Inhaled Recombinant Non-immunogenic Staphylokinase vs Placebo in Patients With COVID-19 - FORRIF Trial (FORRIF)

Objective: to evaluate the tolerability, safety and efficacy of inhaled usage of the Recombinant Non-immunogenic Staphylokinase (Fortelyzin®) vs placebo in patients with COVID-19.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Recombinant nonimmunogenic staphylokinase; Drug: Placebo

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 (Gusev EI, Martynov MYu, Nikonov AA et al. 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; 20(9): 721-728).

Complex coagulation and hematologic abnormalities, including significantly elevated D-dimer and fibrin/fibrinogen values are the distinct features identified in severe SARS-CoV-2. In the list of antithrombotic therapy drugs in conjunction with anticoagulant and antiplatelet therapy in patients with COVID-19, published by Liverpool Drug Interactions Group, fibrinolytic therapy is also included.

So the main objectives of this study are to assess the tolerability, safety and efficacy of inhaled usage of fibrinolytic agent the recombinant non-immunogenic staphylokinase (Fortelyzin®) in patients with COVID-19.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 123182
    • City Clinical Hospital No.52
  • Moscow, Russian Federation, 129090
    • N.V. Sklifosovsky Research Institute of Emergency Medicine

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 over
• Clinical status according to the WHO scale - 6, 7, 8 and 9 points.
• Verified respiratory infection COVID-19 by real-time PCR (quantitative)

• 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:

• Clinical status according to the WHO scale - 1, 2, 3, 4 and 5 points.

• Increased risk of bleeding:

  • extensive bleeding at the present time;
  • intracranial (including subarachnoid) hemorrhage at the present time.
• Lactation, pregnancy
• Known hypersensitivity to Fortelyzin®.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo control; Placebo	Drug: Placebo; 6 ml of 0.9% solution of NaCl for inhalation; Other Names: Saline solution
Experimental: Experimental; Recombinant nonimmunogenic staphylokinase lyophilisate for preparation of a solution for inhaled administration, 5 mg (745,000 IU) complete with a solvent. 15 mg (2,235,000 IU) - 3 vials, regardless of body weight.	Drug: Recombinant nonimmunogenic staphylokinase; 15 mg of drug reconstituted in 6 ml of 0.9% solution of NaCl for inhalation Other Name: Fortelyzin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients discharged from the hospital with clinical status according to the WHO Ordinal Scale For Clinical Improvement - 3 points or less	The efficacy is evaluated in terms of the number of patients discharged from the hospital with clinical status according to the WHO Ordinal Scale For Clinical Improvement - 3 points or less	28 days post randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients discharged from the hospital with clinical status according to the WHO Ordinal Scale For Clinical Improvement - 3 points or less	The efficacy is evaluated in terms of the number of patients discharged from the hospital with clinical status according to the WHO Ordinal Scale For Clinical Improvement - 3 points or less	14 days post randomization
Hospital length of stay	The efficacy is evaluated in terms of the hospital length of stay	28 days post randomization
Number of ICU-free days	The efficacy is evaluated in terms of the number of ICU-free days	28 days post randomization
Number of ventilation-free days	The efficacy is evaluated in terms of the number of ventilation-free days	28 days post randomization
Number of oxygen support-free days	The efficacy is evaluated in terms of the number of oxygen support-free days	28 days post randomization
SpO2 level	The efficacy is evaluated in terms of the SpO2 level	7, 14 and 28 days post randomization

Collaborators and Investigators

• Sponsor: Supergene, LLC
• Collaborators: Russian Academy of Medical Sciences
• Investigators: Principal Investigator: Sergey S. Markin, MD, PhD, LLC "SuperGene"

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 27, 2021
• Primary Completion (Actual): February 1, 2023
• Study Completion (Actual): May 31, 2023

Study Registration Dates

• First Submitted: November 24, 2021
• First Submitted That Met QC Criteria: November 24, 2021
• First Posted (Actual): November 26, 2021

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 29, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: FORRIF

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