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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Inhaled Recombinant Non-immunogenic Staphylokinase vs Placebo in Patients With COVID-19 - FORRIF Trial

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Recombinant nonimmunogenic staphylokinase
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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®.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: At clinical centers, patients will be randomly distributed by the envelope method into two groups to receive Fortelyzin® or placebo. The drugs will be administered after the signed informed consent. Fortelyzin® will be administered by inhalation of a dose of 15 mg.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>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<br>* 15 mg of drug reconstituted in 6 ml of 0.9% solution of NaCl for inhalation Other Name: Fortelyzin®<br>|
| Placebo Comparator: Placebo control<br>Placebo | Drug: Placebo<br>* 6 ml of 0.9% solution of NaCl for inhalation<br>* Other names: Saline solution;|

What is the study measuring?
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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 |