Stroke
Conditions
Brief summary
To evaluate the safety and efficacy of alteplase when administered between 3 and 4.5 hours after onset of stroke symptoms in Chinese patients with acute ischemic stroke
Interventions
DRUGalteplase
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Age \>= 18 years at screening(visit 1A) but \<= 80 years Signed and dated written informed consent in accordance with good clinical practice and local legislation prior to admission to the trial Diagnosis of ischemic stroke with a measureable neurological deficit on National Institute of Health Stroke Scale (NIHSS) Thrombolytic therapy can be initiated within 3 to 4.5 hours of stroke onset Further inclusion criteria apply
Exclusion criteria
Evidence of intracranial haemorrhage (ICH) on the (Computer Tomography) CT/(Magnetic Resonance Imaging)MRI-scan or symptoms suggestive of subarachnoid haemorrhage, even if the CT/MRI-scan is normal Acute bleeding diathesis Severe stroke as assessed clinically( e.g. National Institute of Health Stroke Scale\>25) and/ or imaging demonstrates multi-lobar infarction (hypodensity \>1/3 cerebral hemisphere) Severe uncontrolled arterial hypertension, e.g. systolic blood pressure\>185 mmHg or diastolic blood pressure\>110mmHg, or aggressive management (intravenous medication) necessary to reduce blood pressure to these limits Blood glucose \<50mg/ dL or \>400 mg/dL Any history of prior stroke in previous 3 months, or any history of prior stroke with concomitant diabetes Seizure at stroke onset Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | 90 days | The percentage of patients with modified Rankin Scale (mRS 0-1) (favourable outcome) response at Visit 5 (Day 90) after stroke onset by face-to-face interview with patient. Modified Rankin Scale (mRS): 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead. |
| The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period | 90 days | The percentage of patients with symptomatic intracranial haemorrhage (sICH) centrally evaluated by data-monitoring committee (DMC) consultants according to European Cooperative Acute Stroke Study (ECASS) III definition within the whole study period. According to the protocol, sICH (ECASS III criteria) was defined as: any apparently extravascular blood in the brain or within the cranium that was associated with clinical deterioration (defined by an increase in the NIHSS score of 4 or more points), or that led to death and that was identified as the predominant cause of the neurological deterioration. sICH event was firstly evaluated by investigator. The DMC consultants evaluated all the patients with NIHSS score increase of at least 4 any time after treatment (including all fatal patients and sICH events evaluated by investigator). Wilson score confidence interval is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients With Death Related to Stroke or of Neurological Causes | 90 days | The percentage of patients with death related to stroke or of neurological causes. |
| The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 | 90 days | Percentage of global outcome responder at day 90 if he/she obtains the following results at day 90 for the endpoints mRS score of 0 to 1; Barthel Index score \>= 95; NIHSS score of 0 to 1; Glasgow Outcome Scale score of 1. mRS: 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead. NIHSS is composed of 11 items, and for each item a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. Glasgow Outcome Score applies to patients with brain damage allowing the objective assessment of their recovery in five categories: 1 Good Recovery, 2 Moderately Disabled, 3 Severely Disabled, 4 Vegetative State, 5 Dead. Barthel Index score to measure performance in activities of daily living with the scale ranging from 0 to 100. Global outcome response is the intersection of above four respective outcomes. |
| The Percentage of Patients With Incidence of Cerebral Herniation and Symptomatic Edema | 90 days | The percentage of patients with incidence of cerebral herniation and symptomatic edema. |
| The Percentage of Patients With Severity of Adverse Events | On-treatment period, that is, within 7 days from the start of bolus | The percentage of patients with severity of adverse events (AEs). The percentage of patients with different categories of AEs are presented. |
| Patient Survival Probability at Visit 5 (Censoring at Day 90) | 90 days | Patient survival probability at visit 5 (censoring at day 90). The percentage of patients who died until Day 1, Day 7, Day 30, Day 90. |
Countries
China
Participant flow
Recruitment details
A total of 121 patients were screened from 11 centres across China. Of the screened patients, 1 patient did not meet the study entry criteria. The first patient visit was on 12 December 2016 and the last patient visit was on 11 December 2017.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they met all strictly implemented inclusion/exclusion criteria. Patients were not to be entered to trial if any one of the specific entry criteria was violated. Rescue medication was allowed for all patients as required.
Participants by arm
| Arm | Count |
|---|---|
| Alteplase (Rt-PA) Patients were administered single dose of Alteplase (rt-PA) 0.9 milligram/kilogram (mg/kg) (with an upper limit of 90 milligram (mg)), ten percent of the total dose was administered as a bolus over 1 - 2 minutes. The remaining 90% of the dose was given by continuous intravenous (IV) infusion over 60 minutes if there was no evidence of an allergic reaction within 5 minutes following the administration of the test dose. | 120 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Alteplase (Rt-PA) |
|---|---|
| Age, Continuous | 61.1 Years STANDARD_DEVIATION 10.85 |
| Baseline NIHSS | 6.9 Unit on Scale STANDARD_DEVIATION 4.68 |
| Baseline NIHSS by class 0-3 | 36 Participants |
| Baseline NIHSS by class 10-15 | 19 Participants |
| Baseline NIHSS by class 16-20 | 7 Participants |
| Baseline NIHSS by class >20 | 2 Participants |
| Baseline NIHSS by class 4-9 | 56 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 120 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 120 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 120 |
| other Total, other adverse events | 72 / 120 |
| serious Total, serious adverse events | 12 / 120 |
Outcome results
Primary
The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient
The percentage of patients with modified Rankin Scale (mRS 0-1) (favourable outcome) response at Visit 5 (Day 90) after stroke onset by face-to-face interview with patient. Modified Rankin Scale (mRS): 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead.
Time frame: 90 days
Population: Treated Set, worst and last observation carried forward were used for the imputation of efficacy endpoints
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | No symptom at all | 42.5 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | No sign. disability | 20.8 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | Slight disability | 8.3 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | Moderate disability | 14.2 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | Moderate Severe disability | 1.7 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | Severe disability | 7.5 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Modified Rankin Scale (mRS 0-1) (Favourable Outcome) Response at Day 90 After Stroke Onset by Face-to-face Interview With Patient | Dead | 5.0 Percentage of patients |
Comparison: A null hypothesis of p ≤40% versus the alternative hypothesis of p \>40% was tested using a one sample test at two-sided significance level of 0.05, where p denoted the response rate in Chinese patients who were treated within 3-4.5 h after stroke onset.p-value: <0.000195% CI: [54.42, 71.42]One-sample test
Primary
The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period
The percentage of patients with symptomatic intracranial haemorrhage (sICH) centrally evaluated by data-monitoring committee (DMC) consultants according to European Cooperative Acute Stroke Study (ECASS) III definition within the whole study period. According to the protocol, sICH (ECASS III criteria) was defined as: any apparently extravascular blood in the brain or within the cranium that was associated with clinical deterioration (defined by an increase in the NIHSS score of 4 or more points), or that led to death and that was identified as the predominant cause of the neurological deterioration. sICH event was firstly evaluated by investigator. The DMC consultants evaluated all the patients with NIHSS score increase of at least 4 any time after treatment (including all fatal patients and sICH events evaluated by investigator). Wilson score confidence interval is presented.
Time frame: 90 days
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase (Rt-PA) | The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period | Day 31-90 | 0.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period | Day>90 | 0.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period | Day 0-1 | 2.5 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period | Day 2-7 | 0.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Symptomatic Intracranial Haemorrhage (sICH) Centrally Evaluated by Data-monitoring Committee (DMC) Consultants According to European Cooperative Acute Stroke Study (ECASS) III Definition Within the Whole Study Period | Day 8-30 | 0.0 Percentage of patients |
Secondary
Patient Survival Probability at Visit 5 (Censoring at Day 90)
Patient survival probability at visit 5 (censoring at day 90). The percentage of patients who died until Day 1, Day 7, Day 30, Day 90.
Time frame: 90 days
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase (Rt-PA) | Patient Survival Probability at Visit 5 (Censoring at Day 90) | Day 2-7 | 3.3 Percentage of patients |
| Alteplase (Rt-PA) | Patient Survival Probability at Visit 5 (Censoring at Day 90) | Day 8-30 | 1.7 Percentage of patients |
| Alteplase (Rt-PA) | Patient Survival Probability at Visit 5 (Censoring at Day 90) | Day 31-90 | 0.0 Percentage of patients |
| Alteplase (Rt-PA) | Patient Survival Probability at Visit 5 (Censoring at Day 90) | Day 0-1 | 0.0 Percentage of patients |
Secondary
The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1
Percentage of global outcome responder at day 90 if he/she obtains the following results at day 90 for the endpoints mRS score of 0 to 1; Barthel Index score \>= 95; NIHSS score of 0 to 1; Glasgow Outcome Scale score of 1. mRS: 0 = no symptom at all, 1 = no significant disability, 2 = slight disability, 3 = moderate disability, 4 = moderately severe disability, 5 = severe disability, and 6 = dead. NIHSS is composed of 11 items, and for each item a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. Glasgow Outcome Score applies to patients with brain damage allowing the objective assessment of their recovery in five categories: 1 Good Recovery, 2 Moderately Disabled, 3 Severely Disabled, 4 Vegetative State, 5 Dead. Barthel Index score to measure performance in activities of daily living with the scale ranging from 0 to 100. Global outcome response is the intersection of above four respective outcomes.
Time frame: 90 days
Population: Treated Set, worst and last observation carried forward were used for the imputation of efficacy endpoints
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase (Rt-PA) | The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 | Global outcome response | 55.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 | A response of 0 or 1 on mRS | 63.3 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 | A response of least 95 on the Barthel index score | 65.8 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 | A response of 0 or 1 on NIHSS | 56.7 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Global Outcome Responder at Day 90 if he/She Obtains the Following Results at Day 90 (for All of the 4 Endpoints) mRS Score of 0 to 1; Barthel Index Score >= 95; NIHSS Score of 0 to 1; Glasgow Outcome Scale Score of 1 | A Glasgow outcome of 1 | 69.2 Percentage of patients |
Secondary
The Percentage of Patients With Death Related to Stroke or of Neurological Causes
The percentage of patients with death related to stroke or of neurological causes.
Time frame: 90 days
Population: Treated Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase (Rt-PA) | The Percentage of Patients With Death Related to Stroke or of Neurological Causes | 4.2 Percentage of patients |
Secondary
The Percentage of Patients With Incidence of Cerebral Herniation and Symptomatic Edema
The percentage of patients with incidence of cerebral herniation and symptomatic edema.
Time frame: 90 days
Population: Treated Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase (Rt-PA) | The Percentage of Patients With Incidence of Cerebral Herniation and Symptomatic Edema | 4.2 Percentage of patients |
Secondary
The Percentage of Patients With Severity of Adverse Events
The percentage of patients with severity of adverse events (AEs). The percentage of patients with different categories of AEs are presented.
Time frame: On-treatment period, that is, within 7 days from the start of bolus
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Any AE | 85.8 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Severe AE | 20.8 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Investigator defined drug-related AEs | 12.5 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | AEs leading to discontinuation of study drug | 0.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Serious AEs | 10.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Results in death | 4.2 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Immediately life threatening | 3.3 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Persistent or significant disability/ incapacity | 1.7 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Required/prolonged hospitalization | 5.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Congenital anomaly/ birth defect | 0.0 Percentage of patients |
| Alteplase (Rt-PA) | The Percentage of Patients With Severity of Adverse Events | Other comparable medical criteria | 0.0 Percentage of patients |