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Clinical Study of Argatroban in the Treatment of Acute Progressive Ischemic Stroke

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ClinicalTrials.gov Identifier: NCT04275180
Recruitment Status : Recruiting
First Posted : February 19, 2020
Last Update Posted : May 12, 2020
Sponsor:
Information provided by (Responsible Party):
Second Affiliated Hospital, School of Medicine, Zhejiang University

Brief Summary:

Acute ischemic stroke (AIS) has the characteristics of high morbidity, high mortality, high disability rate and high recurrence rate. Progressive cerebral infarction (PIS) is a subtype of AIS, accounting for 10% - 40%. Because of the gradual aggravation of neurological deficit symptoms, it has a higher rate of disability and death, which brings heavy mental and economic burden to families, society and the country.

The progress of acute cerebral infarction is generally within 6 hours to 1 week after the onset of the disease. At present, it is considered that thrombus prolongation is one of the important pathogenesis of PIS. Heparin can reduce the incidence of post-stroke embolism, but its benefits are offset by the risk of hemorrhage due to the high risk of hemorrhage. The 2013AHA guidelines in the United States do not recommend it as a routine anticoagulant therapy. Therefore, reducing the risk of bleeding is the key to the anticoagulation therapy of PIS.

Argatroban is a new thrombin inhibitor. Its mechanism of action is to bind and inactivate thrombin (factor Ⅱ a) directly.Compared with traditional anticoagulants, argatroban not only has the advantages of good anticoagulant effect and rapid onset, but also has high safety. Therefore, this study aims to verify the clinical efficacy of Argatroban in the treatment of PIS in a large population.

In this study, 628 patients are expected to be enrolled into the study group. The experimental group and the control group are selected by dynamic random method. Both groups are given standard medical treatment, including routine antiplatelet, blood pressure control, statins to stabilize plaque, etc. The control group is only given standard medical treatment. In the experimental group, Argatroban is used on the basis of standard medical treatment. Both groups are treated for 7 days, and the second-class prevention standard medical treatment is given from the 8th to the 90th day. The main outcome measure is the good prognosis rate at the third month after PIS. The good prognosis was defined as the modified Rankin Scale (mRS) ≤ 3.


Condition or disease Intervention/treatment Phase
Acute Progressive Ischemic Stroke Drug: Argatroban Phase 4

Detailed Description:

Acute ischemic stroke (AIS) has the characteristics of high morbidity, high mortality, high disability rate and high recurrence rate. Progressive cerebral infarction (PIS) is a subtype of AIS, accounting for 10% - 40%. Because of the gradual aggravation of neurological deficit symptoms, it has a higher rate of disability and death, which brings heavy mental and economic burden to families, society and the country.

The progression of acute cerebral infarction is generally within 6 hours to 1 week after onset. At present, the guidelines recommend early intravenous thrombolysis and endovascular thrombectomy for patients with PIS. However, due to the limitation of time window, family economy and other factors, less than 5% of patients can really receive intravenous thrombolysis and endovascular therapy. Therefore, most of the patients with PIS are still treated with conventional antiplatelet aggregation therapy. At present, the pathogenesis of PIS has not been clear. The study considers that stroke progress is formed by a variety of risk factors and mechanisms, including poor collateral circulation, thrombus prolongation, stroke recurrence, brain edema, reocclusion of arteries, hemorrhagic transformation, etc. Thrombus prolongation is one of the important mechanisms. At present, there is a lack of effective treatment for PIS, including anticoagulation, antiplatelet and so on. Heparin is a commonly used anticoagulant. It is believed that heparin can reduce the risk of post-stroke embolism, but its benefits are offset by the risk of bleeding. The 2013AHA guidelines in the United States do not recommend it as a routine anticoagulant therapy. Therefore, reducing the risk of bleeding is the key to the anticoagulation therapy of PIS.

Argatroban is a new thrombin inhibitor. Its mechanism of action is reversible binding via thrombin catalytic site, independent of antithrombin level in vivo, and directly binding and inactivating thrombin (factor IIA). Argatroban has a strong inhibition on fibrin formation and platelet aggregation caused by thrombin, but does not inhibit other serine proteases such as trypsin, XA factor Fibrinolytic enzyme and kallikrein can effectively improve the hypercoagulability of patients. Compared with traditional anticoagulants, argatroban not only has the advantages of good anticoagulant effect and rapid onset, but also has high safety. According to a study in Japan, argatroban is superior to heparin in the treatment of cardiogenic stroke and has higher safety; a meta-analysis involving 14 small sample studies in China shows that argatroban can effectively improve the neurological deficit of PIS and improve the ability of daily life. In terms of safety, compared with the control group, argatroban treatment group has no increase in bleeding events. Therefore, this study aims to verify the clinical efficacy of argatroban in the treatment of PIS in a large population.

In this study, 628 patients are expected to be enrolled into the study group. The experimental group and the control group are selected by dynamic random method. Both groups are given standard medical treatment, including routine antiplatelet, blood pressure control, statins to stabilize plaque, etc. The control group is only given standard medical treatment. In the experimental group, Argatroban is used on the basis of standard medical treatment. Both groups are treated for 7 days, and the second-class prevention standard medical treatment is given from the 8th to the 90th day. The main outcome measure is the good prognosis rate at the third month after PIS. The good prognosis was defined as the modified Rankin Scale (mRS) ≤ 3. Secondary efficacy evaluation indexes: 1. The proportion of mRS ≤ 2 in the third month of PIS; 2. mRS score in the first and third months of PIS; 3. NIHSS score in the seventh, first and third months of PIS; 4. The rate of composite events in the first and third months of PIS, including cerebrovascular events, myocardial infarction, angina pectoris and systemic embolism; 5. Recent changes in living ability, Barthel Index in the first and third months. Safety evaluation indicators: symptomatic intracranial hemorrhage within 7 days after PIS; cerebral hemorrhage within 7 days after PIS; adverse reactions and events reported by researchers.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 628 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Study of Argatroban in the Treatment of Acute Progressive Ischemic Stroke
Actual Study Start Date : March 21, 2020
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Argatroban

Arm Intervention/treatment
No Intervention: control
Standard medical treatment, including routine antiplatelet, blood pressure control, statins to stabilize plaque, etc.
Experimental: Argatroban group
Argatraban is used on the basis of standard medical treatment.
Drug: Argatroban
Argatroban plus standard medical treatment




Primary Outcome Measures :
  1. proportion of patients with a 3-month modified Rankin Scale (mRS) score≤ 3 [ Time Frame: 3 months ]
    mRS 0-6, higher indicate worse outcome


Secondary Outcome Measures :
  1. proportion of patients with a 3-month modified Rankin Scale (mRS) score≤ 2 [ Time Frame: 3 months ]
    mRS 0-6, higher indicate worse outcome

  2. mRS score in the first and third months of PIS [ Time Frame: 1 month and 3 months ]
    mRS 0-6, higher indicate worse outcome

  3. National Institute of Health stroke scale(NIHSS) scores in the seventh day, first and third months of PIS [ Time Frame: 7 day, 1 month and 3 months ]
    NIHSS 0-42, higher indicate worse outcome

  4. The rate of composite events in the first and third months of PIS, including cerebrovascular events, myocardial infarction, angina pectoris and systemic embolism [ Time Frame: 1month and 3 months ]
    Complex events include cerebrovascular events, myocardial infarction, angina pectoris and systemic embolism.

  5. Recent changes in living ability, Barthel Index in the first and third months [ Time Frame: 1month and 3 months ]
    Barthel Index 0-100, higher indicate better outcome


Other Outcome Measures:
  1. Symptomatic hemorrhage transformation within 7 days after PIS [ Time Frame: 7 days ]
    Increase of National Institute of Health stroke scale(NIHSS) scores caused by intracranial hemorrhage confirmed by imaging ≥ 4 points.

  2. Parenchymal hemorrhage within 7 days after PIS [ Time Frame: 7 days ]
    parenchymal hematoma is assessed on MRI or CT according to the second European-Australasian acute stroke study (ECASS II).

  3. Adverse reactions and events reported by researchers [ Time Frame: 3 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • AIS patients with typical symptoms and signs within 48h, including those who received intravenous thrombolysis for 24 hours.
  • The neurologic function deteriorated from 6h to 48h after the onset of the disease, and the NIHSS score increased by ≥ 2 points;
  • Sign informed consent.

Exclusion Criteria:

  • The diagnosis was cardiogenic cerebral embolism;
  • In the patients with large area cerebral infarction of anterior circulation, the focus area was larger than 2 / 3 of the area of cerebral hemisphere;
  • Patients with NIHSS score ≥ 21;
  • Patients with conversion of intracranial hemorrhage;
  • Patients with tirofiban;
  • Patients with blood pressure ≥ 180 / 110mmhg after treatment;
  • There were severe heart, liver and kidney dysfunction, such as LVEF < 40%, serum AST and ALT increased to 3 times of the upper limit of normal, creatinine clearance < 30ml / min;
  • Patients with hematological diseases and those with bleeding tendency;
  • In the past 6 months, the patients had a history of severe gastrointestinal hemorrhage;
  • Allergic to argatraban;
  • Patients (such as those with mental and mental disorders) who are not suitable for the clinical study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04275180


Contacts
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Contact: Min Lou, PhD 86057187784810 loumingxc@vip.sina.com

Locations
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China, Zhejiang
Min Lou Not yet recruiting
Hangzhou, Zhejiang, China, 310000
Contact: Zexin Chen    13757118366    HREC2013@126.com   
China
People's Hospital of Anji Recruiting
Anji, China
Contact: Fujian Chen         
Jiaxing Second Hospital Recruiting
Jiaxing, China
Contact: Xiaoling Zhang         
Ninghai First Hospital Recruiting
Ninghai, China
Contact: Liqun Gu         
Quzhou Kecheng People's Hospital Recruiting
Quzhou, China
Contact: Xiaofen Zhu         
Tongxiang Diyi Renmin Hospital Recruiting
Tongxiang, China
Contact: Ninyuan Zhang         
Sponsors and Collaborators
Second Affiliated Hospital, School of Medicine, Zhejiang University
Investigators
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Study Chair: Ze Xin Chen 2nd affiliated hospital of Zhejiang University, School of Medicine
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Responsible Party: Second Affiliated Hospital, School of Medicine, Zhejiang University
ClinicalTrials.gov Identifier: NCT04275180    
Other Study ID Numbers: Yan-2019-293
First Posted: February 19, 2020    Key Record Dates
Last Update Posted: May 12, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Stroke
Cerebral Infarction
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Argatroban
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants
Platelet Aggregation Inhibitors