Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamic Characteristics of HHT120 in Healthy Subjects

Study Overview
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Brief Summary
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This is a first in human clinical trial with HHT120. The purpose of this study is to characterize the safety, pharmacokinetic (PK) and Pharmacodynamic (PD) profile of single and multiple twice-daily doses of HHT120 in healthy Subjects and to assess the effects of food on the PK profile of single-dose of HHT120 in healthy Subjects.

Detailed Description
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There are 3 parts of the study: Part 1: Single asending dose trial; Part 2: Multiple asending dose trial; Part 3: Food effect trial ( 2-Period Crossover)

Official Title
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A Single and Multiple Assending Doses Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamic Characteristics and Food Effect After Administration of HHT120 Capsule in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: HHT120
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who understand and are willing to follow the clinical trial protocol to complete the study and sign the informed consent voluntarily ≥50 kg, BMI 19.0-26.0 kg/m2 (including the critical value); Those who have been proved healthy by medical history inquiry, physical examination and laboratory examination. Exclusion Criteria: Have a blood coagulation dysfunction or bleeding tendency, such as repeated bleeding gums, or nearly six months increased risk of bleeding events, or platelet count < 100 x 109 / L, or always have intracranial hemorrhage (after the accident, for example), gastrointestinal bleeding, purpura, or with active pathological bleeding, bleeding or have any family history, etc. History of motor system, nervous/psychiatric system, endocrine system, blood circulation system, respiratory system, digestive system, urinary system, reproductive system abnormalities or existing diseases mentioned above, which the researcher judged to be clinically significant; History of drug or food allergy, or are allergic to the active ingredients of the test drug and any excipient ingredients; History of postural hypotension, fainting or coma; High risk factors of TdP (hypokalemia, hypomagniemia, bradycardia, heart failure, hereditary long QT syndrome, etc.); QTc interval greater than 450ms during screening; Undergone surgery within 3 months prior to or during screening, or have undergone surgery that affects drug absorption, distribution, metabolism or excretion, or plan to undergo surgery during the study period; Blood donation or massive blood loss (≥400 mL) within 3 months before screening or during screening (except female menstrual period); History of drug abuse or positive urine drug screening (morphine, THC, methylamphetamine, dimethylene dioxy-amphetamine, ketamine) within 5 years before screening; Excessive consumption of tea, coffee or caffeinated beverages (more than 8 cups per day, 1 cup =250 mL) within 3 months prior to screening or during screening; Drank regularly within 3 months prior to screening or during screening, i.e. drinking more than 14 units of alcohol per week (1 unit =360 mL beer or 45mL 40% alcohol spirits or 150mL wine), who could not abstain from drinking during the test, or whose alcohol breath test results were > 0 mg/100mL; Smoking ≥5 cigarettes per day in the previous 3 months in the screening period; Or unable to stop using any tobacco products in the treatment period; Consumed a large amount of drinks or food (such as grapefruit, grapefruit juice, grapefruit jam, etc.) rich in grapefruit, pomelo, star fruit, mango and dragon fruit within the previous 14 days prior to screening; Or any beverage or food containing grapefruit (i.e. grapefruit), pomelo, star fruit, mango, dragon fruit within 48 hours before the first dose; Special dietary requirements, unable to follow the uniform diet or dysphagia; Lactose intolerant (who had diarrhea after drinking milk); Have used any prescription drugs, over-the-counter drugs, Chinese herbal medicines or health care products within 14 days prior to screening; Received vaccination within 28 days prior to or during screening; Have participated in other clinical trials within 3 months prior to or during screening or who are not themselves participating in clinical trials; Pregnant or lactating women, or abnormal pregnancy tests that are clinically significant as determined by the investigator; Male subjects (or their partners) or female subjects who have planned to have children during the entire study period and within 6 months after the study end and are unwilling to use one or more non-drug contraceptive methods (e.g., complete abstinence, condoms, vasectomy, etc.) during the study period; Female subjects with irregular menstruation or menstrual disorder (including menstrual cycle disorder, menstrual disorder and menorrhagia); Those who cannot tolerate venipuncture or have difficulty in collecting blood; Abnormal physical examination, blood routine examination, blood biochemistry, coagulation function, urine routine examination, 12-lead electrocardiogram examination, chest X-ray examination and clinical significance determined by the investigator; Abnormal vital signs and abnormal retest; Hepatitis B surface antigen, treponema pallidum antibody, human immunodeficiency virus antibody and hepatitis C antibody are abnormal and clinically significant as determined by researchers; The investigator considers that the subjects are not suitable to participate in the study for other reasons or the subjects withdraw from the study for their own reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD HHT120<br>Subjects will receive a single dose of HHT120 from 7 doses. | Drug: HHT120<br>* Capsule, oral administration<br>* Other names: PTI-011-Cl;|
| Placebo Comparator: SAD Placebo<br>Subjects will receive a single dose of matched Placebo. | Drug: Placebo<br>* Capsule, oral administration<br>|
| Experimental: MAD HHT120<br>Subjects will receive a mutiple-dose of HHT120 twice daily for 7 days from 3 doses. | Drug: HHT120<br>* Capsule, oral administration<br>* Other names: PTI-011-Cl;|
| Placebo Comparator: MAD Placebo<br>Subjects will receive a mutiple-dose of matched placebo twice daily for 7 days. | Drug: Placebo<br>* Capsule, oral administration<br>|
| Experimental: FE K-C<br>Subjects will receive a single dose of HHT120 in the morning in fasted condition in Period 1; followed by a single dose of HHT120 administered in the morning in fed condition in Period 2. A washout period of 7 days will be maintained between 2 periods. | Drug: HHT120<br>* Capsule, oral administration<br>* Other names: PTI-011-Cl;|
| Experimental: FE C-K<br>Subjects will receive a single dose of HHT120 in the morning in fed condition in Period 1; followed by a single dose of HHT120 administered in the morning in fasted condition in Period 2. A washout period of 7 days will be maintained between 2 periods. | Drug: HHT120<br>* Capsule, oral administration<br>* Other names: PTI-011-Cl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital signs | Abnormal changes in vital signs from baseline | Up to Day 14 | 
| Physical examination | Abnormal changes in physical examination from baseline | Up to Day 14 | 
| Laboratory examination | Abnormal changes in laboratory examination from baseline | Up to Day 14 | 
| Electrocardiogram | Abnormal changes in electrocardiogram from baseline | Up to Day 14 | 
| Chest radiography | Abnormal changes in chest radiography from baseline | Up to Day 14 | 
| Adverse events | Incidence of adverse events, serious adverse events, adverse events of special interest | Up to Day 14 | 
| Maximum tolerable dose (MTD) | Maximum tolerable dose (MTD) | Up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Cmax | Cmax of single dose administration | Up to Day 4 | 
| Part 1: Tmax | Tmax of single dose administration | Up to Day 4 | 
| Part 1: t1/2 | t1/2 of single dose administration | Up to Day 4 | 
| Part 1: Vz/F | Vz/F of single dose administration | Up to Day 4 | 
| Part 1: CLz/F | CLz/F of single dose administration | Up to Day 4 | 
| Part 1: AUC | AUC of single dose administration | Up to Day 4 | 
| Part 2: Cmax,ss | Cmax,ss of multiple dose administration | Up to Day 10 | 
| Part 2: AUC,ss | AUC,ss of multiple dose administration | Up to Day 10 | 
| Part 2: Tmax,ss | tmax,ss of multiple dose administration | Up to Day 10 | 
| Part 2: Cmin,ss | Cmin,ss of multiple dose administration | Up to Day 10 | 
| Part 2: Cav,ss | Cav,ss of multiple dose administration | Up to Day 10 | 
| Part 2: t1/2 | t1/2 of multiple dose administration | Up to Day 10 | 
| Part 2: MRTss | MRTss of multiple dose administration | Up to Day 10 | 
| Part 2: Accumulation index | accumulation index of multiple dose administration | Up to Day 10 | 
| Part 1 & Part 2: aPTT, INR and TT | Maximum percentage of aPTT, INR and TT to baseline (Emax) | Up to Day 10 | 
| Part 3: Cmax in fasted or fed condition | Geometric mean ratios of Cmax (fed/fasted) and their 90% confidence intervals | Up to Day 4 | 
| Part 3: AUC in fasted or fed condition | Geometric mean ratios of AUC (fed/fasted) and their 90% confidence intervals | Up to Day 4 |