A Phase I, Double-Blind Single and Multiple Ascending Dose Study to Assess Safety and Pharmacokinetics of A4250 as Monotherapy, and in Combination With Colonic Release Cholestyramine (A3384) or Commercially Available Cholestyramine (Questran™) in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Albireo
- 入组人数
- 94
- 主要终点
- Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma C4
研究概览
简要总结
The primary objectives of the study are to evaluate the safety, tolerability and pharmacokinetics of A4250 after single or multiple oral doses in healthy subjects. In addition, will evaluate A4250 in combination with cholestyramine.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Healthy males or non-pregnant, non-lactating healthy females
- •BMI of 18 to 32 kg/m2 or, if outside the range, considered not clinically significant by the investigator
- •Willing and able to communicate and participate in the whole study
- •Provided written informed consent
- •Agreed to use an adequate method of contraception
排除标准
- •Had participated in a clinical research study within the previous 3 months
- •Were study site employees, or immediate family members of a study site or sponsor employee
- •Had previously been enrolled in this study
- •History of any drug or alcohol abuse in the past 2 years
- •Regular alcohol consumption, in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
- •Current smokers and those who had smoked within the last 12 months. A breath carbon monoxide (CO) reading of greater than 10 ppm at screening
- •Females of childbearing potential who were pregnant or lactating (female subjects must have had a negative urine pregnancy test at admission)
- •Did not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
- •Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator
- •Positive drugs of abuse test result
- •Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
- •History of cardiovascular, renal, hepatic, chronic respiratory or GI disease as judged by the investigator
- •Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients eg lactose or contraindications to cholestyramine/Questran
- •Presence or history of clinically significant allergy requiring treatment as per the judgement of the investigator Hayfever was allowed unless it was active
- •Donation or loss of greater than 400 mL of blood within the previous 3 months
- •Were taking, or had taken, any prescribed or over-the-counter drug (other than up to 4 g per day paracetamol, hormone replacement therapy [HRT] and hormonal contraception) or herbal remedies in the 14 days before IMP administration unless they were not considered to have interfered with the objectives of the study, as agreed by the PI and sponsor's medical monitor on a case by case basis
- •Failed to satisfy the investigator of fitness to participate for any other reason
研究组 & 干预措施
Cohort 1 SAD - 0.1 mg A4250
Dose: 0.1 mg of A4250. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart).
干预措施: A4250 (Drug)
Cohort 2 SAD - 0.3 mg A4250
Dose: 0.3 mg of A4250.
干预措施: A4250 (Drug)
Cohort 3 SAD - 1 mg A4250
Dose: 1 mg A4250.
干预措施: A4250 (Drug)
Cohort 4 SAD - 3 mg A4250
Dose: 3 mg A4250.
干预措施: A4250 (Drug)
Cohort 5 SAD - 10 mg A4250
Dose: 10 mg A4250.
干预措施: A4250 (Drug)
Cohort 1 SAD placebo
Dose: 0.1 mg of A4250 matching placebo. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart).
干预措施: Placebo (Drug)
Cohort 2 SAD placebo
Dose: 0.3 mg A4250 matching placebo.
干预措施: Placebo (Drug)
Cohort 3 SAD placebo
Dose: 1 mg A4250 matching placebo.
干预措施: Placebo (Drug)
Cohort 4 SAD placebo
Dose: 3 mg A4250 matching placebo.
干预措施: Placebo (Drug)
Cohort 5 SAD placebo
Dose: 10 mg A4250 matching placebo.
干预措施: Placebo (Drug)
Cohort 1 MAD - 1 mg A4250 qd
Dose: 1 mg A4250 qd for 7 days.
干预措施: A4250 (Drug)
Cohort 1 MAD placebo
Dose: 1 mg A4250 matching placebo qd for 7 days.
干预措施: Placebo (Drug)
Cohort 2 MAD - 3 mg A4250
Dose: 3 mg A4250 qd for 7 days
干预措施: A4250 (Drug)
Cohort 2 MAD placebo
Dose: 3 mg A4250 matching placebo qd for 7 days.
干预措施: Placebo (Drug)
Cohort 3 MAD - 1.5 mg A4250 b.i.d for 7 days.
Dose: 1.5 mg A4250 b.i.d. for 7 days.
干预措施: A4250 (Drug)
Cohort 3 MAD placebo
Dose: 1.5 A4250 matching placebo b.i.d for 7 days.
干预措施: Placebo (Drug)
Cohort 4 MAD - 3 mg A4250 qd + 1 mg Questran b.i.d
Dose: 3 mg A4250 qd + 1 mg Questran b.i.d for 7 days.
干预措施: A4250 (Drug)
Cohort 4 MAD - 3 mg A4250 qd + 1 mg Questran b.i.d
Dose: 3 mg A4250 qd + 1 mg Questran b.i.d for 7 days.
干预措施: Questran (Drug)
Cohort 4 MAD A4250 placebo + 1 mg Questran b.i.d
Dose: 3 mg A4250 matching placebo + 1 mg Questran b.i.d for 7 days.
干预措施: Questran (Drug)
Cohort 4 MAD A4250 placebo + 1 mg Questran b.i.d
Dose: 3 mg A4250 matching placebo + 1 mg Questran b.i.d for 7 days.
干预措施: Placebo (Drug)
Cohort 5 MAD - 3 mg A4250 qd + 1 g CRC b.i.d
Dose: 3 mg A4250 qd + 1 g CRC b.i.d for 7 days.
干预措施: A4250 (Drug)
Cohort 5 MAD - 3 mg A4250 qd + 1 g CRC b.i.d
Dose: 3 mg A4250 qd + 1 g CRC b.i.d for 7 days.
干预措施: CRC (A3384) (Drug)
Cohort 5 MAD A4250 placebo + CRC placebo
Dose: 3 mg A4250 matching placebo qd + 1 g CRC placebo b.i.d for 7 days
干预措施: Placebo (Drug)
Cohort 6 MAD - 1 g CRC
Dose: 1 g CRC b.i.d
干预措施: CRC (A3384) (Drug)
Cohort 6 MAD CRC placebo
Dose: 1 g CRC matching placebo b.i.d.
干预措施: Placebo (Drug)
Cohort 7 MAD - 3 mg A4250 qd + 1 g CRC b.i.d
Dose: 3 mg A4250 qd + 1 g CRC b.i.d
干预措施: A4250 (Drug)
Cohort 7 MAD - 3 mg A4250 qd + 1 g CRC b.i.d
Dose: 3 mg A4250 qd + 1 g CRC b.i.d
干预措施: CRC (A3384) (Drug)
Cohort 7 MAD A4250 placebo + CRC placebo
Dose: 3 mg A4250 matching placebo qd + 1 g CRC matching placebo b.i.d.
干预措施: Placebo (Drug)
结局指标
主要结局
Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma C4
时间窗: AUC(0-12) on Day 7 (only Part II)
Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma Total Bile Acids
时间窗: AUC(0-12) on Day 7 (only Part II)
Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following A Single Oral 10 mg A4250 Dose - Tmax
时间窗: Pharmacokinetic blood samples were taken pre-dose, and post-dose at: 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours
Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - Cmax
时间窗: Pharmacokinetic blood samples were taken pre-dose, and post-dose at: 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours
Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - AUC 0-t
时间窗: Pharmacokinetic blood samples were taken pre-dose, and post-dose at: 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours
Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 4 h Post-Dose
时间窗: Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 24 h Post-Dose
时间窗: Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Change in C4 from Day 1 Pre-Dose to 4 h Post-Dose
时间窗: Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Change in Faecal Total Bile Acids Excreted (ng) from Day 1 Pre-Dose on Day 7 Post-Dose
时间窗: Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose
Mean (SD) Change in C4 from Day 1 Pre-Dose to 24 h Post-Dose
时间窗: Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Changes in Total Bile Acids for A4250 24 h compared to pre-dose
时间窗: Samples were taken pre-dose, and post-dose at 4 hours and 24 hours.
Mean (SD) Changes in Total Bile Acids for A4250 4 h compared to pre-dose
时间窗: Samples were taken pre-dose and post-dose at 4 hours and 24 hours.
Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma FGF19
时间窗: AUC(0-12) on Day 7 (only for Part II)
Mean (SD) Changes in Faecel Total Bile Acids from Day 1 Pre-Dose on Day 7 at 24 h Post-dose
时间窗: Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose
次要结局
未报告次要终点