Study on Safety and Clinical Efficacy of AZVUDINE in COVID-19 Patients (SARS-CoV-2 Infected)

Evaluation of Safety and Clinical Efficacy of AZVUDINE in COVID-19 Patients (SARS-CoV-2 Infected): Phase III, Randomized, Double-blind, PLACEBO Controlled Trial

Estimated number of participants: 342 participants with COVID-19 Design: Phase III, single-center, randomized, double-blind, parallel, placebo-controlled clinical study.

In December 2021, there was a drop in the number of hospitalizations and the cases of COPD, tuberculosis and HIV associated with COVID-19, which are outside the inclusion criteria of this study. After the initial data of the study, there was a discussion with Anvisa and the size of the sample calculation was revised by amendment 4 (180 participants), and the methodology of statistical analysis for a new sample calculation was "a formula for sample calculation for superiority studies using proportions, according to the book do Chow et al (Chow, S.-C., Shao, J., Wang, H., &Lokhnygina, Y. Eds. 2017. Sample Size Calculations in Clinical Research: Third Edition, Chapman and Hall/CRC). Thus, Anvisa concluded that the adjustments are in accordance with the agency's guidelines, approving E4, which was later also approved by the Ethics Committee.

Hypothesis:

AZVUDINE has therapeutic potential and safety profile for the treatment of patients infected with SARS-CoV-2.

Goals:

Primary objective • To assess the efficacy and safety of AZVUDINE (FNC) in relation to placebo, in patients infected with SARS-COV-2 in moderate to severe stage;

Secondary objective

• To evaluate the clinical outcome of the AZVUDINE group (FNC) compared to the placebo group in patients infected by SARS-COV-2 in moderate to severe stage;

Pharmaceutical form of the experimental medicine:

AZVUDINE 1 mg tablets

Comparators:

AZVUDINE placebo

Statistical planning:

The analyzes will be performed by FAS, PPS and SS and should be stratified by the severity of the disease (moderate, severe) and age (<60 years, ≥ 60 years), to assess the following parameters:

• Progression of the disease (moderate to severe, severe type);
• Negative viral load conversion rate;
• Time of negative conversion of viral load;
• Temperature recovery time;
• Time necessary to improve diarrhea, myalgia, fatigue, and other symptoms;
• Time to improve the pulmonary image;
• Frequency of supplemental oxygenation or non-invasive ventilation;
• Frequency of AEs;
• Mortality rate.

All statistical tests will be bilateral tests. If the P value is ≤0.05, it is considered that there is statistical significance between the difference in the tests.

Inclusion Criteria:

1. Individuals aged 18 or over, regardless of gender;
2. Patients hospitalized in moderate to severe stages in line with the Ministry of Health classification;
3. Positive diagnosis for SARS-CoV-2 by molecular amplification of the virus in RT-PCR diagnosed from a respiratory sample (nasopharynx, oropharyngeal, lower respiratory tract [eg, sputum]) collected <96 hours before randomization;
4. Time of onset of symptoms and inclusion ≤ 14 days;
5. Internation within 48 hours after inclusion in the study;
6. Follow-up availability during the study period;
7. Voluntary membership to participate in the study and signing the Informed Consent Form.

Exclusion Criteria:

1. Patients known or suspected of being sensitive to AZVUDINE or excipients (inactive ingredients: microcrystalline cellulose, hydrated lactose, polyvinylpyrrolidone K30, croscarmellose sodium, magnesium stearate);
2. Patients diagnosed with pneumonia caused by other pathogens;
3. Patients with liver disease (total bilirubin ≥2 times above the normal limit, ALT / TGP and AST / TGO ≥5 times above the normal limit)
4. Patients with renal failure (glomerular filtration rate ≤60mL / min / 1.73 m2) or are receiving continuous renal replacement therapy, hemodialysis or peritoneal dialysis;
5. Individuals with malabsorption syndrome, or other conditions that affect gastrointestinal absorption, and circumstances in which patients need intravenous nutrition, or cannot take drugs orally or nasogastrically;
6. Pregnant or lactating women, or women with the potential to become pregnant during the study period and within 6 months after the end of administration;
7. Patients already included in other clinical trials;
8. Patient under treatment for HIV;
9. Patients being treated with other antivirals (eg lopinavir / ritonavir, remdesivir, umifenovir / arbidol, favipiravir, interferon-α)
10. Patients undergoing treatment with monoclonal antibodies (eg tocilizumab and sarilumab / kevzara);
11. Patients who are on a clinical treatment plan that includes the concomitant administration of any other experimental treatment or off-label use of drugs already on the market (eg hydroxychloroquine sulfate;
12. Patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at the time of randomization;
13. Any clinically significant medical condition or medical history that, in the investigator's opinion, might discourage participation in the study.