A Clinical Trial of TQC3721 Suspension for Inhalation

Study Overview
=================
Brief Summary
-----------------
To evaluate the safety, tolerability and pharmacokinetic characteristics of TQC3721 suspension for inhalation in single/multiple administration(s) in healthy subjects; to evaluate the safety,tolerability and efficacy TQC3721 suspension for inhalation in multiple administrations in patients with Chronic Obstructive Pulmonary Disease（COPD）and asthma.

Official Title
-----------------
Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics, and Primary Efficacy of TQC3721 Suspension for Inhalation

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: TQC3721 suspension for inhalation
* Drug: TQC3721 suspension placebo for inhalation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sign the informed consent form before the trial, fully understand the content, process and possible adverse reactions of the test; Able to complete the study according to the requirements of protocol; Aged between 18 and 65 years old, both men and women; For healthy subjects: Male ≥50kg, female ≥45kg,body mass index(BMI)=weight (kg)/height 2 (m2), BMI is 18-28 kg/m2 (including the critical value); For patients: BMI is 18-28 kg/m2 (including the critical value), and body weight is ≥45kg. For healthy subjects: normal or abnormal vital signs, physical examination, laboratory examination, electrocardiogram, and imageological examination have no clinical significance; For healthy subjects: FEV1 and forced vital capacity(FVC) are at least 90% of the predicted values; Subjects (including male subjects) have no pregnancy plan and have voluntarily taken effective contraceptive measures for at least 1 month after being screened to the last use of the study drug; For patients: Vital signs range: systolic blood pressure 90 to 140mmHg, diastolic blood pressure 50 to 90 mmHg, heart rate 50 to 90 bpm; For patients: 12-lead electrocardiogram with QT interval corrected ≤450 msec (males) or ≤470 msec (females), QRS interval ≤120 msec, PR interval ≤200 msec and no morphologic and other clinical significant abnormalities (such as left band branch block, atrioventricular node dysfunction, ischemic ST segment abnormalities); For patients: Ability to perform acceptable and reproducible spirometry; For patients: According to the diagnostic criteria of 2018 Practical Edition of Guidelines for the Diagnosis and Treatment of COPD, the patient was diagnosed with COPD for at least 1 year;Post-bronchodilator spirometry at screening must demonstrate FEV1/FVC ratio of ≤0.70 and FEV1 must be ≥40 % to ≤80% of predicted normal; For patients: mMRC Scoring at screening ≥2; For patients: Clinically stable COPD in the previous 4 weeks; For patients: Capable of withdrawing long acting bronchodilators until the end of the treatment period, and short acting bronchodilators for 8 hours prior to administration of study medication; For patients: Current and former smokers with a smoking history of ≥10 pack years（smoking at least 20 cigarettes a day for 10 years or at least 10 cigarettes a day for 20 years）; For patients: beta agonists are currently used only when needed; For patients: Never smoked or An ex-smoker for ≥6 months； Exclusion Criteria: Preexisting or existing the neuropsychiatric system, respiratory system, cardiovascular system, digestive system, hemo-lymphatic system, immune system, liver and kidney dysfunction, endocrine system, musculoskeletal system, or other disease that the investigator assesses that may affect drug metabolism or safety. For healthy subjects: Have a history of fainting needles, fainting blood. For healthy subjects: Known allergy to the study drug and their metabolites or any of the excipients of the formulation. For healthy subjects: Those who smoked more than 5 cigarettes per day during the 3 months before the trial. A history of alcohol abuse in the past 6 months (14 units of alcohol consumed per week: 1 unit =360 ml of beer or 45 ml of 40% alcohol spirits or 150 ml of wine). For healthy subjects: Donated blood or had substantial loss of blood (more than 400 mL) within 2 months before the test. For healthy subjects: Had taken any prescription, over-the-counter, vitamin product or herbal medicine within 1 month prior to the use of the study drug. Participated in other clinical trials within 3 months prior to this study. Positive for hepatitis (including hepatitis B and C), human immunodeficiency virus（HIV） or syphilis at screening. Women who are pregnant or breast-feeding. Positive test for alcohol. For healthy subjects: Blood collection is difficult or cannot tolerate venipuncture blood collection. For healthy subjects: The subject is unable or can not comply with ward management regulations. For healthy subjects: The subject is unable to complete the study due to personal reasons. For healthy subjects: Any circumstances that the investigator considers to pose a safety risk to the subject during the study or may interfere with the conduct of the study. For patients: Intolerance to salbutamol, tiotropium, or this product or prior exposure to Ensifentrine (RPL554). For patients: Use of any medicine within 4 weeks prior to initiation of the study drug, including non-prescription medications and herbs, except vitamins. For patients: Physical examination findings that researchers consider clinically significant at the time of screening. For patients: A history of cardiovascular disease (including arrhythmias) or active hyperthyroidism. For patients: History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localised basal cell carcinoma of the skin.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TQC3721 suspension for inhalation<br>Participants will receive 0.2 mg/1.0 mg/3.0 mg/6.0 mg/12.0 mg/24.0 mg single dose of TQC3721 suspension for inhalation on Day 1. | Drug: TQC3721 suspension for inhalation<br>* Participants will receive 0.2 mg/1.0 mg/3.0 mg/6.0 mg/12.0 mg/24.0 mg single dose of TQC3721 suspension for inhalation.<br>|
| Placebo Comparator: TQC3721 suspension placebo for inhalation<br>Participants will receive 0mg single dose of TQC3721 suspension placebo for inhalation on Day 1. | Drug: TQC3721 suspension placebo for inhalation<br>* Participants will receive 0mg single dose of TQC3721 suspension placebo for inhalation .<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events | The Number of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | From the enrollment of the subjects to 72 hours after the last administration | 
| Incidence of adverse events | The Incidence of adverse events as assessed by CTCAE v5.0 | From the enrollment of the subjects to 72 hours after the last administration | 
| Number of adverse events related to the study drug | The number of adverse events associated with the study drug assessed by CTCAE V5.0 | From the enrollment of the subjects to 72 hours after the last administration | 
| Incidence of adverse events associated with the study drug | Incidence of adverse events associated with the study drug as assessed by CTCAE V5.0 | From the enrollment of the subjects to 72 hours after the last administration | 
| Area Under The Curve（AUC） | Area under the curve | Within 60 minutes before each administration, to 72 hours after administration | 
| Plasma drug peak concentration（Cmax ） | Plasma drug peak concentration | Within 60 minutes before each administration, to 72 hours after administration | 
| Time to peak（Tmax） | Time to maximum concentration following drug administration | Within 60 minutes before each administration, to 72 hours after administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elimination half-life time（t1/2） | Apparent terminal elimination half-life following drug administration | Within 60 minutes before each administration, to 72 hours after administration | 
| Apparent volume of distribution（Vd） | Apparent volume of distribution | Within 60 minutes before each administration, to 72 hours after administration | 
| Clearance（CL） | Clearance | Within 60 minutes before each administration, to 72 hours after administration | 
| Forced Expiratory Volume in the first second (FEV1) for patients with Chronic Obstructive Pulmonary Disease（COPD） or asthma | Mean Change From Baseline in Peak FEV1 (Over 3 Hours) | From before administration to 3 hours after administration | 
| Mean Change From Baseline FEV1 to Morning Trough FEV1 | Mean Change From Baseline FEV1 to Morning Trough FEV1 | From the enrollment of the subjects to to 72 hours after administration | 
| Mean Change From Baseline FEV1 to Average FEV1 | Mean Change From Baseline FEV1 to Average FEV1 | From the enrollment of the subjects to to 72 hours after administration | 
| COPD Assessment Test (CAT) for patients with COPD | Mean Change From Baseline in COPD Assessment Test (CAT) Scoring at Week 4.The score range is 0 to 40 (0 to 10 is minor influence;11 to 20 is moderate; 21 to30 is severe;31 to 40 is very severe), and more than 10 indicates more symptoms. | From enrollment to 4 weeks after administration | 
| Modified medical research council(mMRC) for patients with COPD or asthma | Mean Change From Baseline in mMRC Scoring at Week 4.The severity is measured on a five-point scale from 0 to 4, with a higher score indicating more severe respiratory distress. | From enrollment to 4 weeks after administration |