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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: AZVUDINE
* Drug: AZVUDINE placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals aged 18 or over, regardless of gender; Patients hospitalized in moderate to severe stages in line with the Ministry of Health classification; 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; Time of onset of symptoms and inclusion ≤ 14 days; Internation within 48 hours after inclusion in the study; Follow-up availability during the study period; Voluntary membership to participate in the study and signing the Informed Consent Form. Exclusion Criteria: Patients known or suspected of being sensitive to AZVUDINE or excipients (inactive ingredients: microcrystalline cellulose, hydrated lactose, polyvinylpyrrolidone K30, croscarmellose sodium, magnesium stearate); Patients diagnosed with pneumonia caused by other pathogens; Patients with liver disease (total bilirubin ≥2 times above the normal limit, ALT / TGP and AST / TGO ≥5 times above the normal limit) Patients with renal failure (glomerular filtration rate ≤60mL / min / 1.73 m2) or are receiving continuous renal replacement therapy, hemodialysis or peritoneal dialysis; 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; 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; Patients already included in other clinical trials; Patient under treatment for HIV; Patients being treated with other antivirals (eg lopinavir / ritonavir, remdesivir, umifenovir / arbidol, favipiravir, interferon-α) Patients undergoing treatment with monoclonal antibodies (eg tocilizumab and sarilumab / kevzara); 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; Patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at the time of randomization; Any clinically significant medical condition or medical history that, in the investigator's opinion, might discourage participation in the study.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm AZVUDINE<br>Experimental: AZVUDINE 1mg tablet, Interventions: AZVUDINE 1mg tablet, 5 tablets QD + standard treatment for up to 14 days | Drug: AZVUDINE<br>* 5 tablets QD + standard treatment for up to 14 days<br>* Other names: 1-(4-Azido-2-deoxy-2-fluoro-beta-D- arabino Ribo-furanosyl) cytosine, FNC;|
| Placebo Comparator: Arm Placebo<br>Control: AZVUDINE placebo, Interventions: AZVUDINE placebo, 5 tablets QD + standard treatment for up to 14 days | Drug: AZVUDINE placebo<br>* 5 tablets QD + standard treatment for up to 14 days<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of clinical improvement of AZVUDINE (FNC) in COVID-19 treatment | Rate of participants who reduced at least one level of the Clinical Progression Ordinal Scale category compared to the enrollment status (WHO, Jun/2020) | Day 1 to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical cure outcome rate | Proportion of participants with clinical cure outcome during the study (viral RNA not detected and clinical conditions for discharge) | Day 1 to Day 15 | 
| Recovery of body temperature | Time (days) for normalization of body temperature (below 37.6℃ axillary) | Day 1 to Day 28 | 
| Clinical improvement of diarrhea, myalgia fatigue and other symptoms | Time (days) for clinical improvement of diarrhea, myalgia, fatigue, and other symptoms | Day 1 to Day 28 | 
| Assessment of inflammatory biochemical markers (Reactive C Protein, erythrocyte sedimentation rate, and Procalcitonin) | Rate of change in biochemical markers of inflammatory function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. | Day 1 to Day 60 | 
| Assessment of immunological function biochemical markers (IL-6, IgG, IgM, IgA, and complement factor C3 and C4) | Rate of change in biochemical markers of immunological function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. | Day 1 to Day 60 | 
| Assessment of renal function biochemical markers (serum creatinine and calculated glomerular filtration rate) | Rate of change in biochemical markers of renal function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. | Day 1 to Day 60 | 
| Assessment of liver function biochemical markers (AST/TGO, ALT/TGP, ALP, GGT, BIL total, and direct BIL) | Rate of change in biochemical markers of hepatic function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. | Day 1 to Day 60 | 
| Evaluation of time to negative conversion of SARS-CoV-2 viral load by RT-PCR | Time (days) to negative conversion of the SARS-CoV-2 viral load between AZVUDINE (FNC) and placebo group | Day 1 to Day 28 | 
| Evaluation of the number of cycles for the detection of SARS-CoV-2 viral load by RT-PCR and application of the standard curve for calculating viral load | SARS-CoV-2 viral load determination by standard-curve method of quantification | Day 1 to Day 15 | 
| Analysis of the relationship between the calculated viral load and the clinical evolution of the participants in the experimental group (FNC) and the PLACEBO group | Rating the relationship between viral load calculated and clinical outcomes of participants | Day 1 to Day 28 | 
| Time for improvement of pulmonary condition by imaging exams during treatment | Time (days) for pulmonary image improvement of: (1) Ground glass opacity pattern, (2) mosaic paving, (3) alveolar consolidation, (4) reticular pattern / septal thickening, (5) opaque with inverted halo, (6) pleural / pericardial effusion, (7) fibrosis and / or (8) lymphadenomegaly. | Day 1 to Day 28 | 
| Evaluation of pulmonary condition by imaging exams during treatment | Proportion of pulmonary image improvement of: (1) Ground glass opacity pattern, (2) mosaic paving, (3) alveolar consolidation, (4) reticular pattern / septal thickening, (5) opaque with inverted halo, (6) pleural / pericardial effusion, (7) fibrosis and / or (8) lymphadenomegaly. | Day 1 to Day 28 | 
| Time for clinical improvement of respiratory signs and symptoms | Time (days) for improvement in respiratory signs and symptoms during treatment (pulmonary rales, cough, sputum, or sore throat) | Day 1 to Day 28 | 
| Assessment of clinical improvement of respiratory signs and symptoms | Rate of improvement in respiratory signs and symptoms during treatment (pulmonary rales, cough, sputum, or sore throat) | Day 1 to Day 28 | 
| Time for normalization of O2 saturation | Time (days) to normalize O2 saturation (above 95%) between AZVUDINE (FNC) and placebo group | Day 1 to Day 28 | 
| Respiratory rate evaluation | Time (days) for respiratory rate normalization ≤24 rpm in room air | Day 1 to Day 28 | 
| Frequency of supplemental oxygenation or non-invasive ventilation | Frequency of supplemental oxygenation or non-invasive ventilation | Day 1 to Day 28 | 
| Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO | Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO | Day 1 to Day 28 | 
| Proportion of moderate cases that progressed to severe cases | Proportion of moderate cases that progressed to severe cases requiring care in an intensive care unit | Day 1 to Day 28 | 
| Assessment of hospitalization time | Length (days) of hospital stay | Day 1 to Day 28 | 
| Evaluation of drug interaction events frequency | Frequency of drug interaction events | Day 1 to Day 28 | 
| Evaluation of drug interaction events intensity | Intensity of drug interaction events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) | Day 1 to Day 28 | 
| Assessment of adverse events frequency | Frequency of adverse events | Day 1 to Day 28 | 
| Assessment of adverse events intensity | Intensity of adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) | Day 1 to Day 28 | 
| Assessment of unexpected adverse events frequency | Frequency of unexpected adverse events | Day 1 to Day 28 | 
| Assessment of unexpected adverse events intensity | Intensity of unexpected adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) | Day 1 to Day 28 | 
| Assessment of serious adverse events frequency | Frequency of serious adverse events | Day 1 to Day 28 | 
| Assessment of serious adverse events intensity | Intensity of serious adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) | Day 1 to Day 28 | 
| Overall mortality rate | Mortality rate during the study | Day 1 to Day 28 | 
| Evaluation of the tolerability of azvudine in the 5 mg regimen orally QD up to 14 days | Treatment dropout rate due to AZVUDINE/Placebo intolerance. | Day 1 to Day 28 | 
| Assessment of adherence of azvudine in the 5 mg regimen orally QD up to 14 days | Medication possession rate, to measure the proportion of administered dose episodes observed in relation to the expected number of doses, until treatment interruption. | Day 1 to Day 28 | 
| Time of use of azvudine in the 5 mg regimen orally QD up to 14 days | Total time (days) of use of AZVUDINE / Placebo intolerance. | Day 1 to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZVUDINE, SARS-CoV-2, COVID-19, FNC