Stroke
Conditions
Brief summary
This study is open to Chinese adults who had an ischaemic stroke, which means that blood vessels in the brain are blocked. To resolve blood clots, people in the study get either tenecteplase or alteplase within 4 hours and 30 minutes after stroke. The purpose of this study is to compare how tenecteplase and alteplase improve peoples' recovering of physical activity. Alteplase is standard of care. Tenecteplase is a modified variant of alteplase that is easier to administer and is approved to treat heart attack. This study is to find out whether tenecteplase is as good as alteplase in people with ischaemic stroke. Participants are equally put into 2 treatment groups by chance. Participants in one group get tenecteplase as a single injection into a vein. Participants in the other group get alteplase as an injection into a vein (10% of the dose) and the remainder as an infusion over 1 hour. Participants are in the study for about 3 months. They are in the hospital for the first week after treatment. Then they visit the study site 1 and 3 months after treatment. At these visits, peoples' ability to independently carry out daily activities is assessed. Scores for physical activity are compared between both treatment groups. The doctors also regularly check the general health of the participants.
Interventions
DRUGtenecteplase
tenecteplase
DRUGalteplase
alteplase
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years old * Diagnosis of ischaemic stroke with a measurable neurological deficit on National Institutes of Health Stroke Scale (NIHSS) (0\< NIHSS ≤25); if NIHSS \<4, patients have to be with at least a measurable deficit on motor power (upper or lower limbs ≥1) * Stroke symptoms should have been present for at least 30 minutes (min) without significant improvement prior to randomisation * Thrombolytic therapy can be initiated within 4.5 Hour(s) (h) of Acute ischaemic stroke (AIS) onset * Patients with premorbid modified Rankin Scale (mRS) 0 or 1 * Signed and dated written informed consent in accordance with good clinical practice (GCP) and local legislation prior to trial admission
Exclusion criteria
* Evidence of intracranial haemorrhage on the Computed tomography (CT) scan or symptoms suggestive of subarachnoid haemorrhage, even if the CT scan is normal * Patients who must or are expected to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial * Acute bleeding diathesis, including but not limited to * Known genetic predisposition to bleeding or significant bleeding disorder at present or within the past 6 Month(s) (m) * Administration of heparin within the previous 48 h and activated partial thromboplastin time (aPTT) exceeding the upper limit of normal for laboratory measurement * Current use of vitamin K based oral anticoagulants (e.g. warfarin) and a prolonged prothrombin time (International normalised Ratio (INR) \> 1.7 or Prothrombin time (PT)\>15 seconds (s)) or current use of novel oral anticoagulants (i.e. dabigitran, rivaroxiban, or apixiban) with prolongation of activated partial thromboplastin time (aPTT) and/or PT above the upper limit of the local laboratory reference range * Platelet count of below 100,000/mm3 at screening * Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) * Recent traumatic external heart massage, obstetrical delivery, or recent puncture of a non-compressive blood-vessel (e.g. subclavian or jugular vein puncture) , within the past 10 days * Known history of suspected intracranial haemorrhage or suspected subarachnoid haemorrhage from aneurysm * Neoplasm with increased haemorrhagic risk * Documented ulcerative gastrointestinal disease during the last 3 m, oesophageal varices, arterial aneurysm, or arterial/venous malformations * Any known disorder associated with a significant increased risk of bleeding * Bacterial endocarditis or pericarditis at screening * Acute pancreatitis at screening * Significant trauma or major surgery (according to the investigator's assessment) in the past 3 m * Imaging demonstrates multi-lobar infarction (hypodensity \>1/3 cerebral hemisphere) * Severe uncontrolled arterial hypertension, e.g. systolic blood pressure (BP) \>185 mmHg or diastolic BP \>110 mmHg Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Modified Rankin Scale (mRS) Score of 0 or 1 | At Day 90±7 days | Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. Percentages are rounded to the nearest digits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Modified Rankin Scale (mRS) Score of 0-2 | At Day 90 | Percentage of participants with Modified Rankin Scale (mRS) score of 0-2 is presented. Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. Percentages are rounded to the nearest digits. |
| Change From Baseline of National Institutes of Health Stroke Scale (NIHSS) Score | At baseline and at Day 90 | Total NIHSS score (0-42) = sum of 11 individual item scores, higher total scores meaning more severe deficits. indivudal domains: level of consciousness (LOC), best gaze, visual fields, facial paresis, motor function arms, motor function legs, limb ataxia, sensory, language, dysarthria, extinction and inattention. Restricted maximum likelihood (REML) based MMRM approach used to compare change from baseline in NIHSS score at day 90. If patient misses visit, missing data will not be imputed. The mixed effect model will handle missing data based on a likelihood method under MAR assumption. Change in NIHSS score from baseline = overall mean + treatment + visit + baseline NIHSS + age + time to drug administration since onset of stroke symptoms + treatment by visit interaction + baseline NIHSS by visit interaction + random error. |
| Distribution of Modified Rankin Scale (mRS) | At Day 90 | Distribution of Modified Rankin Scale (mRS) is presented. Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. |
| Percentage of Participants With Major Neurological Improvement (National Institutes of Health Stroke Scale (NIHSS) Score of 0 or Improvement of at Least 4 Points Compared With Baseline | At 24 hours | Total NIHSS score (0-42) = sum of 11 individual item scores, higher total scores meaning more severe deficits. indivudal domains: level of consciousness (LOC), best gaze, visual fields, facial paresis, motor function arms, motor function legs, limb ataxia, sensory, language, dysarthria, extinction and inattention. Mild strokes (NIHSS \< 6): High likelihood of good recovery and independence, Moderate strokes (NIHSS 6-15): Variable outcomes depending on timely intervention, Severe strokes (NIHSS \> 15): Lower likelihood of recovery without significant disability and higher risk of mortality. Percentages are rounded to the nearest digits. |
| Percentage of Participants With Symptomatic Intracerebral Haemorrhage (sICH) Per European Cooperative Acute Stroke Study (ECASS) Ⅲ Definition During On-treatment Period | Up to 7 days. | Percentage of participants with Symptomatic Intracerebral Haemorrhage (sICH) per European Cooperative Acute Stroke Study (ECASS) Ⅲ definition during on-treatment period is presented. Percentages are rounded to the nearest digits. |
| Percentage of Participants Who Died by Day 90 | up to 90 days | Percentage of participants who died by day 90 is presented. Percentages are rounded to the nearest digits. |
| Percentage of Participants With Modified Rankin Scale (mRS) Score of 5 or 6 | At Day 90 | Percentage of participants with Modified Rankin Scale (mRS) score of 5 or 6 is presented. Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. Percentages are rounded to the nearest digits. |
| Percentage of Participants With Barthel Index Score ≥95 | up to 90 days | The Barthel Index is an ordinal scale used to measure performance in activities of daily living (ADL). The Barthel Index consists of 10 items. The total score of the Barthel Index ranges from 0 to 100, and higher scores indicate better outcome. Percentages are rounded to the nearest digits. |
Countries
China
Participant flow
Recruitment details
The main objective of this multi-centre, prospective, randomised, open label, blinded endpoint (PROBE), active-controlled parallel group phase III trial was to assess whether tenecteplase was non-inferior to alteplase in favourable outcome in Chinese patients with acute ischaemic stroke (AIS) who were eligible for intravenous (i.v.) thrombolysis within 4.5 h of symptom onset.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Tenecteplase Treatment Group Chinese patients with AIS were screened (visit 1) and randomised (visit 2a) when admitted. Patients received a single dose of tenecteplase, 0.25 mg/kg via intravenous (iv) bolus no later than 4.5 hours (h) after symptom onset. Visits on Day 1 consisted of two further visits (Visit 2b and Visit 2c) that were performed 1 h and 2 h after the start of the treatment. Visits 3 to 5 for continuous follow-up were performed on day 2, 8 and 30 after the start of the treatment. Treated patients performed a 90-day follow-up visit after the treatment to complete the study. | 732 |
| Alteplase Active Control Group Chinese patients with AIS were screened (visit 1) and randomised (visit 2a) when admitted. Patients received a single dose of alteplase, 0.9 mg/kg, 10% via intravenous (iv) bolus and the remaining 90% of the total dose administered as an iv infusion over 1 h no later than 4.5 hours (h) after symptom onset. Visits on Day 1 consisted of two further visits (Visit 2b and Visit 2c) that were performed 1 h and 2 h after the start of the treatment. Visits 3 to 5 for continuous follow-up were performed on day 2, 8 and 30 after the start of the treatment. Treated patients performed a 90-day follow-up visit after the treatment to complete the study. | 733 |
| Total | 1,465 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 34 | 44 |
| Overall Study | Investigator removed subject | 1 | 2 |
| Overall Study | Lost to Follow-up | 20 | 10 |
| Overall Study | not treated | 3 | 6 |
| Overall Study | questionnaire result not evaluated | 1 | 0 |
| Overall Study | refuse of hospital visit | 1 | 3 |
| Overall Study | Subject withdrew | 1 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 5 |
Baseline characteristics
| Characteristic | Alteplase Active Control Group | Total | Tenecteplase Treatment Group |
|---|---|---|---|
| Age, Continuous | 65.0 Years STANDARD_DEVIATION 11.1 | 65.0 Years STANDARD_DEVIATION 11.1 | 65.1 Years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 733 Participants | 1465 Participants | 732 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| National Institutes of Health Stroke Scale (NIHSS) class 1 at baseline NIHSS total score >=15 | 43 Participants | 86 Participants | 43 Participants |
| National Institutes of Health Stroke Scale (NIHSS) class 1 at baseline NIHSS total score <6 | 297 Participants | 596 Participants | 299 Participants |
| National Institutes of Health Stroke Scale (NIHSS) class 1 at baseline NIHSS total score 6 - 15 | 393 Participants | 783 Participants | 390 Participants |
| Sex: Female, Male Female | 231 Participants | 446 Participants | 215 Participants |
| Sex: Female, Male Male | 502 Participants | 1019 Participants | 517 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 44 / 736 | 34 / 732 |
| other Total, other adverse events | 347 / 736 | 334 / 732 |
| serious Total, serious adverse events | 115 / 736 | 116 / 732 |
Outcome results
Primary
Percentage of Participants With Modified Rankin Scale (mRS) Score of 0 or 1
Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. Percentages are rounded to the nearest digits.
Time frame: At Day 90±7 days
Population: Full Analysis Set (FAS): This patient set included all randomised patients who received any dose of treatment. Treatment assignment was as randomised. This was the primary analysis set for presentation of efficacy according to the intention-to-treat principle.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants With Modified Rankin Scale (mRS) Score of 0 or 1 | 72.7 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants With Modified Rankin Scale (mRS) Score of 0 or 1 | 70.3 Percentage of participants |
95% CI: [0.9678, 1.0915]Modified Possion Regression Model
Secondary
Change From Baseline of National Institutes of Health Stroke Scale (NIHSS) Score
Total NIHSS score (0-42) = sum of 11 individual item scores, higher total scores meaning more severe deficits. indivudal domains: level of consciousness (LOC), best gaze, visual fields, facial paresis, motor function arms, motor function legs, limb ataxia, sensory, language, dysarthria, extinction and inattention. Restricted maximum likelihood (REML) based MMRM approach used to compare change from baseline in NIHSS score at day 90. If patient misses visit, missing data will not be imputed. The mixed effect model will handle missing data based on a likelihood method under MAR assumption. Change in NIHSS score from baseline = overall mean + treatment + visit + baseline NIHSS + age + time to drug administration since onset of stroke symptoms + treatment by visit interaction + baseline NIHSS by visit interaction + random error.
Time frame: At baseline and at Day 90
Population: Full Analysis Set (FAS): This patient set included all randomised patients who received any dose of treatment. Treatment assignment was as randomised. This was the primary analysis set for presentation of efficacy according to the intention-to-treat principle.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tenecteplase Treatment Group | Change From Baseline of National Institutes of Health Stroke Scale (NIHSS) Score | -3.47 score on a scale | Standard Error 0.34 |
| Alteplase Active Control Group | Change From Baseline of National Institutes of Health Stroke Scale (NIHSS) Score | -3.02 score on a scale | Standard Error 0.34 |
p-value: 0.351195% CI: [-1.4, 0.5]Mixed Models Analysis
Secondary
Distribution of Modified Rankin Scale (mRS)
Distribution of Modified Rankin Scale (mRS) is presented. Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90.
Time frame: At Day 90
Population: Full Analysis Set (FAS): This patient set included all randomised patients who received any dose of treatment. Treatment assignment was as randomised. This was the primary analysis set for presentation of efficacy according to the intention-to-treat principle.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 0 | 40.3 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 1 | 30.1 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 2 | 7.8 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 3 | 6.7 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 4 | 4.8 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 5 | 1.9 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 6 | 4.6 Percentage of participants |
| Tenecteplase Treatment Group | Distribution of Modified Rankin Scale (mRS) | missing | 3.8 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | missing | 2.3 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 0 | 40.5 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 4 | 6.4 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 1 | 28.2 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 6 | 6.0 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 2 | 9.4 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 5 | 1.6 Percentage of participants |
| Alteplase Active Control Group | Distribution of Modified Rankin Scale (mRS) | mRS score = 3 | 5.5 Percentage of participants |
p-value: 0.4806Regression, Logistic
Secondary
Percentage of Participants Who Died by Day 90
Percentage of participants who died by day 90 is presented. Percentages are rounded to the nearest digits.
Time frame: up to 90 days
Population: Safety set (SS): This patient set included all patients who were randomised and received any dose of treatment. It was the main analysis set for presentation of safety. Patients were analysed according to the actual treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants Who Died by Day 90 | 4.6 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants Who Died by Day 90 | 5.8 Percentage of participants |
p-value: 0.30395% CI: [0.513, 1.232]Chi-squared
Secondary
Percentage of Participants With Barthel Index Score ≥95
The Barthel Index is an ordinal scale used to measure performance in activities of daily living (ADL). The Barthel Index consists of 10 items. The total score of the Barthel Index ranges from 0 to 100, and higher scores indicate better outcome. Percentages are rounded to the nearest digits.
Time frame: up to 90 days
Population: Full Analysis Set (FAS), No imputation was performed on patients missing Bathel Score at day 90.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants With Barthel Index Score ≥95 | 75.7 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants With Barthel Index Score ≥95 | 73.9 Percentage of participants |
p-value: 0.511695% CI: [0.9635, 1.0774]Regression, Linear
Secondary
Percentage of Participants With Major Neurological Improvement (National Institutes of Health Stroke Scale (NIHSS) Score of 0 or Improvement of at Least 4 Points Compared With Baseline
Total NIHSS score (0-42) = sum of 11 individual item scores, higher total scores meaning more severe deficits. indivudal domains: level of consciousness (LOC), best gaze, visual fields, facial paresis, motor function arms, motor function legs, limb ataxia, sensory, language, dysarthria, extinction and inattention. Mild strokes (NIHSS \< 6): High likelihood of good recovery and independence, Moderate strokes (NIHSS 6-15): Variable outcomes depending on timely intervention, Severe strokes (NIHSS \> 15): Lower likelihood of recovery without significant disability and higher risk of mortality. Percentages are rounded to the nearest digits.
Time frame: At 24 hours
Population: Full Analysis Set (FAS), This endpoint analysis is based on observed cases, no imputation performed for patients missing NIHSS score at 24h.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants With Major Neurological Improvement (National Institutes of Health Stroke Scale (NIHSS) Score of 0 or Improvement of at Least 4 Points Compared With Baseline | 48.0 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants With Major Neurological Improvement (National Institutes of Health Stroke Scale (NIHSS) Score of 0 or Improvement of at Least 4 Points Compared With Baseline | 45.0 Percentage of participants |
p-value: 0.241295% CI: [0.9573, 1.1895]Regression, Linear
Secondary
Percentage of Participants With Modified Rankin Scale (mRS) Score of 0-2
Percentage of participants with Modified Rankin Scale (mRS) score of 0-2 is presented. Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. Percentages are rounded to the nearest digits.
Time frame: At Day 90
Population: Full Analysis Set (FAS): This patient set included all randomised patients who received any dose of treatment. Treatment assignment was as randomised. This was the primary analysis set for presentation of efficacy according to the intention-to-treat principle.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants With Modified Rankin Scale (mRS) Score of 0-2 | 80.9 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants With Modified Rankin Scale (mRS) Score of 0-2 | 79.9 Percentage of participants |
p-value: 0.74895% CI: [0.9614, 1.0564]Regression, Linear
Secondary
Percentage of Participants With Modified Rankin Scale (mRS) Score of 5 or 6
Percentage of participants with Modified Rankin Scale (mRS) score of 5 or 6 is presented. Modified Rankin Scale (mRS) is a standardized measure that describes the extent of disability after a stroke. The mRS is a single item scale. It increases from 0 (no symptoms at all) to 6 (death). It was measured at Day 90. Percentages are rounded to the nearest digits.
Time frame: At Day 90
Population: Full Analysis Set (FAS): This patient set included all randomised patients who received any dose of treatment. Treatment assignment was as randomised. This was the primary analysis set for presentation of efficacy according to the intention-to-treat principle.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants With Modified Rankin Scale (mRS) Score of 5 or 6 | 6.8 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants With Modified Rankin Scale (mRS) Score of 5 or 6 | 7.8 Percentage of participants |
p-value: 0.634595% CI: [0.6578, 1.2908]Regression, Linear
Secondary
Percentage of Participants With Symptomatic Intracerebral Haemorrhage (sICH) Per European Cooperative Acute Stroke Study (ECASS) Ⅲ Definition During On-treatment Period
Percentage of participants with Symptomatic Intracerebral Haemorrhage (sICH) per European Cooperative Acute Stroke Study (ECASS) Ⅲ definition during on-treatment period is presented. Percentages are rounded to the nearest digits.
Time frame: Up to 7 days.
Population: Safety set (SS): This patient set included all patients who were randomised and received any dose of treatment. It was the main analysis set for presentation of safety. Patients were analysed according to the actual treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tenecteplase Treatment Group | Percentage of Participants With Symptomatic Intracerebral Haemorrhage (sICH) Per European Cooperative Acute Stroke Study (ECASS) Ⅲ Definition During On-treatment Period | 1.2 Percentage of participants |
| Alteplase Active Control Group | Percentage of Participants With Symptomatic Intracerebral Haemorrhage (sICH) Per European Cooperative Acute Stroke Study (ECASS) Ⅲ Definition During On-treatment Period | 1.2 Percentage of participants |
p-value: 195% CI: [0.37, 2.701]Suissa-Shuster test