ACT-GLOBAL Adaptive Platform Trial for Stroke

Official title

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

Overview

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.

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.

Interventions

• 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)
• 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)
• 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 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
• Other No deferoxamine mesylate and no colchicine
  No deferoxamine mesylate and no colchicine
• Drug Deferoxamine mesylate only
  Deferoxamine mesylate at a dose of 32mg/kg/day via intravenous infusion immediately (within 1 hour) and continued for 2 consecutive days

Primary outcome measures

• modified Rankin scale (mRS) scores [Time frame: Platform level time frame: 90 days in Ischaemic Stroke State; 6 months in Intracerebral Haemorrhage State; Domain specific time frame may differ (details will be included in domain-specific registration)]

Secondary outcome measures (3)

• Excellent functional neurological outcome [Time frame: Platform level time frame: 90 days in Ischaemic Stroke State; 6 months in Intracerebral Haemorrhage State; Domain specific time frame may differ (details will be included in domain-specific registration)]
• Independent functional neurological outcome [Time frame: Platform level time frame: 90 days in Ischaemic Stroke State; 6 months in Intracerebral Haemorrhage State; Domain specific time frame may differ (details will be included in domain-specific registration)]
• Health Related Quality of Life [Time frame: Platform level time frame: 90 days in Ischaemic Stroke State; 6 months in Intracerebral Haemorrhage State; Domain specific time frame may differ (details will be included in domain-specific registration)]

Eligibility criteria

Platform Inclusion Criteria:

• Age ≥18 years
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Single blind

Primary purpose

Treatment

Study locations

Australia · 1 center

• The George Institute for Global Health — Sydney

Canada · 1 center

• University of Calgary — Calgary

Identifiers

NCT: NCT06352632 · ACT-GLOBAL_Master

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗