A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KR23343, and an Open-Label Assessment of Food's Effect on Its Pharmacokinetics in Healthy Adults
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events, Serious Adverse Event(s) (SAEs), And Adverse Events Leading To Study Discontinuation
研究概览
简要总结
This is a Phase I, single-center trial to assess the safety, tolerability, PK and food effect of KR23343 in healthy volunteers. The study will be conducted in 3 sequential stages:
Stage 1: Single-Ascending-Dose (SAD) study A randomized, double-blind, placebo-controlled, dose-escalation study to assess the safety, tolerability, and PK of single ascending doses of KR23343.
Stage 2: Food-Effect (FE) study An open-label, randomized, two-period, two-sequence crossover study to evaluate the effect of food on the PK of a single dose of KR23343.
Stage 3: Multiple-Ascending-Dose (MAD) study A randomized, double-blind, placebo-controlled, dose-escalation study to investigate the safety, tolerability, and PK of repeated once-daily administration of KR23343 for 10 days.
详细描述
This first-in-human study will investigate the safety, tolerability, and pharmacokinetics (PK) of KR23343 following single and multiple ascending oral doses in healthy subjects, as well as assess the effect of food on the PK of KR23343. The results of this study will be used to select doses for subsequent studies in patients.
Primary objectives:
Stage 1: To assess the safety and tolerability of single ascending oral doses of KR23343 in healthy participants. Stage 3: To assess the safety and tolerability of multiple ascending oral doses of KR23343 in healthy participants.
Secondary objectives:
Stage 1: To assess the PK profile of KR23343 following single oral doses in healthy participants and evaluate the effect of KR23343 tablets on the corrected QT interval (QTcF) and other electrocardiogram (ECG) parameters. Stage 2: To assess the PK profile, safety and tolerability of a single dose of KR23343 following high-fat food intake relative to fasting conditions in healthy participants. Stage 3: To assess the PK profile of KR23343 after repeated oral doses in healthy participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male or female participants aged 18 to 45 years, inclusive.
- •Body mass index (BMI) between 19 and 28 kg/m² (inclusive) and body weight ≥ 50 kg for males or ≥45 kg for females.
- •All screening assessments (vital signs, physical examination, laboratory tests, ECG) must be within normal limits or deemed not clinically significant by the investigator. One repeat assessment is permitted during the screening period to confirm eligibility.
- •Participants must agree not to donate gametes (sperm or ova), must not be planning pregnancy, and must use a reliable contraceptive method from the time of informed consent signing through 3 months following the last dose.
- •Able to understand study requirements, provide written informed consent, and comply with all trial procedures per protocol.
排除标准
- •Hypersensitivity or allergic to KR
- •History of severe hypersensitivity reactions or multiple drug/food allergies
- •Significant disease affecting the central nervous, cardiovascular, gastrointestinal, respiratory, renal, hematologic, metabolic, or musculoskeletal systems, or any condition considered by the Investigator to make the participant unsuitable for the trial.
- •Any surgical or medical condition that may significantly affect drug absorption, distribution, metabolism, or excretion, or compromise participant safety, including but not limited to urinary tract obstruction, dysuria, gastroenteritis, peptic ulcer disease, or history of gastrointestinal bleeding.
- •History of psychiatric disorders or cerebral dysfunction; suicidal ideation identified by the Columbia-Suicide Severity Rating Scale (C-SSRS) or investigator judgment; or history of self-harm behavior.
- •Abnormal screening investigations meeting any of the following criteria: a) Hepatic dysfunction: ALT or AST>1.5x upper limit of normal (ULN), or total bilirubin >1.3x ULN; b) Creatinine clearance <80 mL/min (calculated by Cockcroft-Gault formula: CrCl = [(140 - age) × weight (kg)] / [0.814 × Scr (μmol/L)], multiplied by 0.85 for females); c) Vital signs outside specified ranges (heart rate <50 or >100 bpm, systolic blood pressure <90 or ≥140 mmHg, diastolic blood pressure <60 or ≥90 mmHg, tympanic temperature <35.7 or >38.0°C); d) QTc-F interval ≥450 ms (males) or ≥470 ms (females), or other clinically significant ECG abnormalities; e) Any other screening abnormality deemed clinically significant by the investigator.
- •Blood loss or donation ≥400 mL within 3 months prior to screening, or planned donation during the study.
- •Use of any medication within 2 weeks (or 5 half-lives, whichever is longer) prior to screening or during the study, including prescription drugs, over-the-counter medications, Chinese herbal products, dietary supplements, vaccines, or any drug known to induce or inhibit hepatic metabolizing enzymes (e.g., CYP3A4, CYP3A5).
- •Participation in a clinical trial involving investigational products, vaccines, or devices within 3 months prior to screening, or within 5 half-lives of the last dose, whichever is longer.
- •History of drug abuse or illicit drug use within 6 months prior to screening, or positive urine drug screen.
- •Hazardous alcohol consumption ( >14 units/week; 1 unit = 360 mL beer, 25 mL 40% spirits, or 100 mL wine) within 6 months prior to screening, inability to abstain from screening through end-of-study, or positive alcohol breath test.
- •Smoking >10 cigarettes per day within the 3 months prior to screening, or inability to abstain from smoking and nicotine products during the trial.
- •Regular consumption of >8 cups/day (1 cup = 250 mL) of grapefruit juice, tea, coffee, or caffeinated beverages within the 3 months prior to screening, or inability to abstain during the trial.
- •Positive serology for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, Treponema pallidum antibody, or human immunodeficiency virus (HIV) antibody.
- •Pregnancy, lactation, or clinically significant abnormal pregnancy test as judged by the investigator.
- •Specific dietary restrictions or inability to adhere to the standardized diet during their CPU stay.
- •Difficult venous access, history of vasovagal syncope (needle or blood phobia), or inability to tolerate venipuncture.
- •Any condition or circumstance that, in the opinion of the Investigator, would make the participant unsuitable for the study.
研究组 & 干预措施
Stage 1 Dose 4
Stage 1 Dose 4 Single dose of 45 mg
干预措施: KR23343 (Drug)
Stage 2 30 mg KR23343 Fed state
KR23343 oral single dose with food
干预措施: KR23343 (Drug)
Stage 2 30 mg KR23343 Fasted state
KR23343 oral single dose without food
干预措施: KR23343 (Drug)
Stage 3 Dose 1
KR23343 oral daily dose for 10 days (Dose 20mg QD )
干预措施: KR23343 (Drug)
Stage 3 Dose 2
KR23343 oral daily dose for 10 days (Dose 30mg QD )
干预措施: KR23343 (Drug)
Stage 3 Dose 3
KR23343 oral daily dose for 10 days (Dose 45 mg QD )
干预措施: KR23343 (Drug)
Stage 3 placebo
Placebo oral daily dose for 10 days
干预措施: Matching Placebo (Drug)
Stage 1 Dose 1
Stage 1 Dose 1 Single dose of 10 mg
干预措施: KR23343 (Drug)
Stage 1 Dose 5
Stage 1 Dose 5 Single dose of 60 mg
干预措施: KR23343 (Drug)
Stage 1 placebo
Stage 1 placebo Single dose of placebo
干预措施: Matching Placebo (Drug)
Stage 1 Dose 2
Stage 1 Dose 1 Single dose of 20 mg
干预措施: KR23343 (Drug)
Stage 1 Dose 3
Stage 1 Dose 3 Single dose of 30 mg
干预措施: KR23343 (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events, Serious Adverse Event(s) (SAEs), And Adverse Events Leading To Study Discontinuation
时间窗: 7 days in stage 1；21 days in stage 2; 16 days in stage 3.
The number of participants with recorded treatment emergent adverse events, SAEs, and adverse events leading to study discontinuation following single and multiple doses of KR23343
Number of participants with abnormal laboratory test results, abnormal vital signs, abnormal physical examination findings, and abnormal ECG parameters
时间窗: 7 days in stage 1；21 days in stage 2; 16 days in stage 3.
Hematology, urinalysis, clinical chemistry, coagulation studies, vital signs (tympanic temperature, pulse, sitting blood pressure), and 12-lead ECGs (including heart rate, PR, RR, QRS, QT intervals, and QTcF) will be assessed at screening, pre-dose，and at post-dose timepoints as specified in the study
次要结局
- Elimination Half-life（t1/2）of Stage1(Day 1 up to 144 hours post-dose)
- Peak Plasma Concentration (Cmax) of Stage 2(Day 1 up to 144 hours post-dose)
- Time to Cmax (Tmax) of Stage 3(Day 1 up to 144 hours post-last dose)
- Peak Plasma Concentration (Cmax) of Stage 1(Day 1 up to 144 hours post-dose)
- Area Under the Plasma Concentration Versus Time Curve (AUC) of Stage 1(Day 1 up to 144 hours post-dose)
- Time to Cmax (Tmax) of Stage 1(Day 1 up to 144 hours post-dose)
- Area Under the Plasma Concentration Versus Time Curve (AUC) of Stage 2(Day 1 up to 144 hours post-dose)
- Time to Cmax (Tmax) of Stage 2(Day 1 up to 144 hours post-dose)
- Elimination Half-life（t1/2）of Stage 2(Day 1 up to 144 hours post-dose)
- Peak Plasma Concentration (Cmax) of Stage 3(Day 1 up to 144 hours post-last dose)
- Blood and Plasma Area Under the Concentration-Time Profile From Time 0 to Time Tau (AUCtau) of Stage 3(Day 1 up to 144 hours post-last dose)
- Evaluation of the effect of time-matched plasma concentrations of KR23343 on electrocardiogram (ECG) parameters and the QTc interval, including concentration-QTc analysis for Stage 1(Day 1 up to 144 hours post-dose)