A Phase I, Double-Blind, Placebo-Controlled, Single and Multiple Oral Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEB-1170 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 72
- 试验地点
- 1
- 主要终点
- Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
研究概览
简要总结
Primary Objective: To determine the safety and tolerability of single and multiple ascending oral doses of MEB-1170 in healthy subjects.
Secondary Objectives:
- To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects.
- To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects.
- To assess the pharmacodynamic (PD) response following single and multiple oral doses of MEB-1170
详细描述
Study Design: This will be a double-blind, placebo-controlled, single and multiple oral dose study conducted in two parts:
Part A: SAD+FE:
Part A will comprise a single ascending dose (SAD), sequential cohort study, incorporating a food effect (FE) evaluation. Up to 40 subjects will be studied in 5 cohorts (Cohorts A1 to A5), each cohort consisting of 8 subjects (6 treated with MEB-1170, 2 treated with placebo).
Subjects in Cohorts A1, A2, A4 and A5 will participate in 1 treatment period only, residing at the CRU from Day -1 (the day before dosing) to Day 3 (48 hours postdose). Subjects in Cohort A3 will participate in 2 treatment periods (once in fasted state, once in fed state) separated by a minimum of 6 days. All subjects will return for a poststudy visit approximately 5 to 7 days after their final dose.
Each Cohort will include sentinel dosing such that two subjects (one active and one placebo) will be dosed at least 48 hours before the remaining subjects in the cohort. Continuation to dose the remaining subjects will be at the Investigator's discretion, in consultation with the Sponsor.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
盲法说明
Double Blind
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •To be eligible for this study, subjects must meet all of the following inclusion criteria:
- •Provides written IRB-approved informed consent prior to any study procedures.
- •Male or female between 18 and 55 years old (inclusive) at the time of screening.
- •In good general health at screening, free from clinically significant unstable medical, surgical or psychiatric illness, at the discretion of the Investigator.
- •Subjects have a BMI between ≥ 18.0 and ≤ 32.0 kg/m2 at screening.
- •Vital signs (measured in supine position after a 5-minute rest) at screening:
- •Systolic blood pressure ≥90 and ≤140 mmHg
- •Diastolic blood pressure ≥50 and ≤ 90 mmHg
- •Heart rate ≥45 and ≤100 bpm
- •Temperature ≥35.5 °C and ≤ 37.5 °C
- •Vital signs may be repeated once, within a minimum of 10 minutes of the completion of the last set of vital signs (while maintaining supine position until the repeated set of vital signs are collected), if it is suspected that falsely high or low levels have been obtained.
- •Adequate venous access to allow collection of multiple blood samples.
- •Negative Covid PCR test upon admission to the CRU.
- •a. Subjects in Cohort A3 will need a second COVID test prior to admission the CRU for Period
- •No relevant dietary restrictions and willingness to consume standard meals and snacks.
- •Willing to comply with all study procedures and requirements
- •Ability to tolerate the cold pressor test (determined at screening)
- •Women of childbearing potential (WOCBP) must be non-pregnant and non-lactating, and must use two acceptable, highly effective methods of contraception from screening until study completion, including the follow-up period (please see Section 9.4.2 for acceptable methods of contraception). Abstinence as a lifestyle choice is also acceptable. WOCBP must have a negative serum pregnancy test at Screening and negative urine pregnancy test at Day -1 and be willing to have additional pregnancy tests as required throughout the study. WOCBP must also use two acceptable, highly effective methods of contraception from screening until study completion, including the follow-up period and for 30 days after the last dose (please see Section 10.4.2 for acceptable methods of contraception). Women not of childbearing potential must be post menopausal for ≥12 months or be surgically sterile. Hysterectomy with retention of ovary function is permitted. Post-menopausal status will be confirmed through testing of FSH levels ≥ 40 IU/mL at screening for amenorrhoeic female subjects.
- •Male subjects must be surgically sterile (> 30 days since vasectomy per medical history or verbal confirmation), or, if engaged in sexual relations with a WOCBP, the subject and his partner must use two acceptable, highly effective methods of contraception from screening until study completion, including the follow-up period and 30 days after the last dose (please see Section 9.4.2 for acceptable methods of contraception). Abstinence as a lifestyle choice is also acceptable.
排除标准
- •To be eligible for this study, subjects must not meet any of the following exclusion criteria:
- •Pregnant or lactating at screening or baseline or planning to become pregnant (self or partner) at any time during the study, including the specified follow-up period.
- •History or presence of malignancy at screening or baseline, with the exception of adequately treated localised skin cancer (basal cell or squamous cell carcinoma) or carcinoma in-situ of the cervix.
- •Clinically significant infection within 28 days of the start of dosing, or infections requiring parenteral antibiotics within the 6 months prior to screening.
- •Clinically significant surgical procedure within 3 months of screening, at the discretion of the Investigator.
- •Currently suffering from clinically significant systemic allergic disease at screening or baseline or has a history of significant drug allergies including a history of anaphylactic reaction; allergic reaction due to any drug which led to significant morbidity.
- •Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or other immune-modifying drugs within 3 months prior to study treatment administration; corticosteroids are permitted at the discretion of the Investigator), or exposure to any significantly immune suppressing drug within 30 days prior to screening or 5 half lives, whichever is longer.
- •History or presence at screening or baseline of a condition associated with significant immunosuppression.
- •Positive test for hepatitis C (HCV), hepatitis B (HBsAg), COVID, or human immunodeficiency virus (HIV) antibody at screening.
- •Symptoms of dysphagia at screening or baseline or known difficulty in swallowing capsules.
- •Any condition at screening or baseline (eg, chronic diarrhea, inflammatory bowel disease or prior surgery of the gastrointestinal tract) that would interfere with drug absorption or any disease or condition that is likely to affect drug metabolism or excretion, at the discretion of the Investigator.
- •History or presence at screening or baseline of clinically significant cardiac arrhythmia or congenital long QT syndrome.
- •QT interval corrected using Fridericia's formula (QTcF) > 450 msec for males or >470 msec for females.
- •Use of tobacco or nicotine containing products in the previous month prior to dosing or a positive urine cotinine test at Screening or Baseline.
- •Lack of willingness to abstain from the consumption of tobacco or nicotine-containing products throughout the duration of the study and until completion of the final Follow-up visit.
- •Regular alcohol consumption defined as > 21 alcohol units per week (where 1 unit = 284 mL of beer, 25 mL of 40% spirit or a 125 mL glass of wine) or the subject is unwilling to abstain from alcohol for 48 h prior to admission and 48 h prior to Follow-up study visit.
- •Positive toxicology screening panel [urine test, including qualitative identification of barbiturates, tetrahydrocannabinol (THC), amphetamines, benzodiazepines, opiates and cocaine] or alcohol test (breath or urine) during Screening or at any time during the Study.
- •History of substance abuse or dependency or history of recreational IV drug use, over the last 5 years.
- •Use of any prescription drugs (other than permitted contraception) within 14 days prior to dosing or throughout the duration of the study, without prior approval of the Investigator and written approval of the CRO Medical Monitor.
- •Use of OTC medication including nonsteroidal anti-inflammatory drugs (NSAIDs), herbal remedies, supplements, or vitamins within 7 days prior to dosing. An exception to this is use of acetaminophen up to 4g/day to treat mild discomfort.
- •Use of any investigational drug or device within 30 days or 5 half-lives, whichever is longer, prior to screening.
- •Clinically significant blood loss, or blood or blood product donation >250 mL within 28 days of screening.
- •Subject is unwilling to refrain from strenuous exercise from 7 days prior to admission to the clinical trial unit until completion of the final onsite follow-up visit, where strenuous exercise is defined as a significant increase in the Subject's usual level of physical activity.
- •Any other reason that, in the opinion of the Investigator, might interfere with the evaluation required by the study.
研究组 & 干预措施
A2a MEB-1170
Single MEB-1170 Sentinel 60 mg Dose
干预措施: MEB-1170 (Drug)
A1a Placebo
Single Sentinel Placebo Comparator for 20 mg Dose of MEB-1170
干预措施: Placebo (Drug)
A1a MEB-1170
Single MEB-1170 Sentinel 20 mg Dose
干预措施: MEB-1170 (Drug)
A1b Placebo
Single Placebo comparator for 20 mg dose cohort of MEB-1170
干预措施: Placebo (Drug)
A1b MEB-1170
Single MEB-1170 20 mg dose cohort
干预措施: MEB-1170 (Drug)
A2a Placebo
Single Sentinel Placebo Comparator for 60 mg Dose of MEB-1170
干预措施: Placebo (Drug)
A2b Placebo
Single Placebo comparator for 60 mg dose cohort of MEB-1170
干预措施: Placebo (Drug)
A2b MEB-1170
Single MEB-1170 60 mg dose cohort
干预措施: MEB-1170 (Drug)
A3a Placebo
Single Sentinel Placebo Comparator for 120 mg Dose of MEB-1170
干预措施: Placebo (Drug)
A3a MEB-1170
Single MEB-1170 Sentinel 120 mg Dose
干预措施: MEB-1170 (Drug)
A3b Placebo
Single Placebo comparator for 120 mg dose cohort of MEB-1170
干预措施: Placebo (Drug)
A3b MEB-1170
Single MEB-1170 120 mg dose cohort
干预措施: MEB-1170 (Drug)
A4a Placebo
Single Sentinel Placebo Comparator for 200 mg Dose of MEB-1170
干预措施: Placebo (Drug)
A4a MEB-1170
Single MEB-1170 Sentinel 200 mg Dose
干预措施: MEB-1170 (Drug)
A4b Placebo
Single Placebo comparator for 200 mg dose cohort of MEB-1170
干预措施: Placebo (Drug)
A4b MEB-1170
Single MEB-1170 200 mg dose cohort
干预措施: MEB-1170 (Drug)
A5a Placebo
Single Sentinel Placebo Comparator for 400 mg Dose of MEB-1170
干预措施: Placebo (Drug)
A5a MEB-1170
Single MEB-1170 Sentinel 400 mg Dose
干预措施: MEB-1170 (Drug)
A5b Placebo
Single Placebo comparator for 400 mg dose cohort of MEB-1170
干预措施: Placebo (Drug)
A5b MEB-1170
Single MEB-1170 400 mg dose cohort
干预措施: MEB-1170 (Drug)
B1 Placebo
MAD Placebo 60 mg comparator cohort of MEB-1170
干预措施: Placebo (Drug)
B1 MEB-1170
MAD 60 mg MEB-1170 cohort
干预措施: MEB-1170 (Drug)
B2 Placebo
MAD Placebo 100 mg comparator cohort of MEB-1170
干预措施: Placebo (Drug)
B2 MEB-1170
MAD 100 mg MEB-1170 cohort
干预措施: MEB-1170 (Drug)
B3 Placebo
MAD Placebo 200 mg comparator cohort of MEB-1170
干预措施: Placebo (Drug)
B3 MEB-1170
MAD 200 mg MEB-1170 cohort
干预措施: MEB-1170 (Drug)
B4 Placebo
MAD Placebo 400 mg comparator cohort of MEB-1170
干预措施: Placebo (Drug)
B4 MEB-1170
MAD 400 mg MEB-1170 cohort
干预措施: MEB-1170 (Drug)
A3a Placebo Fed State
Single Sentinel Placebo Comparator for 120 mg Dose of MEB-1170 in Fed State
干预措施: Placebo (Drug)
A3a MEB-1170 Fed State
Single Sentinel 120 mg Dose of MEB-1170 in Fed State
干预措施: MEB-1170 (Drug)
A3b Placebo Fed State
Single Placebo comparator for 120 mg dose cohort of MEB-1170 in Fed State
干预措施: Placebo (Drug)
A3b MEB-1170 Fed State
Single MEB-1170 120 mg dose cohort in Fed State
干预措施: MEB-1170 (Drug)
结局指标
主要结局
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for hematology
时间窗: Through study completion, approximately 12 months
Hematology parameters to be tested are: • Leukocytes with differential (including Eosinophils (ESN), Neutrophils (NEUT), Basophils (BASO), Lymphocytes (LYM) and Reticulocytes (RETI)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 to assess suicidality risk
时间窗: Through study completion, approximately 12 months
Utilize C-SSRS to assess suicidality risks. Performed at screening and in both SAD and MAD
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 to assess adverse events
时间窗: Through study completion, approximately 12 months
Occurrence of all adverse events from first dose through end of study treatment and follow-up last visit will be monitored and treated as adverse events.
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for blood chemistry
时间窗: Through study completion, approximately 12 months
Biochemistry parameters to be tested - Bicarbonate (BICARB)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 including clinical laboratory assessments for urine
时间窗: Through study completion, approximately 12 months
Macroscopic urinalysis parameters to be tested - Leukocytes (WBC)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess vital signs
时间窗: Through study completion, approximately 12 months
Vital sign of respiratory rate will be measured at the time points specified in the study schedules with subjects resting for at least 5 minutes in a supine position. When the time of vital signs measurement coincides with a blood draw, the vital signs will be taken before the scheduled blood draw where possible while ensuring the blood draw is within the window specified in the protocol.
Safety and Tolerability of Single Ascending Doses of MEB-1170 for Fasting SAD and MAD laboratory assessments for blood chemistry
时间窗: Through study completion, approximately 12 months
Biochemistry parameters to be tested - Glucose (GLU) (fasting labs only)
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assessed by ECG
时间窗: Through study completion, approximately 12 months
A 12-lead ECG will be taken at the time points delineated in the study schedules. Additional ECG monitoring may be performed at other times if deemed necessary. Note that triplicate ECGs are required during SAD, while single ECGs are required during MAD. Readout QTcB
Safety and Tolerability of Single and Multiple Ascending Doses of MEB-1170 assess subjects with a physical exam
时间窗: Through study completion, approximately 12 months
Complete physical examinations will be performed by a licensed physician, nurse practitioner or physician's assistant at the time points specified in the study schedules to ensure there are no changes compared to baseline assessment physical exams.
次要结局
- To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects - AUC(Through study completion, approximately 12 months)
- To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects - Cmax(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) response using capnography following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)
- To determine the single and multiple oral dose pharmacokinetic profiles of MEB-1170 and the primary metabolite, M373, in healthy subjects - Cmax(Through study completion, approximately 12 months)
- To determine the effect of food on the pharmacokinetic (PK) profile of a single oral dose of MEB-1170 in healthy subjects - AUC(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) response of Pupillometry following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) response using oximetry following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)
- To assess the pharmacodynamic (PD) effect of analgesia using a Cold Pressor Test following single and multiple oral doses of MEB-1170(Through study completion, approximately 12 months)