A First-in-human, Randomised, Double-blind, Placebo-controlled, Single Ascending Dose Trial to Evaluate Safety, Tolerability, and Pharmacokinetics of APC148 in Healthy Adults
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Incidence and intensity of adverse events (AEs)
研究概览
简要总结
The purpose of this first-in-human trial is to investigate the safety, tolerability, and pharmacokinetics of APC148 after intravenous (IV) infusion of single ascending doses in healthy adults.
详细描述
Participants will receive a single 3-hours IV infusion of APC148 or placebo. 6 sequential cohorts are planned. The first 2 subjects in each cohort will be dosed in a sentinel fashion. The subjects will be followed for 7 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
This is a double-blind trial.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Willing and able to give written informed consent for participation in the trial.
- •Healthy females of non-childbearing potential and healthy males aged ≥18 and ≤60 years at the time of the screening visit.
- •BMI ≥ 18.5 and ≤ 30.0 at the time of the screening visit, and body weight of ≥50 and ≤100 kg.
- •Medically healthy participant without abnormal clinically significant medical history, physical findings, vital signs, ECG and laboratory values at the time of the screening visit, as judged by the Investigator.
- •Male participants must be willing to use condom or be vasectomised or practice sexual abstinence from heterosexual intercourse and refrain from donating sperm from the administration of investigational medicinal product (IMP) until 3 months after the administration of IMP. Any female partner of a non-vasectomised male participant who is of child-bearing potential must use a highly effective method of contraception with a failure rate of <1 % to prevent pregnancy from at least 2 weeks prior to the administration of IMP to 3 months after the administration of IMP.
- •Women of non-childbearing potential.
- •Adequate renal function at the screening visit: Creatinine estimated glomerular filtration rate (eGFR) ≥80 mL/min/1.73 m2 for participants aged 18-50 years and eGFR ≥60 mL/min/1.73 m2 for participants ≥51 years and S-creatinine ≤ upper limit of normal.
排除标准
- •History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or influence the results or the participant's ability to participate in the trial.
- •History of kidney disease or renal stone.
- •Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the administration of IMP.
- •Malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
- •Any planned major surgery within the duration of the trial.
- •After 10 minutes supine rest at the screening visit, any vital signs values outside the following ranges:
- •Systolic blood pressure: <90 or ≥140 mmHg, or
- •Diastolic blood pressure <50 or ≥90 mmHg, or
- •Pulse <40 or >90 bpm
- •A mean QTcF (QT corrected for heart rate by Fredericia's formula) interval of >450 ms after triplicate measurements. The average of the 3 QTc(F) values will be used to determine the participant's eligibility.
- •12-lead ECG:
- •with PR interval shortening < 120 ms.
- •PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre- excitation OR
- •PR interval prolongation > 220 ms OR
- •Intermittent second or third degree atrioventricular (AV) block, or AV dissociation
- •History of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome.
- •History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to APC
- •Regular use of any prescribed or non-prescribed medications, including antacids, analgesics, herbal remedies, vitamins and minerals, within 2 weeks prior to the administration of IMP, except occasional intake of paracetamol (maximum 2000 mg/day and not exceeding 3000 mg/week), as well as nasal decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10 days, at the discretion of the Investigator.
- •Any positive result at the screening visit for serum hepatitis B surface antigen, hepatitis B/C antibodies and/or HIV.
- •Positive result for drugs of abuse or alcohol at the screening visit or on admission to the trial site prior to the administration of the IMP.
- •Planned treatment or treatment with another investigational drug within 3 months prior to Day -
- •Participants consented and screened but not dosed in previous Phase I trials are not to be excluded.
- •Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than 3 times/week is allowed before the screening visit.
- •History of, or current, drug abuse, use of anabolic steroids, alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
- •Excessive caffeine consumption defined by a daily intake of > 5 cups (1 cup = approximately 240 mL) of caffeine containing beverages, as judged by the Investigator.
- •Plasma donation within 1 month of the IMP infusion or blood donation (or corresponding blood loss) during the last 3 months prior to the IMP infusion.
- •Participated in a previous cohort in the trial.
- •The Investigator considers the participant unlikely to comply with trial procedures, restrictions, and requirements.
研究组 & 干预措施
150 mg of APC148 and placebo
Cohort 2: 6 participants receives 3 hours IV administration of 150 mg APC148 and 2 participants placebo.
干预措施: APC148 and Placebo (Drug)
50 mg of APC148 and placebo
Cohort 1: 4 participants receives 3 hours IV administration of 50 mg APC148, and 2 participants placebo.
干预措施: APC148 and Placebo (Drug)
300 mg of APC148 and placebo
Cohort 3: 6 participants receives 3 hours IV administration of 300 mg APC148 and 2 participants placebo.
干预措施: APC148 and Placebo (Drug)
450 mg of APC148 and placebo
Cohort 4: 6 participants receives 3 hours IV administration of 450 mg APC148 and 2 participants placebo.
干预措施: APC148 and Placebo (Drug)
600 mg of APC148 and placebo
Cohort 5: 6 participants receives 3 hours IV administration of 600 mg APC148 and 2 participants placebo.
干预措施: APC148 and Placebo (Drug)
900 mg of APC148 and placebo
Cohort 6: 6 participants receives 3 hours IV administration of 900 mg APC148 and 2 participants placebo.
干预措施: APC148 and Placebo (Drug)
结局指标
主要结局
Incidence and intensity of adverse events (AEs)
时间窗: From start of infusion until end of trial visit Day 8
Frequency, intensity and seriousness of adverse events (AEs) will be assessed. The intensity grades is defined as mild, moderate or severe. AEs will be assessed as not related, possibly or probably related to the investigational medicinal product (IMP)
Incidence and intensity of serious adverse events (SAEs)
时间窗: From start of infusion until end of trial visit Day 8
Frequency, intensity and seriousness of Serious adverse events (SAEs) will be assessed. Assessment of causal relationship to IMP will be assessed.
Incidence and intensity of infusion-related AEs
时间窗: From start of infusion until end of trial visit Day 8
Frequency, intensity and seriousness of infusion-related adverse events (AEs) will be assessed. The intensity grades is defined as mild, moderate or severe. AEs will be assessed as not related, possibly or probably related to the investigational medicinal product (IMP)
Time course of local tolerability reactions
时间窗: Pre-dose, Day 1, Day 2 and Day 8
The infusion site area will be visually inspected before, during and after the IMP infusion. The assessment will include the Investigator's evaluation of swelling, haematoma, and erythema. In addition, each participant will assess their subjective experience of pain and pruritus. Local tolerability reactions will be recorded as infusion-related Adverse events (AEs)
Changes from baseline in blood pressure
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Systolic and diastolic blood pressure and pulse will be measured in supine position after 10 minutes of rest. Any vital signs outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in respiratory rate
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Respiratory rate will be measured in supine position after 10 minutes of rest. Any vital signs outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in physical examination
时间窗: Day -1, Day 1, Day 3 and Day 8
Assessment of different organ systems. Clinically significant and non-clinically significant abnormal findings will be summarised by treatment and dose.
Changes from baseline in Clinical Laboratory Profile
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Safety laboratory data, Clinical chemistry, haematology, and coagulation, will be measured. Any values outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in body temperature
时间窗: Day1, Day 2, Day 3 and Day 8
Body temperature will be measured in supine position after 10 minutes of rest. Any vital signs outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in QRS interval
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG machine. QRS intervals will be recorded. Any values outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in heart rate
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Heart rate will be measured in supine position after 10 minutes of rest. Any vital signs outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in PQ/PR interval
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG machine. PQ/PR intervals will be recorded. Any values outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in QT interval
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG machine. QT intervals will be recorded. Any values outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
Changes from baseline in QTcF interval
时间窗: Day -1, Day 1, Day 2, Day 3 and Day 8
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG machine. QTcF intervals will be recorded. Any values outside of normal ranges will be judged as clinically significant or not clinically significant by the Investigator.
次要结局
- APC148 plasma concentrations(Day 1, Day 2 and Day 3)
- PK parameter in plasma - Vz(Day 1, Day 2, Day 3)
- PK parameter in plasma - AUC0-inf(Day 1, Day 2, Day 3)
- PK parameter in plasma - AUC0-last(Day 1, Day 2, Day 3)
- PK parameter in plasma - T1/2(Day 1, Day 2, Day 3)
- PK parameter in plasma - Clearance (CL)(Day 1, Day 2, Day 3)
- PK parameters in urine - fe(Day 1 and Day 2)
- Pharmacokinetic (PK) parameter in plasma - Area under curve (AUC) 0-24(Day 1, Day 2, Day 3)
- PK parameter in plasma - Cmax(Day 1, Day 2, Day 3)
- PK parameter in plasma - Tmax(Day 1, Day 2, Day 3)
- PK parameter in plasma - Vss determination of plasma concentrations will be collected.(Day 1, Day 2, Day 3)
- PK parameters in urine - A(e)(Day 1 and Day 2)
- APC148 urine concentrations(Day 1 and Day 2)
- PK parameter in urine - renal clearance (CLr)(Day 1 and Day 2)