COVID-19
Conditions
Keywords
AZVUDINE, SARS-CoV-2, COVID-19, FNC
Brief summary
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
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.
Interventions
DRUGAZVUDINE
5 tablets QD + standard treatment for up to 14 days
DRUGAZVUDINE placebo
5 tablets QD + standard treatment for up to 14 days
Sponsors
GALZU INSTITUTE OF RESEARCH, TEACHING, SCIENCE AND APPLIED TECHNOLOGY, Brazil
UNIVERSIDADE ESTADUAL DO NORTE FLUMINENSE (UENF), Brazil
HRH Pharmaceuticals Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of clinical improvement of AZVUDINE (FNC) in COVID-19 treatment | Day 1 to Day 15 | Rate of participants who reduced at least one level of the Clinical Progression Ordinal Scale category compared to the enrollment status (WHO, Jun/2020) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recovery of body temperature | Day 1 to Day 28 | Time (days) for normalization of body temperature (below 37.6℃ axillary) |
| Clinical improvement of diarrhea, myalgia fatigue and other symptoms | Day 1 to Day 28 | Time (days) for clinical improvement of diarrhea, myalgia, fatigue, and other symptoms |
| Assessment of inflammatory biochemical markers (Reactive C Protein, erythrocyte sedimentation rate, and Procalcitonin) | Day 1 to Day 60 | Rate of change in biochemical markers of inflammatory function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. |
| Assessment of immunological function biochemical markers (IL-6, IgG, IgM, IgA, and complement factor C3 and C4) | Day 1 to Day 60 | Rate of change in biochemical markers of immunological function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. |
| Assessment of renal function biochemical markers (serum creatinine and calculated glomerular filtration rate) | Day 1 to Day 60 | Rate of change in biochemical markers of renal function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. |
| Assessment of liver function biochemical markers (AST/TGO, ALT/TGP, ALP, GGT, BIL total, and direct BIL) | Day 1 to Day 60 | Rate of change in biochemical markers of hepatic function in relation to the physiological reference intervals between the AZVUDINA and PLACEBO groups. |
| Evaluation of time to negative conversion of SARS-CoV-2 viral load by RT-PCR | Day 1 to Day 28 | Time (days) to negative conversion of the SARS-CoV-2 viral load between AZVUDINE (FNC) and placebo group |
| 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 | Day 1 to Day 15 | SARS-CoV-2 viral load determination by standard-curve method of quantification |
| 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 | Day 1 to Day 28 | Rating the relationship between viral load calculated and clinical outcomes of participants |
| Time for improvement of pulmonary condition by imaging exams during treatment | Day 1 to Day 28 | 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. |
| Evaluation of pulmonary condition by imaging exams during treatment | Day 1 to Day 28 | 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 for clinical improvement of respiratory signs and symptoms | Day 1 to Day 28 | Time (days) for improvement in respiratory signs and symptoms during treatment (pulmonary rales, cough, sputum, or sore throat) |
| Assessment of clinical improvement of respiratory signs and symptoms | Day 1 to Day 28 | Rate of improvement in respiratory signs and symptoms during treatment (pulmonary rales, cough, sputum, or sore throat) |
| Time for normalization of O2 saturation | Day 1 to Day 28 | Time (days) to normalize O2 saturation (above 95%) between AZVUDINE (FNC) and placebo group |
| Respiratory rate evaluation | Day 1 to Day 28 | Time (days) for respiratory rate normalization ≤24 rpm in room air |
| Clinical cure outcome rate | Day 1 to Day 15 | Proportion of participants with clinical cure outcome during the study (viral RNA not detected and clinical conditions for discharge) |
| Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO | Day 1 to Day 28 | Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO |
| Proportion of moderate cases that progressed to severe cases | Day 1 to Day 28 | Proportion of moderate cases that progressed to severe cases requiring care in an intensive care unit |
| Assessment of hospitalization time | Day 1 to Day 28 | Length (days) of hospital stay |
| Evaluation of drug interaction events frequency | Day 1 to Day 28 | Frequency of drug interaction events |
| Evaluation of drug interaction events intensity | Day 1 to Day 28 | Intensity of drug interaction events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) |
| Assessment of adverse events frequency | Day 1 to Day 28 | Frequency of adverse events |
| Assessment of adverse events intensity | Day 1 to Day 28 | Intensity of adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) |
| Assessment of unexpected adverse events frequency | Day 1 to Day 28 | Frequency of unexpected adverse events |
| Assessment of unexpected adverse events intensity | Day 1 to Day 28 | Intensity of unexpected adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) |
| Assessment of serious adverse events frequency | Day 1 to Day 28 | Frequency of serious adverse events |
| Assessment of serious adverse events intensity | Day 1 to Day 28 | Intensity of serious adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical) |
| Overall mortality rate | Day 1 to Day 28 | Mortality rate during the study |
| Evaluation of the tolerability of azvudine in the 5 mg regimen orally QD up to 14 days | Day 1 to Day 28 | Treatment dropout rate due to AZVUDINE/Placebo intolerance. |
| Assessment of adherence of azvudine in the 5 mg regimen orally QD up to 14 days | Day 1 to Day 28 | Medication possession rate, to measure the proportion of administered dose episodes observed in relation to the expected number of doses, until treatment interruption. |
| Time of use of azvudine in the 5 mg regimen orally QD up to 14 days | Day 1 to Day 28 | Total time (days) of use of AZVUDINE / Placebo intolerance. |
| Frequency of supplemental oxygenation or non-invasive ventilation | Day 1 to Day 28 | Frequency of supplemental oxygenation or non-invasive ventilation |
Countries
Brazil
Outcome results
None listed