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

COVID-19 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04668235
• Other study ID #: FNC IGZ-1
• Status: Completed
• Phase: Phase 3
• Start date: April 23, 2021
• Est. completion date: August 10, 2022

Study information

• Verified date: August 2022
• Source: HRH Pharmaceuticals Limited
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: August 10, 2022
• Est. primary completion date: August 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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-a)

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.

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• AZVUDINE
5 tablets QD + standard treatment for up to 14 days
• AZVUDINE placebo
5 tablets QD + standard treatment for up to 14 days

Locations

Country	Name	City	State
Brazil	Santa Casa de Misericordia de Campos	Campos Dos Goytacazes	RJ

Sponsors (3)

Lead Sponsor	Collaborator
HRH Pharmaceuticals Limited	GALZU INSTITUTE OF RESEARCH, TEACHING, SCIENCE AND APPLIED TECHNOLOGY, Brazil, UNIVERSIDADE ESTADUAL DO NORTE FLUMINENSE (UENF), Brazil

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Recovery of body temperature	Time (days) for normalization of body temperature (below 37.6? axillary)	Day 1 to Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Respiratory rate evaluation	Time (days) for respiratory rate normalization =24 rpm in room air	Day 1 to Day 28
Secondary	Frequency of supplemental oxygenation or non-invasive ventilation	Frequency of supplemental oxygenation or non-invasive ventilation	Day 1 to Day 28
Secondary	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
Secondary	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
Secondary	Assessment of hospitalization time	Length (days) of hospital stay	Day 1 to Day 28
Secondary	Evaluation of drug interaction events frequency	Frequency of drug interaction events	Day 1 to Day 28
Secondary	Evaluation of drug interaction events intensity	Intensity of drug interaction events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)	Day 1 to Day 28
Secondary	Assessment of adverse events frequency	Frequency of adverse events	Day 1 to Day 28
Secondary	Assessment of adverse events intensity	Intensity of adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)	Day 1 to Day 28
Secondary	Assessment of unexpected adverse events frequency	Frequency of unexpected adverse events	Day 1 to Day 28
Secondary	Assessment of unexpected adverse events intensity	Intensity of unexpected adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)	Day 1 to Day 28
Secondary	Assessment of serious adverse events frequency	Frequency of serious adverse events	Day 1 to Day 28
Secondary	Assessment of serious adverse events intensity	Intensity of serious adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)	Day 1 to Day 28
Secondary	Overall mortality rate	Mortality rate during the study	Day 1 to Day 28
Secondary	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
Secondary	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
Secondary	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