Acute Ischemic Stroke
Conditions
Brief summary
The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic stroke (AIS) patients treated with standard of care thrombolysis (0.9mg/kg IV rt-PA or 0.25mg/kg IV tenecteplase or TNK) within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care. Time of onset is defined as the last time the patient was last known to be well.
Interventions
DRUGArgatroban
Direct Thrombin Inhibitor - Argatroban is a derivative of arginine that competitively binds to the active site of thrombin thereby preventing fibrin deposition. With a half-life of 30 minutes, argatroban has an immediate anticoagulant effect after IV administration which is rapidly reversed with discontinuation of the drug.
DRUGEptifibatide
GP 2b/3a Receptor Inhibitor - The final step of platelet aggregation is mediated via the GP2b/3a receptor. Eptifibatide was specifically developed to ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life (\ 2 hours) and rapid dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation.
DRUGPlacebo
IV placebo solution
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Acute ischemic stroke patients 2. Treated with 0.9mg/kg IV rt-PA or 0.25mg/kg IV TNK within 3 hours of stroke onset or time last known well 3. Age ≥ 18 4. NIHSS score ≥ 6 prior to IV thrombolysis 5. Able to receive assigned study drug within 60 minutes but no later than 75 minutes of initiation of IV thrombolysis
Exclusion criteria
1. Known allergy or hypersensitivity to argatroban or eptifibatide 2. Previous stroke in the past 90 days 3. Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation 4. Clinical presentation suggested a subarachnoid hemorrhage, even if initial CT scan was normal 5. Any surgery, or biopsy of parenchymal organ in the past 30 days 6. Trauma with internal injuries or ulcerative wounds in the past 30 days 7. Severe head trauma in the past 90 days 8. Systolic blood pressure persistently \>180mmHg post-IV thrombolysis despite antihypertensive intervention 9. Diastolic blood pressure persistently \>105mmHg post-IV thrombolysis despite antihypertensive intervention 10. Serious systemic hemorrhage in the past 30 days 11. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR \>1.5 12. Positive urine or serum pregnancy test for women of child bearing potential 13. Glucose \<50 or \>400 mg/dl 14. Platelets \<100,000/mm3 15. Hematocrit \<25 % 16. Elevated pre-thrombolysis PTT above laboratory upper limit of normal 17. Creatinine \> 4 mg/dl 18. Ongoing renal dialysis, regardless of creatinine 19. Received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) in full dose within the previous 24 hours 20. Abnormal PTT within 48 hours prior to randomization after receiving heparin or a direct thrombin inhibitor (such as bivalirudin, argatroban, dabigatran or lepirudin) 21. Received Factor Xa inhibitors (such as Fondaparinaux, apixaban or rivaroxaban) within the past 48 hours 22. Received glycoprotein IIb/IIIa inhibitors within the past 14 days 23. Pre-existing neurological or psychiatric disease which confounded the neurological or functional evaluations e.g., baseline modified Rankin score \>3 24. Other serious, advanced, or terminal illness or any other condition that the investigator felt would pose a significant hazard to the patient if rt-PA, TNK, eptifibatide or argatroban therapy was initiated a. Example: known cirrhosis or clinically significant hepatic disease 25. Current participation in another research drug treatment or interventional device trial - Subjects could not start another experimental agent until after 90 days 26. Informed consent from the patient or the legally authorized representative was not or could not be obtained 27. High density lesion consistent with hemorrhage of any degree 28. Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT Scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 90-day Utility Weighted Modified Rankin Scores (UW-mRS) | 90 days after randomization | The modified Rankin scale is a 7 point ordinal scale ranging from 0=no symptoms to 6=death . For the primary analysis, the scale was analyzed with patient-centered utility weights. We assigned the following utility weights to the seven levels: 10, 9.1,, 7.6, 6.5, 3.3, 0, 0 (with higher scores indicating a better outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 24-hour NIHSS | 24 hours after randomization | National Institute of Health Stroke Scale (NIHSS) scores range from 0 to 42, with higher scores indicating worse neurologic deficit. |
| Percentage of Participants With 90-day mRS 0 or 1 (or Return to Their Historical mRS) | 90 days after randomization | The modified Rankin scale (mRS) is a 7 point scale ranging from 0=no symptoms to 6=death where lower scores are better outcomes. For patients with a pre-stroke mRS of greater than 0 or 1, these patients had to return to their historical (pre-stroke) value to be counted as a success. |
| Percentage of Participants With 90-day mRS 0, 1 or 2 (or Return to Their Historical mRS) | 90 days after randomization | modified Rankin scale is a 7 point scale ranging from 0=no symptoms to 6=death where lower scores are better outcomes. |
| 90-day mRS | 90 days after randomization | modified Rankin scale is a 7 point ordinal scale ranging from 0=no symptoms at all to 6=death where lower scores are better outcomes. |
| 90-day EQ-5D | 90 days after randomization | EuroQol Five-Dimension (EQ-5D) is a measure of health-related quality of life ranging from -0.59 to 1 where 1 is the best possible health state. |
| Percentage of Participants With NIHSS Less Than or Equal to 2 at 24 Hours | 24 hours after randomization | National Institute of Health Stroke Scale (NIHSS) scores range from 0 to 42, with higher scores indicating worse neurologic deficit. This is a dichotomous analysis with a cutpoint of 0,1,2 defining the event. |
| Post-thrombectomy Modified TICI Score of 2B or 3 | baseline | The modified thrombolysis in cerebral infarction (TICI) score prior to endovascular thrombectomy procedure. The modified post-thrombectomy TICI score is a 5 point scale with possible values of 0, 1, 2A, 2B, 3. The values are defined as follows: 0=No flow, 1=Penetration without distal branch filling, 2A=\<50% partial reperfusion, 2B=50%-99% partial reperfusion, and 3=Completed reperfusion |
| Pre-thrombectomy Modified TICI Score of 2B. | baseline | The modified thrombolysis in cerebral infarction (TICI) score prior to endovascular thrombectomy procedure. The modified pre-thrombectomy TICI score is a 4 point scale with possible values of 0, 1, 2A, and 2B. The values are defined as follows: 0=No flow, 1=Penetration without distal branch filling, 2A=\<50% partial reperfusion, and 2B=50%-99% partial reperfusion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Type 1 or Type 2 Parenchymal Hemorrhage Within 36 Hours (Safety Outcome) | 36 hours after randomization | — |
| Any Intracranial Hemorrhage Within 36 Hours (Safety Outcome) | 36 hours after randomization | Symptomatic or asymptomatic intracranial hemorrhage within 36 hours of randomization. |
| Other Major Hemorrhage Other Than Intracranial Hemorrhage Within 7 Days (Safety Outcome) | 7 days after randomization | Other major hemorrhage other than intracranial hemorrhage (resulting in the transfusion of \>2 units of packed red cells). |
| Symptomatic Intracranial Hemorrhage Within 36 Hours (Primary Safety Outcome) | 36 hours after randomization | Type 2 parenchymal hemorrhage or a parenchymal hemorrhage remote from the area of infarction with neurologic deterioration (defined as an increase of ≥4 points in the NIHSS score)within 36 hours after randomization. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Argatroban 100µg/kg bolus followed by 3µg/kg per minute for 12 hours | 59 |
| Eptifibatide 135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours | 227 |
| Placebo Placebo: IV placebo solution | 228 |
| Total | 514 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 12 | 14 |
| Overall Study | Not due to the above reasons | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 2 |
Baseline characteristics
| Characteristic | Argatroban | Total | Placebo | Eptifibatide |
|---|---|---|---|---|
| Age, Continuous | 68 years | 67 years | 66 years | 68 years |
| Endovascular Thrombectomy (EVT) received | 27 Participants | 225 Participants | 99 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 40 Participants | 14 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 472 Participants | 213 Participants | 203 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| IV Thrombolytic recombinant tissue plasminogen activator (rt-PA) | 52 Participants | 360 Participants | 151 Participants | 157 Participants |
| IV Thrombolytic tenecteplase (TNK) | 7 Participants | 154 Participants | 77 Participants | 70 Participants |
| IV Thrombolytic Start to Study Drug Bolus | 62 minutes STANDARD_DEVIATION 14.3 | 64 minutes STANDARD_DEVIATION 18.9 | 63 minutes STANDARD_DEVIATION 18.2 | 65 minutes STANDARD_DEVIATION 20.5 |
| NIHSS | 12 units on a scale | 12 units on a scale | 11 units on a scale | 12 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 14 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 129 Participants | 53 Participants | 61 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 41 Participants | 367 Participants | 170 Participants | 156 Participants |
| Sex: Female, Male Female | 28 Participants | 256 Participants | 110 Participants | 118 Participants |
| Sex: Female, Male Male | 31 Participants | 258 Participants | 118 Participants | 109 Participants |
| Stroke Onset to IV Thrombolytic Start | 100 minutes STANDARD_DEVIATION 38.5 | 102 minutes STANDARD_DEVIATION 36.3 | 101 minutes STANDARD_DEVIATION 36.1 | 103 minutes STANDARD_DEVIATION 36 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 54 | 25 / 212 | 17 / 217 |
| other Total, other adverse events | 12 / 59 | 42 / 227 | 33 / 228 |
| serious Total, serious adverse events | 26 / 59 | 85 / 227 | 78 / 228 |
Outcome results
Primary
90-day Utility Weighted Modified Rankin Scores (UW-mRS)
The modified Rankin scale is a 7 point ordinal scale ranging from 0=no symptoms to 6=death . For the primary analysis, the scale was analyzed with patient-centered utility weights. We assigned the following utility weights to the seven levels: 10, 9.1,, 7.6, 6.5, 3.3, 0, 0 (with higher scores indicating a better outcome).
Time frame: 90 days after randomization
Population: Intention-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Argatroban | 90-day Utility Weighted Modified Rankin Scores (UW-mRS) | 5.2 score on a scale | Standard Deviation 3.7 |
| Eptifibatide | 90-day Utility Weighted Modified Rankin Scores (UW-mRS) | 6.3 score on a scale | Standard Deviation 3.2 |
| Placebo | 90-day Utility Weighted Modified Rankin Scores (UW-mRS) | 6.8 score on a scale | Standard Deviation 3 |
p-value: 0.04Bayesian
p-value: 0.002Bayesian
Secondary
90-day EQ-5D
EuroQol Five-Dimension (EQ-5D) is a measure of health-related quality of life ranging from -0.59 to 1 where 1 is the best possible health state.
Time frame: 90 days after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Argatroban | 90-day EQ-5D | 0.6 score on a scale | Standard Deviation 0.3 |
| Eptifibatide | 90-day EQ-5D | 0.6 score on a scale | Standard Deviation 0.4 |
| Placebo | 90-day EQ-5D | 0.7 score on a scale | Standard Deviation 0.3 |
Secondary
90-day mRS
modified Rankin scale is a 7 point ordinal scale ranging from 0=no symptoms at all to 6=death where lower scores are better outcomes.
Time frame: 90 days after randomization
Population: Intention-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Argatroban | 90-day mRS | 3 units on a scale |
| Eptifibatide | 90-day mRS | 2 units on a scale |
| Placebo | 90-day mRS | 2 units on a scale |
Secondary
Change From Baseline to 24-hour NIHSS
National Institute of Health Stroke Scale (NIHSS) scores range from 0 to 42, with higher scores indicating worse neurologic deficit.
Time frame: 24 hours after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Argatroban | Change From Baseline to 24-hour NIHSS | -5.1 units on a scale | Standard Deviation 9.3 |
| Eptifibatide | Change From Baseline to 24-hour NIHSS | -6.1 units on a scale | Standard Deviation 8.4 |
| Placebo | Change From Baseline to 24-hour NIHSS | -6.3 units on a scale | Standard Deviation 6.8 |
Secondary
Percentage of Participants With 90-day mRS 0, 1 or 2 (or Return to Their Historical mRS)
modified Rankin scale is a 7 point scale ranging from 0=no symptoms to 6=death where lower scores are better outcomes.
Time frame: 90 days after randomization
Population: Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Percentage of Participants With 90-day mRS 0, 1 or 2 (or Return to Their Historical mRS) | 26 Participants |
| Eptifibatide | Percentage of Participants With 90-day mRS 0, 1 or 2 (or Return to Their Historical mRS) | 126 Participants |
| Placebo | Percentage of Participants With 90-day mRS 0, 1 or 2 (or Return to Their Historical mRS) | 139 Participants |
Secondary
Percentage of Participants With 90-day mRS 0 or 1 (or Return to Their Historical mRS)
The modified Rankin scale (mRS) is a 7 point scale ranging from 0=no symptoms to 6=death where lower scores are better outcomes. For patients with a pre-stroke mRS of greater than 0 or 1, these patients had to return to their historical (pre-stroke) value to be counted as a success.
Time frame: 90 days after randomization
Population: Intention-to-treat sample
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Percentage of Participants With 90-day mRS 0 or 1 (or Return to Their Historical mRS) | 14 Participants |
| Eptifibatide | Percentage of Participants With 90-day mRS 0 or 1 (or Return to Their Historical mRS) | 82 Participants |
| Placebo | Percentage of Participants With 90-day mRS 0 or 1 (or Return to Their Historical mRS) | 92 Participants |
Secondary
Percentage of Participants With NIHSS Less Than or Equal to 2 at 24 Hours
National Institute of Health Stroke Scale (NIHSS) scores range from 0 to 42, with higher scores indicating worse neurologic deficit. This is a dichotomous analysis with a cutpoint of 0,1,2 defining the event.
Time frame: 24 hours after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Percentage of Participants With NIHSS Less Than or Equal to 2 at 24 Hours | 14 Participants |
| Eptifibatide | Percentage of Participants With NIHSS Less Than or Equal to 2 at 24 Hours | 84 Participants |
| Placebo | Percentage of Participants With NIHSS Less Than or Equal to 2 at 24 Hours | 89 Participants |
Secondary
Post-thrombectomy Modified TICI Score of 2B or 3
The modified thrombolysis in cerebral infarction (TICI) score prior to endovascular thrombectomy procedure. The modified post-thrombectomy TICI score is a 5 point scale with possible values of 0, 1, 2A, 2B, 3. The values are defined as follows: 0=No flow, 1=Penetration without distal branch filling, 2A=\<50% partial reperfusion, 2B=50%-99% partial reperfusion, and 3=Completed reperfusion
Time frame: baseline
Population: Only participants that received endovascular thrombectomy are analyzed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Post-thrombectomy Modified TICI Score of 2B or 3 | 22 Participants |
| Eptifibatide | Post-thrombectomy Modified TICI Score of 2B or 3 | 92 Participants |
| Placebo | Post-thrombectomy Modified TICI Score of 2B or 3 | 93 Participants |
Secondary
Pre-thrombectomy Modified TICI Score of 2B.
The modified thrombolysis in cerebral infarction (TICI) score prior to endovascular thrombectomy procedure. The modified pre-thrombectomy TICI score is a 4 point scale with possible values of 0, 1, 2A, and 2B. The values are defined as follows: 0=No flow, 1=Penetration without distal branch filling, 2A=\<50% partial reperfusion, and 2B=50%-99% partial reperfusion.
Time frame: baseline
Population: Only participants that received endovascular thrombectomy are analyzed for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Pre-thrombectomy Modified TICI Score of 2B. | 2 Participants |
| Eptifibatide | Pre-thrombectomy Modified TICI Score of 2B. | 5 Participants |
| Placebo | Pre-thrombectomy Modified TICI Score of 2B. | 6 Participants |
Other Pre-specified
Any Intracranial Hemorrhage Within 36 Hours (Safety Outcome)
Symptomatic or asymptomatic intracranial hemorrhage within 36 hours of randomization.
Time frame: 36 hours after randomization
Population: Participants that took any amount of study drug (safety sample).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Any Intracranial Hemorrhage Within 36 Hours (Safety Outcome) | 20 Participants |
| Eptifibatide | Any Intracranial Hemorrhage Within 36 Hours (Safety Outcome) | 51 Participants |
| Placebo | Any Intracranial Hemorrhage Within 36 Hours (Safety Outcome) | 51 Participants |
Other Pre-specified
Other Major Hemorrhage Other Than Intracranial Hemorrhage Within 7 Days (Safety Outcome)
Other major hemorrhage other than intracranial hemorrhage (resulting in the transfusion of \>2 units of packed red cells).
Time frame: 7 days after randomization
Population: Participants that took any amount of study drug (safety sample).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Other Major Hemorrhage Other Than Intracranial Hemorrhage Within 7 Days (Safety Outcome) | 1 Participants |
| Eptifibatide | Other Major Hemorrhage Other Than Intracranial Hemorrhage Within 7 Days (Safety Outcome) | 2 Participants |
| Placebo | Other Major Hemorrhage Other Than Intracranial Hemorrhage Within 7 Days (Safety Outcome) | 3 Participants |
Other Pre-specified
Symptomatic Intracranial Hemorrhage Within 36 Hours (Primary Safety Outcome)
Type 2 parenchymal hemorrhage or a parenchymal hemorrhage remote from the area of infarction with neurologic deterioration (defined as an increase of ≥4 points in the NIHSS score)within 36 hours after randomization.
Time frame: 36 hours after randomization
Population: Participants that took any amount of study drug (safety sample)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Symptomatic Intracranial Hemorrhage Within 36 Hours (Primary Safety Outcome) | 2 Participants |
| Eptifibatide | Symptomatic Intracranial Hemorrhage Within 36 Hours (Primary Safety Outcome) | 7 Participants |
| Placebo | Symptomatic Intracranial Hemorrhage Within 36 Hours (Primary Safety Outcome) | 4 Participants |
Other Pre-specified
Type 1 or Type 2 Parenchymal Hemorrhage Within 36 Hours (Safety Outcome)
Time frame: 36 hours after randomization
Population: Participants that took any amount of study drug (safety sample).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Argatroban | Type 1 or Type 2 Parenchymal Hemorrhage Within 36 Hours (Safety Outcome) | 3 Participants |
| Eptifibatide | Type 1 or Type 2 Parenchymal Hemorrhage Within 36 Hours (Safety Outcome) | 18 Participants |
| Placebo | Type 1 or Type 2 Parenchymal Hemorrhage Within 36 Hours (Safety Outcome) | 11 Participants |