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

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: AZVUDINE; Drug: AZVUDINE placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • RJ
    • Campos Dos Goytacazes, RJ, Brazil
      • Santa Casa de Misericordia de Campos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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: AZVUDINE 1 mg tablets; FNC; 4-amino-1-((2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2(1H)-one; 1-(4-Azido-2-deoxy-2-fluoro-beta-D- arabino Ribo-furanosyl) cytosine, FNC
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: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: HRH Pharmaceuticals Limited
• Collaborators: 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 record dates

Study Major Dates

• Study Start (Actual): April 23, 2021
• Primary Completion (Actual): August 10, 2022
• Study Completion (Actual): August 10, 2022

Study Registration Dates

• First Submitted: December 4, 2020
• First Submitted That Met QC Criteria: December 14, 2020
• First Posted (Actual): December 16, 2020

Study Record Updates

• Last Update Posted (Actual): August 12, 2022
• Last Update Submitted That Met QC Criteria: August 10, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; AZVUDINE; FNC
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: FNC IGZ-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No