To assess the safety and tolerability of single and multiple doses of HMPL004-6599 in healthy male volunteers
This is a Phase I study with two parts: Part A: Double blind, randomized, placebo-controlled, dose-escalating, single dose study in healthy volunteers. Subjects will receive a single dose of up to 1800 mg HMPL004-6599 or matching placebo on Day 1. The planned dose levels are: 600, 1200, and 1800 mg under fed conditions with a standard meal, according to the randomization schedule. Dose levels may be repeated, or reduced if deemed appropriate by the Safety Monitoring Committee (SMC). Part B: Double blind, randomized, placebo-controlled, dose-escalating, multiple dose study in healthy male volunteers. Dose levels in Part B for 14 days are planned as 200mg TID, 400mg TID, 600mg BID and 600mg TID. These dose were jointly decided by the PI, SMC and the Sponsor based on the results from Part A. On day 14, only one dose in the morning will be administrated for all cohorts. Dose levels may be repeated, or reduced if deemed appropriate by the Safety Monitoring Committee (SMC). In Part A, cohort 1 will consist of a blinded sentinel group of two subjects; one subject will receive HMPL004-6599 and the other will receive placebo, at least 24 hours prior to dosing the remaining 6 subjects in the cohort. The remaining subjects will only be dosed after review of available safety data from the sentinel subjects. During Part A and Part B, PK sample collections will take place. During Part A, a full PK profile will be measured throughout Day 1. Samples will be collected from pre-dose to 24 hours post dose. Part B PK sample collection is based on Part A study data. A full PK testing of plasma samples from pre-dose to 8 (TID) or 12 (BID) hours post dose will be collected on the first and last dosing days. Stool samples produced at baseline before dose and day 14-15 post last dose will be collected. Concentrations of Andrographolide (AND), 14-deoxy-11,12- didehydroandrographolide (DDAND), HM5013620, neoandrographolide (NAND) and 14-deoxyandrographolide (DAND) in plasma (Part A and B) and fecal samples (Part B) will be determined for each dose level. The plasma samples will be analyzed at the lab contracted by the Sponsor.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
32
For each cohort, 6 subjects will receive HMPL004-6599
For each cohort, 2 subjects will receive placebo
Linear Clinical Research
Perth, Western Australia, Australia
Incidence of Treatment-Emergent Adverse Events
A primary objective of this study is to assess the safety of a single dose of up to 1800 mg in Part A (evaluated in planned steps of 600, 1200, and 1800 mg HMPL004-6599 under fed conditions of a standard meal), followed by multiple doses of up to 1800mg in Part B (evaluated in planned steps of 200mg TID, 400mg TID, 600mg BID and 600mg TID HMPL004-599 under fed conditions of a standard meal for 14 days ) in healthy male volunteers. The occurrence of Serious Adverse Events and Adverse Events will be evaluated during the study in order to determine this primary objective.
Time frame: Part A: single dose; Part B: 21 days
Incidence of Participants with Abnormal Laboratory Values
A further primary objective of this study is to assess the tolerability of a single dose of up to 1800 mg in Part A (evaluated in planned steps of 600, 1200, and 1800 mg HMPL004-6599 under fed conditions of a standard meal), followed by multiple doses of up to 1800mg in Part B (evaluated in planned steps of 200mg TID, 400mg TID, 600mg BID and 600mg TID HMPL004-599 under fed conditions of a standard meal for 14 days ) in healthy male volunteers. The occurrence of abnormal laboratory values will be reviewed during the study in order to determine this primary objective.
Time frame: Part A: single dose; Part B: 21 days
Maximum Plasma Concentration [Cmax]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the Cmax determination after single (Part A) and multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part A: single dose; Part B: 21 days
Area Under The Concentration Time Curve Up To The Time 't' [AUC0-t]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the AUC0-t determination after single (Part A) and multiple (Part B) oral doses in healthy male volunteers.
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Time frame: Part A: single dose; Part B: 21 days
Time of Maximum Plasma Drug Concentration [Tmax]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the Tmax determination after single (Part A) and multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part A: single dose; Part B: 21 days
Area Under The Concentration Time Curve Up To The Last Data Point Above LOQ [AUClast]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the AUClast determination after single (Part A) and multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part A: single dose; Part B: 21 days
Apparent Half-Life For Designated Elimination Phases [t1/2]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the t1/2 determination after single (Part A) and multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part A: single dose; Part B: 21 days
Area Under The Concentration-Time Curve During Once Dosing Interval [AUCTau or AUC0-_]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the AUCTau or AUC0-\_determination after multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part B: 21 days
Minimum Observed Concentration [Cmin]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the AUCTau or AUC0-\_determination after multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part B: 21 days
Average Concentration [Cavg]
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the Cavg determination after multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part B: 21 days
%_Fluctuation
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the %\_Fluctuation determination after multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part B: 21 days
Accumulation Ratio_obs
Plasma concentration of HMPL004-6599 to evaluate protocol specified Pharmacokinetic parameters. Where these PK parameters are derived from plasma concentrations of AND, DDAND, HM5013620, DAND and NAND and include but are not limited to the Accumulation Ratio\_obs determination after multiple (Part B) oral doses in healthy male volunteers.
Time frame: Part B: 21 days