Thrombolysis With Recombinant Non-immunogenic Staphylokinase vs Surgery in Patients With Acute Limb Ischemia FORAT Trial (FORAT)

Multicenter, Open-label, Randomized Clinical Trial of Efficacy and Safety of the Thrombolysis With Recombinant Non-immunogenic Staphylokinase (Fortelyzin®) in Patients With ALI vs Surgery

Objective: to evaluate the efficacy and safety of intra-arterial intrathrombus administration of the recombinant non-immunogenic staphylokinase (Fortelyzin®) in patients with acute limb ischemia (ALI) vs surgery.

Study Overview

• Status: Recruiting
• Conditions: Acute Limb Ischemia
• Intervention / Treatment: Drug: Recombinant non-immunogenic staphylokinase (Fortelyzin®); Procedure: surgical methods of treatment

Detailed Description

Fortelyzin® (the active substance Forteplase) is a recombinant non-immunogenic staphylokinase with high fibrinselective thrombolytic activity. In a multicentre, randomised clinical trial in patients with ST-segment elevation myocardial infarction (FRIDOM), non-immunogenic staphylokinase was administered as a single intravenous bolus of 15 mg in all patients, regardless of bodyweight, and showed similar high reperfusion patency and fewer minor bleeding events compared with tenecteplase, as well as the absence of neutralising IgGs. Results of the multicentre, randomised clinical trial in patients with an acute ischaemic stroke (FRIDA) suggested that the non-immunogenic staphylokinase administrated as a single intravenous bolus of 10 mg in all patients within the 4-5 h after the onset of symptoms is non-inferior to alteplase. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ between treatment groups.

Mortality in the ALI continues to be high. According to the Guidelines on the management of patients with ALI, intravenous systemic thrombolysis is ineffective in patients with this condition. In contrast, catheter-directed thrombolysis based on the principle that activation of fibrin-bound plasminogen to the active enzyme plasmin is the most effective approach of lysing pathologic thrombi in the lower extremities of I-II b degree of ALI (Evidence level I-A).

So the main objective of this study is to evaluate the efficacy and safety of intra-arterial intrathrombus administration of the recombinant non-immunogenic staphylokinase (Fortelyzin®) in patients with ALI vs surgery.

• Study Type: Interventional
• Enrollment (Anticipated): 170
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sergey S. Markin, MD, PhD; Phone Number: +7 (906) 796-89-06; Email: amsemenof@gmail.com

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115446
    • Recruiting
    • S.S. Yudin City Clinical Hospital
    • Contact: Bogdan B. Orlov, PhD
    • Principal Investigator: Bogdan B. Orlov, PhD
  • Moscow, Russian Federation, 123182
    • Not yet recruiting
    • Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies of the Federal Medical and Biological Agency
    • Contact: Troitskiy V. Alexander, MD, PhD; Phone Number: +7 (495) 395-61-97; Email: dr.troitskiy@gmail.com
    • Principal Investigator: Troitskiy V. Alexander, MD, PhD
  • Rostov-on-Don, Russian Federation, 344022
    • Not yet recruiting
    • Rostov State Medical University
    • Contact: Igor I. Prostov, PhD; Phone Number: +7 (863) 250-40-75; Email: igor-prostov@mail.ru
    • Principal Investigator: Igor I. Prostov, PhD
  • Tver, Russian Federation, 170036
    • Not yet recruiting
    • Tver Regional Clinical Hospital
    • Contact: Vladimir V. Bobkov, PhD; Phone Number: +7 4822775454; Email: vladibo73@gmail.com
    • Principal Investigator: Vladimir V. Bobkov, PhD
  • Volgograd, Russian Federation, 400138
    • Not yet recruiting
    • Volgograd City Clinical Hospital of Emergency #25
    • Contact: Eduard A. Ponomarev, MD, PhD; Phone Number: +7 8442585426; Email: ponomarev67@mail.ru
    • Principal Investigator: Eduard A. Ponomarev, MD, PhD
  • Moscow Region
    • Sergiyev Posad, Moscow Region, Russian Federation, 141301
      • Recruiting
      • Sergiyev Posad Regional Clinical Hospital
      • Contact: Anton G. Koledinskyi, MD, PhD; Phone Number: +7 (49654) 2-22-84
      • Principal Investigator: Anton G. Koledinskyi, MD, PhD
  • Republic Of Tatarstan
    • Kazan, Republic Of Tatarstan, Russian Federation, 420012
      • Recruiting
      • Kazan State Medical University
      • Contact: Ivan I. Klushkin, MD, PhD; Phone Number: +7 (843) 223-04-13; Email: hirurgivan@mail.ru
      • Principal Investigator: Ivan I. Klushkin, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women aged 18 and older;
• Diagnosis of I-II b degree of ALI;

• 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:

• Extensive bleeding at present;
• Intracranial (including subarachnoid) hemorrhage at present;
• Recent gastrointestinal bleeding (within 10 days);
• Major surgery or major trauma within the previous 3 months, recent traumatic brain injury;
• Systolic blood pressure above 180 mm Hg or diastolic blood pressure above 110 mm Hg or the need for intravenous drugs to lower blood pressure to these limits;
• Pregnancy, lactation;
• Known hypersensitivity to Fortelyzin®;
• Platelet count less than 100,000/µL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Recombinant non-immunogenic staphylokinase; lyophilisate for preparation a solution, 5 mg (745,000 IU) in 20 ml over 1 minute through a perforated multihole catheter intrathrombally. 30 minutes after this injection, infusion of recombinant non-immunogenic staphylokinase will be continued at a dose of 1 mg/hour, maximum 10 mg (50 ml) for 10 hours through a perforated multihole catheter intrathrombally.	Drug: Recombinant non-immunogenic staphylokinase (Fortelyzin®); lyophilisate for preparation a solution; Other Names: Fortelyzin®
Experimental: Surgical methods of treatment; endovascular intervention, open surgery and/or bypass surgery in accordance with the current National Guidelines	Procedure: surgical methods of treatment; Endovascular intervention, open surgery and/or bypass surgery in accordance with the current National Guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients without amputations	Outcome Measure is evaluated in terms of the number of patients without amputations	30 days post randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety endpoint - Death from all causes	The safety is evaluated in terms of the number of deaths from all causes	30 days post randomization
Safety endpoint - hemorrhagic stroke	The safety is evaluated in terms of the number of hemorrhagic stroke	30 days post randomization
Safety endpoint - BARC type 3 and 5 bleeding	The safety is evaluated in terms of the number of BARC type 3 and 5 bleeding	30 days post randomization
Safety endpoint - Number and severity of serious adverse events (SAEs) and AEs in organs and systems	The safety is evaluated in terms of the number and severity of SAEs and AEs in organs and systems	30 days post randomization

Collaborators and Investigators

• Sponsor: Supergene, LLC
• Investigators: Principal Investigator: Igor I. Zatevakhin, MD, PhD, N.I. Pirogov Russian Medical University, President of the Russian Society of Surgeons; Study Director: Sergey S. Markin, MD, PhD, Supergene, LLC

Publications and helpful links

General Publications

• Gusev EI, Martynov MY, Nikonov AA, Shamalov NA, Semenov MP, Gerasimets EA, Yarovaya EB, Semenov AM, Archakov AI, Markin SS; FRIDA Study Group. Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4.5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial. Lancet Neurol. 2021 Sep;20(9):721-728. doi: 10.1016/S1474-4422(21)00210-6.

Study record dates

Study Major Dates

• Study Start (Actual): December 26, 2022
• Primary Completion (Anticipated): May 1, 2025
• Study Completion (Anticipated): July 1, 2025

Study Registration Dates

• First Submitted: April 28, 2022
• First Submitted That Met QC Criteria: May 12, 2022
• First Posted (Actual): May 13, 2022

Study Record Updates

• Last Update Posted (Actual): April 19, 2023
• Last Update Submitted That Met QC Criteria: April 18, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: thrombolysis; thrombosis; acute limb ischemia
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: FORAT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No