Multicenter Randomized Double-blind Placebo-controlled Study to Investigate Azvudine in Symptomatic Adults With COVID-19 at Increased Risk of Progressing to Severe Illness

Study Overview
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Brief Summary
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To investigate whether treatment with Azvudine reduces the risk of severe illness or death in patients who are at a potential risk of progressing to severe COVID-19 infection.

Detailed Description
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The study is designed as a randomized, parallel, double-blind, placebo-controlled trial, in which all participants will be randomized to a test group or control group in a 1:1 ratio. The test group will be given Azvudine in combination with conventional therapy excluding anti-viral therapy and observed for efficacy. The control group will be given placebo in combination with conventional therapy excluding anti-viral therapy and observed for efficacy. Test Group will recruit 548 participants who will be given Azvudine + conventional therapy other than antiviral*5 mg/day, oral, up to 7 days (1 mg/tablet). Control Group will recruit 548 who will be given Placebo + conventional therapy other than antiviral* 5 tablets/day, oral, up to 7 days.

Official Title
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A Multicenter Randomized Double-blind Placebo-controlled Study to Investigate Azvudine in Symptomatic Adult Participants With COVID-19 Who Are at Increased Risk of Progressing to Severe Illness

Conditions
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COVID-19 Respiratory Infection

Intervention / Treatment
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* Drug: Azvudine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (1) An age of 18 years or over (inclusive); (2) Not more than five days since the development of COVID-19 symptoms, and positive for nucleic acid or antigen test for COVID-19 within five days before enrollment; (3) Presence of at least one symptom related to COVID-19 infection at the time of enrollment; (4) Agreement to practice effective birth control (for females of child-bearing potential); (5) Presence of at least one high risk factor for severe COVID-19 infection: Age ≥ 60 years; BMI>25； Fever (body temperature ≥ 38℃) for ≥ 3 days; Current smokers (still being smoking within 30 days before enrollment and have used at least 100 cigarettes up to date); Immunosuppressive diseases, including but not limited to: myelosuppression or organ transplantation or primary immunodeficiency disease; prolonged use of immunosuppressive agents (≥ 20 mg/d for at least 14 days in the case of prednisone within the last 30 days); biologic therapy (such as infliximab, etc.); use of immunomodulators (including but not limited to methotrexate, azathioprine, etc.); radiotherapy and/or chemotherapy for any malignancies within 90 days (for chest radiotherapy, this time interval should be more than 6 months); Chronic lung disease (such as asthma requiring intervention daily, bronchiectasis, COPD, pulmonary hypertension, OSAS, interstitial lung disease, etc.); Hypertension; ⑧ Cardiovascular diseases (previously diagnosed as myocardial infarction or stroke, TIA (transient ischemic attack), cardiac insufficiency, angina pectoris requiring nitrate therapy, CABG, post-PCI, post-carotid endarterectomy and aortic bypass surgery, etc.); ⑨ Type 1 or type 2 diabetes; ⑩ Neurodevelopmental abnormalities (such as cerebral palsy, Down's syndrome) or other genetic or metabolic syndromes and severe congenital malformations; ⑪ Active tumors (excluding localized skin cancer); ⑫ No vaccination against COVID-19 Exclusion Criteria: (1) Known or suspected allergy to the components of Azvudine Tablets; (2) Patients diagnosed as severe or critical COVID-19 infection (Severe: 1. shortness of breath with RR ≥ 30 breaths/min; 2. oxygen saturation ≤ 93% when inhaling air at rest; 3. partial pressure of arterial oxygen (PaO2) / fraction of inspired oxygen (FiO2) ≤ 300 mmHg; 4. progressive worsening of clinical symptoms, and obvious lesion progression > 50% on lung images within 24 to 48 hours. Critical: 1. respiratory failure, requiring mechanical ventilation; 2. shock; 3. concomitant organ failure, requiring care in ICU); (3) Patients with severe liver disease (total bilirubin [TBIL] ≥ 2 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 3 × ULN; (4) Patients with severe renal insufficiency (glomerular filtration rate ≤ 60 mL/min/1.73 m2) or currently on continuous renal replacement therapy, hemodialysis, and/or peritoneal dialysis; (5) Patients with malabsorption syndrome or any other condition compromising gastrointestinal absorption, or patients requiring parenteral nutrition or with difficulty in taking the investigational product orally; (6) Known HIV infection; (7) Presence of diabetic ketosis or hyperosmolar hyperglycemic state (HHS); (8) Total neutrophil count < 750 cells/L; (9) Pregnant or lactating women or those who plan to have a child during participation in this study and within six months after the end of this study; (10) Currently participating in another clinical trial or currently using another investigational product; (11) Presence of other active infections (must be etiologically confirmed) in addition to COVID-19 infection; (12) Presence of any comorbidities requiring hospitalization and/or a surgical procedure within 7 days prior to the start of this study or a comorbidity considered life-threatening within 30 days prior to the start of this study; (13) Patients who have received or are expected to receive convalescent plasma for COVID-19; (14) Previous treatment with anti-viral agents that have been proved to be effective against COVID-19, including but not limited to Nirmatrelvir/Ritonavir or Molnupiravir (this criterion does not apply to use of glucocorticoids for reasons other than COVID-19); (15) Other conditions that make it inappropriate for the participant to take part in this trial at the investigator's discretion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azvudine<br>Azvudine in Patients at Potential Risk of Progressing to Severe COVID-19 Infection | Drug: Azvudine<br>* Azvudine po. 5mg daily for 7 days<br>|
| Placebo Comparator: Placebo<br>Placebo in Patients at Potential Risk of Progressing to Severe COVID-19 Infection | Drug: Placebo<br>* Placebo po. 5 tablets daily for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of COVID-19-related critical illness or all-cause death within 28 days. | Proportion of COVID-19-related critical illness or all-cause death within 28 days. COVID-19-related critical illness is defined as: a patient with an SpO2 of 90% to 95% requiring high-flow oxygen inhalation with a fraction of inspired oxygen (FiO2) not less than 60% or requiring non-invasive ventilation with a FiO2 not less than 60%; or requiring mechanical ventilation or ECMO for organ support. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rates of Azvudine-related adverse events and serious adverse events | Incidence rates of Azvudine-related adverse events and serious adverse events | 28 days | 
| Duration of COVID-19-related symptoms | Duration of COVID-19-related symptoms | 14 days | 
| All-cause death | All-cause death | 6 months | 
| COVID-19 viral load in pharyngeal swabs | COVID-19 viral load in pharyngeal swabs | D1, D3, D7 | 
| Days of hospitalization and ICU stay | Days of hospitalization and ICU stay | 28 days |