Non-immunogenic Recombinant Staphylokinase vs Placebo in Patients With Intermediate High-risk Pulmonary Embolism

Pulmonary Embolism Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06362746
• Other study ID #: FORPE-2
• Status: Recruiting
• Phase: Phase 3
• Start date: May 23, 2024
• Est. completion date: December 1, 2028

Study information

• Verified date: June 2024
• Source: Supergene, LLC
• Contact: Sergey S. Markin, MD, PhD
• Phone: (906) 796-89-06
• Email: ssmarkin2153[@]mail.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Description:

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 (NCT04688320) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 486
• Est. completion date: December 1, 2028
• Est. primary completion date: June 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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 echocardiography.

• Increased risk of early death or hemodynamic collapse, defined by one of the following criteria:

1. systolic blood pressure less than 110 mm Hg, but not less than 90 mm Hg for more than 15 minutes;

2. respiratory rate more than 20 per minute or SpO2 less than 90% without oxygen support;

3. 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.

Exclusion Criteria:

• 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 mon-immunogenic recombinant staphylokinase.

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism

Intervention

Drug:
• Non-immunogenic recombinant staphylokinase
15 mg of drug reconstituted in 15 ml of 0.9% solution of NaCl given as single i.v. bolus over 10-15 seconds
• 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

Locations

Country	Name	City	State
Russian Federation	Belgorod Regional Clinical Hospital of St. Joseph	Belgorod
Russian Federation	Kuzbass Cardiology center	Kemerovo
Russian Federation	City Clinical Hospital ?1	Kirov
Russian Federation	Regional Clinical Hospital ?2	Krasnodar
Russian Federation	S.P. Botkin City Clinical Hospital	Moscow
Russian Federation	S.S. Yudin City Clinical Hospital	Moscow
Russian Federation	V.V. Vinogradov City Clinical Hospital	Moscow
Russian Federation	G.A. Zakharyin Clinical hospital ?6	Penza
Russian Federation	N.N. Burdenko Penza Regional Clinical hospital	Penza
Russian Federation	City Clinical Hospital ?4	Perm
Russian Federation	I.P. Pavlov Ryazan State Medical University	Ryazan'	Ryazan
Russian Federation	V.P. Polyakov Samara Regional Clinical Cardiology Dispensary	Samara
Russian Federation	V.F. Dolgopolov Vyselki Central District Hospital	Vyselki	Krasnodar Region

Sponsors (1)

Lead Sponsor	Collaborator
Supergene, LLC

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of death from any cause or hemodynamic collapse or recurrent PE	The efficacy is evaluated in terms of the number of death from any cause or hemodynamic collapse or recurrent PE	within 30 days
Secondary	Right/left ventricular (RV/LV) end-diastolic diameter ratio	The efficacy is evaluated in terms of the RV/LV end-diastolic diameter ratio according to echocardiography	within 24 hours
Secondary	RV/LV end-diastolic diameter ratio	The efficacy is evaluated in terms of the RV/LV end-diastolic diameter ratio according to computed tomography pulmonary angiography (CTPA)	within 24 hours
Secondary	RV/LV end-diastolic diameter ratio	The efficacy is evaluated in terms of the RV/LV end-diastolic diameter ratio according to echocardiography	within 30 days
Secondary	Right ventricular (RV) end-diastolic volume	The efficacy is evaluated in terms of the RV end-diastolic volume according to CTPA	within 24 hours
Secondary	Qanadli index	The efficacy is evaluated in terms of Qanadli index according to CTPA in points from 0 to 40, where 0 points - absence of thrombotic masses in the pulmonary artery, 40 points - complete occlusion of the pulmonary artery	within 24 hours
Secondary	Systolic pulmonary artery pressure	The efficacy is evaluated in terms of the systolic pulmonary artery pressure according to echocardiography	within 24 hours
Secondary	In hospital death from all causes (assessed up to day 7)	The efficacy is evaluated in terms of the in hospital death from all causes (assessed up to day 7)	In hospital period (assessed up to day 7)
Secondary	Death from all causes	The efficacy is evaluated in terms of the death from all causes	within 30 days
Secondary	Safety endpoint - hemorrhagic stroke	The efficacy is evaluated in terms of the hemorrhagic stroke	within 30 days
Secondary	Safety endpoint - BARC type 3 and 5 bleeding	The efficacy is evaluated in terms of the Bleeding Academic Research Consortium definitions, where type 3a is an overt bleeding with hemoglobin drop of 3 to 5 g/dL and any transfusion with overt bleeding; type 3b is a bleeding requiring surgical intervention or intravenous vasoactive agents; type 3c is an intracranial hemorrhage; type 5 is fatal bleeding.	within 30 days
Secondary	Safety endpoint - number and severity of adverse events (AEs) and serious AEs in organs and systems	The efficacy is evaluated in terms of the number and severity of AEs and serious AEs in organs and systems	within 30 days