Multicenter, Double-blind, Randomized, Placebo-controlled Trial of the Efficacy and Safety of a Single Bolus Administration of Non-immunogenic Recombinant Staphylokinase in Patients With Intermediate High-risk Pulmonary Embolism (FORPE-2)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 486
- 试验地点
- 24
- 主要终点
- Composite of death from any cause or hemodynamic collapse or recurrent PE
研究概览
简要总结
Objective: to evaluate the efficacy and safety of the non-immunogenic recombinant staphylokinase with its single bolus administration in comparison with placebo in normotensive patients with intermediate high-risk pulmonary embolism (PE)
详细描述
For patients with massive PE thrombolysis can be life-saving and may reduce a pulmonary obstruction, pulmonary hypertension, and right ventricle dysfunction. Efficacy of the thrombolytic therapy has been proven in patients with high-risk pulmonary embolism accompanied by shock or systemic hypotension. However, the question of whether thrombolytic therapy can improve the clinical outcome of hemodynamically stable patients, i.e. with PE of intermediate high-risk, still remains controversial.
In PEITHO trial tenecteplase, administered as a single bolus at a dose of 30-50 mg depending on body weight was compared with a placebo in patients with intermediate high-risk PE with right ventricular dysfunction. Efficacy of tenecteplase was combined with a significant (6.3%) risk of hemorrhagic stroke, which did not allow tenecteplase to be included in the list of recommended thrombolytics for PE treatment.
PEITHO-3 trial has now begun, in which patients with intermediate high-risk PE are given a reduced dose of alteplase (0.6 mg/kg infusion with the total dose not exceeding 50 mg) compared with placebo.
Staphylokinase is a thrombolytic agent with high biological activity. Amino acid substitutions - including Lys74Ala, Glu75Ala, and Arg77Ala - resulted in a more than 200-times reduction in titres of neutralising antistaphylokinase IgGs in patients with ST-elevation myocardial infarction. In FORPE trial non-immunogenic recombinant staphylokinase was non-inferior as compared with alteplase in patients with high-risk massive PE.
The main objectives of this study: to assess the efficacy, safety and possible adverse events of the non-immunogenic recombinant staphylokinase with its single bolus administration in normotensive patients with intermediate high-risk PE in comparison with placebo.
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
- Double (Participant, Investigator)
盲法说明
Neither patient nor investigator knows treatment assignment. All eligible patients will be randomized in two equal groups for administration of non-immunogenic recombinant staphylokinase or placebo.
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 intermediate high-risk PE using CTPA, no more than two weeks from the symptoms onset.
- •RV dysfunction, defined as a RV/LV ventricular end-diastolic diameter ratio more than 1.0 assessed by CTPA.
- •Increased risk of early death or hemodynamic collapse, defined by one of the following criteria:
- •systolic blood pressure less than 110 mm Hg, but not less than 90 mm Hg for more than 15 minutes;
- •respiratory rate more than 20 per minute or SpO2 less than 90% without oxygen support;
- •chronic heart failure with left ventricular ejection fraction less than 40%.
- •Serum troponin I level more than 14 pg/mL in patients under 75 years, and more than 45 pg/mL in patients aged 75 years or older.
- •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
- •High-risk PE with hemodynamic instability.
- •Increased risk of bleeding:
- •extensive bleeding at present or within the previous 6 months;
- •intracranial (including subarachnoid) hemorrhage at present or in history;
- •hemorrhagic stroke within the last 6 months;
- •a history of diseases of the central nervous system (including neoplasms, aneurysms);
- •intracranial or spinal surgical interventions within the last 2 months;
- •major surgery or major trauma within the previous 4 weeks;
- •recent puncture of an incompressible 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 3 months;
- •neoplasm with an increased risk of bleeding;
- •simultaneous administration of Dabigatran without prior administration of idarucizumab;
- •arterial aneurysms, developmental defects of arteries / veins;
- •acute pancreatitis;
- •bacterial endocarditis, pericarditis;
- •suspicion of aortic dissecting aneurysm;
- •any other conditions, in the opinion of the investigator, associated with a high risk of bleeding.
- •Lactation, pregnancy.
- •Known hypersensitivity to the non-immunogenic recombinant staphylokinase.
研究组 & 干预措施
Non-immunogenic recombinant 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: Non-immunogenic recombinant staphylokinase (Drug)
Placebo
15 mg of placebo reconstituted in 15 ml of 0.9% solution of NaCl given as single i.v. bolus over 10-15 seconds
干预措施: Placebo (Drug)
结局指标
主要结局
Composite of death from any cause or hemodynamic collapse or recurrent PE
时间窗: within 30 days
The efficacy is evaluated in terms of the number of death from any cause or hemodynamic collapse or recurrent PE
次要结局
- Right/left ventricular (RV/LV) end-diastolic diameter ratio(within 24 hours)
- RV/LV end-diastolic diameter ratio(within 30 days)
- Qanadli index(within 24 hours)
- Systolic pulmonary artery pressure(within 24 hours)
- In hospital death from all causes (assessed up to day 7)(In hospital period (assessed up to day 7))
- Death from all causes(within 30 days)
- Right ventricular (RV) end-diastolic volume(within 24 hours)
- Safety endpoint - hemorrhagic stroke(within 30 days)
- Safety endpoint - BARC type 3 and 5 bleeding(within 30 days)
- Safety endpoint - number and severity of adverse events (AEs) and serious AEs in organs and systems(within 30 days)