Multicenter, Open Label, Randomized Comparative Trial of the Efficacy and Safety of a Single Bolus Recombinant Non-immunogenic Staphylokinase and Bolus-infusion of Alteplase in Patients With Massive Pulmonary Embolism (FORPE)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 310
- 试验地点
- 23
- 主要终点
- Death From All Causes
研究概览
简要总结
Objective: to evaluate the efficacy and safety of the Recombinant Non-immunogenic Staphylokinase with its single bolus administration in comparison with the bolus-infusion administration of the Alteplase in patients with massive pulmonary embolism
详细描述
The main goal of treating massive PE is to save the lives of patients by restoring pulmonary perfusion, preventing the development of chronic postembolic pulmonary hypertension and recurrent PE. According to data of clinical trials, with timely initiation of therapy for massive pulmonary embolism, mortality can be significantly reduced.
Recombinant protein which contains aminoacid sequence of staphylokinase - Fortelizin® (the active substance is Forteplase). It is single chain molecula, consists of 138 aminoacids, weight 15.5 kDa. When staphylokinase is added to human plasma containing a fibrin clot, it preferentially reacts with plasmin at the clot surface, forming a plasmin-staphylokinase complex. This complex activates plasminogen trapped in the thrombus. The plasmin-staphylokinase complex and plasmin bound to fibrin are protected from inhibition by alpha2-antiplasmin. Once liberated from the clot (or generated in plasma), however, they are rapidly inhibited by alpha2-antiplasmin. This selectivity of action confines the process of plasminogen activation to the thrombus, preventing excessive plasmin generation, alpha2-antiplasmin depletion, and fibrinogen degradation in plasma. In rabbits anti forteplase antibodies are not produced. It was achieved by replacement of amino acids in immunogenic epitop of molecule staphylokinase. Blood fibrinogen decrease after i.v. injection of Fortelyzin less 10% within first 24 hours. Angiographic data suggests that restoration of coronary blood flow appears in up to 80% of patients with STEMI after i.v. injection of Fortelyzin.
The main objectives of the study: to assess the efficacy, safety and possible adverse events of the drug Recombinant Non-immunogenic Staphylokinase with its single bolus administration in comparison with the bolus-infusion administration of the drug Alteplase® in patients with massive pulmonary embolism.
Study Design. Multicenter, open-label, randomized, comparative clinical study of non-inferiority study of efficacy and safety in parallel groups. At clinical centers, patients will be equally randomly distributed by the "envelope" method into two groups of 155 patients each (310 people in total, including 10% of those who may have dropped out)to receive Recombinant Non-immunogenic Staphylokinase or Alteplase®.
The drugs will be administered after the signed informed consent. Recombinant Non-immunogenic Staphylokinase will be administered intravenously at a dose of 15 mg as a single bolus for 10-15 seconds. Alteplase® will be administered in accordance with the instructions for use.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
All eligible patients will be randomized in two equal groups for administration recombinant nonimmunogenic staphylokinase (Fortelyzin) or alteplase (Actilize) by using "envelope method" of randomization.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women aged 18 and over
- •Verified diagnosis of massive PE (using MSCT with PA contrast)
- •Signs of overload / dysfunction of the right ventricle (at least one) in combination with persistent arterial hypotension or shock
- •Patient consent to use reliable contraceptive methods throughout the study and for 3 weeks after:
- •women who have a negative pregnancy test and use the following contraceptives: intrauterine devices, oral contraceptives, contraceptive patch, prolonged injectable contraceptives, double barrier method of contraception. Women who are not fertile can also take part in the study (documented conditions: hysterectomy, tubal ligation, infertility, menopause for more than 1 year);
- •men using barrier contraception. The study may also involve men who are not fertile (documented conditions: vasectomy, infertility)
- •Availability of signed and dated informed consent of the patient to participate in the study.
排除标准
- •• Increased risk of bleeding:
- •Extensive bleeding at present or within the previous 6 months, hemorrhagic diathesis;
- •Intracranial (including subarachnoid) hemorrhage at present or in history, suspected hemorrhagic stroke;
- •A history of hemorrhagic stroke or stroke of unknown etiology;
- •Ischemic stroke or transient ischemic attack within the last 6 months, except for the current acute ischemic stroke within 4.5 hours;
- •A history of diseases of the central nervous system (including neoplasms, aneurysms, surgery on the brain or spinal cord);
- •Major surgery or major trauma within the previous 3 months, recent traumatic brain injury;
- •Long-term or traumatic cardiopulmonary resuscitation (> 2 min), delivery within the previous 10 days, recent puncture of an uncompressible blood vessel (eg, subclavian or jugular vein);
- •Severe liver disease, including liver failure, cirrhosis, portal hypertension (including esophageal varices) and active hepatitis;
- •Confirmed gastric or duodenal ulcer within the last three months;
- •Neoplasm with an increased risk of bleeding;
- •Concurrent administration of oral anticoagulants, for example, warfarin with an INR> 1.3;
- •Arterial aneurysms, developmental defects of arteries / veins;
- •Severe uncontrolled arterial hypertension;
- •Acute pancreatitis;
- •Bacterial endocarditis, pericarditis;
- •suspicion of aortic dissecting aneurysm;
- •any other conditions, in the opinion of the doctor, associated with a high risk of bleeding.
- •Lactation, pregnancy
- •Known hypersensitivity to Alteplase, Fortelizin.
研究组 & 干预措施
Recombinant nonimmunogenic staphylokinase
lyophilisate for preparation of a solution for intravenous administration, 5 mg (745,000 IU) complete with a solvent. 15 mg (2,235,000 IU) - 3 vials, intravenously as a quick single bolus injection for 10-15 seconds, regardless of body weight.
干预措施: Recombinant nonimmunogenic staphylokinase (Drug)
Alteplase
Alteplase® is administered in accordance with the instructions for use for pulmonary embolism( 10 mg bolus and 90 mg as IV infusion over 2 hours, maximum 100 mg). In patients weighing less than 65 kg, the total dose should not exceed 1.5 mg / kg.
干预措施: Alteplase (Drug)
结局指标
主要结局
Death From All Causes
时间窗: within 7 days
The efficacy is evaluated in terms of the number of deaths from all causes
次要结局
- Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5)(baseline and day 1, 7, 14 after randomisation)
- Haemodynamic Collapse(within 7 days)
- Recurrent Pulmonary Embolism (PE)(within 7 days)
- Death From PE(within 30 days)
- Death From All Causes(within 30 days)
- Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days(within 30 days)
- Safety Endpoint - Haemorrhagic Stroke(within 7 days)
- Safety Endpoint - BARC Type 3+5 Bleeding(within 30 days)
- Safety Endpoint - Number and Severity of Serious Adverse Events (SAEs)(within 30 days)