Criteria:

There are no platform level exclusion criteria

Each state and domain will specify additional inclusion and exclusion criteria in the respective Domain-Specific Registration. Patients who fulfill the overall platform criteria will be assessed for enrollment into each active domain.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IV thrombolysis domain; This domain has a prospective, randomized, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design to optimize the use of intravenous Tenecteplase in participants with Acute Ischemic Stroke.	Drug: Standard-dose intravenous tenecteplase; Standard-dose intravenous tenecteplase (0.25 mg/kg body weight); one-time IV bolus injection soon after randomisation; Drug: Low-dose intravenous tenecteplase; Low-dose intravenous tenecteplase (0.18 mg/kg body weight); one-time IV bolus injection soon after randomisation; Other: No intravenous tenecteplase; No intravenous tenecteplase only in subjects on direct oral anticoagulant (DOACs) or those planned for emergency endovascular thrombectomy (EVT)
Experimental: ACT-42 domain; This domain has a Phase 2b, multicenter, prospective, randomized, open label, blinded-endpoint (PROBE) controlled single-dose adaptive design and aim to determine the efficacy and safety of NoNO-42 in participants with Acute Ischaemic Stroke selected for thrombolysis with or without Endovascular Thrombectomy.	Other: Placebo; 100 mL of 0.9% normal saline, administered as a single IV infusion with a 20-minute dosing duration.; Drug: NoNO-42; NoNO-42 at weight-based dosing - 2.6 mg/Kg, administered as a single IV infusion with a 20-minute dosing duration
Experimental: Blood Pressure domain; Third Enhanced Control of Hypertension and Thrombectomy Stroke Study (ENCHANTED3/MT) as a domain of ACT-GLOBAL to compare three BP lowering management strategies, that of conservative, moderate and intensive BP lowering in patients with Acute Ischaemic Stroke admitted to participating hospitals who has an elevated SBP after reperfusion therapy via Endovascular Thrombectomy, and reliably determine, which approach leads to improved functional outcome. Locally available and approved i.v. BP lowering agents can be used in this domain.	Other: Moderate Blood Pressure Control; SBP reduction by 10-20mmHg or a target of 160 ± 5, whichever is higher; no control if low-high baseline SBP (150-160mmHg); the timing of administration of interventions is specified to be immediately after randomisation; the intervention target is to be achieved ideally at 1 hour after randomisation and maintained for 24 hours (or until hospital discharge or death if this should occur earlier); Other: Intensive Blood Pressure Control; SBP reduction by 30-50mmHg or a target of 140±5 mmHg, whichever is higher after endovascular thrombectomy (EVT); the timing of administration of interventions is specified to be immediately after randomisation; the intervention target is to be achieved ideally at 1 hour after randomisation and maintained for 24 hours (or until hospital discharge or death if this should occur earlier); Other: Conservative Blood Pressure Control; No or minimal Systolic Blood Pressure (SBP) control; SBP reduction by 5-10mmHg or a target of 175-180mmHg if very-high baseline SBP (≥180mmHg); the timing of administration of interventions is specified to be immediately after randomisation; the intervention target is to be achieved ideally at 1 hour after randomisation and maintained for 24 hours (or until hospital discharge or death if this should occur earlier)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin scale (mRS) scores	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	Platform level time frame: 90 days in Ischaemic Stroke State; Domain specific time frame may differ (details will be included in domain-specific registration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Excellent functional neurological outcome	Excellent functional neurological outcome means modified Rankin scale (mRS) scores 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.	Platform level time frame: 90 days in Ischaemic Stroke State; Domain specific time frame may differ (details will be included in domain-specific registration)
Independent functional neurological outcome	Independent functional neurological outcome means modified Rankin scale (mRS) scores 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.	Platform level time frame: 90 days in Ischaemic Stroke State; Domain specific time frame may differ (details will be included in domain-specific registration)
Health Related Quality of Life	Health Related Quality of Life 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.	Platform level time frame: 90 days in Ischaemic Stroke State; Domain specific time frame may differ (details will be included in domain-specific registration)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality status equals to death which will be collected at all visits during the trial period	Platform level time frame: 90 days in Ischaemic Stroke State; Domain specific time frame may differ (details will be included in domain-specific registration)

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: University of Calgary; Berry Consultants
• Investigators: Principal Investigator: Andrew Demchuk, MD, University Of Calgary; Principal Investigator: Michael D Hill, MD, University Of Calgary; Principal Investigator: Craig Anderson, MD, PhD, The George Institute; Principal Investigator: Bijoy Menon, MD, University Of Calgary; Principal Investigator: Xiaoying Chen, PhD, The George Institute

Publications and helpful links

Helpful Links

• ACT-GLOBAL IV Thrombolysis Domain Registration Link
• ACT-GLOBAL Blood Pressure Domain Registration Link

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): April 1, 2034

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 (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Blood Pressure; Tenecteplase; Ischaemic stroke; Intracerebral Haemorrhage; Adaptive Platform Trial
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tenecteplase
• Other Study ID Numbers: ACT-GLOBAL_Master

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After a 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 unless specified otherwise in domain-specific registration.
• 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