A Randomized, Investigator and Subject Blinded, Sponsor Unblinded Placebo-Controlled Phase I Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Multiple Doses of TAK-831 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event (TEAE)
研究概览
简要总结
The purpose of this study is to evaluate the safety and tolerability of TAK-831 when administered as multiple oral doses at escalating dose levels in healthy participants.
详细描述
This study is a randomized, investigator and participant blinded, sponsor unblinded, placebo-controlled, study of the safety, tolerability and pharmacokinetics of TAK-831 in up to 48 healthy volunteers, with 8 subjects in each of the 6 cohorts.
In each cohort, participants will be randomized in a 3:1 ratio to receive TAK-831 or placebo. Two formulations, oral suspension and tablet will be tested in this study. Both blood and cerebrospinal fluid (CSF) samples will be collected from selected cohorts (CSF cohorts); for the rest of the cohorts, only blood samples will be collected (non-CSF cohorts).
This single-center trial will be conducted in the United States. The overall time to participate in this study is 58 days. Participants will make multiple visits to the clinic, and 30 days after last dose of study drug for a follow-up assessment.
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 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Has at least 45 kg weight and has a body mass index (BMI) from 18.0 to 30.0 kilogram per square meter (kg/m^2), inclusive at Screening.
- •The participant is a healthy male or female not of childbearing potential adult who is aged 18 to 55 years, inclusive, at the time of informed consent and first study drug dose.
- •A male participant who is non-sterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 90 days plus half-lives (95 days) after last study drug dose.
- •A female participant with no childbearing potential, defined as a participant that has been surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who is postmenopausal (defined as continuous amenorrhea of at least 12 months and follicle stimulating hormone [FSH] greater than [>] 40 international unit per liter [IU/L]).
排除标准
- •Has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at Screening or Check-in.
- •Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as >3 drinks per day) within 5 years before the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. (1 drink=12 ounce [oz]. beer=5 oz. wine=1.5 oz. liquor.)
- •Has a QT interval with Fridericia's correction method (QTcF) >450 milliseconds (ms) (male participants) or >470 ms (female participants) or PR outside the range of 120 to 220 ms, confirmed with 1 repeat testing, at the Screening Visit or Check-in. When triplicate electrocardiogram (ECG) assessments are collected, the mean of the 3 QTcF and PR values should be used to assess this criterion.
- •Has a positive test result for hepatitis B surface antigen (HBsAg), anti- human chorionic gonadotropin (HCV), or human immunodeficiency virus (HIV) antibody/antigen at Screening.
- •Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days before Check-in. Cotinine test is positive at Screening or Check-in.
- •Has poor peripheral venous access.
- •Has donated or lost 450 milliliter (mL) or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 45 days before the first dose of study medication.
- •Has a Screening or Check-in abnormal (clinically significant) ECG. Entry of any participant with an abnormal (not clinically significant) ECG must be approved and documented by signature by the principal investigator or designee.
- •Has a supine blood pressure outside 90 to 140 millimeter of mercury (mm Hg) for systolic and 50 to 90 mm Hg for diastolic, confirmed on repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in.
- •Has a resting heart rate outside 40 to 100 beats per minute confirmed on repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in (heart rate from the ECG does not apply).
- •Has a risk of suicide according to the Investigator's clinical judgment (example, per Columbia-Suicide Severity Rating Scale [C-SSRS]), or has scored "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self-Injurious Behavior", if this behavior occurred in the past 2 years.
- •Additional Exclusion Criteria for Cohort(s) with cerebrospinal fluid (CSF) Collection:
- •Has had CSF collection performed within 30 days before Check-in.
- •Has a history of clinically significant back pain and/or injury.
- •Has local infection at the puncture site.
- •Has thrombocytopenia or other suspected bleeding tendencies noted before procedure.
- •Has developed signs and symptoms of spinal radiculopathy, including lower extremity pain and paresthesia.
- •Has any focal neurological deficit that might suggest an increase in intracranial pressure.
- •Has any abnormal findings on ophthalmological assessment/fundoscopy suggestive of raised intracranial pressure (that is, optic disc swelling/edema; (uncontrolled) hypertensive retinopathy).
- •Suffers regularly from moderate to severe headaches requiring analgesics.
- •Has lower spinal malformations (on physical examination or lumbar spine radiography), local spinal infection, or other abnormalities that would exclude lumbar puncture (LP).
研究组 & 干预措施
Placebo (Pooled)
TAK-831 placebo-matching suspension, orally, once daily (QD) for up to Day 16.
干预措施: Placebo (Drug)
TAK-831 100 mg
TAK-831 100 mg, tablets, orally, QD on Days 1 and 3 to 16.
干预措施: TAK-831 Tablet T2 (Drug)
TAK-831 300 mg
TAK-831 300 mg, tablets, orally, QD on Days 1 and 3 to 16.
干预措施: TAK-831 Tablet T2 (Drug)
TAK-831 600 mg
TAK-831 600 mg, tablets, orally, QD on Days 1 and 3 to 16.
干预措施: TAK-831 Tablet T2 (Drug)
TAK-831 15 mg
TAK-831 15 mg, suspension, orally, multiple doses (MD) daily, on Days 1 and 3 to 16.
干预措施: TAK-831 Suspension (Drug)
TAK-831 800 mg
TAK-831 800 mg, suspension, orally, QD on Day 1, MD on Days 3 to 16.
干预措施: TAK-831 Suspension (Drug)
TAK-831 1200 mg
TAK-831 1200 mg, suspension, orally, QD on Day 1, MD on Days 3 to 16.
干预措施: TAK-831 Suspension (Drug)
结局指标
主要结局
Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event (TEAE)
时间窗: Baseline up to 30 days after the last dose (Up to 48 days)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug.
Percentage of Participants Who Met the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Postdose
时间窗: Baseline up to 30 days after the last dose (Up to 48 days)
Vital signs included temperature, pulse rate and blood pressure. Markedly abnormal values during treatment period were categorized as: Pulse Rate (beats/min) \<50-\>120, Systolic Blood Pressure (SBP) (mmHg) \<85-\>180, Diastolic Blood Pressure (DBP) (mmHg) \<50-\>110 and Temperature (degree centigrades) \<35.6- \>37.7.
Percentage of Participants Who Met the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Postdose
时间窗: Baseline up to 30 days after the last dose (Up to 48 days)
Clinical Laboratory parameters included tests for chemistry, hematology and urinalysis. Markedly abnormal values during treatment period were categorized as: alanine aminotransferase (ALT)\>3.0 U/L\*upper limit of normal(ULN), albumin\<25 g/L, alkaline phosphatase \>3.0 U/L\*ULN, aspartate aminotransferase \>3.0 U/L\*ULN, bilirubin \>3.42 umol/L creatinine \>177umol/L, gamma glutamyl transferase (GGT) \>3 U/L\*ULN, glucose \<2.8 mmol/L, \>19.4 mmol/L, potassium\<3 mmol/L, \>6 mmol/L, sodium \<130 mmol/L, \>150 mmol/L, protein \<0.8 g/L,\* lower limit of normal (LLN), \>1.2 g/L\*ULN, erythrocytes \<0.8 (10\^12/L)\*LLN, \>1.2 (10\^12/L)\*ULN, hematocrit (%) \<0.8\*LLN, \>1.2\*ULN, hemoglobin \<0.8 g/L\*LLN, \>1.2 g/L\*ULN, leukocytes \<0.5 (10\^9/L)\*LLN, \>1.5 (10\^9/L)\*ULN, platelets \<75(10\^9/L), \>600(10\^9/L). Only categories with values have been reported.
Percentage of Participants Who Met the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose
时间窗: Baseline up to 30 days after the last dose (Up to 48 days)
A 12-lead ECG was performed. Markedly abnormal values during treatment period were categorized as: ECG Mean Heart Rate (beats/min) \<50-\>120, PR Interval, Aggregate (msec) \<=80-\>=200, QRS Duration, Aggregate (msec) \<=80-\>=180, QT Interval, Aggregate (msec) \<=300-\>=460, QTcF Interval, Aggregate (msec) \<=300-\>=500 OR \>=30 change from baseline and \>=450 milliseconds.
次要结局
- Cmax: Maximum Observed Plasma Concentration for TAK-831(0.5 hours pre-dose and at multiple timepoint (Up to 24 hours) post-dose on Day 1)
- Cmax ss: Maximum Observed Steady-state Plasma Concentration During a Dosing Interval for TAK-831(0.5 hours pre-dose and at multiple timepoint (Up to 24 hours) post-dose on Day 16)
- Tmax: Time of First Occurrence of Cmax for TAK-831(0.5 hours pre-dose and at multiple timepoint (Up to 24 hours) post-dose on Days 1 and 16)
- AUC0-24: Area Under the Plasma Concentration-time Curve During a Dosing Interval for TAK-831(0.5 hours pre-dose and at multiple timepoint (Up to 24 hours) post-dose on Days 1 and 16)