Clinical trial NCT04668235: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: AZVUDINE
SARS-CoV-2
COVID-19
FNC
Lead sponsor: HRH Pharmaceuticals Limited
Sponsor class: OTHER
Collaborators: name: GALZU INSTITUTE OF RESEARCH, TEACHING, SCIENCE AND APPLIED TECHNOLOGY, Brazil
name: UNIVERSIDADE ESTADUAL DO NORTE FLUMINENSE (UENF), Brazil
First posted: 2020-12-16
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Evaluation of clinical improvement of AZVUDINE (FNC) in COVID-19 treatment
timeFrame: Day 1 to Day 15
Secondary outcomes:
measure: Clinical cure outcome rate
timeFrame: Day 1 to Day 15
measure: Recovery of body temperature
timeFrame: Day 1 to Day 28
measure: Clinical improvement of diarrhea, myalgia fatigue and other symptoms
timeFrame: Day 1 to Day 28
measure: Assessment of inflammatory biochemical markers (Reactive C Protein, erythrocyte sedimentation rate, and Procalcitonin)
timeFrame: Day 1 to Day 60
measure: Assessment of immunological function biochemical markers (IL-6, IgG, IgM, IgA, and complement factor C3 and C4)
timeFrame: Day 1 to Day 60
measure: Assessment of renal function biochemical markers (serum creatinine and calculated glomerular filtration rate)
timeFrame: Day 1 to Day 60
measure: Assessment of liver function biochemical markers (AST/TGO, ALT/TGP, ALP, GGT, BIL total, and direct BIL)
timeFrame: Day 1 to Day 60
measure: Evaluation of time to negative conversion of SARS-CoV-2 viral load by RT-PCR
timeFrame: Day 1 to Day 28
measure: 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
timeFrame: Day 1 to Day 15
measure: 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
timeFrame: Day 1 to Day 28
measure: Time for improvement of pulmonary condition by imaging exams during treatment
timeFrame: Day 1 to Day 28
measure: Evaluation of pulmonary condition by imaging exams during treatment
timeFrame: Day 1 to Day 28
measure: Time for clinical improvement of respiratory signs and symptoms
timeFrame: Day 1 to Day 28
measure: Assessment of clinical improvement of respiratory signs and symptoms
timeFrame: Day 1 to Day 28
measure: Time for normalization of O2 saturation
timeFrame: Day 1 to Day 28
measure: Respiratory rate evaluation
timeFrame: Day 1 to Day 28
measure: Frequency of supplemental oxygenation or non-invasive ventilation
timeFrame: Day 1 to Day 28
measure: Frequency of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO
timeFrame: Day 1 to Day 28
measure: Proportion of moderate cases that progressed to severe cases
timeFrame: Day 1 to Day 28
measure: Assessment of hospitalization time
timeFrame: Day 1 to Day 28
measure: Evaluation of drug interaction events frequency
timeFrame: Day 1 to Day 28
measure: Evaluation of drug interaction events intensity
timeFrame: Day 1 to Day 28
measure: Assessment of adverse events frequency
timeFrame: Day 1 to Day 28
measure: Assessment of adverse events intensity
timeFrame: Day 1 to Day 28
measure: Assessment of unexpected adverse events frequency
timeFrame: Day 1 to Day 28
measure: Assessment of unexpected adverse events intensity
timeFrame: Day 1 to Day 28
measure: Assessment of serious adverse events frequency
timeFrame: Day 1 to Day 28
measure: Assessment of serious adverse events intensity
timeFrame: Day 1 to Day 28
measure: Overall mortality rate
timeFrame: Day 1 to Day 28
measure: Evaluation of the tolerability of azvudine in the 5 mg regimen orally QD up to 14 days
timeFrame: Day 1 to Day 28
measure: Assessment of adherence of azvudine in the 5 mg regimen orally QD up to 14 days
timeFrame: Day 1 to Day 28
measure: Time of use of azvudine in the 5 mg regimen orally QD up to 14 days
timeFrame: Day 1 to Day 28
Other outcomes:
Locations:
city: Campos Dos Goytacazes
country: Brazil
facility: Santa Casa de Misericordia de Campos
state: RJ
Study officials:
affiliation: Galzu Institute
name: Sheila P Figueiredo, MSc
role: STUDY_DIRECTOR
References: