Clinical trial NCT06362746: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Pulmonary Embolism
Keywords: Intermediate high-risk pulmonary embolism
Fibrinolysis
Recombinant Non-immunogenic Staphylokinase
Lead sponsor: Supergene, LLC
Sponsor class: INDUSTRY
First posted: 2024-04-12
Enrollment: 486
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: At clinical sites patients will be equally randomized into two groups to receive non-immunogenic recombinant staphylokinase or placebo.

Non-immunogenic recombinant staphylokinase or placebo will be administered intravenously at a dose of 15 mg as a single bolus for 10-15 seconds. All patients will be examined for 30 days.
Primary purpose: TREATMENT

Brief 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)

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.

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:

  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.

Primary outcomes:
measure: Composite of death from any cause or hemodynamic collapse or recurrent PE
timeFrame: within 30 days
Secondary outcomes:
measure: Right/left ventricular (RV/LV) end-diastolic diameter ratio
timeFrame: within 24 hours
measure: RV/LV end-diastolic diameter ratio
timeFrame: within 24 hours
measure: RV/LV end-diastolic diameter ratio
timeFrame: within 30 days
measure: Right ventricular (RV) end-diastolic volume
timeFrame: within 24 hours
measure: Qanadli index
timeFrame: within 24 hours
measure: Systolic pulmonary artery pressure
timeFrame: within 24 hours
measure: In hospital death from all causes (assessed up to day 7)
timeFrame: In hospital period (assessed up to day 7)
measure: Death from all causes
timeFrame: within 30 days
measure: Safety endpoint - hemorrhagic stroke
timeFrame: within 30 days
measure: Safety endpoint - BARC type 3 and 5 bleeding
timeFrame: within 30 days
measure: Safety endpoint - number and severity of adverse events (AEs) and serious AEs in organs and systems
timeFrame: within 30 days
Other outcomes:
Locations:
city: Vyselki
country: Russian Federation
facility: V.F. Dolgopolov Vyselki Central District Hospital
state: Krasnodar Region
city: Asino
country: Russian Federation
facility: Asinovskaya District Hospital
state: Tomsk Region
city: Belgorod
country: Russian Federation
facility: Belgorod Regional Clinical Hospital of St. Joseph
city: Kemerovo
country: Russian Federation
facility: Kuzbass Cardiology center
city: Kirov
country: Russian Federation
facility: Center of Neurology and Cardiology
city: Krasnodar
country: Russian Federation
facility: Regional Clinical Hospital №2
city: Moscow
country: Russian Federation
facility: F.I. Inozemtsev City Clinical Hospital
city: Moscow
country: Russian Federation
facility: Moscow Multidisciplinary Clinical Center "Kommunarka"
city: Moscow
country: Russian Federation
facility: S.S. Yudin City Clinical Hospital
city: Moscow
country: Russian Federation
facility: City Clinical Hospital №52
city: Moscow
country: Russian Federation
facility: S.P. Botkin City Clinical Hospital
city: Nizhny Novgorod
country: Russian Federation
facility: N.A. Semashko Nizhny Novgorod Regional Clinical Hospital
city: Penza
country: Russian Federation
facility: N.N. Burdenko Penza Regional Clinical hospital
city: Penza
country: Russian Federation
facility: G.A. Zakharyin Clinical hospital №6
city: Perm
country: Russian Federation
facility: City Clinical Hospital №4
city: Samara
country: Russian Federation
facility: V.P. Polyakov Samara Regional Clinical Cardiology Dispensary
city: Tver
country: Russian Federation
facility: Tver Regional Clinical Hospital
city: Volgograd
country: Russian Federation
facility: City Clinical Hospital of Emergency medicine №25
Study officials:
affiliation: National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
name: Sergey N. Tereschenko, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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 Haemost. 2025 Feb;23(2):657-667. doi: 10.1016/j.jtha.2024.09.035. Epub 2024 Oct 23.