Clinical trial NCT06813651: Safety, Tolerability and Efficacy of Adjunctive TBO-309 in Reperfusion for Stroke With Tandem Occlusion
Official title: Safety, Tolerability and Efficacy of Adjunctive TBO-309 in Reperfusion for Stroke With Tandem Occlusion
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Ischemic Stroke
Tandem Occlusion
Keywords: Ischaemic stroke
Stenting
Endovascular thrombectomy
tandem occlusion
Lead sponsor: ThromBio Pty. Ltd.
Sponsor class: INDUSTRY
First posted: 2025-02-07
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Multicenter, prospective, open-label, Bayesian Optimal Phase 2 (BOP2) trial.

Two intervention doses will be tested sequentially for TBO-309, with 60mg tested first. Then either a higher (120mg) or lower (30mg) dose will be tested, based on results of the 60 mg dose.

The maximum number of subjects is estimated to be 78 in this two-dose BOP2 design study.
Primary purpose: TREATMENT

Brief summary: Co-STAR is a multicenter, prospective, open-label, Bayesian Optimal Phase 2 (BOP2) trial that aims to assess the safety and efficacy of adjunctive intravenous TBO-309 in Acute Ischaemic Stroke (AIS) patients with tandem occlusion receiving intra-cranial endovascular thrombectomy (EVT) and acute extracranial carotid artery stenting.

Co-STARS study will test the hypothesis that patients with tandem occlusion treated with EVT and acute stenting in conjunction with TBO-309 will:

* have persistent stent patency without requiring rescue therapy with GPIIb/IIIa inhibitors and
* not experience high rates of symptomatic intra-cranial haemorrhage (sICH).

Patients with tandem occlusion undergoing EVT and acute stenting will receive intravenous TBO-309 bolus and infusion. TBO-309 is a potent, selective and ATP competitive PI3K\[beta\] inhibitor which reduces platelet activation adhesion/aggregation particularly under conditions of disturbed blood flow and promotes platelet disaggregation. By targeting PI3K\[beta\], TBO-309 specifically inhibits thrombosis whilst minimizing the impact on normal hemostasis.

Detailed description: Stroke due to large vessel occlusion (LVO) typically causes large infarcts and results in severe disability and a high case fatality rate. Treating LVO by thrombectomy poses technical challenges, especially when the lesion involves not only the extracranial (cervical) part of the internal carotid artery but also its concomitant intracranial distal segment or the ipsilateral middle cerebral artery (tandem occlusion). For patients with tandem occlusion, stenting of the internal carotid is considered acceptable, but it requires the use of antiplatelet therapy to avoid stent thrombosis, often necessitating rescue therapy with GPIIb/IIIa inhibitors. This can lead to an increased risk of hemorrhage especially when potent antiplatelet agents such as GPIIb/IIIa inhibitors are used.

The novel investigational agent TBO-309 is a potent, selective and ATP competitive PI3K\[beta\] inhibitor which reduces platelet activation adhesion/aggregation particularly under conditions of disturbed blood flow and promotes platelet disaggregation. By targeting PI3K\[beta\], TBO-309 specifically inhibits thrombosis whilst minimizing the impact on normal hemostasis. This study aims to assess the safety and efficacy of adjunctive TBO-309 in acute ischaemic stroke with tandem occlusion eligible to undergo intra-cranial EVT and acute extracranial carotid artery stenting.

The primary endpoint of this trial is a composite outcome of efficacy and safety, defined by:

1. Avoidance of intra-procedural GPIIb/IIIa inhibitor rescue therapy due to stent thrombosis, combined with persistent stent patency seen on angiographic imaging at 24-36 hours, and
2. no sICH.

This trial will use Bayesian Optimal Phase 2 (BOP2) trial design, and two intervention doses will be tested sequentially for TBO-309. TBO-309 at the dose of 60 mg will be tested first. Then either a higher dose of 120 mg or a lower dose of 30 mg will be tested based on the results of the 60 mg dose.

Eligibility criteria: Inclusion Criteria:

1. Patient aged 18 years or more
2. Patient has an AIS due to tandem occlusion, including large vessel occlusion (LVO) within the intra-cranial anterior circulation and presumed atherosclerotic occlusion of the cervical internal carotid artery origin
3. CT perfusion indicates the presence of salvageable brain tissue, defined as ischaemic core \<70mL with a mismatch ratio \>1.8 and absolute mismatch \>15mL.
4. Patient has at least a mild grade of neurological impairment (NIHSS \>4)
5. Patient has an estimated pre-stroke mRS of less than 4

Exclusion Criteria:

1. Patient is considered unlikely to benefit from study intervention defined by one of the following:

   1. Advanced dementia
   2. Severe pre-stroke disability (mRS score 4-5)
   3. Glasgow Coma Score (GCS) 3 to 5
   4. Evidence of a large well-defined ischaemic lesion measuring more than one third of the middle cerebral artery (MCA) territory
2. Uncontrolled hypertension (SBP \>180 or DBP \>110, refractory to medical therapy)
3. Intracranial haemorrhage within the last 90 days
4. Myocardial infarction or stroke within the last 30 days
5. Patient has an underlying disease process with a life expectancy of \<90 days
6. Known treatment with anticoagulants
7. Known severe liver disease
8. Known bleeding disorder
9. Cardiopulmonary resuscitation or arterial puncture at non-compressible site or lumbar puncture within 7 days
10. Another medical illness or social circumstance that may interfere with outcome assessments and follow-up
11. Known or suspected pregnancy
12. Patients currently participating in another interventional clinical trial
13. Informed consent unable to be obtained from the patient or their Person Responsible/Medical Treatment Decision Maker prior to study interventions

Primary outcomes:
measure: Proportion of patients achieving a composite outcome of efficacy and safety
timeFrame: 24-36 hours
Secondary outcomes:
measure: Proportion of patients achieving reperfusion.
timeFrame: 24 hours
measure: Infarct volume 24-36 hours post study drug commencement
timeFrame: 24-36 hours
measure: Proportion of all patients with any ICH within 24-36 hours post study drug commencement
timeFrame: 24-36 hours
measure: Proportion of patients experiencing any bleeding within 24-36 hours of study drug commencement.
timeFrame: 24-36 hours
measure: National Institutes of Health Stroke Scale (NIHSS) at 24 hours, and 7 days/at hospital Discharge
timeFrame: 24 hours and 7 days
measure: Modified Rankin Scale (mRS) score at discharge and 90 days
timeFrame: 90 days
measure: Proportion of patients with all-cause mortality at 90 days.
timeFrame: 90 days
Other outcomes:
measure: Proportion of patients with sICH
timeFrame: 24-36 hours
Locations:
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
Study officials:
affiliation: John Hunter Hospital, Newcastle, NSW Australia
name: Ferdinand Miteff - Interventional Neurologist, RACP, CCINR
role: PRINCIPAL_INVESTIGATOR
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