Back to resultsStudy on Safety and Clinical Efficacy of AZVUDINE in COVID-19 Patients (SARS-CoV-2 Infected)
Primary Purpose
COVID-19
Status
Completed
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
AZVUDINE
AZVUDINE placebo
Sponsored by
About this trial
This is an interventional treatment trial for COVID-19 focused on measuring AZVUDINE, SARS-CoV-2, COVID-19, FNC
Eligibility Criteria
Inclusion Criteria:
- Individuals aged 18 or over, regardless of gender;
- Patients hospitalized in moderate to severe stages in line with the Ministry of Health classification;
- 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;
- Time of onset of symptoms and inclusion ≤ 14 days;
- Internation within 48 hours after inclusion in the study;
- Follow-up availability during the study period;
- Voluntary membership to participate in the study and signing the Informed Consent Form.
Exclusion Criteria:
- Patients known or suspected of being sensitive to AZVUDINE or excipients (inactive ingredients: microcrystalline cellulose, hydrated lactose, polyvinylpyrrolidone K30, croscarmellose sodium, magnesium stearate);
- Patients diagnosed with pneumonia caused by other pathogens;
- Patients with liver disease (total bilirubin ≥2 times above the normal limit, ALT / TGP and AST / TGO ≥5 times above the normal limit)
- Patients with renal failure (glomerular filtration rate ≤60mL / min / 1.73 m2) or are receiving continuous renal replacement therapy, hemodialysis or peritoneal dialysis;
- 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;
- 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;
- Patients already included in other clinical trials;
- Patient under treatment for HIV;
- Patients being treated with other antivirals (eg lopinavir / ritonavir, remdesivir, umifenovir / arbidol, favipiravir, interferon-α)
- Patients undergoing treatment with monoclonal antibodies (eg tocilizumab and sarilumab / kevzara);
- 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;
- Patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at the time of randomization;
- Any clinically significant medical condition or medical history that, in the investigator's opinion, might discourage participation in the study.
Sites / Locations
- Santa Casa de Misericordia de Campos
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Arm AZVUDINE
Arm Placebo
Arm Description
Experimental: AZVUDINE 1mg tablet, Interventions: AZVUDINE 1mg tablet, 5 tablets QD + standard treatment for up to 14 days
Control: AZVUDINE placebo, Interventions: AZVUDINE placebo, 5 tablets QD + standard treatment for up to 14 days
Outcomes
Primary Outcome Measures
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)
Secondary Outcome Measures
Clinical cure outcome rate
Proportion of participants with clinical cure outcome during the study (viral RNA not detected and clinical conditions for discharge)
Recovery of body temperature
Time (days) for normalization of body temperature (below 37.6℃ axillary)
Clinical improvement of diarrhea, myalgia fatigue and other symptoms
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)
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)
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)
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)
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
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
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
Rating the relationship between viral load calculated and clinical outcomes of participants
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.
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 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)
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 for normalization of O2 saturation
Time (days) to normalize O2 saturation (above 95%) between AZVUDINE (FNC) and placebo group
Respiratory rate evaluation
Time (days) for respiratory rate normalization ≤24 rpm in room air
Frequency of supplemental oxygenation or non-invasive ventilation
Frequency of supplemental oxygenation or non-invasive ventilation
Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO
Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO
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
Assessment of hospitalization time
Length (days) of hospital stay
Evaluation of drug interaction events frequency
Frequency of drug interaction events
Evaluation of drug interaction events intensity
Intensity of drug interaction events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Assessment of adverse events frequency
Frequency of adverse events
Assessment of adverse events intensity
Intensity of adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Assessment of unexpected adverse events frequency
Frequency of unexpected adverse events
Assessment of unexpected adverse events intensity
Intensity of unexpected adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Assessment of serious adverse events frequency
Frequency of serious adverse events
Assessment of serious adverse events intensity
Intensity of serious adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Overall mortality rate
Mortality rate during the study
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.
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 of use of azvudine in the 5 mg regimen orally QD up to 14 days
Total time (days) of use of AZVUDINE / Placebo intolerance.
Full Information
NCT ID
NCT04668235
First Posted
December 4, 2020
Last Updated
August 10, 2022
Sponsor
HRH Pharmaceuticals Limited
Collaborators
GALZU INSTITUTE OF RESEARCH, TEACHING, SCIENCE AND APPLIED TECHNOLOGY, Brazil, UNIVERSIDADE ESTADUAL DO NORTE FLUMINENSE (UENF), Brazil
1. Study Identification
Unique Protocol Identification Number
NCT04668235
Brief Title
Study on Safety and Clinical Efficacy of AZVUDINE in COVID-19 Patients (SARS-CoV-2 Infected)
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
April 23, 2021 (Actual)
Primary Completion Date
August 10, 2022 (Actual)
Study Completion Date
August 10, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
HRH Pharmaceuticals Limited
Collaborators
GALZU INSTITUTE OF RESEARCH, TEACHING, SCIENCE AND APPLIED TECHNOLOGY, Brazil, UNIVERSIDADE ESTADUAL DO NORTE FLUMINENSE (UENF), Brazil
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
AZVUDINE, SARS-CoV-2, COVID-19, FNC
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
180 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm AZVUDINE
Arm Type
Experimental
Arm Description
Experimental:
AZVUDINE 1mg tablet,
Interventions:
AZVUDINE 1mg tablet, 5 tablets QD + standard treatment for up to 14 days
Arm Title
Arm Placebo
Arm Type
Placebo Comparator
Arm Description
Control:
AZVUDINE placebo,
Interventions:
AZVUDINE placebo, 5 tablets QD + standard treatment for up to 14 days
Intervention Type
Drug
Intervention Name(s)
AZVUDINE
Other Intervention Name(s)
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
Intervention Description
5 tablets QD + standard treatment for up to 14 days
Intervention Type
Drug
Intervention Name(s)
AZVUDINE placebo
Other Intervention Name(s)
Placebo
Intervention Description
5 tablets QD + standard treatment for up to 14 days
Primary Outcome Measure Information:
Title
Evaluation of clinical improvement of AZVUDINE (FNC) in COVID-19 treatment
Description
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 Outcome Measure Information:
Title
Clinical cure outcome rate
Description
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
Title
Recovery of body temperature
Description
Time (days) for normalization of body temperature (below 37.6℃ axillary)
Time Frame
Day 1 to Day 28
Title
Clinical improvement of diarrhea, myalgia fatigue and other symptoms
Description
Time (days) for clinical improvement of diarrhea, myalgia, fatigue, and other symptoms
Time Frame
Day 1 to Day 28
Title
Assessment of inflammatory biochemical markers (Reactive C Protein, erythrocyte sedimentation rate, and Procalcitonin)
Description
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
Title
Assessment of immunological function biochemical markers (IL-6, IgG, IgM, IgA, and complement factor C3 and C4)
Description
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
Title
Assessment of renal function biochemical markers (serum creatinine and calculated glomerular filtration rate)
Description
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
Title
Assessment of liver function biochemical markers (AST/TGO, ALT/TGP, ALP, GGT, BIL total, and direct BIL)
Description
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
Title
Evaluation of time to negative conversion of SARS-CoV-2 viral load by RT-PCR
Description
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
Title
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
Description
SARS-CoV-2 viral load determination by standard-curve method of quantification
Time Frame
Day 1 to Day 15
Title
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
Description
Rating the relationship between viral load calculated and clinical outcomes of participants
Time Frame
Day 1 to Day 28
Title
Time for improvement of pulmonary condition by imaging exams during treatment
Description
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
Title
Evaluation of pulmonary condition by imaging exams during treatment
Description
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
Title
Time for clinical improvement of respiratory signs and symptoms
Description
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
Title
Assessment of clinical improvement of respiratory signs and symptoms
Description
Rate of improvement in respiratory signs and symptoms during treatment (pulmonary rales, cough, sputum, or sore throat)
Time Frame
Day 1 to Day 28
Title
Time for normalization of O2 saturation
Description
Time (days) to normalize O2 saturation (above 95%) between AZVUDINE (FNC) and placebo group
Time Frame
Day 1 to Day 28
Title
Respiratory rate evaluation
Description
Time (days) for respiratory rate normalization ≤24 rpm in room air
Time Frame
Day 1 to Day 28
Title
Frequency of supplemental oxygenation or non-invasive ventilation
Description
Frequency of supplemental oxygenation or non-invasive ventilation
Time Frame
Day 1 to Day 28
Title
Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO
Description
Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO
Time Frame
Day 1 to Day 28
Title
Proportion of moderate cases that progressed to severe cases
Description
Proportion of moderate cases that progressed to severe cases requiring care in an intensive care unit
Time Frame
Day 1 to Day 28
Title
Assessment of hospitalization time
Description
Length (days) of hospital stay
Time Frame
Day 1 to Day 28
Title
Evaluation of drug interaction events frequency
Description
Frequency of drug interaction events
Time Frame
Day 1 to Day 28
Title
Evaluation of drug interaction events intensity
Description
Intensity of drug interaction events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Time Frame
Day 1 to Day 28
Title
Assessment of adverse events frequency
Description
Frequency of adverse events
Time Frame
Day 1 to Day 28
Title
Assessment of adverse events intensity
Description
Intensity of adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Time Frame
Day 1 to Day 28
Title
Assessment of unexpected adverse events frequency
Description
Frequency of unexpected adverse events
Time Frame
Day 1 to Day 28
Title
Assessment of unexpected adverse events intensity
Description
Intensity of unexpected adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Time Frame
Day 1 to Day 28
Title
Assessment of serious adverse events frequency
Description
Frequency of serious adverse events
Time Frame
Day 1 to Day 28
Title
Assessment of serious adverse events intensity
Description
Intensity of serious adverse events (1= Mild; 2= Moderate; 3= Severe; 4= Critical)
Time Frame
Day 1 to Day 28
Title
Overall mortality rate
Description
Mortality rate during the study
Time Frame
Day 1 to Day 28
Title
Evaluation of the tolerability of azvudine in the 5 mg regimen orally QD up to 14 days
Description
Treatment dropout rate due to AZVUDINE/Placebo intolerance.
Time Frame
Day 1 to Day 28
Title
Assessment of adherence of azvudine in the 5 mg regimen orally QD up to 14 days
Description
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
Title
Time of use of azvudine in the 5 mg regimen orally QD up to 14 days
Description
Total time (days) of use of AZVUDINE / Placebo intolerance.
Time Frame
Day 1 to Day 28
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Individuals aged 18 or over, regardless of gender;
Patients hospitalized in moderate to severe stages in line with the Ministry of Health classification;
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;
Time of onset of symptoms and inclusion ≤ 14 days;
Internation within 48 hours after inclusion in the study;
Follow-up availability during the study period;
Voluntary membership to participate in the study and signing the Informed Consent Form.
Exclusion Criteria:
Patients known or suspected of being sensitive to AZVUDINE or excipients (inactive ingredients: microcrystalline cellulose, hydrated lactose, polyvinylpyrrolidone K30, croscarmellose sodium, magnesium stearate);
Patients diagnosed with pneumonia caused by other pathogens;
Patients with liver disease (total bilirubin ≥2 times above the normal limit, ALT / TGP and AST / TGO ≥5 times above the normal limit)
Patients with renal failure (glomerular filtration rate ≤60mL / min / 1.73 m2) or are receiving continuous renal replacement therapy, hemodialysis or peritoneal dialysis;
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;
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;
Patients already included in other clinical trials;
Patient under treatment for HIV;
Patients being treated with other antivirals (eg lopinavir / ritonavir, remdesivir, umifenovir / arbidol, favipiravir, interferon-α)
Patients undergoing treatment with monoclonal antibodies (eg tocilizumab and sarilumab / kevzara);
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;
Patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at the time of randomization;
Any clinically significant medical condition or medical history that, in the investigator's opinion, might discourage participation in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sheila P Figueiredo, MSc
Organizational Affiliation
Galzu Institute
Official's Role
Study Director
Facility Information:
Facility Name
Santa Casa de Misericordia de Campos
City
Campos Dos Goytacazes
State/Province
RJ
Country
Brazil
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Study on Safety and Clinical Efficacy of AZVUDINE in COVID-19 Patients (SARS-CoV-2 Infected)
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