Study of Flonoltinib Maleate Tablets in the Treatment of Severe Novel Coronavirus (COVID-19) Infection

Study Overview
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Brief Summary
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Flonoltinib Maleate as a JAK/FLT3 dual target inhibitor, previous pharmacological experiments showed that the IC50 inhibition of JAK2 kinase was as low as 0.8 nM, while the IC50 inhibition of JAK1, JAK3 and TYK2 kinases was 26 nM, 39 nM and 2 nM, respectively, and the IC50 of FLT3 kinase was 15 nM. It has high inhibitory activity for JAK2 kinase and good selectivity for JAK family.Multiple pharmacodynamic models evaluating the anti-inflammatory effect of Flonoltinib Maleate showed that Flonoltinib Maleate showed better therapeutic effect than the clinical drug Ruxolitinib with lower toxicity.

Official Title
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Preliminary Clinical Study of Efficacy and Safety of Flunotinib Maleate Tablets Combined With Antiviral Therapy in Patients With Severe Novel Coronavirus (COVID-19) Infection

Conditions
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COVID-19

Intervention / Treatment
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* Drug: SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥ 18 years old, gender is not limited; COVID-19 infection inclusion criteria: hospitalized with coronavirus (COVID-19) within 14 days, samples collected 72 hours before enrollment confirmed by polymerase chain reaction (PCR) test or antigen test (if due to lack of testing supplies, testing capacity and conditions are limited, but indicate a progressive disease with persistent infection with COVID-19), the investigator judged that the condition was aggravated, and any of the following criteria were met as severe COVID-19 patients: Respiratory distress, respiratory rate≥ 30 times/min; At rest, oxygen saturation ≤ 93% when inhaling air; Arterial partial pressure of oxygen (PaO2)/oxygen inhalation concentration (FiO2)≤ 300 mmHg; Clinical symptoms are progressively aggravated, lung imaging shows that the lesions within 24 48h have progressed significantly > 50%. Adults with any of the following are defined as critically ill with COVID-19: respiratory failure requiring mechanical ventilation; Appearance of shock; Other organ failure requires ICU monitoring; Severe and critical cases of novel coronavirus infection, collectively referred to as severe cases. Severe cases can also be managed as severe cases if pneumonia caused by novel coronavirus infection does not meet the diagnostic criteria for severe cases: age > 65 years old, incomplete full vaccination, and more serious chronic diseases (including hypertension, diabetes, coronary heart disease, chronic lung disease, malignant tumors, and immunocompromise, etc.) Patients with risk of progression before enrollment: at least one inflammatory index greater than the upper limit of normal (IL-6, CRP, d-dimer, LDH, ferritin≥ULN) within 2 days; willing and/or able to comply with research-related procedures and assessments; Those who can understand and agree to participate in this research and sign the informed consent form; Exclusion Criteria: Known or suspected allergy to the test drug and its excipients; Are receiving cytotoxic or biological therapy (such as TNF inhibitors, IL-1 inhibitors, IL-6 inhibitors (tocilizumab, adalimumab, etc.), T cell or B cell targeted therapy (rituximab, interferon, etc.), or Janus kinase (JAK) inhibitors, except for this study. Have received convalescent new coronary pneumonia plasma or intravenous human immunoglobulin; have received clearly effective COVID-19 virus neutralizing antibodies; In addition to the new crown infection, there are other serious infections, suspected serious bacteria, fungal viruses, active tuberculosis, NTM, etc. Known positive for HIV antibody, positive test for active hepatitis B virus (HBsAg positive, HBV-DNA positive or ≥1000 copies/mL), anti-HCV antibody or HCV-RNA positive; Have received a live vaccine within 1 week prior to screening, or are expected to be vaccinated during the study period. Severe liver disease (total bilirubin (TBIL) ≥ 3 times the upper limit of normal value, alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥5 times the upper limit of normal value); Those with severe renal insufficiency (glomerular filtration rate ≤ 30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis; Blood routine: neutrophil count < 1.0×109/L, lymphocyte count < 0.2×109/L, platelet < 30×109/L, hemoglobin < 60g/L; Patients with malabsorption syndrome, or any other condition that affects gastrointestinal absorption, requiring intravenous nutrition or unable to take oral medications; Invasive respiratory support or advanced life support, such as ECMO, is required. Patients who have suffered from malignant tumors in the past 5 years and are currently uncontrolled; (13) Patients who participated in other new drugs or medical devices within 1 month before screening and took the investigational drug and used the investigational device; (14) Pregnant or lactating female patients, female patients with fertility and male patients who refuse to use contraception during the trial and within 6 months after the end of the test; (15) having taken a strong CYP3A inhibitor (such as ketoconazole, clarithromycin, itraconazole) or a strong CYP3A4 inducer (rifampicin) within two weeks before the first dose; (16) Patients with congenital coagulation abnormalities, such as patients with a history of multiple thrombosis and bleeding diseases; (17) Alcohol dependence or drug abuse; The researchers believe that patients with rapid disease progression are unlikely to survive for at least 48 hours after screening; or other factors that are not suitable for participation in the trial。

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FM+SOC<br> | Drug: SOC<br>* In this study, the standard treatment plan (SOC) for COVID-19 in the Department of Respiratory and Critical Care Medicine was used as the best accessible treatment, and the treatment plan principle was based on the latest national guidance document (Expert Recommendations for Clinical Treatment of Severe Novel Coronavirus Infection Caused by Omicron Variant; Diagnosis and Treatment Plan for Novel Coronavirus Infection (Trial Version 10); Diagnosis and Treatment Plan for Severe Cases of Novel Coronavirus Infection (Trial Fourth Edition)). In this study, the drug flunotinib maleate (FM) 100mg is a class of JAK inhibitors of anti-inflammatory therapy of SOC as standard clinical treatment regimen, and will be used in combination with SOC according to the judgment of the investigator.<br>|
| Placebo Comparator: FM安慰剂 +SOC<br> | Drug: SOC<br>* In this study, the standard treatment plan (SOC) for COVID-19 in the Department of Respiratory and Critical Care Medicine was used as the best accessible treatment, and the treatment plan principle was based on the latest national guidance document (Expert Recommendations for Clinical Treatment of Severe Novel Coronavirus Infection Caused by Omicron Variant; Diagnosis and Treatment Plan for Novel Coronavirus Infection (Trial Version 10); Diagnosis and Treatment Plan for Severe Cases of Novel Coronavirus Infection (Trial Fourth Edition)). In this study, the drug flunotinib maleate (FM) 100mg is a class of JAK inhibitors of anti-inflammatory therapy of SOC as standard clinical treatment regimen, and will be used in combination with SOC according to the judgment of the investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary efficacy endpoints | The primary endpoint will assess the proportion of patients who die or require non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation (including extracorporeal membrane oxygenation [ECMO]) at day 28. | 28 day | 
| Primary efficacy endpoints | Non-invasive ventilation/high-flow oxygen includes ventilatory support without the use of invasive artificial airways (endotracheal tubes or tracheostomy tubes). | 28 day | 
| Primary efficacy endpoints | High-flow oxygen includes respiratory support through masks, nasal masks, etc. | 28 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary efficacy endpoints | Number of days hospitalized and admitted to the ICU (D1-D28); | 28 day | 
| Secondary efficacy endpoints | If it is separated from oxygen therapy and maintained for 24 hours or without oxygen in the room, SpO2≥93 can be reached and maintained for 24 hours (D1-D28) | 28 day | 
| Secondary efficacy endpoints | Duration of symptoms associated with COVID-19 infection (D1-D14) | 14 day | 
| Secondary efficacy endpoints | The proportion and time of the WHO clinical status rating (from 0 (no viral infection) to 10 (death) decreased by two levels | 28 day | 
| Secondary efficacy endpoints | To improve clinical time | 28 day | 
| Secondary efficacy endpoints | Rehabilitation time (D1-D28) (Rehabilitation is defined as a patient meeting any of the minimum 3 scores on the NIAID-OS scale (see Appendix) on the first day or time of study initiation: hospitalization, no need for supplemental oxygen - no ongoing medical care is required; not hospitalized, limited mobility, and/or requiring home oxygen; Not hospitalized and with unlimited activities (also applies to normal discharge home) | 28 day | 
| Secondary efficacy endpoints | Improvement of inflammatory factor levels. | 28 day | 
| Secondary efficacy endpoints | Nucleic acid negative time (nucleic acid negative is defined as CT value≥35) | 28 day |