A Study of r-PA Treating Patients With Acute Ischemic Stroke（RAISE）

A Phase III, Multicenter, Randomized, Blind Endpoint and Positive Drug Control Study of Recombinant Human Tissue Plasminogen Kinase Derivatives for Injection in the Treatment of Patients With Acute Ischemic Stroke

The purpose of this study is to assess the efficacy and safety of recombinant human tissue plasminogen kinase derivatives for injection and alteplase in the treatment of patients with acute ischemic stroke within 4.5 hours.

Study Overview

• Status: Completed
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Injection of recombinant human tissue plasminogen kinase derivatives; Drug: Recombinant human tissue plasminogen activator

Detailed Description

This study is a multicenter, randomized, blind endpoint and positive drug control study.

The study plans to recruit 1412 AIS patients within 4.5 hours of onset. Qualified subjects are assigned to the test drug and control drug alteplase group according to the ratio of 1:1. After receiving thrombolytic drugs, the subjects need to carry out a series of safety and effectiveness tests. The mRS score and Barthel index score visits are carried out on the 90th day (± 7 days) after thrombolysis. After the visit, the subjects can leave the group.

In this study, independent blind endpoint evaluators were set up in each research center to evaluate the mRS and Barthel index score 30 and 90 days after thrombolysis.

• Study Type: Interventional
• Enrollment (Actual): 1412
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Anhui
    • Bengbu, Anhui, China, 233070
      • The First Affiliated Hospital of Bengbu Medical College
  • Beijing
    • Beijing, Beijing, China, 100053
      • Xuanwu Hospital of Capital Medical University
    • Beijing, Beijing, China, 100071
      • Beijing Tiantan Hospital
  • Chongqing
    • Chongqing, Chongqing, China, 400014
      • Chongqing Emergency Medical Center
  • Guangdong
    • Gaozhou, Guangdong, China, 525299
      • Gaozhou People's Hospital
    • Jiangmen, Guangdong, China, 529030
      • Jiangmen Central Hospital
    • Meizhou, Guangdong, China, 514000
      • Meizhou People's hospital
    • Shaoguan, Guangdong, China, 512026
      • Yue Bei People's Hospital
    • Zhuhai, Guangdong, China, 519099
      • Zhuhai People's Hospital
  • Hebei
    • Cangzhou, Hebei, China, 061000
      • Cangzhou Central Hospital
    • Cangzhou, Hebei, China, 061007
      • Hebei CangZhou Hospital of Integrated Traditional Chinese and Western Medicine
    • Handan, Hebei, China, 056002
      • HanDan Central Hospital
    • Hengshui, Hebei, China, 053000
      • Hengshui People's Hospital
    • Shijiazhuang, Hebei, China, 050030
      • The First Hospital of Hebei Medical University
    • Shijiazhuang, Hebei, China, 050004
      • The Second Hospital of Hebei Medical University
    • Tangshan, Hebei, China, 063007
      • Tangshan Workers'Hospital
  • Heilongjiang
    • Daqing, Heilongjiang, China, 163001
      • Daqing Oilfield General Hospital
    • Daqing, Heilongjiang, China, 163711
      • Daqing People's Hospital
    • Harbin, Heilongjiang, China, 150001
      • The Fourth Affiliated Hospital of Harbin Medical University
    • Qiqihar, Heilongjiang, China, 161099
      • The Third Affiliated Hospital of Qiqihar Medical College
  • Henan
    • Anyang, Henan, China, 456550
      • Anyang People's Hospital
    • Jiaozuo, Henan, China, 454002
      • Jiaozuo People's Hospital
    • Kaifeng, Henan, China, 475001
      • Huaihe Hospital of Henan University
    • Luoyan, Henan, China, 471003
      • The first affiliated hospital of Henan University of science and technology
    • Luoyang, Henan, China, 471003
      • The first affiliated hospital of Henan University of science and technology
    • Luoyang, Henan, China, 471006
      • Luoyang Central Hospital
    • Nanyang, Henan, China, 473006
      • Nanyang Nanshi Hospital
    • Nanyang, Henan, China, 474599
      • Nanyang Second People's Hospital
    • Xinxiang, Henan, China, 453099
      • Xinxiang Central Hospital
    • Zhengzhou, Henan, China, 450002
      • Zhengzhou People's Hospital
    • Zhumadian, Henan, China, 463000
      • Zhumadian Central Hospital
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Wuhan Fourth Hospital (Wuhan Puai Hospital, Wuhan Orthopaedic Hospital)
  • Hunan
    • Hengyang, Hunan, China, 421000
      • The First Affiliated Hospital of Nanhua University
    • Yiyang, Hunan, China, 413099
      • Yiyang Central Hospital
  • Inner Mongolia
    • Baotou, Inner Mongolia, China, 014010
      • Inner Mongolia Baogang Hospital
    • Baotou, Inner Mongolia, China, 014017
      • The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology
    • Hohhot, Inner Mongolia, China, 010050
      • Affiliated Hospital of Inner Mongolia Medical University
    • Hohhot, Inner Mongolia, China, 010010
      • Inner Mongolia Autonomous Region People's Hospital
  • Jiangsu
    • Huai'an, Jiangsu, China, 223002
      • Huai'an Second People's Hospital
    • Xuzhou, Jiangsu, China, 221006
      • Affiliated Hospital of Xuzhou Medical University
    • Xuzhou, Jiangsu, China, 221399
      • Xuzhou Central Hospital
  • Jiangxi
    • Ganzhou, Jiangxi, China, 341001
      • Ganzhou People's Hospital
    • Nanchang, Jiangxi, China, 330008
      • The Second Affiliated Hospital of Nanchang University
    • Pingxiang, Jiangxi, China, 337005
      • Pingxiang People's Hospital
    • Yichun, Jiangxi, China, 336099
      • Yichun People's Hospital
  • Jilin
    • Changchun, Jilin, China, 130021
      • First Hospital of Jilin University
    • Jilin, Jilin, China, 132000
      • Jilin People's Hospital
    • Meihekou, Jilin, China, 135099
      • Meihekou Central Hospital
    • Siping, Jilin, China, 136199
      • Jilin Guowen Hospital
    • Tonghua, Jilin, China, 134099
      • Tonghua Central Hospital
  • Liaoning
    • Fushun, Liaoning, China, 113012
      • Fukuang General Hospital of Liaoning Health Industry Group
    • Jinzhou, Liaoning, China, 121004
      • First Affiliated Hospital of Jinzhou Medical University
    • Shenyang, Liaoning, China, 110000
      • Shenyang First People's Hospital
    • Shenyang, Liaoning, China, 110000
      • PLA Northern Theater Command General Hospital
    • Shenyang, Liaoning, China, 110075
      • Central Hospital Affiliated to Shenyang Medical College
  • Shandong
    • Dezhou, Shandong, China, 253014
      • Dezhou People's Hospital
    • Jinan, Shandong, China, 250013
      • Jinan Central Hospital
    • Jinan, Shandong, China, 250014
      • Shandong Qianfo Mountain Hospital
    • Jining, Shandong, China, 272007
      • Affiliated Hospital of Jining Medical College
    • Liaocheng, Shandong, China, 252037
      • Liaocheng People's Hospital
    • Linyi, Shandong, China, 276004
      • Linyi People's Hospital
    • Qingdao, Shandong, China, 266042
      • Qingdao Central Hospital
    • Tai'an, Shandong, China, 271099
      • Tai'an Central Hospital
    • Weifang, Shandong, China, 261041
      • Weifang Hospital of Traditional Chinese Medicine
    • Yantai, Shandong, China, 264099
      • Yantai Yuhuangding Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 201399
      • Shanghai Pudong Hospital
  • Shanxi
    • Datong, Shanxi, China, 037021
      • General Hospital of Tongmei Group
    • Xi'an, Shanxi, China, 710016
      • Xi'an Daxing Hospital
    • Xi'an, Shanxi, China, 710065
      • Xi'an High-tech Hospital 204 Hospital
    • Xianyang, Shanxi, China, 712099
      • Yan'an University Xianyang Hospital
  • Sichuan
    • Zigong, Sichuan, China, 643099
      • Zigong First People's Hospital
  • Tianjin
    • Tianjin, Tianjin, China, 300121
      • Tianjin People's Hospital
    • Tianjin, Tianjin, China
      • Tianjin Medical University General Hospital
  • Xinjiang
    • Kashgar, Xinjiang, China, 844099
      • First People's Hospital of Kashgar Region
    • Urumqi, Xinjiang, China, 830001
      • People's Hospital of Xinjiang Uygur Autonomous Region
  • Zhejiang
    • Jiaxing, Zhejiang, China, 314001
      • Jiaxing First Hospital
    • Taizhou, Zhejiang, China, 318020
      • Taizhou First People's Hospital
    • Wenzhou, Zhejiang, China, 325015
      • The First Affiliated Hospital of Wenzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18 to 80 years（including the critical value);
2. Acute ischemic stroke is diagnosed according to the WHO (World Health Organization) stroke diagnostic criteria, the symptoms of acute ischemic stroke are expected to be less than 4.5 hours after the time of acute ischemic stroke which is defined as the last time the patient functions well;
3. NIHSS score at the time of treatment: from 4 points to 25 points (including 4 points and 25 points);
4. From the signing of informed consent form to 3 months after treatment, fertile men and women of childbearing age should be absent of a birth plan and willing to take effective contraceptive measures;
5. Participants who can understand and follow the research process, voluntarily participate, and sign an informed consent form (informed consent is voluntarily signed by the person or legal representative).

Exclusion Criteria:

1. Known to be allergic to research drugs or similar ingredients, or materials used in imaging studies;
2. Weight >120kg or <45kg;
3. The timing of stroke symptoms is not known;
4. mRS score before stroke≥ 2 points;
5. NIHSS score 1a (level of consciousness) ≥ 2 points during screening;
6. Patients with intracerebral hemorrhage history;
7. CT/MRI imaging examination shows signs of intracranial hemorrhage or suspected subarachnoid hemorrhage despite CT/MRI imaging findings do not show abnormalities;
8. Severe cerebral trauma or stroke history or other severe traumas within 3 months;
9. Assessment of Intracranial tumor, arteriovenous malformation and aneurysm before admission;
10. Intracranial surgery, intraspinal surgery or other major surgeries within 3 months (based on the assessment of the investigators);
11. Patients with gastrointestinal or urinary system hemorrhage in recent 3 weeks;
12. Active visceral hemorrhage;
13. Assessment or with history of aortic arch dissection before admission;
14. Arterial puncture in 1 week which can not be oppressed;
15. Subjects who have an acute bleeding tendency, including but not limited to：1) a platelet count of less than 100 × 109 / L；2) application of low molecular heparin within 24 hours before onset ; 3) Using of thrombin inhibitors or factor Xa inhibitor within 48 hours before onset ; 4) application of oral anticoagulant drugs and with an INR > 1.7 or PT>15s;
16. Hypertension remains uncontrolled after active antihypertensive therapy, uncontrolled hypertension refers to a systolic blood pressure >185 mmHg and/or a diastolic blood pressure >110 mmHg;
17. Blood glucose <50 mg/dl (equivalent to 2.78mmol/L) or >400 mg/dl (equivalent to 22.2mmol/L);
18. Imaging (CT or MRI)shows large area cerebral infarction;
19. Severe liver damage, including liver failure, cirrhosis, portal hypertension (esophageal varices), and active hepatitis;
20. Bacterial endocarditis or pericarditis, acute pancreatitis at admission;
21. With history of gastrointestinal ulcers, esophageal varices, aneurysms, or arterial / venous malformations within 3 months before admission;
22. Patients who are unable to cooperate or are unwilling to cooperate with epileptic seizures, or other mental illnesses during stroke episodes;
23. Patients who are ready to go or have undergone endovascular treatment;
24. The restricted drug specified in the protocol or any drug that may interfere with the test results must be ingested or desired to continue to be ingested;
25. An expected survival time of no more than 1 year due to other diseases;
26. Patients who are participating in other trials or have participated in other trials within 30 days before randomization;
27. Pregnancy or lactation, or women who have a positive pregnancy test result;
28. The subject who is unsuitable for this study in the opinion of the investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: experimental group; Recombinant human tissue plasminogen kinase derivatives(r-PA) for injection: the first intravenous bolus injection of 18mg, after 30mins, the second intravenous bolus injection of 18 mg, Push slowly for more than 2mins each time. Subjects were closely monitored during the treatment period and within 24 hours after administration.	Drug: Injection of recombinant human tissue plasminogen kinase derivatives; 18mg/10ml/stick, provided by Angde Biotech; Other Names: Reteplase; brand name: Ruitongli; r-PA
Active Comparator: comparative group; Recombinant human tissue plasminogen activator (rt-PA) for injection: 0.9 mg/kg (maximum dose of 90 mg) intravenous, 10% of which was injected intravenously within the first 1min, and the rest continued intravenous infusion for 1 h. Subjects should be closely monitored during the treatment period and within 24 hours after administration.	Drug: Recombinant human tissue plasminogen activator; 20mg/stick, 50mg/stick, provided by Shanghai Boehringer Ingelheim Pharmaceutical Co. Ltd.; Other Names: Alteplase; rt-PA; brand name: Actilyse

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional handicap	Proportion of patients achieving a Modified Rankin Scale score of 0 to 1 on the 90th day after treatment. The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0-5. A separate category of 6 is usually added for patients who expire. The higher the score, the more severe the stroke.	on the 90th day after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Neurological Improvement	The proportion of subjects with NIHSS score ≤1 or the decrease of 4 points or more from the baseline at 24 hours and the 7th day after treatment. The National Institutes of Health Stroke Scale (NIHSS) is a 11-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on level of consciousness, eye movements, integrity of visual fields, facial movements,arm and leg muscle strength, sensation, coordination, language,speech and neglect. Each impairment is scored on an ordinal scale ranging from 0 to 2, 0 to 3, or 0 to 4. Item scores are summed to a total score ranging from 0 to 42 (the higher the score, the more severe the stroke).	at 24hours and the 7th day after treatment
Proportion of Long-term Improvement	Proportion of patients achieving a mRS of 0 to 2 on the 90th day after treatment.	on the 90th day after treatment
Barthel Index score	Proportion of patients achieving a Barthel Index score ≥95 on the 90th day after treatment. The Barthel Index of Activities of Daily Living (ADLs) measures functional disability by quantifying patient performance in 10 activities of daily life. These activities can be grouped according to self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and mobility (ambulation, transfers, and stair climbing). 5-point increments are used in scoring, with a maximal score of 100 indicating that a patient is fully independent in physical functioning, and a lowest score of 0 representing a totally dependent bed-ridden state.	on the 90th day after treatment
Ordinary distribution of mRS scores	Ordinary distribution of mRS scores on the 90th day after treatment.	on the 90th day after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects died of all cause	All-cause mortality within 7 days and 90 days after treatment.	within 7 days and 90 days after treatment
Percentage of subjects with symptomatic intracranial hemorrhage (sICH)	sICH definition: 1. SITS criteria: local or remote parenchymal hematoma type 2 on the imaging scan obtained within 36 hours after treatment, plus neurologic deterioration, as indicated by a score on the NIHSS that was higher by 4 points or more than the baseline value or the lowest value between baseline and 24 hours, or hemorrhage leading to death. 2. The ECASS III criteria：any hemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by 4 points or more than the value at baseline or the lowest value in the first 7 days , or any hemorrhage leading to death. In addition, the hemorrhage must have been identified as the predominant cause of the neurologic deterioration (This study will be evaluated and recorded according to the above two standards).	SITS criteria: within 36 hours after treatment; ECASS III criteria: within 36 hours and 7 days after treatment
Proportion of subjects with major hemorrhage and clinically relevant non-major hemorrhage（ISTH criteria）	ISTH：International Society of Thrombosis and Hemostasis.	within 90 days after treatment
The Proportion of subjects with AE、SAE	The Proportion of subjects with AE、SAE within 90 days after treatment.	within 90 days after treatment

Collaborators and Investigators

• Sponsor: Angde Biotech Pharmaceutical Co., Ltd.
• Collaborators: Beijing Tiantan Hospital
• Investigators: Principal Investigator: Yongjun Wang, Beijing Tiantan Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2022
• Primary Completion (Actual): June 22, 2023
• Study Completion (Actual): June 22, 2023

Study Registration Dates

• First Submitted: February 24, 2022
• First Submitted That Met QC Criteria: March 15, 2022
• First Posted (Actual): March 25, 2022

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Plasminogen; Reteplase
• Other Study ID Numbers: CRAD-001-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No