A randomized, double-blind, placebo-controlled dose-escalation study of AND017 capsules in healthy subjects following oral single and multiple dose administration

INTERVENTION: This is a phase I, randomized, double‐blind, placebo‐controlled, dose‐escalation study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AND017 in healthy subjects. The study will involve two sequential parts: a single ascending dose (SAD) phase (Part A) followed by a multiple ascending dose (MAD) phase (Part B). In the SAD doses of 1, 4, 10, 20, 30, and 50 mg AND017 (n=6/dose) or placebo (n=2/dose) will be assessed in six consecutive cohorts of 8 subjects except Cohort 1 (6 subjects randomized at 4:2 to receive AND017 or placebo). In the MAD doses of 4, 10, 20, and 30 mg AND017 (n=6/dose) or placebo (n=2/dose) will be administered daily for 10 days and assessed in four consecutive cohorts of 8 subjects. Subjects will be fasted for at least 10 hours before oral administrating the investigational product AND017 or placebo capsules with 240 mL water on dosing days. Subjects in the SAD will be inpatients for approximately 4 days with study drug administered on Day 1, and subjects in the MAD will be inpatients for approximately 14 days with study drug administered on Days 1‐10. Subjects will be enrolled only in one study part and randomized to one cohort per the randomization schedule. SAD. Healthy subjects will be screened within 21 days prior to dosing. Subjects will be admitted to the clinical facility on Day ‐1 for up to 4 days. Oral administration of a single dose of AND017 or placebo capsules will occur on Day 1. Following completion of all safety assessments and sampling for PK analyses, subjects will be discharged on Day 4. Double‐blind dosing will occur in cohorts 1 through 6. In all cohorts except cohort 1, 6 participants will receive oral administrating AND017 capsules and 2 participants will receive mat CONDITION: Anaemia; ; Anaemia Blood ‐ Anaemia SECONDARY OUTCOME: Preliminarily evaluate the pharmacodynamics response of AND017 following single and multiple oral dose administration.[The parameters by which the pharmacodynamics (PD) of AND017 will be measured as below: ; ; SAD cohort evaluation (Part A): EPO and absolute reticulocyte count: actual values, maximum change and maximum percent change from baseline and time to achieve the maximum, percent of change from baseline; ; MAD cohort evaluation (Part B): EPO, Hemoglobin, absolute reticulocyte count and total RBCs: actual values, maximum change and maximum percent change from baseline and time to achieve the maximum, percent of change from baseline. ; ; SAD cohort evaluation (Part A: Cohorts 1‐6): ; 1) EPO: Blood samples will be collected on Day‐1, dosing Day at time 0 (within 1 h pre‐dose) and at 4 h, 6 h, 10 h, 12 h and 24 h post dose; ; 2) Absolute reticulocyte count: Blood samples will be collected on Day1, dosing Day at time 0 (within 1 h pre‐dose) and at, 24 h, 48 h, 72 h post dose and on Day of Follow‐up. ; ; MAD cohort evaluation (Part B: Cohorts 1‐4): ; 1) EPO: Blood samples will be collected on Day ‐1, the 1st and the 10th dosing Day at time 0 (within 1h pre‐dose) and at 4 h, 6 h, 10 h, 12 h and 24 h post dose; ; 2) Hemoglobin, RBC, absolute reticulocyte count: Blood samples will be collected on Day ‐1, at time 0(within 1h pre‐dose) on the 1st, 2nd, 4th, 6th, 8th, 10th dosing Days, 24h after the last dose, and Days of Exit and Follow‐up. ; ; Test methods: ; ; ; SAD cohort evaluation (Part A:single dose cohort): PK parameters including but not limit to ; 1) Maximum (peak) plasma concentration (Cmax), ; 2) Time to reach maximum(peak) plasma concentration following drug administration (Tmax), ; 3) Elimination half‐life (t1/2), ; 4) Area under the plasma concentration‐time curve from time zero to the last measurable concentration (AUC0‐t), PRIMARY OUTCOME: To evaluate the safety and tolerability of AND017 following single and multiple dose oral administration in healthy adult subjects.[The safety and tolerability of AND017 will be assessed from screening until the end of study or early termination visit (if applicable).; ; Safety Evaluation:; 1) Adverse Event;; 2) Clinical laboratory tests (CBC, serum biochemistry, urinalysis,; coagulation);; 3) Physical examination including cardiovascular, respiratory,; gastrointestinal and neurological systems;; 4) 12‐lead safety ECG (HR, PR, QRS, QT, QTc interval);; 5) Vital signs (blood pressure (BP), heart rate (HR), respiration rate; (RR), and temperature).; ; Part A (SAD cohort evaluation): ; 1) Physical examination will be conducted on screening, Day 1 (check‐in) and D7 (follow‐up); 2) Alcohol breath test will be conducted on screening and Day 1 (check‐in); 3) Pregnancy test will be conducted on screening, Day1 (check‐in) and Day 4 (Exit).; 4) Virology screening will be conducted on screening.; 5) Blood samples will be collected for clinical laboratory test on screening, Day 1, Day 2, Day 4 (Exit) and Day 7 (follow‐up); 6) 12‐lead ECG will be done on screening, Day 1 (check‐in and dosing period), Day 2, Day 3, Day 4 (Exit) and Day 7 (follow‐up).; 7) Vital signs will be measured on screening, Day 1 (check‐in and dosing period), Day 2, 3, 4 (Exit), and 7 (follow‐up). ; ; AE monitoring and concomitant medications monitoring will be performed the entire period from screening to follow‐up.; ; Part B (MAD cohort evaluation): ; 1) Physical examination will be conducted on screening, Day 1 (check‐in) and D17 (follow‐up); 2) Alcohol breath test and drugs of abuse screen will be conducted on screening and Day 1 (check‐in); 3) Pregnancy test will be conducted on screening, Day1 (check‐in) and Day 15 (Exit).; 4) Virology screening will be conducted on screening.; 5) Blood samples will be collected for clinical laboratory test on screening, Day 1 (check‐in), Day 2, Day 4, Day 6, Day 8, Day10, Day 15 (Exit) and Day 17 (follow‐up); 6) 12‐lead ECG will be done on screening, Day 1 (check‐in and dosing period), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 (Exit) and Day 17 (follow‐up).; 7) Vital signs will be measured on screening, Day 1 (check‐in and dosing period), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 (Exit) and Day 17 (follow‐up). ; ; AE monitoring and concomitant medications monitoring will be performed the entire period from screening to follow‐up.] ; 1. EPO: Blood was collected to the 5ml Gold‐top SST tube. The tube is filled to capacity. Invert the tube 5‐10 times after filling. Do not shake. Centrifuge the tube at 1300g for 10 min after the clot is fully formed. Transfer serum into a 5ml aliquot tube. The level of EPO in serum was measured by EPO ELISA assay. ; 2. Hemoglobin, RBC, and absolute reticulocyte count: Blood was collected to a 4ml Lavender‐top blood collection tube (EDTA), invert the tube 5‐10 times after filling to capacity. Sent sample in primary tube to a pathology lab for testing as part of routine haematology test.] To characterize the pharmacokinetics properties of AND017 in plasma following single and multiple oral dose administration.[The parameters by which the pharmacokinetics (PK) of AND017 will be measured are as below: ; 5) Area under the plasma concentration‐time curve from time zero to infinity (AUC0‐inf), ; 6) Apparent total body clearance of the drug from plasma (CL/F), ; 7) Apparent volume of distribution (Vz/F), ; 8) Mean residence time (MRT), ; 9) Terminal disposition rate constant ; 10) Percentage of AUC(0‐infinity) obtained by extrapolation (%AUCex) ; ; MAD cohort evaluation (Part B: Multiple dose cohort): PK parameters including but not limit to: ; 1) Minimum steady‐state plasma concentration during a dosage interval (Css,min) ; SAD cohort evaluation (Part A) (Cohorts 1‐6): Blood samples will be obtained on dosing Day at time 0 (within 1h pre‐dose), 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h, 72 h post dose. ; MAD cohort evaluation (Part B) (Cohorts 1‐4): Blood samples will be collected on the 1st dosing Day at time 0 (within 1 h pre‐dose), 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h post dose; within 1 h pre‐dose on the 6th, 7th, 8th dosing Day (for steady state assessment); on the 10th dosing Day at time 0 (within 1 h pre‐dose), 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 48 h and 72 h post dose. ; 2) Maximum(peak) steady‐state plasma concentration during a dosage interval (Css,max), ; 3) Average steady‐state plasma drug concentration during multiple‐dose administration (Css,avg), ; 4) Elimination half‐life (t1/2), ; 5) Time to reach Css. Max (Tss,max), ; 6) Area under the plasma concentration‐time curve during a dosage interval(t) (AUC0‐t), ; 7) Apparent total body clearance after oral administration at steady state (CLss/F), ; 8) Apparent volume of distribution at steady‐state after oral administration (Vss/F), ; 9) Terminal disposition rate constant ; 10) Accumulation ratio calculated from AUCt,ss adn AUCt (Rac (AUC)), ; 11) Accumulation ratio calculated from Cmax,ss and Cmax (Rac (Cmax)) ; 12) Dose bioavailability (DF)] INCLUSION CRITERIA: Each subject must meet the following criteria to be enrolled in this study: 1. Healthy male or female, 18‐45 years of age (both inclusive); 2. Able to give signed written informed consent form; 3. Able to remain in house for the duration of the study without interruption; 4. Body mass index (BMI, weight [kg]/height2 [m]2) within 18.0‐30.0 kg/m2 (both inclusive); 5. Blood Pressure (BP) and 12‐lead electrocardiogram (ECG) showing no clinically significant abnormalities during screening; 6. Subjects have no clinically significant abnormal values on physical examination, clinical laboratory test, liver function or kidney function; 7. Agree to completely refrain from consuming alcohol, caffeinated beverages (i.e. tea, coffee, etc.), and tobacco from 24 h pre the 1st dose until the last PK blood sample collection is finished; 8. If male, a willingness not to donate sperm and if engaging in sexual intercourse with a female partner wh