Stroke
Conditions
Keywords
Acute ischemic stroke, Angiography, Desmoteplase, Thrombolytic
Brief summary
The purpose of the study is to determine whether desmoteplase is effective and safe in the treatment of patients with acute ischaemic stroke when given within 3 to 9 hours from onset of stroke symptoms.
Detailed description
Acute stroke is a major cause of mortality and long-term disability in the developed world. The only currently approved thrombolytic intervention for acute ischemic stroke, which constitutes the majority of strokes, is alteplase (recombinant tissue plasminogen activator; rtPA). The use of alteplase is limited as it is approved for use within 3 hours after symptom onset and by the risk of inducing intracerebral haemorrhage; consequently fewer than 3% of acute stroke subjects are treated. The thrombolytic agent desmoteplase (recombinant Desmodus Salivary Plasminogen Activator alpha-1; rDSPAalpha-1) produced by recombinant biotechnology has its naturally occurring counterpart in the saliva of the vampire bat Desmodus rotundus. Compared to alteplase, desmoteplase has a more favourable profile in terms of high fibrin specificity and non neurotoxicity. The study aims to confirm efficacy and safety of desmoteplase for thrombolytic therapy of patients with acute ischaemic stroke in the extended time window of 3 to 9 hours after onset of stroke symptoms.
Interventions
DRUGDesmoteplase
90 μg/kg bodyweight, IV, single bolus over 1 to 2 minutes on 1st day
DRUGPlacebo
IV, single bolus over 1 to 2 minutes on 1st day
Sponsors
H. Lundbeck A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of acute ischemic stroke * Informed consent * Age between 18 and 85 years * Treatment can be initiated within 3 to 9 hours after the onset of stroke symptoms * NIHSS Score of 4 to 24 * Vessel occlusion or high-grade stenosis on MRI or CTA in proximal cerebral arteries
Exclusion criteria
* Pre-stroke mRS \>1 * Previous exposure to desmoteplase * Extensive early infarction on MRI or CT in any affected area * Imaging evidence of ICH or SAH; AV malformation; cerebral aneurysm; or cerebral neoplasm * Internal carotid artery occlusion on the side of the stroke lesion * Treatment with heparin in the past 48 hours and a prolonged partial thromboplastin time * Treatment with oral anticoagulants and a prolonged prothrombin time * Treatment with glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single agent oral platelet inhibitors is permitted * Treatment with a thrombolytic agent within the past 72 hours
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale Score (mRS) (Percentage of Participants With mRS Scores 0-2) | Day 90 | The mRS is a clinician-rated scale designed to provide a global assessment of the patients dependency after stroke. The scale consists of a single item measuring the patient's function based on the ability to perform daily activities. The patient is rated on a 7-point scale from 0 to 6, where a score of 5 corresponds to severe disability, and 6 to death. Assessment of a pre-stroke mRS score is based on an interview addressing the status of the patient prior to the stroke |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| National Institutes of Health Stroke Scale (NIHSS) Score. (Percentage of Participants With NIHSS Scores <=1 or NIHSS Decrease >=8) | 90 days | The NIHSS is a clinician-rated, 15-item scale designed to assess the severity of stroke-related neurological deficits: level of consciousness, eye movements, visual fields, facial symmetry, motor strength (arm and leg), coordination, sensation, language (aphasia and dysarthria), and neglect. Each item is rated on a 3-, 4-, or 5-point scale ranging from 0 (normal) to the maximum score (extremely severe symptoms). The total score of the 15 items ranges from 0 to 42, where lower scores indicate less impairment. |
| Composite of mRS & NIHSS Response (Percentage of Participants With mRS Scores 0-2 and (NIHSS <= 1 or NIHSS Decrease >= 8) | Day 90 | Please see outcomes measure one and two for detailed description of the scales |
| Modified Ranking Scale Score (Using the Ordinal Scale) | Day 90 | Please see outcomes measure one for detailed description of the mRS scale |
Countries
Belgium, Brazil, Canada, Chile, Denmark, Finland, Ireland, Italy, Mexico, Norway, South Africa, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Desmoteplase Desmoteplase: 90 μg/kg bodyweight, IV, single bolus over 1 to 2 minutes 3-9 hours after symptoms onset | 135 |
| Placebo Placebo: IV, single bolus over 1 to 2 minutes 3-9 hours after symptoms onset | 135 |
| Total | 270 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 18 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Physician Judgement | 8 | 5 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Desmoteplase |
|---|---|---|---|
| Age, Continuous | 68.2 years STANDARD_DEVIATION 12.5 | 68.6 years STANDARD_DEVIATION 11.8 | 69.1 years STANDARD_DEVIATION 11.1 |
| Race/Ethnicity, Customized Asian | 6 participants | 13 participants | 7 participants |
| Race/Ethnicity, Customized Black or african americal | 9 participants | 20 participants | 11 participants |
| Race/Ethnicity, Customized Other | 5 participants | 11 participants | 6 participants |
| Race/Ethnicity, Customized White | 115 participants | 226 participants | 111 participants |
| Sex: Female, Male Female | 69 Participants | 141 Participants | 72 Participants |
| Sex: Female, Male Male | 66 Participants | 129 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 107 / 131 | 98 / 126 |
| serious Total, serious adverse events | 56 / 131 | 61 / 126 |
Outcome results
Primary
Modified Rankin Scale Score (mRS) (Percentage of Participants With mRS Scores 0-2)
The mRS is a clinician-rated scale designed to provide a global assessment of the patients dependency after stroke. The scale consists of a single item measuring the patient's function based on the ability to perform daily activities. The patient is rated on a 7-point scale from 0 to 6, where a score of 5 corresponds to severe disability, and 6 to death. Assessment of a pre-stroke mRS score is based on an interview addressing the status of the patient prior to the stroke
Time frame: Day 90
Population: Two and three patients from the desmoteplase and placebo group, respectively, had no valid functional assessment done. Hence, the full analysis set consisted of 124 and 128 patients, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Desmoteplase | Modified Rankin Scale Score (mRS) (Percentage of Participants With mRS Scores 0-2) | 41.9 Percentage of participants |
| Placebo | Modified Rankin Scale Score (mRS) (Percentage of Participants With mRS Scores 0-2) | 35.9 Percentage of participants |
Comparison: All patients who were treated and had at least one valid post-baseline assessment of the mRS. As death is a valid outcome on the mRS, patients who died within 90 days after IMP administration were included.p-value: 0.22995% CI: [0.79, 2.64]Regression, Logistic
Secondary
Composite of mRS & NIHSS Response (Percentage of Participants With mRS Scores 0-2 and (NIHSS <= 1 or NIHSS Decrease >= 8)
Please see outcomes measure one and two for detailed description of the scales
Time frame: Day 90
Population: Two and three patients from the desmoteplase and placebo group, respectively, had no valid functional assessment done. Hence, the full analysis set consisted of 124 and 128 patients, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Desmoteplase | Composite of mRS & NIHSS Response (Percentage of Participants With mRS Scores 0-2 and (NIHSS <= 1 or NIHSS Decrease >= 8) | 32.3 Percentage of participants |
| Placebo | Composite of mRS & NIHSS Response (Percentage of Participants With mRS Scores 0-2 and (NIHSS <= 1 or NIHSS Decrease >= 8) | 28.9 Percentage of participants |
Comparison: All patients treated, who had at least one valid post-baseline assessment of the mRS and with a baseline NIHSS score of 8 to 24. If no assessment was available for last observation carried forward after baseline, the mRS score was set to 5 if the patient was known to be alive, or 6, if otherwise = dead.p-value: 0.507695% CI: [0.68, 2.18]Regression, Logistic
Secondary
Modified Ranking Scale Score (Using the Ordinal Scale)
Please see outcomes measure one for detailed description of the mRS scale
Time frame: Day 90
Population: Two and three patients from the desmoteplase and placebo group, respectively, had no valid functional assessment done. Hence, the full analysis set consisted of 124 and 128 patients, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Desmoteplase | Modified Ranking Scale Score (Using the Ordinal Scale) | 3.02 Scores on a scale | Standard Error 0.14 |
| Placebo | Modified Ranking Scale Score (Using the Ordinal Scale) | 3.12 Scores on a scale | Standard Error 0.15 |
Comparison: all patients treated, who had at least one valid post-baseline assessment of the mRS. As death is a valid outcome on the mRS, patients who died within 90 days after IMP administration were includedp-value: 0.614695% CI: [0.72, 1.75]Regression, Logistic
Secondary
National Institutes of Health Stroke Scale (NIHSS) Score. (Percentage of Participants With NIHSS Scores <=1 or NIHSS Decrease >=8)
The NIHSS is a clinician-rated, 15-item scale designed to assess the severity of stroke-related neurological deficits: level of consciousness, eye movements, visual fields, facial symmetry, motor strength (arm and leg), coordination, sensation, language (aphasia and dysarthria), and neglect. Each item is rated on a 3-, 4-, or 5-point scale ranging from 0 (normal) to the maximum score (extremely severe symptoms). The total score of the 15 items ranges from 0 to 42, where lower scores indicate less impairment.
Time frame: 90 days
Population: Two and three patients from the desmoteplase and placebo group, respectively, had no valid functional assessment done. Hence, the full analysis set consisted of 124 and 128 patients, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Desmoteplase | National Institutes of Health Stroke Scale (NIHSS) Score. (Percentage of Participants With NIHSS Scores <=1 or NIHSS Decrease >=8) | 49.2 Percentage of participants |
| Placebo | National Institutes of Health Stroke Scale (NIHSS) Score. (Percentage of Participants With NIHSS Scores <=1 or NIHSS Decrease >=8) | 50.8 Percentage of participants |
p-value: 0.940195% CI: [0.59, 1.62]Regression, Logistic