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

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)

Overview

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)

Detailed 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 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.

Interventions

• 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
• 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

Primary outcome measures

• Composite of death from any cause or hemodynamic collapse or recurrent PE [Time frame: within 30 days]

Secondary outcome measures (11)

• Right/left ventricular (RV/LV) end-diastolic diameter ratio [Time frame: within 24 hours]
• RV/LV end-diastolic diameter ratio [Time frame: within 24 hours]
• RV/LV end-diastolic diameter ratio [Time frame: within 30 days]
• Right ventricular (RV) end-diastolic volume [Time frame: within 24 hours]
• Qanadli index [Time frame: within 24 hours]
• Systolic pulmonary artery pressure [Time frame: within 24 hours]
• In hospital death from all causes (assessed up to day 7) [Time frame: In hospital period (assessed up to day 7)]
• Death from all causes [Time frame: within 30 days]
• Safety endpoint - hemorrhagic stroke [Time frame: within 30 days]
• Safety endpoint - BARC type 3 and 5 bleeding [Time frame: within 30 days]
• Safety endpoint - number and severity of adverse events (AEs) and serious AEs in organs and systems [Time frame: within 30 days]

Eligibility criteria

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 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.

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 the non-immunogenic recombinant staphylokinase.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Russia · 24 centers

• RZD Medicine hospital — Barnaul
• V.F. Dolgopolov Vyselki Central District Hospital — Vyselki
• Asinovskaya District Hospital — Asino
• Belgorod Regional Clinical Hospital of St. Joseph — Belgorod
• Kuzbass Cardiology center — Kemerovo
• Center of Neurology and Cardiology — Kirov
• Regional Clinical Hospital №2 — Krasnodar
• Lipetsk City Hospital No. 4 "Lipetsk-Med" — Lipetsk
• … and 16 more centers

Publications

• Kirienko AI, Leontyev SG, Tereschenko SN, Yavelov IS, Shakhnovich RM, Erlikh AD, Talibov OB, Yarovaya EB, Semenov AM, Semenov MP, Ivanov SV, Beregovykh VV, Archakov AI, Markin SS; FORPE study group. Non-immunogenic recombinant staphylokinase versus alteplase for patients with massive pulmonary embolism: a randomized open-label, multicenter, parallel-group, non-inferiority trial, FORPE. J Thromb Ha PMID 39454884
• Leontyev SG, Yarovaya EB, Kutsenko VA, Ivlev OE, Soplenkova AG, Semenov AM, Semenov MP, Ivanov SV, Romashova YA, Markin SS. The Safety of Non-immunogenic Recombinant Staphylokinase in Elderly Patients With Massive Pulmonary Embolism: A Randomized Clinical Trial FORPE. Health Sci Rep. 2025 May 19;8(5):e70826. doi: 10.1002/hsr2.70826. eCollection 2025 May. PMID 40391253

Identifiers

NCT: NCT06362746 · FORPE-2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗