A Study to Evaluate the Tolerability and Pharmacokinetics of Jiashen Tablets in Healthy Subjects

Study Overview
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Brief Summary
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Jiashen Tablets as an oral, compound traditional chinese medicine prepatations, have an effect on improvement of the heart failure. This study will assess the safety, tolerability and pharmacokinetics (PK) of Jiashen Tablets, following oral administration of single and multiple ascending dose of Jiashen Tablets.

Detailed Description
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This study will include a randomized, double-blind, placebo-controlled, single ascending dose design study (Part A), and an open-label SDAD pre-multiple daily ascending dose (MDAD) study (Part B) and an open-label MDAD study (Part C) study. The study will be conducted in healthy participants and performed at a single study center. 70 healthy participants are planned to be included in the study. Part A will include six cohorts, 40 participants. Within each cohort, 2 participants will be randomized to receive placebo and other participants randomized to receive Jiashen Tablets. Each participant will receive Jiashen Tablets at the selected dose level or placebo by oral administration in a fasted state once daily. Part B will include two cohorts, 6 participants, minimum dose group and maximum dose group respectively depending on the findings. Within each cohort, participant will receive Jiashen Tablets at the selected dose level by oral administration in a fasted state once daily. Part C will include three cohorts, 24 participants. Within each cohort, participant will receive Jiashen Tablets at the selected dose level by oral administration in a fasted state once daily for 7 days.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics of Jiashen Tablets in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Jiashen Tablets
* Drug: Jiashen Tablets
* Drug: Jiashen Tablets
* Drug: Jiashen Tablets
* Drug: Jiashen Tablets
* Drug: Jiashen Tablets
* Drug: Jiashen Tablets Placebo
* Drug: Jiashen Tablets Placebo
* Drug: Jiashen Tablets Placebo
* Drug: Jiashen Tablets Placebo
* Drug: Jiashen Tablets Placebo
* Drug: Jiashen Tablets Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers, half male and half female, aged 18-50 years (including the boundary value), the age difference of the same batch of subjects should not exceed 10 years. Have a body mass index of all subjects between 19 and 24kg /m2 (inclusive) and weight of the male subject should be no less than 50Kg and the weight of the female subject should be no less than 45Kg. Passed the smoke test, alcohol and drug abuse test, general physical examination and laboratory examination, chest film, ultrasound, electrocardiogram and other physical and chemical tests. No history of major diseases, no history of smoking and drinking, negative blood pregnancy test of women of childbearing age and no lactation. Obtain informed consent and volunteer to be tested in accordance with the provisions of the Drug clinical trial quality management standard. Exclusion Criteria: Have primary diseases of cardiovascular，hepatic or renal disease or any other condition. With history of digestive tract diseases, metabolic diseases, and neurological diseases. QTc extension (male >430ms, female >450ms). History of drug allergy or allergic constitution. Family history of hypokalemia, long QT syndrome or other TdP risk factors. Mentally or physically disabled. Any clinically significant abnormalities in physical examination, biochemical and hematuria routine examination, electrocardiogram, chest film and ultrasound examination,. Any positive result on Screening for serum hepatitis B tests (except surface antibodies), hepatitis C antibody , human immunodeficiency virus (HIV) and treponema pallidum antibody test. Those who had taken a drug known to damage an organ within 3 months, taken any drug within 2 weeks, and participated in other clinical trials within 4 weeks. Bleeding tendency. Women during menstruation, pregnancy and lactation. Abnormal vital signs (systolic pressure <90mmHg or >140mmHg, diastolic pressure <60mmHg or >90mmHg;Heart rate <60bpm or >100bpm). Have smoked more than one cigarette per day or used a considerable amount of nicotine products within the previous 3 months, and could not quit smoking during the experiment. Positive screen for the smoke test. Regular drinkers who drank more than 14 units of alcohol per week (1 unit =360mL beer or 45mL spirits with a 40% alcohol content or 150mL wine) during the 6 months prior to the trial, or who tested positive for alcohol, or who do not abstain during the trial. Excessive daily consumption of tea, coffee and/or caffeinated beverages (more than 8 cups, 1 cup =250mL) or caffeine test positive. Have a history of blood transfusion or donation in the last 3 months (blood volume greater than 200mL). Have a history of drug abuse and tested positive for drug abuse (morphine, methamphetamine, ketamine, dimethyldimethamphetamine, THC, cocaine). Have a history of antibiotic use in the last month. Have taken lactobacillus products (including yogurt) in the last week. Judgment by the Investigator that the participant should not participate in the study (such as weak, etc).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: treatment group 1<br>Jiashen tablet, 0.47g, oral, once a day | Drug: Jiashen Tablets<br>* 1 tablet<br>* Other names: treatment group 1;|
| Active Comparator: treatment group 2<br>Jiashen tablet, 0.94g, oral, once a day | Drug: Jiashen Tablets<br>* 2 tablets<br>* Other names: treatment group 2;|
| Active Comparator: treatment group 3<br>Jiashen tablet,1.88g, oral, once a day | Drug: Jiashen Tablets<br>* 4 tablets<br>* Other names: treatment group 3;|
| Active Comparator: treatment group 4<br>Jiashen tablet,2.82g, oral, once a day | Drug: Jiashen Tablets<br>* 6 tablets<br>* Other names: treatment group 4;|
| Active Comparator: treatment group 5<br>Jiashen tablet,3.76g, oral, once a day | Drug: Jiashen Tablets<br>* 8 tablets<br>* Other names: treatment group 5;|
| Active Comparator: treatment group 6<br>Jiashen tablet,4.23g, oral, once a day | Drug: Jiashen Tablets<br>* 9 tablets<br>* Other names: treatment group 6;|
| Placebo Comparator: control group 1<br>Jiashen placebo tablet,0.47g, oral, once a day | Drug: Jiashen Tablets Placebo<br>* 1 tablet<br>* Other names: control group 1;|
| Placebo Comparator: control group 2<br>Jiashen placebo tablet,0.94g, oral, once a day | Drug: Jiashen Tablets Placebo<br>* 2 tablets<br>* Other names: control group 2;|
| Placebo Comparator: control group 3<br>Jiashen placebo tablet,1.88g, oral, once a day | Drug: Jiashen Tablets Placebo<br>* 4 tablets<br>* Other names: control group 3;|
| Placebo Comparator: control group 4<br>Jiashen placebo tablet,2.82g, oral, once a day | Drug: Jiashen Tablets Placebo<br>* 6 tablets<br>* Other names: control group 4;|
| Placebo Comparator: control group 5<br>Jiashen placebo tablet,3.76g, oral, once a day | Drug: Jiashen Tablets Placebo<br>* 8 tablets<br>* Other names: control group 5;|
| Placebo Comparator: control group 6<br>Jiashen placebo tablet,4.23g, oral, once a day | Drug: Jiashen Tablets Placebo<br>* 9 tablets<br>* Other names: control group 6;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. Serious AEs will be recorded from the time of screening. | From screening (Day-7) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal blood pressure (BP) | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. Blood pressure includes both systolic and diastolic BP. | From screening (Day-7) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal pulse | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day-7) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal temperature | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day-7) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal respiratory | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day-7) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal findings in 12-lead safety Electrocardiogram (ECG) | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day-7) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal findings in 24h Holter | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day -1) till end of trial period | 
| Number of participants with abnormal physical examination findings | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy Japanese participants. The complete physical examinations will include an assessment of the general appearance, skin, cardiovascular, abdomen, head, and neck, lymph nodes, musculoskeletal and neurological systems. | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Hematology - absolute count of Red blood cell (RBC), White blood cell (WBC), Platelets | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Hematology-Hematocrit (HCT) | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Hematology - Hemoglobin (Hb) | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Hematology-percentage of Basophils, Eosinophils, Monocytes, Neutrophils, Lymphocytes | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Clinical Chemistry- Liver function, Renal function, Electrolyte | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants. Liver function: Alanine aminotransferase, Aspartate aminotransferase,Alkaline phosphatase, Gamma-glutamyltransferase,Total Bilirubin, Direct Bilirubin. Renal function: Creatinine,Urea,β2-microglobulin. Electrolyte: Potassium,Sodium,Chloridion,Calcium. | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Urinalysis - Urine leukocyte, urine erythrocyte,specific grvity,Glucose, Protein, urobilinogen,bilirubin, ketone, bacteria | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: coagulation function -Prothrombin Time, Activated Partial Thromboplastin Time,Thrombin Time,Fibrinogen, International Normalized Ratio | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants | From screening (Day -1) till follow-up visit (Up to 1 week) | 
| Number of participants with abnormal laboratory assessments: Fecal -Fecal Routine and Occult Blood | To investigate the safety and tolerability of Jiashen Tablets following oral administration of single and multiple ascending doses at steady state in healthy participants | From screening (Day -1) till follow-up visit (Up to 1 week) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma PK analysis: Area under curve at steady state (AUCss) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Maximum observed plasma concentration (Cmax) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Time to reach peak or maximum observed concentration following drug administration (tmax) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Observed concentration at the end of the dosing interval following drug administration at steady state (Cssmin) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Elimination half-life(t1/2) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Maximum observed plasma concentration at steady state (Cmax,ss), time to reach peak or maximum observed concentration following drug administration at steady state (tmax,ss) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve following drug administration (λz) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose | 
| Plasma PK analysis: Terminal half-life, estimated as (ln2)/λz (t½λz) | To characterize the multiple dose PK of Jiashen Tablets and assess the time required to reach steady state, the degree of accumulation and the time dependency of the PK in healthy participants. | Day 1,7/8: Pre-dose and 0.5,1.0,1.5,2.0,3.0,4.0,5.0,6.0,7.0,8.0,9.0,10,12,16,24,36,48 hours post-dose and Day 5-6/6-7: Pre-dose |