Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events(TRACE)

Study Overview
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Brief Summary
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To explore the safe and efficacious dose of rhTNK-tPA injection administered within 3 hours after onset of hyperacute ischemic stroke; to provide dose evidence for phase III clinical trial.

Detailed Description
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To evaluate the safety and efficacy of rhTNK-tPA at different doses of 0.10 mg/kg, 0.25 mg/kg and 0.32 mg/kg compared with standard rt-PA intravenous thrombolytic therapy within 3 hours after onset of ischemic stroke. The primary objective of this study is to evaluate the differences of NIHSS scores among the four treatment groups at 14 days after intravenous thrombolysis.

Official Title
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Phase II Dose-finding Open Study of Recombinant Human TNK Tissue-type Plasminogen Activator (rhTNK-tPA) Injection Administered Within 3 Hours After Onset of Hyperacute Ischemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: TNK-tPA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age over 18 years. Time from onset to treatment < 3 hours; the time symptoms start is defined as the last moment they appear normal. Diagnosis of ischemic stroke according to 2014 China Guideline for Diagnosis and Treatment of Acute Ischemic Stroke with assessable neurological impairment e.g., language, motor function, cognitive impairment, gaze impairment, visual field deficit and/or visual neglect. Ischemic stroke is defined as sudden acute focal neurological impairment with suspected cerebral ischemia, hemorrhage ruled out by CT scan. mRS > 2 at the first onset or prior onset. Baseline NIHSS score is > 4 and < 26. Signed informed consent. Exclusion Criteria: Absolute contraindications: 1.1 History of severe head trauma or stroke within 3 months; 1.2 Suspected subarachnoid hemorrhage; 1.3 Arterial puncture at a non-compressible site within the previous 1week; 1.4 History of intracranial hemorrhage; 1.5 Intracranial tumor, vascular malformation, or arterial aneurysm; 1.6 Recent intracranial or intraspinal surgery; 1.7 Systolic blood pressure ≧ 180 mm Hg, or diastolic blood pressure ≧ 100 mm Hg; Increased blood pressure; 1.8 Active internal bleeding ; 1.9 Acute bleeding tendency, including platelet count below 100×109/L or otherwise; 1.10 Heparin treatment was performed within 48 h ( APTT exceeded the upper limit of normal range ) ; 1.11 Warfarin has been taken orally , and the international standardized ratio is INR > 1.7 or PT > 15 s ; 1.12 Anticoagulant drugs such as thrombin inhibitor or Xa factor inhibitor , argatroban ( including new anticoagulants with unclear mechanism ) are currently being used , and various sensitive laboratory tests are abnormal ( such as live ) APTT , INR , Platelet count , Serpentine ECT of pulse enzyme setting time ; thrombin time TT or appropriate determination of Xa factor activity ) ; 1.13 Blood glucose < 2.7 mmol/L; 1.14 CT showed multilobular infarction ( low density > 1 / 3 cerebral hemisphere ) Relative contraindications : The risks and benefits of thrombolysis should be carefully considered and weighed in the following cases ( that is , although there is one or more relative contraindications , it is not absolutely impossible to thrombolysis ). 2.1 Mild stroke or stroke with rapid improvement of symptoms; 2.2 Women in pregnancy ; 2.3 Symptoms of neurological impairment after seizures ; 2.4 There have been major surgical operations or serious injuries in the last 2 weeks; 2.5 There were gastrointestinal or urinary system bleeding in recent 3 weeks ; 2.6 History of myocardial infarction within 3 months. Have been enrolled in rhTNK-tPA in pre-study or participated in other clinical trials within 3 months prior to screening. Lactating women, or childbearing women who do not use effective contraception. Known allergy to rhTNK-tPA and/or rt-PA or relevant excipients. The researchers judged that not suitable to participate in this study or participate in this study may lead to greater risk for patients ; Can not comply with the test program or follow-up requirements .

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentre, prospective, randomization, open label, active and parallel control
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (rhTNK-tPA 0.10 mg/kg)<br>Dissolve one vial of rhTNK-tPA in 3 ml sterile water for injection to prepare a solution of 5.33 mg/ml. Calculate the required volume according to the body weight of the subject, then measure the required volume. Administer as a single 0.10 mg/kg IV bolus over 5-10 seconds. | Drug: TNK-tPA<br>* Experimental arms for low, middle, and high dosing; and active control arm for the standard protocol<br>* Other names: rtPA;|
| Experimental: Group 2 (rhTNK-tPA 0.25 mg/kg)<br>Dissolve one vial of rhTNK-tPA in 3 ml sterile water for injection to prepare a solution of 5.33 mg/ml. Calculate the required volume according to the body weight of the subject, then measure the required volume. Administer as a single 0.25 mg/kg IV bolus over 5-10 seconds. | Drug: TNK-tPA<br>* Experimental arms for low, middle, and high dosing; and active control arm for the standard protocol<br>* Other names: rtPA;|
| Experimental: Group 3 (rhTNK-tPA 0.32 mg/kg)<br>Dissolve one vial of rhTNK-tPA in 3 ml sterile water for injection to prepare a solution of 5.33 mg/ml. Calculate the required volume according to the body weight of the subject, then measure the required volume. Administer as a single 0.32 mg/kg IV bolus over 5-10 seconds. | Drug: TNK-tPA<br>* Experimental arms for low, middle, and high dosing; and active control arm for the standard protocol<br>* Other names: rtPA;|
| Active Comparator: Group 4 (rt-PA 0.9 mg/kg)<br>10% of rt-PA 0.9 mg/kg administered as an initial IV bolus followed by the remaining 90% as an IV infusion over the next 1 hour. | Drug: TNK-tPA<br>* Experimental arms for low, middle, and high dosing; and active control arm for the standard protocol<br>* Other names: rtPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| National Institutes of Health Stroke Scale (NIHSS) | Proportion of subjects with NIHSS 1 or at least 4 on the NIHSS score decreased from the baseline at day14. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale (mRS) | Proportion of subjects of excellent outcome defined as mRS (0-1) at 90 days. Ordinal distribution of mRS and change of proportion of subjects with mRS (0-2) at 90 days. | 90 days | 
| National Institutes of Health Stroke Scale (NIHSS) | Neurological impairment defined as change of NIHSS score at 90 days. | 90 days | 
| Barthel(BI) | Global function of daily living defined as BI ≥ 95 at 90 days. | 90 days | 
| EQ-5D | Quality of life measured by EQ-5D scale. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rhTNK-tPA, acute, stroke, phaseII, Acute Ischemic Stroke, rt-PA