Randomized open-label multicenter parallel-group study of efficacy and safety of TL-FVP-t vs. standard of care therapy in patients with mild to moderate coronavirus disease (SARS-CoV-2/COVID-19)

This was an open label, randomized, controlled, multicenter Phase 3 study of TL-FVP-t in outpatients and inpatients with mild to moderate COVID-19. After stratification by the severity of their disease (mild or moderate), age (18-44 or ≥ 45 years) and CT severity subjects were randomized at a rate of 2:1 to receive either TL-FVP-t + standard concomitant therapy or standard ethiptropic therapy (standard of care - SOC) including standard concomitant therapy. Standard ethiptropic therapy according to MoH of Russian Federation included umifenovir + intranasal recombinant interferon alpha, hydroxichloroquine, or chloroquine.

The dose regimen was the following: TL-FVP-t at a dose of 1800 mg BID on the Day 1 followed by 800 mg BID during the next 9 days. The study included the period of therapy (10 days) and follow-up period (18 days).

Inclusion Criteria:

1. Informed consent form signed.
2. Males and females aged 18-60 years;
3. Diagnosis of coronavirus disease caused by SARS-CoV-2 (COVID-19) in a mild or moderate form (without respiratory failure).
4. Duration of infection symptoms shall be no more than 6 days before randomization.
5. SARS-CoV-2 infection should be verified by PCR at the screening.
6. Ability to follow the protocol and fulfill all the clinical study procedures.
7. Ability and willingness of the subjects and their sexual partners with retained childbearing potential to use reliable contraception methods throughout the study and for 3 months after the treatment completion.
8. Willingness not to take alcohol throughout the study.

Exclusion Criteria:

1. Age < 18 and > 60 years.

2. Any etiotropic therapy of coronavirus SARS-CoV-2 (COVID-19) infection prior to the study.

3. Moderate infection with respiratory failure, severe or extremely severe SARS-CoV-2 (COVID-19) disease.

4. Respiratory failure (RR > 30/min, SpO2 ≤ 93 %) or the need for mechanical ventilation at the screening.

5. Decreased level of consciousness (disorientation of place, time and personality), agitation at the screening.

6. Unstable hemodynamics (systolic BP < 100 mm Hg or diastolic BP < 60 mm Hg) found at the screening.

7. Subtotal diffuse ground-glass induration of pulmonary tissue and pulmonary consolidation combined with reticular changes; involvement of ≥ 75 % of lung parenchyma; hydrothorax (CT findings corresponding to ≥ CT-4 according to Department of Health of Moscow guidelines).

8. Presence of comorbidities:

   1. moderate or severe chronic obstructive pulmonary disease or asthma;
   2. severe chronic cardiovascular disorders (arrhythmia or conduction disorders, implanted pacemaker device, myocardial infarction or unstable angina in the medical history, heart failure);
   3. immunocompromised subjects (HIV, cancer, autoimmune diseases, immunodepressant therapy);
   4. severe obesity (body mass index [BMI] ≥ 40);
   5. diabetes mellitus;
   6. chronic renal failure;
   7. chronic moderate or severe hepatic disorders.

9. Any of the following abnormal laboratory tests at the screening: AST or ALT level > 2.5 x upper normal level (UNL), platelet count < 50х109/L.

10. Any history findings which, in the investigator's opinion, may complicate the interpretation of the study results or generate an additional risk for the subject due to his/her participation in the study.

11. More than 2 CT diagnostic procedures within the last 6 months prior to randomization (except for chest CT no earlier than 4 days prior to enrollment).

12. The subject takes the products significantly inhibiting CYP28С, and administration those products cannot be interrupted for the study duration.

13. Malabsorption syndrome or another clinically relevant gastrointestinal disease which may affect the study product absorption (uncontrollable vomiting, diarrhea, ulcerative colitis, etc.).

14. Pregnancy or breast-feeding; women with probable pregnancy at the screening, those planning to conceive during the study.

15. Known (from the history) or suspected alcohol or psychotropic drug abuse; medicinal or illicit drug addiction.

16. Mental disorders including those in the medical history.

17. Condition or disease which, according to the investigator or medical monitor, will compromise the subject's safety or affect assessment of the study product safety.