A Randomised, Double-blind, Placebo-controlled, Phase 1 First-in-human Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Food Effect of Single- and Multiple-ascending Doses of BEN8744 in Healthy Subjects.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 76
- 试验地点
- 1
- 主要终点
- Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part A)
研究概览
简要总结
BEN8744 is an experimental new medicine for treating inflammatory bowel diseases such as Ulcerative Colitis.
The study will test single and repeated oral doses of BEN8744 or placebo. BEN8744 is a first in human study, so will start with a small dose and the dose will be increased as the study progresses. The goal is to find out its side effects and blood levels when taken by mouth and whether food affects the blood levels.
This is a 3-part study (Parts A, B and C) in up to 108 healthy people, aged 18-65.
Part A, will include up to 64 participants, single doses of BEN8744 or placebo. They'll take about 2 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row and make 2 outpatient visits.
Part B, will include up to 12 participants, single doses of BEN8744 with and without food. They'll take up to 3 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row on 2 occasions, and make 2 outpatient visits.
Part C will include up to 32 participants repeat doses of the BEN8744 or placebo for 14 days. They'll take about 4 weeks to complete the study, stay on the ward for 17 nights and 18 days in a row and make 2 outpatient visits.
详细描述
This first time in human, study will investigate the safety, tolerability, pharmacokinetics (PK) of BEN8744 after single and multiple ascending oral doses in healthy subjects, in both the fed and fasted state. The results of this study will be used to select doses for subsequent studies in patients. This is an exploratory study in healthy volunteers, with no anticipated therapeutic benefit to the participants; involvement of patients, service users or members of the public in the design of the trial is not appropriate.
Primary objectives Part A: To assess the safety and tolerability of single ascending oral doses of BEN8744 in healthy subjects Part B: To characterise the effect of food on the pharmacokinetic profile of at least 1 dose of BEN8744 Part C: To assess the safety and tolerability of multiple ascending oral doses of BEN8744 in healthy subjects
Secondary objectives Part A: To assess the PK profile of BEN8744 after single oral doses in healthy subjects Part B: To assess the safety and tolerability of a single dose of BEN8744 following high-fat food intake relative to fasting conditions in healthy subjects Part C: To assess the PK profile of BEN8744 after repeated oral doses in healthy subjects
Exploratory objective
Part B (and optional in Part C):
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female healthy volunteer in good health
- •Aged 18-65 years
- •Body mass index 18.0-30.9 and weight ≥ 50 kg
排除标准
- •Woman who is pregnant or lactating, or pre-menopausal woman who is sexually active and not using a reliable method of contraception
研究组 & 干预措施
Part A Dose 1
Part A Dose 1 Single dose of 2 mg BEN8744
干预措施: BEN8744 (Drug)
Part A Dose 2
Part A Dose 2 Single dose of 6 mg BEN8744
干预措施: BEN8744 (Drug)
Part A Dose 3
Part A Dose 3 Single dose of 20 mg BEN8744
干预措施: BEN8744 (Drug)
Part A Dose 4
Part A Dose 4 Single dose of 60 mg BEN8744
干预措施: BEN8744 (Drug)
Part A Dose 5
Part A Dose 5 Single dose of 100 mg BEN8744
干预措施: BEN8744 (Drug)
Part A Dose 6
Part A Dose 6 Single dose of 120 mg BEN8744
干预措施: BEN8744 (Drug)
Part A placebo
Part A placebo Single dose of placebo
干预措施: Matching Placebo (Drug)
Part B Dose 1 fed
Part B Dose 1 Fed Single dose of BEN8744 after high-fat meal (Dose 30mg QD)
干预措施: BEN8744 (Drug)
Part B Dose 1 Fasted
Part B Dose 1 Fasted Single dose of BEN8744 after 10 hours fasting (Dose 30mg QD)
干预措施: BEN8744 (Drug)
Part B Dose 2 Fed
Part B Dose 2 Fed Single dose of BEN8744 after high-fat meal (Dose 50mg QD)
干预措施: BEN8744 (Drug)
Part B Dose 2 Fasted
Part B Dose 2 Fasted Single dose of BEN8744 after 10 hours fasting (Dose 50mg QD)
干预措施: BEN8744 (Drug)
Part C Dose 1
Part C Dose 1 14 daily doses of BEN8744 (Dose 30mg BID)
干预措施: BEN8744 (Drug)
Part C Dose 2
Part C Dose 2 14 daily doses of BEN8744 (Dose 50mg BID)
干预措施: BEN8744 (Drug)
Part C placebo
Part C placebo 14 daily doses of placebo
干预措施: Matching Placebo (Drug)
结局指标
主要结局
Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part A)
时间窗: From Baseline (predose on Day 1) through 72 hours postdose
The investigator/designee scored the participant's level of alertness on a scale of 0 (absence of response to stimulus) to 5 (readily responsive to the subject's name in a normal tone) in each of 4 components (responsiveness, speech, facial expression, eyes). The composite score corresponds to the lowest score for any component. The sum is the sum of the 4 component scores, ranging from 9 to 20. Positive change in composite score or sum is a better outcome; negative change is a worse outcome.
Change From Baseline in Visual Analogue Scale (VAS) (Part A)
时间窗: From Baseline (predose on Day 1) through 72 hours postdose
The participant graded level of alertness by placing a mark on a linear scale from 0 (very alert) to 100 (very drowsy). Negative change is a better outcome; positive change is a worse outcome.
Cmax (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Maximum (peak) plasma concentration. Calculated from plasma concentrations at time points below.
Tmax (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Time to reach maximum (peak) plasma concentration. Calculated from plasma concentrations at time points below.
AUC24 (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose in each of the 2 treatment periods (fasted and fed)
Area under the plasma concentration-time curve from time 0 to 24 hours postdose. Calculated from plasma concentrations at time points below.
AUClast (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Area under the plasma concentration-time curve from time zero to time of last measurable concentration. Calculated from plasma concentrations at time points below.
VZ/F (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Apparent volume of distribution relative to absolute bioavailability. Calculated from plasma concentrations at time points below.
AUC72 (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Area under the plasma concentration-time curve from time 0 to 72 hours postdose. Calculated from plasma concentrations at time points below.
%AUCextrap (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Percentage of AUCinf extrapolated from time of last measurable concentration to infinity. Calculated from plasma concentrations collected at time points below.
Change From Baseline in Visual Analogue Scale (VAS) (Part C)
时间窗: From Baseline (predose on Day 1) through 48 hours postdose
The participant graded level of alertness by placing a mark on a linear scale from 0 (very alert) to 100 (very drowsy). Negative change is a better outcome; positive change is a worse outcome.
Columbia-Suicide Severity Rating Scale (C-SSRS) (Part C)
时间窗: Completed during screening and on Days 17 and 24
The C-SSRS is a questionnaire completed by the Investigator, who asks yes/no questions of the participant It I used to categorise risk levels based on the responses.
AUCinf (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Area under the plasma concentration-time curve from time 0 to infinity. Calculated from plasma concentrations at time points below.
t1⁄2 (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Terminal half-life. Calculated from plasma concentrations at time points below.
Terminal Rate Constant (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Calculated from plasma concentrations at time points below.
CL/F (PK Part B)
时间窗: Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose in each of the 2 treatment periods (fasted and fed)
Systemic clearance relative to absolute bioavailability. Calculated from plasma concentrations at time points below.
Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part C)
时间窗: From Baseline (predose on Day 1) through 48 hours postdose
The investigator/designee scored the participant's level of alertness on a scale of 0 (absence of response to stimulus) to 5 (readily responsive to the subject's name in a normal tone) in each of 4 components (responsiveness, speech, facial expression, eyes). The composite score corresponds to the lowest score for any component. The sum is the sum of the 4 component scores, ranging from 9 to 20. Positive change in composite score or sum is a better outcome; negative change is a worse outcome.
次要结局
- Tmax (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- AUC72 (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Terminal Rate Constant (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Change From Baseline in Observer's Assessment of Alertness/Sedation Scale (OAAS/S) (Part B)(From Baseline (predose on Day 1) through 72 hours postdose)
- Ctrough (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- AUClast (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- %AUCextrap (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- t1⁄2 (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Cmax (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- Cmax (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- AUC24 (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours postdose)
- AUCinf (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- CL/F (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- VZ/F (PK Part A)(Plasma concentrations measured predose on Day 1 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Tmax (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- Change From Baseline in Visual Analogue Scale (VAS) (Part B)(From Baseline (predose on Day 1) through 72 hours postdose)
- AUCtau (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- AUClast (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- AUC72 (PK Part C)(At 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14)
- t1⁄2 (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- AUCinf (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- %AUCextrap (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- Terminal Rate Constant (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- CLSS/F (PK Part C)(Plasma concentrations measured at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 12.5, 13, 14, 15, 16, 20, 24, 36, 48, and 72 hours after the morning dose on Day 14)
- VZ/F (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- Rac(AUCtau) (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- Rac(Cmax) (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))
- SR(AUC) (PK Part C)(Plasma concentrations measured from predose on Day 1 through 72 hours after Day 14 dose (see specific time points above))