Phase III, randomized, double-blind, placebo-controlled clinical study: a study on the safety and clinical efficacy of AZVUDINE in moderate COVID-19 patients

Background In 2019, a highly pathogenic coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surfaced and resulted in the outbreak of coronavirus disease 2019 (COVID-19). With the aim of finding effective drugs to fight against the disease, several trials have been conducted since COVID-19 can only be considered a treatable disease, from a clinical point of view, after the availability of specific and effective antivirals. AZVUDINE (FNC), initially developed for treating HIV, is a potential treatment for COVID-19 as it has the capability to lower the patient’s viral load and promote recovery. Methods Volunteers infected with SARS-CoV-2 confirmed by reverse transcription polymerase chain reaction (RT-PCR), with good kidney and liver function, who were not using other antivirals or monoclonal antibodies were eligible. Samples from patients were assessed for viral load every 48 h during treatment using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and droplet digital polymerase chain reaction (ddPCR). Results The study’s primary outcome measure was the percentage of participants showing an improvement in clinical scores, while the secondary outcome measure was the percentage of participants with a clinical outcome of cure. These measures were used to assess the safety and efficacy of FNC for treating COVID-19. In the analysis of sociodemographic variables, no significant differences were detected between patients in the FNC and the placebo group for race, age group, or sex. The results showed a potential benefit to participants who received FNC during the study, as observed in the shorter hospital stay, shorter negative conversion time of SARS-CoV-2, and a significant reduction in viral load. Furthermore, the reduction in fever and chills were significant at D1, D2, and D3. In this study, a total of 112 adverse events cases were noted, with 105 cases being categorized as non-serious and only 7 cases as serious adverse events. Conclusion The pandemic is not being effectively controlled and is causing multiple waves of infection that require extensive medical resources. However, FNC has demonstrated potential to reduce the treatment duration of moderate COVID-19 cases, thereby saving significant medical resources. This makes FNC a promising candidate for COVID-19 treatment. Clinical trial registration: [clinicaltrials.gov], identifier [NCT04668235].

In preclinical trials, exposure to the drug for a prolonged period of time has shown that of the observable adverse events appear when the dose is exceeded by 20-30 times, but as the tests were carried out for a much longer time than suggested, AZVUDINE proved to be safe at the dose used.
For the IGZ-1 study, the proposed treatment period is 14 days (in view of the average incubation time of the coronavirus) and the maximum dose of Azvudine used in the 14 days is 70mg, remembering that the dose may be lower, because the participant may be discharged earlier.
The results of the pre-clinical study of FNC, in dogs, show that NOAEL=0.1mg/kg.Using the calculation formula 60×{[NOAEL]/(human kg/animal kg)}/10}) to calculate the equivalent dosage corresponding to the human body based on the NOAEL dosage of the most sensitive species and then dividing by safety coefficient ( 10) to obtain the initial dosage for the human body, the initial dosage for the human body was 0.36mg.
According to long-term toxicity data from dogs, taking 1/3 dose and maximum tolerance 0.3mg/kg, that is, 0.1mg/kg, to calculate human dosage (weight was calculated as 60kg), the maximum test dose would be 6mg/human/day.
As for the safety profile related to the dose used in humans, the maximum study of the safety dose of AZVUDINE was carried out for 5 mg, and a daily dose of 5 mg has an average life of 13.8 h, being excreted in the urine in up to 24 hours.
The proposed therapeutic regimen for the phase III clinical trial in patients with COVID-19 is based on preliminary studies conducted in China in 41 patients with pneumonia caused by SARS-CoV-2.The dose used was 5 mg/day, and the observed AEs Based on these studies, there was evidence that the 5 mg dose would have a good safety profile commensurate with use in the proposed target population.
were mild to moderate, with no need for medical intervention.All patients were discharged after two consecutive RT-PCR tests.Dose explorer phase I clinical trial (GQ-FNC-2014) evaluated the safety of Azvudine in HIV-positive patients for 7 days and demonstrated that Azvudine has clinical safety.Azvudine regiment dose groups for 2mg, 3mg, 4mg and 5mg showed good safety.No participants in the Azvudine 3mg and 5mg groups reported any AEs and no serious adverse events were attributed to Azvudine.8 patients with HIV received a dose of Azvudine 5mg, and no adverse drug reactions were observed.In these patients the plasma concentration of Azvudine was similar to the concentration observed in patients who received a dose of 2 to 4 mg.Furthermore, the 5 mg dose led to a human plasma concentration (2.42 ng/mL) which is 3,099 times lower than the concentration at the dose used in the CHL cell chromosome structure aberration test at a concentration of 7.5μg/mL after 4 hour exposure with or without S9 metabolic activation system.

Table :
Dose ratio and time of use

Table 5 : Analysis of urinary phosphorus excretion in 24 hours.
2 Wilcoxon rank sum test; Wilcoxon rank sum exact test Supplementary

Table 6 : Demonstration of serum cholinesterase values during the study days.
1 Mean ± SD (Median); n (%)2 Wilcoxon rank sum test; Wilcoxon rank sum exact test Supplementary

Table 10 : Demonstration of respiratory symptoms values during the study days
1 Mean ± SD (Median)2 Wilcoxon rank sum test Supplementary

Table 13 : Demonstration of the distribution of participants in the type of ventilatory support during the study days.
1 Mean ± SD (Median); n (%)2 Wilcoxon rank sum test; Pearson's Chi-squared test; Fisher's exact test; Wilcoxon rank sum

exact test Supplementary Table 14: Demonstration of O2 consumption during ventilatory support on the study days.
Wilcoxon rank sum test; Pearson's Chi-squared test; Fisher's exact test; Wilcoxon rank sum exact test 1 Mean ± SD (Median); n (%) 2