A Phase Ib/II Clinical Study in Patients With Refractory Chronic Cough

Exclusion Criteria

• •1. Pre-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) \< 70% of the expected value at screening;
• •2. History of upper or lower respiratory tract infection (including bacterial, fungal, viral and other pathogenic microorganism infections) or recent significant change in pulmonary conditions (including acute exacerbation of respiratory disease or significant change in chest imaging) within 4 weeks prior to screening or randomization;
• •3. Diagnosed as chronic obstructive pulmonary disease (COPD), bronchiectasis, idiopathic pulmonary fibrosis (IPF), active pulmonary tuberculosis before screening;
• •4. Past medical history of hypogeusia or taste disorder, or known taste abnormality;
• •5. With malignancy within 5 years prior to screening (except adequately treated basal cell or squamous cell skin cancer or cervical carcinoma in situ);
• •6. Moderate renal insufficiency: glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m2 prior to screening or prior to randomization;
• •7. Moderate to severe hepatic insufficiency (Child-Pugh Class B or C) prior to screening or prior to randomization;
• •8. History of unstable or worsening cardiovascular disease prior to screening or prior to randomization, including but not limited to: unstable angina, myocardial infarction, thromboembolism;
• •9. Those who are smoking or have quitted smoking for less than 1 year, or have a smoking history of annual consumption of more than 20 pack-years at screening;
• •10. Recent (within the past 1 year) history of drug or alcohol abuse or dependence;
• •11. Known hypersensitivity to any ingredient of this medication;
• •12. Systemic or topical use of drugs or foods that may affect the PK characteristics of the study drug, including strong inducers, strong inhibitors or substrates of CYP2C19 and CYP3A, and drinking grapefruit or grapefruit juice within 14 days prior to screening and during the trial (see Table 6 for details);
• •13. Systemic or topical use of antitussive drugs, including opioids, pregabalin, gabapentin, dextromethorphan, traditional Chinese medicine and over-the-counter drugs with antitussive effect, etc., within 4 weeks prior to screening and during the trial \[participants are allowed to receive a stable (≥ 4 weeks prior to the first dose of study drug) treatment for cough etiology, including antihistamines, leukotriene receptor antagonists, inhaled or oral glucocorticoids, long-acting bronchodilators, etc., or receive stable (≥ 8 weeks prior to the first dose of study drug) treatment with proton pump inhibitors\];
• •14. Receiving an angiotensin converting enzyme inhibitor currently or within 3 months prior to screening;
• •15. Participation in any other clinical study with the last dose of an study drug within 4 weeks prior to screening, or within 5 half-lives at screening (whichever is longer);
• •16. Systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg at screening and baseline (the test should be performed after resting for at least 5 minutes and the criterion is still met after a repeat examination);
• •17. Family history of long QT syndrome and sudden death, or significant ECG abnormalities at screening, including but not limited to: QTcF interval \> 450 ms, atrial fibrillation or flutter, heart rate \< 40 beats/min or \> 110 beats/min, second or third degree atrioventricular block, left bundle branch block;
• •18. Clinically significant abnormalities in laboratory test results at screening, including but not limited to:
• •1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) or glutamyl transpeptidase (GGT) \> 2 times the upper limit of normal, and total bilirubin \> 1.5 times the upper limit of normal;
• •2. Creatinine \> times the upper limit of normal;
• •3. Coagulation abnormalities including but not limited to abnormal platelet count (\< 100 × 103/mm3), prolonged PT or INR ≥ 1.5;
• •19. Positive hepatitis B virus surface antigen, or positive hepatitis B virus core antibody, negative hepatitis B virus surface antibody and positive HBV-DNA, or positive hepatitis C virus antibody or positive HCV-RNA, or positive treponema pallidum antibody, or positive human immunodeficiency virus (HIV) antibody at screening;
• •20. Pregnant or breast-feeding;
• •21. Any past or current acute or chronic illness, psychiatric illness, or laboratory abnormality that, in the judgment of the investigator, may compromise the safety or compliance of the participant, or affect the absorption of the study drug and study assessments, or render the participant unable to complete the study.