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

HRH Pharmaceuticals Limited180 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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)

Time frame: Day 1 to Day 15

Secondary Outcomes

Clinical cure outcome rate

Proportion of participants with clinical cure outcome during the study (viral RNA not detected and clinical conditions for discharge)

Time frame: Day 1 to Day 15

Recovery of body temperature

Time (days) for normalization of body temperature (below 37.6℃ axillary)

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: Day 1 to Day 28

Respiratory rate evaluation

Time (days) for respiratory rate normalization ≤24 rpm in room air

Time frame: Day 1 to Day 28

Frequency of supplemental oxygenation or non-invasive ventilation

Time frame: Day 1 to Day 28

Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO

Time frame: 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

Time frame: Day 1 to Day 28

Assessment of hospitalization time

Length (days) of hospital stay

Time frame: Day 1 to Day 28

Evaluation of drug interaction events frequency

Frequency of drug interaction events

Time frame: Day 1 to Day 28

Evaluation of drug interaction events intensity

Intensity of drug interaction events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)

Time frame: Day 1 to Day 28

Assessment of adverse events frequency

Frequency of adverse events

Time frame: Day 1 to Day 28

Assessment of adverse events intensity

Intensity of adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)

Time frame: Day 1 to Day 28

Assessment of unexpected adverse events frequency

Frequency of unexpected adverse events

Time frame: Day 1 to Day 28

Assessment of unexpected adverse events intensity

Intensity of unexpected adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)

Time frame: Day 1 to Day 28

Assessment of serious adverse events frequency

Frequency of serious adverse events

Time frame: Day 1 to Day 28

Assessment of serious adverse events intensity

Intensity of serious adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)

Time frame: Day 1 to Day 28

Overall mortality rate

Mortality rate during the study

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 1 to Day 28

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes