Clinical trial NCT00781378: Low Dosage of rt-PA in the Treatment of Pulmonary Thromboembolism in China
Official title: Efficacy and Safety Evaluation of Low Dosage of Recombinant Tissue Plasminogen Activator (rt-PA) in the Treatment of Pulmonary Thromboembolism: A Multi-Center, Randomized Controlled Trial in China
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Embolism
Thromboembolism
Keywords: Thrombolytic therapy
Recombinant tissue plasminogen activator
Efficacy
Safety
Lead sponsor: Beijing Chao Yang Hospital
Sponsor class: OTHER
First posted: 2008-10-29
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Recombinant tissue plasminogen activator (rt-PA) is currently the most commonly used thrombolytic drug in patients with pulmonary thromboembolism (PTE). Optimal dosing with maximal benefits and minimal risks is of great importance. Considering the lower body weight in general Chinese population, we compared the efficacy and safety of lower dose rt-PA 50mg/2h regimen with the FDA-approved rt-PA 100mg/2h regimen in selected PTE patients.

Detailed description: Pulmonary thromboembolism (PTE) is a severe and common clinical problem with substantial morbidity and mortality both in US and in Europe. Used to be considered as a rare disease in China, PTE has been increasingly diagnosed in recent years due to the increased awareness and the improvement of imaging techniques. PTE is life threatening without proper intervention at the early onset. Effective treatment can decrease the mortality and the complication of chronic thromboembolic pulmonary hypertension (CTEPH).

Recombinant tissue-type plasminogen activator (rt-PA) is currently the most commonly used drug for PTE thrombolysis. Like most thrombolytic medications, rt-PA carries a risk of significant bleeding, which is dose dependent. Thus, optimal dosing that can maximize benefits and minimize risks is of great importance. There is substantial controversy and debate regarding the optimal rt-PA dosage for thrombolytic therapy and whether the same dose should be used in all patients. Low dose of intravenous rt-PA for thrombolysis after acute myocardial infarction (AMI) had been suggested by previous studies. Experimental and clinical studies have indicated that a lower dose of rt-PA bolus may be potentially safer, and yet equally effective then the 2-h 100 mg rt-PA continuous infusion for PTE.

Considering lower body weight in Chinese population, a lower dose of 50mg rt-PA/2h may exhibit similar efficacy and safety as 100mg/2-h rt-PA for treating acute PTE in this population. We, therefore, compared these two regimens in a multi-center, randomized, controlled trial. The efficacy was assessed by the improvement of the right ventricular function on echocardiograms, perfusion defect score of lung V/Q scans or quantitative computed tomographic (CT) evaluation, safety was evaluated by incidence of major or minor bleeding, death rate, and PTE recurrence on 24h,14d after treatment.

110 patients will be randomized in the study. The patients included in the study will be randomized, in a double blind fashion, to receive rt-PA 100mg 2h (55 patients) or rt-PA50mg 2h(55 patients).Study treatment should be administered within 72 hours from echocardiography. Echocardiography will be repeated at 24 hours and 14 days from rt-PA injection. A Follow-up visit at 14 days from randomization will include: clinical history, physical examination and ECG and an echocardiographic examination CTPA and V/Q scan.

Eligibility criteria: Inclusion Criteria:

* age between 18 and 75
* symptomatic PE confirmed by: a high probability ventilation-perfusion lung scanning (V/Q scan) or the presence of intraluminal filling defect on spiral computed tomographic pulmonary angiography (CTPA)
* PTE patients with haemodynamic instability, or cardiogenic shock
* anatomic obstruction more than 2 lobes on CTPA, or defect more than 7 segments on V/Q scan combined with evidence of right ventricular dysfunction(RVD) and pulmonary hypertension on echocardiography
* written informed consent

Exclusion Criteria:

* active bleeding or spontaneous intracranial hemorrhage
* major surgery, organ biopsy or recent puncture of a non-compressible vessel less than 10 days
* cerebral arterial thrombosis within 2 months
* gastro-intestinal bleeding within 10 days
* major trauma within the past 15 days
* neurosurgery or ophthalmologic operation with 30 days
* uncontrolled hypertension (systolic blood pressure \> 180 mmHg and/or diastolic blood pressure \> 110 mmHg)
* recent external cardiac resuscitation manoeuvres
* platelet count \< 100 000/mm3 at admission
* pregnancy, puerperium or lactation with 2 weeks
* infectious pericarditis or endocarditis
* severe hepatic and kidney dysfunction
* hemorrhagic retinopathy due to diabetes
* a known bleeding disorder

Primary outcomes:
measure: The improvement of the right hart function on echocardiograms
timeFrame: within the 1st 14 days
measure: Perfusion defect score of lung V/Q scans
timeFrame: within the 1st 14 days
measure: Quantitative computed tomographic pulmonary angiography (CTPA) score on 2d, 14d after treatment.
timeFrame: within the 1st 14 days
Secondary outcomes:
measure: Major or minor bleeding
timeFrame: within 1st 14 days
measure: PE recurrence
timeFrame: within the 1st 14 days
measure: Death
timeFrame: within the 1st 14 days
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Chaoyang Hospital, Capital University of Medical Sciences
state: Beijing
city: Beijing
country: China
facility: Beijing University People's Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Hospital, Chinese Academy of Medical Sciences
state: Beijing
city: Beijing
country: China
facility: The Omni-hospital of Air-force
state: Beijing
city: Shenzhen
country: China
facility: Shenzhen People's Hospital
state: Guangdong
city: Nanning
country: China
facility: The First Affiliated Hospital of Guangxi Medical University
state: Guangxi
city: Guangdong
country: China
facility: Guangzhou Institute of Respiratory Disease
state: Guangzhou
city: Shijiazhuang
country: China
facility: The Second Affiliated Hospital of Hebei University
state: Hebei
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University:
state: Henan
city: Shenyang
country: China
facility: Shenyang Military Hospital
state: Liaoning
city: Shenyang
country: China
facility: The Affiliated Hospital of Shenyang Medical University
state: Liaoning
city: Yinchuang
country: China
facility: The Affiliated Hospital of Ningxia Medical University
state: Ningxia
city: Yantai
country: China
facility: Shangdong Yantaishan Hospital
state: Shandong
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shangdong
city: Jinan
country: China
facility: The First Affiliated Hospital of Jining Medical College
state: Shangdong
city: Qingdao
country: China
facility: The First Affiliated Hospital of Qingdao University CHENG Zhao-zhong
state: Shangdong
city: Shanghai
country: China
facility: Shanghai Hospital of Lung Disease
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Ruijin Hospital HUANG Shao-guang
state: Shanghai
city: Tai-yuan
country: China
facility: The First Affiliated Hospital of Shanxi University
state: Shanxi
city: Tai-yuan
country: China
facility: The Second Affiliated Hospital of Shanxi University
state: Shanxi
city: Tianjin
country: China
facility: Tianjin Hospital of Medical Sciences
state: Tianjin
city: Wenzhou
country: China
facility: The Affiliated Hospital of Wenzhou Medical College
state: Zhejiang
city: Hangzhou
country: China
facility: Zhejiang Shaoyifu Hospital
state: Zhenjiang
Study officials:
affiliation: Beijing Institute of Respiratory Medicine,Beijing Chao-Yang Hospital,Capital Medical University
name: Chen WANG, Prof
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Zhu L, Yang Y, Wu Y, Zhai Z, Wang C. Value of right ventricular dysfunction for prognosis in pulmonary embolism. Int J Cardiol. 2008 Jun 23;127(1):40-5. doi: 10.1016/j.ijcard.2007.06.093. Epub 2007 Aug 22.
citation: Zhu L, Wang C, Yang Y, Wu Y, Zhai Z, Dai H, Pang B, Tong Z. Value of transthoracic echocardiography in therapy regimens evaluation in pulmonary embolism. J Thromb Thrombolysis. 2008 Dec;26(3):251-6. doi: 10.1007/s11239-007-0087-8. Epub 2007 Aug 21.
citation: Zhu L, Yang YH, Wu YF, Zhai ZG, Wang C; National Project of the Diagnosis and Treatment Strategies for Pulmonary Thromboembolism investigators. Value of transthoracic echocardiography combined with cardiac troponin I in risk stratification in acute pulmonary thromboembolism. Chin Med J (Engl). 2007 Jan 5;120(1):17-21.
citation: Zhai ZG, Wang C, Yang YH, Pang BS, Xiao B, Liu YM, Mao YL, Weng XZ. [Relationship between polymorphisms of plasminogen activator inhibitor-1 promoter gene and pulmonary thromboembolism in Chinese Han population]. Zhonghua Yi Xue Za Zhi. 2006 May 23;86(19):1313-7. Chinese.
citation: Wang C, Cheng XS, Zhong NS. [Promoting the clinical and research work on pulmonary thromboembolism in China]. Zhonghua Jie He He Hu Xi Za Zhi. 2004 Nov;27(11):721-2. No abstract available. Chinese.
citation: Wang C, Zhai Z, Yang Y, Wu Q, Cheng Z, Liang L, Dai H, Huang K, Lu W, Zhang Z, Cheng X, Shen YH; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254-62. doi: 10.1378/chest.09-0765. Epub 2009 Sep 9.