Stroke
Conditions
Brief summary
PRISMS is a double-blind, multicenter, randomized, Phase IIIb study to evaluate the efficacy and safety of intravenous (IV) alteplase in participants with mild acute ischemic strokes that do not appear to be clearly disabling. Participants will be randomized in a 1:1 ratio to receive within 3 hours of last known well time either 1) one dose of IV alteplase and one dose of oral aspirin placebo or 2) one dose of IV alteplase placebo and one dose of oral aspirin 325 milligrams (mg).
Interventions
DRUGAlteplase
Single dose of alteplase will be administered at 0.9 milligrams per kilogram (mg/kg) IV (maximal dose of 90 mg).
DRUGAlteplase Placebo
Single dose of alteplase placebo will be administered as IV injection.
DRUGAspirin
Single dose of aspirin will be administered at 325 mg orally.
DRUGAspirin Placebo
Single dose of aspirin placebo will be administered orally.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Mild ischemic stroke defined as the most recent pre-treatment NIHSS score of less than or equal to(\</=) 5 and determined as not clearly disabling by the investigator * Study treatment initiated within 3 hours of last time participant seen normal
Exclusion criteria
* Computed tomography (CT) or magnetic resonance imaging (MRI) findings of one of the following: 1. CT with clear large hypodensity that is greater than (\>) one-third middle cerebral artery (MCA) territory (or \>100 cubic centimeter \[cc\] if not in MCA territory) 2. MRI with clear large hyperintensity on concurrent diffusion-weighted (DW) and fluid-attenuated inversion recovery (FLAIR) that is greater than one-third MCA territory (or greater than 100 cc if not in MCA territory), 3. Imaging lesion consistent with acute hemorrhage, or 4. Evidence of intraparenchymal tumor * Disability prior to the presenting stroke * Standard contraindications to IV alteplase within 3 hours of symptom onset, including: 1. Head trauma, myocardial infarction, or previous stroke within the previous 3 months 2. Gastrointestinal or urinary tract hemorrhage within the previous 21 days 3. Major surgery within the previous 14 days 4. Arterial puncture at non-compressible site within the previous 7 days 5. Any history of ICH with the exception of those less than (\<) 5 chronic microbleeds on MRI 6. Elevated blood pressure defined by systolic blood pressure \>185 millimeters of mercury (mm Hg) or diastolic blood pressure \>110 mm Hg, or treatments requiring aggressive measures to achieve acceptable levels 7. Treatment with unfractioned heparin within past 48 hours and activated partial thromboplastin time outside normal range 8. Blood glucose \<50 milligrams per deciliter (mg/dL) 9. International normalized ratio \>1.7 10. Platelet count \<100,000 per cubic millimeter (/mm\^3) 11. Treatment with a direct thrombin inhibitor (dabigatran) or a factor Xa inhibitor (apixaban, rivaroxaban, edoxaban) within the last 48 hours * Allergic reaction to study drug, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) * Females of childbearing age who are known to be pregnant and/or lactating * Inability to swallow, which would prevent oral intake of aspirin or aspirin placebo tablet * Other serious, advanced, or terminal illness that would confound the clinical outcome at 90 days * Current or recent (within 3 months) participation in another investigational drug treatment protocol * Anticipated inability to obtain 3-month follow-up assessments * Previous enrollment in PRISMS * Any other condition deemed by the investigator that would pose hazard to the participant with alteplase treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90 | Day 90 | mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities, 2: Slight disability, unable to carry out all previous activities but able to look after own affairs without assistance, 3: Moderate disability requiring some help, but able to walk without assistance, 4: Moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability, bedridden, incontinent and requiring constant nursing care and attention, 6: death prior to Day 90. Reported is the percentage of participants with scores of 0 or 1 on the mRS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | Day 90 | Global favorable recovery is an integrated assessment of participants who meet the following: mRS Score 0-1, National Institutes of Health Stroke Scale (NIHSS) Score 0-1, Barthel Index \[BI\] greater than or equal to 95, and Glasgow Outcome Scale \[GOS\] equal to 1. mRS Score 0-1: 0= No symptoms at all, 1= No significant disability despite symptoms, able to carry out all usual duties and activities. NIHSS Score 0-1: 0= No stroke symptoms and 1= Minor stroke symptoms. BI is a 10 question index with a total score range of 0-100 with 100 being the best outcome. GOS =1: Good recovery. Reported here are the percentages of participants who achieved a favorable score on each of these scales. |
| Percentage of Participants With Symptomatic Intracranial Hemorrhage (ICH ) | Within 36 hours after study drug administration on Day 1 | ICH was considered symptomatic if it was not seen on computed tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and any neurologic decline was attributed to it by the local investigator. To detect intracranial hemorrhage, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration. |
| Percentage of Participants With Any ICH | Within 36 hours after study drug administration on Day 1 | To detect ICH, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration. |
| Distribution of Participants Across the Ordinal mRS | Day 90 | mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities, 2: Slight disability, unable to carry out all previous activities but able to look after own affairs without assistance, 3: Moderate disability requiring some help, but able to walk without assistance, 4: Moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability, bedridden, incontinent and requiring constant nursing care and attention, 6: death before Day 90. Reported are the percentages of participants for all scores on the mRS. |
| Percentage of Participants Who Died Due to Stroke and Neurological Disorders | From baseline to Day 90 | Reported here is the percentage of participants who died due to stroke and neurological disorders. |
| Percentage of Participants With Adverse Events | From baseline up to Day 90: Non-serious adverse events were collected through the Day 30 visit. Serious adverse events were collected through the end of study at Day 90. | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Percentage of Participants With Serious Adverse Events | From baseline to Day 90 | A serious adverse event (SAE) was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here. |
| Overall Mortality | From baseline to Day 90 | Reported here is the percentage of participants who died due to any cause during the study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alteplase + Aspirin Placebo Participants received single dose of 0.9 mg/kg (maximal dose of 90 mg) IV alteplase and aspirin placebo orally. | 156 |
| Alteplase Placebo + Aspirin Participants received single dose of IV alteplase placebo and 325 mg aspirin orally. | 157 |
| Total | 313 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 11 | 7 |
| Overall Study | Patient Non-compliance | 2 | 3 |
| Overall Study | Patient Withdrawal of Consent | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Alteplase + Aspirin Placebo | Alteplase Placebo + Aspirin |
|---|---|---|---|
| Age, Continuous | 61.57 years STANDARD_DEVIATION 13.27 | 61.94 years STANDARD_DEVIATION 13.53 | 61.20 years STANDARD_DEVIATION 13.05 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 62 Participants | 35 Participants | 27 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 32 Participants | 14 Participants | 18 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 273 Participants | 138 Participants | 135 Participants |
| Race/Ethnicity, Customized Not Reported | 7 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 243 Participants | 117 Participants | 126 Participants |
| Sex: Female, Male Female | 144 Participants | 79 Participants | 65 Participants |
| Sex: Female, Male Male | 169 Participants | 77 Participants | 92 Participants |
| Total National Institutes of Health Stroke Scale (NIHSS) | 2.2 units on a scale STANDARD_DEVIATION 1.18 | 2.3 units on a scale STANDARD_DEVIATION 1.21 | 2.1 units on a scale STANDARD_DEVIATION 1.15 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 154 | 0 / 153 |
| other Total, other adverse events | 49 / 154 | 53 / 153 |
| serious Total, serious adverse events | 40 / 154 | 20 / 153 |
Outcome results
Primary
Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90
mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities, 2: Slight disability, unable to carry out all previous activities but able to look after own affairs without assistance, 3: Moderate disability requiring some help, but able to walk without assistance, 4: Moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability, bedridden, incontinent and requiring constant nursing care and attention, 6: death prior to Day 90. Reported is the percentage of participants with scores of 0 or 1 on the mRS.
Time frame: Day 90
Population: Intent-to-Treat (ITT) population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90 | 78.2 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90 | 81.5 percentage of participants |
95% CI: [-9.44, 7.25]
Secondary
Distribution of Participants Across the Ordinal mRS
mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities, 2: Slight disability, unable to carry out all previous activities but able to look after own affairs without assistance, 3: Moderate disability requiring some help, but able to walk without assistance, 4: Moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability, bedridden, incontinent and requiring constant nursing care and attention, 6: death before Day 90. Reported are the percentages of participants for all scores on the mRS.
Time frame: Day 90
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase + Aspirin Placebo | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 0 | 44.9 percentage of participants |
| Alteplase + Aspirin Placebo | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 1 | 33.3 percentage of participants |
| Alteplase + Aspirin Placebo | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 2 | 11.5 percentage of participants |
| Alteplase + Aspirin Placebo | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 3 | 2.6 percentage of participants |
| Alteplase + Aspirin Placebo | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 4 | 5.1 percentage of participants |
| Alteplase + Aspirin Placebo | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 5 or 6 (death) | 2.6 percentage of participants |
| Alteplase Placebo + Aspirin | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 4 | 2.5 percentage of participants |
| Alteplase Placebo + Aspirin | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 0 | 50.3 percentage of participants |
| Alteplase Placebo + Aspirin | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 3 | 3.2 percentage of participants |
| Alteplase Placebo + Aspirin | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 1 | 31.2 percentage of participants |
| Alteplase Placebo + Aspirin | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 5 or 6 (death) | 1.3 percentage of participants |
| Alteplase Placebo + Aspirin | Distribution of Participants Across the Ordinal mRS | mRS at Day 90 - 2 | 11.5 percentage of participants |
95% CI: [0.527, 1.244]
Secondary
Overall Mortality
Reported here is the percentage of participants who died due to any cause during the study.
Time frame: From baseline to Day 90
Population: Safety Population included all participants, who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase + Aspirin Placebo | Overall Mortality | 0.6 percentage of participants |
| Alteplase Placebo + Aspirin | Overall Mortality | 0 percentage of participants |
Secondary
Percentage of Participants Who Died Due to Stroke and Neurological Disorders
Reported here is the percentage of participants who died due to stroke and neurological disorders.
Time frame: From baseline to Day 90
Population: Safety Population included all participants, who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants Who Died Due to Stroke and Neurological Disorders | 0 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants Who Died Due to Stroke and Neurological Disorders | 0 percentage of participants |
Secondary
Percentage of Participants With Adverse Events
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: From baseline up to Day 90: Non-serious adverse events were collected through the Day 30 visit. Serious adverse events were collected through the end of study at Day 90.
Population: Safety Population included all participants, who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants With Adverse Events | 77.3 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Adverse Events | 68.0 percentage of participants |
Secondary
Percentage of Participants With Any ICH
To detect ICH, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration.
Time frame: Within 36 hours after study drug administration on Day 1
Population: Safety Population included all participants, who received any amount of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants With Any ICH | Any ICH within 36 hours reported by site | 7.1 percentage of participants |
| Alteplase + Aspirin Placebo | Percentage of Participants With Any ICH | Any ICH within 36 hours reported by central reader | 7.1 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Any ICH | Any ICH within 36 hours reported by site | 2.6 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Any ICH | Any ICH within 36 hours reported by central reader | 3.3 percentage of participants |
Comparison: Any ICH within 36 hours reported by site95% CI: [-0.34, 10.07]
Comparison: Any ICH within 36 hours reported by central reader95% CI: [-1.23, 9.49]
Secondary
Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS
Global favorable recovery is an integrated assessment of participants who meet the following: mRS Score 0-1, National Institutes of Health Stroke Scale (NIHSS) Score 0-1, Barthel Index \[BI\] greater than or equal to 95, and Glasgow Outcome Scale \[GOS\] equal to 1. mRS Score 0-1: 0= No symptoms at all, 1= No significant disability despite symptoms, able to carry out all usual duties and activities. NIHSS Score 0-1: 0= No stroke symptoms and 1= Minor stroke symptoms. BI is a 10 question index with a total score range of 0-100 with 100 being the best outcome. GOS =1: Good recovery. Reported here are the percentages of participants who achieved a favorable score on each of these scales.
Time frame: Day 90
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | mRS 0 - 1 at Day 90 | 78.2 percentage of participants |
| Alteplase + Aspirin Placebo | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | NIHSS 0 - 1 at Day 90 | 85.0 percentage of participants |
| Alteplase + Aspirin Placebo | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | BI >= 95 at Day 90 | 79.3 percentage of participants |
| Alteplase + Aspirin Placebo | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | GOS = 1 at Day 90 | 81.5 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | GOS = 1 at Day 90 | 85.6 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | mRS 0 - 1 at Day 90 | 81.5 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | BI >= 95 at Day 90 | 88.7 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Global Favorable Recovery on mRS, NIHSS, BI, and GOS | NIHSS 0 - 1 at Day 90 | 81.7 percentage of participants |
95% CI: [0.529, 1.393]
Secondary
Percentage of Participants With Serious Adverse Events
A serious adverse event (SAE) was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.
Time frame: From baseline to Day 90
Population: Safety Population included all participants, who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants With Serious Adverse Events | 26.0 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Serious Adverse Events | 13.1 percentage of participants |
Secondary
Percentage of Participants With Symptomatic Intracranial Hemorrhage (ICH )
ICH was considered symptomatic if it was not seen on computed tomography (CT) or magnetic resonance imaging (MRI) scan at baseline and any neurologic decline was attributed to it by the local investigator. To detect intracranial hemorrhage, neuroimaging (CT or MRI) scan was performed at 22 to 36 hours after study drug administration.
Time frame: Within 36 hours after study drug administration on Day 1
Population: Safety Population included all participants, who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase + Aspirin Placebo | Percentage of Participants With Symptomatic Intracranial Hemorrhage (ICH ) | 3.2 percentage of participants |
| Alteplase Placebo + Aspirin | Percentage of Participants With Symptomatic Intracranial Hemorrhage (ICH ) | 0 percentage of participants |
95% CI: [0.75, 7.38]