Study on Safety and Clinical Efficacy of AZVUDINE in COVID-19 Patients (SARS-CoV-2 Infected)
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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:
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Progression of the disease (moderate to severe, severe type);
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Negative viral load conversion rate;
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Time of negative conversion of viral load;
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Temperature recovery time;
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Time necessary to improve diarrhea, myalgia, fatigue, and other symptoms;
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Time to improve the pulmonary image;
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Frequency of supplemental oxygenation or non-invasive ventilation;
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Frequency of AEs;
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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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm AZVUDINE Experimental: AZVUDINE 1mg tablet, Interventions: AZVUDINE 1mg tablet, 5 tablets QD + standard treatment for up to 14 days |
Drug: AZVUDINE
5 tablets QD + standard treatment for up to 14 days
Other Names:
|
| Placebo Comparator: Arm Placebo Control: AZVUDINE placebo, Interventions: AZVUDINE placebo, 5 tablets QD + standard treatment for up to 14 days |
Drug: AZVUDINE placebo
5 tablets QD + standard treatment for up to 14 days
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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)
- 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
- Frequency of supplemental oxygenation or non-invasive ventilation [Day 1 to Day 28]
Frequency of supplemental oxygenation or non-invasive ventilation
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Individuals aged 18 or over, regardless of gender;
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Patients hospitalized in moderate to severe stages in line with the Ministry of Health classification;
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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;
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Time of onset of symptoms and inclusion ≤ 14 days;
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Internation within 48 hours after inclusion in the study;
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Follow-up availability during the study period;
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Voluntary membership to participate in the study and signing the Informed Consent Form.
Exclusion Criteria:
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Patients known or suspected of being sensitive to AZVUDINE or excipients (inactive ingredients: microcrystalline cellulose, hydrated lactose, polyvinylpyrrolidone K30, croscarmellose sodium, magnesium stearate);
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Patients diagnosed with pneumonia caused by other pathogens;
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Patients with liver disease (total bilirubin ≥2 times above the normal limit, ALT / TGP and AST / TGO ≥5 times above the normal limit)
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Patients with renal failure (glomerular filtration rate ≤60mL / min / 1.73 m2) or are receiving continuous renal replacement therapy, hemodialysis or peritoneal dialysis;
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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;
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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;
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Patients already included in other clinical trials;
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Patient under treatment for HIV;
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Patients being treated with other antivirals (eg lopinavir / ritonavir, remdesivir, umifenovir / arbidol, favipiravir, interferon-α)
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Patients undergoing treatment with monoclonal antibodies (eg tocilizumab and sarilumab / kevzara);
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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;
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Patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at the time of randomization;
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Any clinically significant medical condition or medical history that, in the investigator's opinion, might discourage participation in the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Santa Casa de Misericordia de Campos | Campos Dos Goytacazes | RJ | Brazil |
Sponsors and Collaborators
- HRH Pharmaceuticals Limited
- GALZU INSTITUTE OF RESEARCH, TEACHING, SCIENCE AND APPLIED TECHNOLOGY, Brazil
- UNIVERSIDADE ESTADUAL DO NORTE FLUMINENSE (UENF), Brazil
Investigators
- Study Director: Sheila P Figueiredo, MSc, Galzu Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- FNC IGZ-1