THROMBOLYSIS
Conditions
Brief summary
This study will evaluate the efficacy and safety of tenecteplase compared with placebo in participants with acute ischemic stroke (AIS). All participants will receive standard-of-care therapy according to AmericanHeart Association/American Stroke Association clinical guidelines (2018). To determine eligibility for randomization, all participants will undergo multimodal CT or MRI at baseline. Only participants with a vessel occlusion (ICA or MCA M1/M2) and penumbral tissue will be randomized. The primary analysis is to compare the efficacy of tenecteplase versus placebo in all participants at Day 90.
Interventions
BIOLOGICALTenecteplase
The investigational medicinal product (IMP) for this study is tenecteplase. The recommended total dose for this study is weight-based with 0.25 mg of tenecteplase per kg, not exceeding a maximum dose of 25 mg. A single bolus dose should be administered over 5 seconds based on patient weight.
OTHERPlacebo
Placebo is being used as the comparator since a thrombolytic is only FDA-approved in the United States for use out to 3 hours, and the standard of care guidelines support use out to 4.5 hours.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient/legally authorized representative has signed the Informed Consent Form * Age \>= 18 years * AIS symptom onset within 4.5 to 24 hours Signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke involving occlusion of the ICA, M1, or M2 vessels * Functionally independent (mRS 0-2) prior to stroke onset * Baseline NIHSS \>=5 and that remains \>=5 immediately prior to randomization * Neuroimaging: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial, with or without tandem MCA lesions) by magnetic resonance angiography (MRA) or computed tomography angiography (CTA) AND target mismatch profile on CT perfusion or MR perfusion (ischemic core volume \<70 mL, mismatch ratio is \>=1.8 and mismatch volume is \>= 15 mL) * The mismatch volume is determined by FDA-approved imaging software in real time based on the difference between the ischemic core lesion volume and the Tmax\>6s lesion volume. If both a CT perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is assessed to determine eligibility. Only an intracranial MRA is required for patients screened with MRA; cervical MRA is not required. Cervical and intracranial CTA are typically obtained simultaneously in patients screened with CTA, but only the intracranial CTA is required for enrollment. Alternative neuroimaging: * If CTA (or MRA) is technically inadequate: Tmax\>6s perfusion deficit consistent with an ICA or M1, M2 occlusion AND target mismatch profile (ischemic core volume \<70 mL, mismatch ratio \>= 1.8 and mismatch volume \>= 15 mL as determined by RAPID software) * If magnetic resonance perfusion (MRP) is technically inadequate: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND diffusion-weighted imaging (DWI) lesion volume \<=25 mL for an M1 or ICA occlusion and =\<15 mL for an M2 occlusion * If CTP is technically inadequate: patient can be screened with MRI and randomized if neuroimaging criteria are met. * Ability to comply with the study protocol, in the investigator's judgment
Exclusion criteria
General * Current participation in another investigational drug or device study * Active internal bleeding * Known hypersensitivity or allergy to any ingredients of tenecteplase * Known bleeding diathesis * Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR \>1.7 * Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban) * Pregnant * Intracranial neoplasm (except small meningioma), arteriovenous malformation, or aneurysm * Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS * Severe, uncontrolled hypertension (systolic blood pressure \>180 mmHg or diastolic blood pressure \> 110 mmHg) * For participants with suspected coagulopathy, platelet count must be checked prior to randomization and participant is excluded if baseline platelet count \<100,000/microL * Baseline blood glucose \>400 mg/dL (22.20 mmol/L) * Baseline blood glucose \<50 mg/dL needs to be normalized prior to randomization * Clot retrieval attempted using a neurothrombectomy device prior to randomization * Intracranial or intraspinal surgery or trauma within 2 months * Treatment with a thrombolytic within the last 3 months prior to randomization * Other serious, advanced, or terminal illness (investigator judgment) with life expectancy less than 6 months * Pre-existing medical, neurological, or psychiatric disease that would confound the neurological or functional evaluations * History of cerebrovascular accident in the last 90 days * Presumed septic embolus; suspicion of bacterial endocarditis * Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was to be performed Imaging * Unable to undergo a contrast brain perfusion scan with either MRI or CT * Extensive early ischemic change (hypodensity) on non-contrast CT estimated to be \>1/3 MCA territory, or significant hypodensity outside the Tmax\>6s perfusion lesion that invalidates mismatch criteria (if patient is enrolled based on CT perfusion criteria) * Significant mass effect * Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion) * Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ordinal Modified Rankin Scale (mRS) Score at Day 90 | Day 90 | The the modified Rankin score (mRS) is a 6-point scale commonly used to assess disability due to stroke, with higher values indicating worse outcomes. 0 = No symptoms 1. = No significant disability 2. = Slight disability 3. = Moderate disability 4. = Moderately severe disability 5. = Severe disability 6. = Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Recanalization at 24 Hours Post-randomization | Day 2 | This endpoint measured complete or partial recanalization (restored blood flow) on CT angiography (CTA)/magnetic resonance angiography (MRA) post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA). |
| Proportion of Patients With Reperfusion at 24 Hours Post-randomization | Day 2 | This endpoint was defined by the proportion of participants with reperfusion (the restoration of blood flow to an organ or tissue after having been blocked) at 24 hours post-randomization, defined as \> 90% reduction in Tmax \> 6s lesion volume. |
| Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure | Day 1 | Angiographic reperfusion was evaluated using the modified Thrombolysis in Cerebral Infarction (TICI) Scale: 0: No perfusion or anterograde flow beyond site of occlusion. 1. Contrast passes the area of occlusion but fails to opacify the entire cerebral bed distal to the obstruction during angiographic run. 2. Partial perfusion wherein the contrast passes the occlusion and opacifies the distal arterial bed but rate of entry or clearance from the bed is slower than non-involved territories 2A: \< 50% of territory visualized 2B: ≥ 50% of territory is visualized 2C: Near complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli 3. Complete reperfusion with normal filling. |
| Median NIHSS Score at Day 90 | Day 90 | The National Institutes of Health Stroke Score (NIHSS) is a 15-item scale that measures neurological deficit in acute stroke patients. Each item is ranked using a 3-, 4-, or 5-point scale, including allowances for items that cannot be scored due to the patient's condition, with higher scores indicating more severe deficit. Total scores range from 0-42, with higher scores indicating more severe deficits. |
| Proportion of Patients With Functional Independence at Day 90 | Day 90 | Functional independence, was defined as an mRS of 0-2 (no symptoms to mild symptoms), at Day 90. |
| Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90 | Day 90 | The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: 1. = Death 2. = Persistent vegetative state 3. = Severe disability 4. = Moderate disability 5. = Good recovery The GOS was re-scaled from observed data. For this measure, 1 = good recovery and 5 = death. |
| Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours | Within 36 hours (Day 2) of treatment | — |
| Mortality Rate up to Day 30 and Day 90 | Day 30 and Day 90 | — |
| Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit | Day 3 | — |
| Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90 | Day 90 | The Barthel Index (BI) is a 10-item ordinal scale used to measure performance in activities of daily living (ADL) and mobility. The BI scoring range is from 0-100, with lower scores representing greater dependency. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tenecteplase Participants received Tenecteplase (0.25 mg/kg, maximum 25 mg) administered as a single bolus injection over 5 seconds, administered within 4.5 - 24 hours of the onset of internal carotid artery (ICA) or middle cerebral artery (MCA) stroke. | 228 |
| Placebo Participants received placebo administered as a single bolus injection over 5 seconds, administered within 4.5 - 24 hours of the onset of internal carotid artery (ICA) or middle cerebral artery (MCA) stroke. | 230 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 44 | 42 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Tenecteplase |
|---|---|---|---|
| Age, Continuous | 71.3 Years STANDARD_DEVIATION 13.6 | 70.8 Years STANDARD_DEVIATION 13.5 | 70.2 Years STANDARD_DEVIATION 13.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 39 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 197 Participants | 398 Participants | 201 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 21 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 20 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants | 63 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 29 Participants | 15 Participants |
| Race (NIH/OMB) White | 170 Participants | 339 Participants | 169 Participants |
| Sex: Female, Male Female | 123 Participants | 245 Participants | 122 Participants |
| Sex: Female, Male Male | 107 Participants | 213 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 44 / 228 | 44 / 230 |
| other Total, other adverse events | 145 / 218 | 136 / 214 |
| serious Total, serious adverse events | 91 / 218 | 102 / 214 |
Outcome results
Primary
Ordinal Modified Rankin Scale (mRS) Score at Day 90
The the modified Rankin score (mRS) is a 6-point scale commonly used to assess disability due to stroke, with higher values indicating worse outcomes. 0 = No symptoms 1. = No significant disability 2. = Slight disability 3. = Moderate disability 4. = Moderately severe disability 5. = Severe disability 6. = Death
Time frame: Day 90
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 3 | 34 Count of participants |
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 5 | 15 Count of participants |
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 2 | 31 Count of participants |
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 6 | 44 Count of participants |
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 4 | 29 Count of participants |
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 0 | 35 Count of participants |
| Tenecteplase | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 1 | 38 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 0 | 31 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 1 | 30 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 2 | 36 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 3 | 41 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 4 | 34 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 5 | 13 Count of participants |
| Placebo | Ordinal Modified Rankin Scale (mRS) Score at Day 90 | 6 | 44 Count of participants |
Secondary
Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours
Time frame: Within 36 hours (Day 2) of treatment
Population: The safety population consisted of all randomized participants who received tenecteplase or placebo, with participants grouped according to the treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase | Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours | 3.2 Percentage of participants |
| Placebo | Incidence of Symptomatic Intracranial Hemorrhage (sICH) Within 36 Hours | 2.3 Percentage of participants |
Secondary
Median NIHSS Score at Day 90
The National Institutes of Health Stroke Score (NIHSS) is a 15-item scale that measures neurological deficit in acute stroke patients. Each item is ranked using a 3-, 4-, or 5-point scale, including allowances for items that cannot be scored due to the patient's condition, with higher scores indicating more severe deficit. Total scores range from 0-42, with higher scores indicating more severe deficits.
Time frame: Day 90
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tenecteplase | Median NIHSS Score at Day 90 | 1.0 Scores on a scale |
| Placebo | Median NIHSS Score at Day 90 | 1.0 Scores on a scale |
Secondary
Mortality Rate up to Day 30 and Day 90
Time frame: Day 30 and Day 90
Population: The safety population consisted of all randomized participants who received tenecteplase or placebo, with participants grouped according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Mortality Rate up to Day 30 and Day 90 | Death within 30 days | 14.7 Percentage of participants |
| Tenecteplase | Mortality Rate up to Day 30 and Day 90 | Death within 90 days | 19.7 Percentage of participants |
| Placebo | Mortality Rate up to Day 30 and Day 90 | Death within 90 days | 18.2 Percentage of participants |
| Placebo | Mortality Rate up to Day 30 and Day 90 | Death within 30 days | 15.0 Percentage of participants |
Secondary
Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90
The Barthel Index (BI) is a 10-item ordinal scale used to measure performance in activities of daily living (ADL) and mobility. The BI scoring range is from 0-100, with lower scores representing greater dependency.
Time frame: Day 90
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90 | BI score ≥ 95 at Day 90 | 60.5 Percentage of participants |
| Tenecteplase | Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90 | BI score < 95 at Day 90 | 39.5 Percentage of participants |
| Placebo | Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90 | BI score ≥ 95 at Day 90 | 58.4 Percentage of participants |
| Placebo | Proportion of Patients With a Barthel Index (BI) Score ≥ 95 at Day 90 | BI score < 95 at Day 90 | 41.6 Percentage of participants |
Secondary
Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure
Angiographic reperfusion was evaluated using the modified Thrombolysis in Cerebral Infarction (TICI) Scale: 0: No perfusion or anterograde flow beyond site of occlusion. 1. Contrast passes the area of occlusion but fails to opacify the entire cerebral bed distal to the obstruction during angiographic run. 2. Partial perfusion wherein the contrast passes the occlusion and opacifies the distal arterial bed but rate of entry or clearance from the bed is slower than non-involved territories 2A: \< 50% of territory visualized 2B: ≥ 50% of territory is visualized 2C: Near complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli 3. Complete reperfusion with normal filling.
Time frame: Day 1
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure | Achieving TICI < 2b | 10.9 Percentage of participants |
| Tenecteplase | Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure | Achieving TICI 2b or TICI 3 | 89.1 Percentage of participants |
| Placebo | Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure | Achieving TICI 2b or TICI 3 | 85.4 Percentage of participants |
| Placebo | Proportion of Patients With Angiographic Reperfusion at Completion of Angiographic Procedure | Achieving TICI < 2b | 14.6 Percentage of participants |
Secondary
Proportion of Patients With Functional Independence at Day 90
Functional independence, was defined as an mRS of 0-2 (no symptoms to mild symptoms), at Day 90.
Time frame: Day 90
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Proportion of Patients With Functional Independence at Day 90 | mRS ≤ 2 at Day 90 | 46.0 Percentage of participants |
| Tenecteplase | Proportion of Patients With Functional Independence at Day 90 | mRS > 2 at Day 90 | 54.0 Percentage of participants |
| Placebo | Proportion of Patients With Functional Independence at Day 90 | mRS ≤ 2 at Day 90 | 42.4 Percentage of participants |
| Placebo | Proportion of Patients With Functional Independence at Day 90 | mRS > 2 at Day 90 | 57.6 Percentage of participants |
Secondary
Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90
The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: 1. = Death 2. = Persistent vegetative state 3. = Severe disability 4. = Moderate disability 5. = Good recovery The GOS was re-scaled from observed data. For this measure, 1 = good recovery and 5 = death.
Time frame: Day 90
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90 | Good recovery GOS score (=1) | 36.5 Percentage of participants |
| Tenecteplase | Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90 | GOS score > 1 | 63.5 Percentage of participants |
| Placebo | Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90 | Good recovery GOS score (=1) | 30.8 Percentage of participants |
| Placebo | Proportion of Patients With Good Recovery Based on the Glasgow Outcome Scale (GOS) at Day 90 | GOS score > 1 | 69.2 Percentage of participants |
Secondary
Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit
Time frame: Day 3
Population: The safety population consisted of all randomized participants who received tenecteplase or placebo, with participants grouped according to the treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase | Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit | 3.7 Percentage of participants |
| Placebo | Proportion of Patients With Parenchymal Hematoma Type 2 (PH2) at the 72-96 Hour Visit | 2.8 Percentage of participants |
Secondary
Proportion of Patients With Recanalization at 24 Hours Post-randomization
This endpoint measured complete or partial recanalization (restored blood flow) on CT angiography (CTA)/magnetic resonance angiography (MRA) post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA).
Time frame: Day 2
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Proportion of Patients With Recanalization at 24 Hours Post-randomization | Complete recanalization | 76.7 Percentage of participants |
| Tenecteplase | Proportion of Patients With Recanalization at 24 Hours Post-randomization | None or partial recanalization | 23.3 Percentage of participants |
| Placebo | Proportion of Patients With Recanalization at 24 Hours Post-randomization | Complete recanalization | 63.9 Percentage of participants |
| Placebo | Proportion of Patients With Recanalization at 24 Hours Post-randomization | None or partial recanalization | 36.1 Percentage of participants |
Secondary
Proportion of Patients With Reperfusion at 24 Hours Post-randomization
This endpoint was defined by the proportion of participants with reperfusion (the restoration of blood flow to an organ or tissue after having been blocked) at 24 hours post-randomization, defined as \> 90% reduction in Tmax \> 6s lesion volume.
Time frame: Day 2
Population: The ITT population consisted of all randomized participants who provided informed consent, with participants grouped according to their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase | Proportion of Patients With Reperfusion at 24 Hours Post-randomization | > 90% reduction in Tmax > 6s lesion volume | 56.9 Percentage of participants |
| Tenecteplase | Proportion of Patients With Reperfusion at 24 Hours Post-randomization | ≤ 90% reduction | 43.1 Percentage of participants |
| Placebo | Proportion of Patients With Reperfusion at 24 Hours Post-randomization | > 90% reduction in Tmax > 6s lesion volume | 57.7 Percentage of participants |
| Placebo | Proportion of Patients With Reperfusion at 24 Hours Post-randomization | ≤ 90% reduction | 42.3 Percentage of participants |