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

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Sponsor:

Information provided by (Responsible Party):

Second Affiliated Hospital, School of Medicine, Zhejiang University

Study Description

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.

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

Detailed Description:

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.

Study Design

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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

U.S. FDA Resources

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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 :

proportion of patients with a 3-month modified Rankin Scale (mRS) score≤ 2 [ Time Frame: 3 months ]
mRS 0-6, higher indicate worse outcome
mRS score in the first and third months of PIS [ Time Frame: 1 month and 3 months ]
mRS 0-6, higher indicate worse outcome
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
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.
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:

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

Eligibility Criteria

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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.

Contacts and Locations

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

More Information

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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

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