Safety and Tolerability of Adjunctive TBO-309 in Reperfusion for Stroke

Acute Ischemic Stroke Clinical Trial

— STARS  

Official title:

Safety and Tolerability of Adjunctive TBO-309 in Reperfusion for Stroke

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05363397
• Other study ID #: CCD78277
• Secondary ID: U1111-1270-5195
• Status: Recruiting
• Phase: Phase 2
• Start date: September 27, 2023
• Est. completion date: May 1, 2025

Study information

• Verified date: November 2023
• Source: The George Institute
• Contact: Candice Delcourt, Dr
• Phone: +61 2 8052 4601
• Email: cdelcourt[@]georgeinstitute.org.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

STARS is a prospective, multicentre, open-label, dose escalation, Phase IIa study to assess the safety and tolerability of TBO-309, an adjuvant antiplatelet therapy, in patients with AIS.

Acute ischaemic stroke (AIS) is caused by a severe blockage of an artery leading to immediate reduced blood flow to part of the brain. Standard therapies target the blocked artery by either dissolving the blockage or removing the blockage. However, even after successful treatment, re-blockage of arteries can occur. The use of an antiplatelet therapy, TBO-309, in addition to standard therapies offers the possibility of improved restoration of blood flow and reduced rates of artery re-blockage.

Description:

Stroke is a leading cause of disability worldwide, with most strokes in Australia being Acute ischaemic stroke (AIS). AIS is caused by a severe blockage of an artery leading to immediate reduced blood flow to part of the brain. Timely restoration of blood flow is critical to preserve brain function. Standard therapies target the blocked artery by either dissolving the blockage (intravenous thrombolysis (IVT)) or removing the blockage (endovascular thrombectomy (EVT)). However, even after successful treatment, re-blockage of arteries can occur. The use of an antiplatelet therapy in addition to IVT/EVT offers the possibility of improved restoration of blood flow and reduced rates of artery re-blockage.

STARS is a prospective, multicentre, open-label, dose escalation, Phase IIa study to assess the safety and tolerability of TBO-309, an adjuvant antiplatelet therapy, in patients with AIS. The study will test the hypothesis that AIS patients who are treated with TBO-309 in conjunction with standard therapy (IVT alone or IVT + EVT) will not experience higher rates of ICH compared to the expected rates of ICH in patients treated with only standard therapy (IVT alone or IVT + EVT).

TBO-309 is a potent, selective and ATP competitive PI3Kβ inhibitor which blocks platelet activation adhesion/aggregation and promotes platelet disaggregation, thereby specifically inhibiting thrombosis without interfering with normal haemostasis. In order to evaluate safety at lower doses, four dose levels in total will be administered using a serial dose-escalation design. Doses will be assigned based on a dose escalation methodology commencing with lower doses assigned early in the study. As safety criteria are satisfied (based on ICH rates) doses will be increased. The dosage strength of TBO-309 to be administered (30mg, 60mg, 120mg or 180mg) will be assigned by the study database.

Patients presenting to hospital with an AIS will be assessed according to the trial inclusion and exclusion criteria by the Principal Investigator, or nominated delegate, on admission to the Emergency Department. Consent will be sought from either the patient or their Person Responsible/Medical Treatment Decision Maker prior to enrolment into the study. Standard therapy, either IVT alone or IVT + EVT, will commence and the TBO-309 will be administered at the same time as standard therapy. Following administration of study drug and treatment with standard therapies, patients will receive usual supportive care either in the Intensive Care Unit or in the hospital ward. Any significant neurological deterioration will require an emergency non-contrast CT head to assess for the presence of ICH. All patients will receive a 24-36 hour MRI or a multimodal CT to assess asymptomatic bleeding, recanalisation and infarct volume.

During the patients hospital stay clinical outcome data will be collected during the study period to document response to treatment and to monitor safety. Study patients will be followed-up for 90 days post-enrolment, or to death, whichever is the earlier.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: May 1, 2025
• Est. primary completion date: February 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

1. Patient aged 18 years or more

2. Patient has an acute ischaemic stroke (AIS)

3. Patient will be treated with either:

1. Intravenous thrombolysis (IVT) with alteplase or tenecteplase for a diagnosis of AIS that is confirmed by CT imaging;

alone/OR WITH

2. Endovascular Thrombectomy (EVT) for LVO in the internal carotid artery, proximal middle cerebral artery (M1 segment), proximal M2 or with tandem occlusion of both the cervical carotid and intracranial large arteries who either:

i. presented within 6 hours of stroke onset

OR

ii. presented between 6-24 hours after they were last known to be well and clinical observations and either CT perfusion or MRI features indicate 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 MCA territory

2. High likelihood of undergoing stent insertion and requiring additional antithrombotic(s)

3. Uncontrolled hypertension (SBP >180 or DBP >110, refractory to medical therapy)

4. ICH within the last 90 days

5. Myocardial infarction or stroke within the last 30 days

6. Patient has an underlying disease process with a life expectancy of <90 days

7. Contraindication to thrombolysis i.e. increased bleeding risk

8. Contraindication to intravenous contrast agents including renal impairment or allergy

9. Known treatment with dual antiplatelet therapy or anticoagulant medication

10. Known severe liver disease

11. Known bleeding disorder

12. Cardiopulmonary resuscitation or arterial puncture at non-compressible site or lumbar puncture within 7 days

13. Another medical illness or social circumstance that may interfere with outcome assessments and follow-up

14. Known or suspected pregnancy

15. Patients currently participating in another interventional clinical trial

16. Informed consent unable to be obtained from the patient or their Person Responsible/Medical Treatment Decision Maker prior to study interventions

17. Study drug cannot be given within one hour of thrombolytic drug bolus

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Ischemic Stroke
• Stroke

Intervention

Drug:
• TBO-309
TBO-309 is a potent, selective and ATP competitive PI3Kß inhibitor which blocks platelet activation adhesion/aggregation and promotes platelet disaggregation, thereby specifically inhibiting thrombosis without interfering with normal haemostasis.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Timothy Ang	Camperdown	New South Wales
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Prince of Wales Hospital	Randwick	New South Wales

Sponsors (2)

Lead Sponsor	Collaborator
The George Institute	Heart Research Institute

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Recanalisation rate	CT Angiogram (CTA) or MR angiogram (MRA) assessment to measure recanalisation rate by the Thrombolysis in Myocardial Infarction (TIMI) scale	Within 24-36 hours of study drug administration
Other	Reperfusion rates	Reperfusion rates by expanded thrombolysis in Cerebral Infarction scale (eTICI) 2b (50 or better = 50% to 100%)	Within 24-36 hours of study drug administration
Other	Infarct volume	Infarct volume measured with diffusion weighted imaging (DWI) MRI and fluid attenuated inversion recovery (FLAIR) MRI	Within 24-36 hours of study drug administration
Other	NIHSS score	Quantifies stroke severity	At 24 hours, 72 hours and 7 days post study drug administration or hospital discharge (whichever is sooner)
Other	Modified Rankin Scale (mRS) score	Measures the degree of disability or dependence in the daily activities of people who have suffered a stroke.	At hospital discharge and 90 days post study drug administration
Other	Mortality	All-cause mortality	At 90 days post study drug administration
Other	Plasma levels of TBO-309	Plasma levels of TBO-309 will be measured to generate a population pharmacokinetic model	At the end of infusion, and 1 and 3 hours post end of infusion
Other	AKT phosphorylation relative to total AKT	AKT phosphorylation relative to total AKT (pAKT/AKT) from platelets at the end of infusion	At the end of infusion and 24 hours post end of infusion
Other	Genomic markers	Genomic markers of delayed TBO-309 clearance when individuals with delayed clearance are identified	24 hours post end of infusion
Other	Genetic markers for stroke outcome	Putative genetic markers for stroke outcome, including bleeding and reperfusion, following TBO-309 administration	24 hours post end of infusion
Primary	Proportion of patients with intracerebral hemorrhage (ICH)	Proportion of patients with ICH within 24-36 hours of study drug (TBO-309) commencement. This includes parenchymal haemorrhage type II based on the Heidelberg Bleeding Classification and any intracranial haemorrhage leading to an increase in NIHSS of 4 points or more.	Within 24-36 hours of initiation of study drug
Secondary	All bleeding	All bleeding within 72 hours of study drug (TBO-309) administration according to a modified WHO scale	Within 72 hours of study drug administration
Secondary	All intracerebral hemorrhage (ICH)	All ICH as demonstrated on CT/MRI up to 90 days	Up to 90 days post study drug administration
Secondary	All bleeding	All bleeding reported up to 90 days according to a modified WHO scale	Up to 90 days post study drug administration