Acute Ischaemic Stroke, Transient Ischaemic Attack
Conditions
Keywords
Acute ischaemic stroke; Transient Ischaemic Attack (TIA); Stroke
Brief summary
Study to investigate if the study drug ticagrelor and ASA is more effective than Placebo (inactive tablet) and ASA in preventing new stroke events
Interventions
DRUGTicagrelor
Ticagrelor arm: Day 1, loading dose of ticagrelor followed by daily maintenance dose until Day 30.
DRUGPlacebo
Placebo arm: Day 1, loading dose of placebo followed by placebo daily maintenance dose until Day 30.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed informed consent prior to any study-specific procedure 2. ≥40 years of age 3. Acute onset of cerebral ischaemia due to 1. AIS with NIHSS ≤5. AIS is defined as acute onset of neurological deficit attributed to focal brain ischaemia, and either of the following: * Persistent signs or symptoms of the ischaemic event at the time o randomisation, OR * Acute ischaemic brain lesion documented before randomisation by computed tomography (CT) scan or magnetic resonance imaging (MRI) (diffusion-weighted imaging) and that could account for the clinical presentation 2. High-risk TIA, defined as neurological deficit of acute onset attributed to focal ischaemia of the brain by history or examination with complete resolution of the deficit, and at least one of the following: * ABCD2 score ≥6 and TIA symptoms not limited to isolated numbness, isolated visual changes, or isolated dizziness/vertigo * Symptomatic intracranial arterial occlusive disease that could account for the clinical presentation, documented by transcranial Doppler or vascular imaging and defined as at least 50% narrowing in the diameter of the vessel lumen * Internal carotid arterial occlusive disease that could account for the clinical presentation, documented by Doppler, ultrasound, or vascular imaging and defined as at least 50% narrowing in diameter of the vessel lumen 4. Randomisation occurring within 24 hours after onset of symptoms; for wake-up strokes (when the time of symptom onset is not known), within 24 hours from the time point at which the patient was reported to be in their normal condition 5. CT or MRI performed after symptom onset ruling out intracranial haemorrhage or other pathology, such as vascular malformation, tumour, or abscess that according to the Investigator could explain symptoms or contraindicate study treatment
Exclusion criteria
1. Need for or an anticipated need for any of the following: 1. Dual antiplatelet therapy with ASA and P2Y12 inhibitors (including patients with carotid artery stenting and percutaneous coronary intervention) 2. Antiplatelets other than ASA (eg, GPIIb/IIIa inhibitors, clopidogrel, ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol, ticagrelor) and other antithrombotic agents with antiplatelet effects, including traditional/herbal medicine agents 3. Anticoagulants (eg, warfarin, oral thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, fondaparinux, or unfractionated heparin and long-term treatment with low-molecular weight heparins). Short-term treatment (≤7 days) with low-dose low-molecular weight heparin may be used in immobilised patients at the discretion of the Investigator 2. Any history of atrial fibrillation/flutter, ventricular aneurysm, or suspicion of other cardioembolic pathology for TIA or stroke 3. Patients who should receive or have received any intravenous or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomisation 4. Planned carotid endarterectomy that requires halting investigational product within 3 days of randomisation or is expected to require unblinding of investigational product (planned carotid endarterectomy is in itself not an exclusion criterion) 5. History of previous intracranial haemorrhage at any time (asymptomatic microbleeds do not qualify), gastrointestinal haemorrhage within the past 6 months, or major surgery within 30 days 6. Patients considered to be at risk of bradycardic events (eg, known sick sinus syndrome or second- or third-degree atrioventricular block) unless already treated with a permanent pacemaker 7. Inability of the patient to understand and/or comply with study procedures and/or follow-up, in the opinion of the Investigator 8. Known hypersensitivity to ticagrelor or ASA 9. Need for or an anticipated need for oral or intravenous therapy with any of the following: 1. Strong cytochrome P450 3A (CYP3A4) inhibitors (eg, ketoconazole, clarithromycin \[but not erythromycin or azithromycin\], nefazadone, ritonavir, atazanavir) that cannot be stopped for the course of the study 2. Long-term (\>7 days) non-steroidal anti-inflammatory drugs 10. Known bleeding diathesis or coagulation disorder (eg, thrombotic thrombocytopenic purpura) 11. Known severe liver disease (eg, ascites or signs of coagulopathy) 12. Renal failure requiring dialysis 13. Pregnancy or breastfeeding. Women of child-bearing potential who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the Investigator 14. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 15. Previous enrolment or randomisation in the present study 16. Participation in another clinical study with an investigational product at any time during the 30 days prior to randomisation (regardless of when treatment with the investigational product was discontinued)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Subsequent Stroke or Death | From randomisation (day 1) to visit 3 (day 30-34) | Participants with subsequent stroke or death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ischaemic Stroke | From randomisation (day 1) to visit 3 (day 30-34) | Number of participants with ischaemic stroke |
| Number of Participants With Modified Rankin Scale (mRS) Score >1 at Visit 3 | Visit 3 (day 30-34) | The modified Rankin Scale (mRS) is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death.0 - No symptoms,1 - No significant disability. Able to carry out all usual activities, despite some symptoms. 2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Severe | From randomisation (day 1) to visit 3 (day 30-34) | Participants with bleeding event that fulfils serious adverse event criteria and is categorised as GUSTO Severe. GUSTO is a bleeding scale (GUSTO = Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries). GUSTO Severe bleeding is defined as any of the following: (1) fatal bleeding, (2) intracranial bleeding, or (3) bleeding that caused haemodynamic compromise requiring intervention |
| Premature Permanent Discontinuation of IP Due to Bleeding | From randomisation (day 1) to visit 3 (day 30-34) | Participants with premature permanent discontinuation of IP due to bleeding |
| ICH or Fatal Bleeding Event | From randomisation (day 1) to visit 3 (day 30-34) | Participants with ICH or fatal bleeding event |
| Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Moderate/Severe | From randomisation (day 1) to visit 3 (day 30-34) | Participants with bleeding event that fulfils serious adverse event criteria and is categorised as GUSTO Moderate/Severe. GUSTO is a bleeding scale (GUSTO = Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries). GUSTO Severe bleeding is defined as any of the following: (1) fatal bleeding, (2) intracranial bleeding, or (3) bleeding that caused haemodynamic compromise requiring intervention. GUSTO Moderate bleeding is a bleeding requiring transfusion of whole blood or packed red blood cells without haemodynamic compromise |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, France, Germany, Hong Kong, Hungary, India, Italy, Mexico, Peru, Poland, Romania, Russia, Saudi Arabia, Slovakia, South Korea, Spain, Sweden, Taiwan, Thailand, Ukraine, Vietnam
Participant flow
Recruitment details
414 study sites in 28 countries enrolled patients. The first patient was enrolled on 22 January 2018. The last patient visit took place on 13 December 2019.
Pre-assignment details
11073 patients screened; 11016 patients randomised. 57 patients who were not randomised (patient did not meet inclusion/exclusion criteria n=52, patient decision n=5).
Participants by arm
| Arm | Count |
|---|---|
| TICAGRELOR Ticagrelor 180 mg day 1, followed by 90 mg twice daily day 2-30 | 5,523 |
| PLACEBO Placebo 180 mg day 1, followed by 90 mg twice daily day 2-30 | 5,493 |
| Total | 11,016 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | TICAGRELOR | PLACEBO | Total |
|---|---|---|---|
| Age, Continuous | 65.2 Years STANDARD_DEVIATION 11 | 65.1 Years STANDARD_DEVIATION 11.1 | 65.1 Years STANDARD_DEVIATION 11 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 173 Participants | 168 Participants | 341 Participants |
| Race/Ethnicity, Customized Asian | 2353 Participants | 2339 Participants | 4692 Participants |
| Race/Ethnicity, Customized Black or African American | 21 Participants | 32 Participants | 53 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 2973 Participants | 2948 Participants | 5921 Participants |
| Sex: Female, Male Female | 2108 Participants | 2171 Participants | 4279 Participants |
| Sex: Female, Male Male | 3415 Participants | 3322 Participants | 6737 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 40 / 5,523 | 32 / 5,493 |
| other Total, other adverse events | 0 / 5,523 | 0 / 5,493 |
| serious Total, serious adverse events | 571 / 5,523 | 609 / 5,493 |
Outcome results
Primary
Composite of Subsequent Stroke or Death
Participants with subsequent stroke or death
Time frame: From randomisation (day 1) to visit 3 (day 30-34)
Population: Full analysis set including all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | Composite of Subsequent Stroke or Death | 303 Participants |
| PLACEBO | Composite of Subsequent Stroke or Death | 362 Participants |
p-value: 0.01595% CI: [0.71, 0.96]Regression, Cox
Secondary
Ischaemic Stroke
Number of participants with ischaemic stroke
Time frame: From randomisation (day 1) to visit 3 (day 30-34)
Population: Full analysis set including all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | Ischaemic Stroke | 276 Participants |
| PLACEBO | Ischaemic Stroke | 345 Participants |
p-value: 0.00495% CI: [0.68, 0.93]Regression, Cox
Secondary
Number of Participants With Modified Rankin Scale (mRS) Score >1 at Visit 3
The modified Rankin Scale (mRS) is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6, running from perfect health without symptoms to death.0 - No symptoms,1 - No significant disability. Able to carry out all usual activities, despite some symptoms. 2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 - Dead.
Time frame: Visit 3 (day 30-34)
Population: Full analysis set including all randomised patients. Patients with missing mRS score or missing covariates, NIHSS (National Institutes of Health Stroke Scale) score and history of stroke (yes/no), were excluded
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | Number of Participants With Modified Rankin Scale (mRS) Score >1 at Visit 3 | 1282 Participants |
| PLACEBO | Number of Participants With Modified Rankin Scale (mRS) Score >1 at Visit 3 | 1284 Participants |
p-value: 0.61395% CI: [0.89, 1.07]Regression, Logistic
Other Pre-specified
Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Moderate/Severe
Participants with bleeding event that fulfils serious adverse event criteria and is categorised as GUSTO Moderate/Severe. GUSTO is a bleeding scale (GUSTO = Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries). GUSTO Severe bleeding is defined as any of the following: (1) fatal bleeding, (2) intracranial bleeding, or (3) bleeding that caused haemodynamic compromise requiring intervention. GUSTO Moderate bleeding is a bleeding requiring transfusion of whole blood or packed red blood cells without haemodynamic compromise
Time frame: From randomisation (day 1) to visit 3 (day 30-34)
Population: Full analysis set including all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Moderate/Severe | 36 Participants |
| PLACEBO | Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Moderate/Severe | 11 Participants |
p-value: <0.00195% CI: [1.67, 6.43]Regression, Cox
Other Pre-specified
Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Severe
Participants with bleeding event that fulfils serious adverse event criteria and is categorised as GUSTO Severe. GUSTO is a bleeding scale (GUSTO = Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries). GUSTO Severe bleeding is defined as any of the following: (1) fatal bleeding, (2) intracranial bleeding, or (3) bleeding that caused haemodynamic compromise requiring intervention
Time frame: From randomisation (day 1) to visit 3 (day 30-34)
Population: Full analysis set including all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Severe | 28 Participants |
| PLACEBO | Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Severe | 7 Participants |
p-value: 0.00195% CI: [1.74, 9.14]Regression, Cox
Other Pre-specified
ICH or Fatal Bleeding Event
Participants with ICH or fatal bleeding event
Time frame: From randomisation (day 1) to visit 3 (day 30-34)
Population: Full analysis set including all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | ICH or Fatal Bleeding Event | 22 Participants |
| PLACEBO | ICH or Fatal Bleeding Event | 6 Participants |
p-value: 0.00595% CI: [1.48, 9.02]Regression, Cox
Other Pre-specified
Premature Permanent Discontinuation of IP Due to Bleeding
Participants with premature permanent discontinuation of IP due to bleeding
Time frame: From randomisation (day 1) to visit 3 (day 30-34)
Population: Full analysis set including all randomised patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TICAGRELOR | Premature Permanent Discontinuation of IP Due to Bleeding | 152 Participants |
| PLACEBO | Premature Permanent Discontinuation of IP Due to Bleeding | 32 Participants |
p-value: <0.00195% CI: [3.28, 7.02]Regression, Cox