Multiple Ascending Dose Phase I Study of the M1 Positive Allosteric Modulator VU0467319
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Safety and Tolerability
研究概览
简要总结
This is a safety study of the molecule VU319 to ascertain pharmacokinetic and pharmacodynamic data and test cognitive enhancement in healthy volunteers.
详细描述
Alzheimer's Disease (AD) is a chronic and irreversible neurodegenerative disease characterized by the deterioration of memory and other cognitive functions, progressive impairments in normal daily living, and severe neuropsychiatric symptoms and behavioral disturbances. Currently, there is no available prevention or cure for AD. Therapeutic strategies for the cognitive impairments in AD involve only symptomatic treatments, primarily through enhancement of cholinergic neurotransmission using AChEIs.
Primary objectives To establish the safety and tolerability of multiple dose (up to VU319 steady state) VU319 administration in healthy volunteers To establish the maximum tolerated dose of multiple dose (up to VU319 steady state) VU319 administration in healthy volunteers To characterize the plasma pharmacokinetics and urinary excretion of VU319 and metabolite after single dose oral administration in healthy volunteers Secondary objectives To establish the effect of food on the bioavailability and pharmacokinetic parameters of VU319 in healthy volunteers Exploratory Objectives To gain preliminary evidence that tolerable doses of VU319 engage central M1 receptors by 1) altering/enhancing cognitive performance, and 2) enhancing cortical event related potentials (ERP) as a measure of increased cognitive function in healthy volunteers
This will be a double blind, randomized, placebo controlled, and sequential dose escalation in male or female healthy volunteers. Gender will be balanced to the extent possible. Volunteers will receive oral VU319 multiple dose administration in the fasted state. Subjects meeting entry criteria will be enrolled in successive dose escalating cohorts of 8 subjects each (2 placebo and 6 active drug per dose level). The dose levels will be tested sequentially until the Maximum Tolerated Dose (MTD) is reached, or saturation of exposure occurs, or sustained VU319 plasma level above the safe daily exposure determined from animal toxicokinetic studies is achieved.
Clinical safety endpoints include adverse event and symptoms data, vital signs (HR, BP, Respiratory Rate, body weight), 12-lead ECG changes, and laboratory safety assessments (hematology, plasma biochemistry, coagulation, urinalysis).
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, Care Provider, Investigator)
盲法说明
Triple-blind safety study. The pharmacist is unblinded.
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
- •Men and women aged 18 through 55 years, inclusive.
- •Body mass index 18 through 32 kg/m2
- •Determined as healthy based on screening medical history, physical examination, vital signs, complete neurological examination and 12-lead ECG without clinically significant abnormalities. QTc interval with Fridericia's correction method recorded on screening and predose must be less than 450 msec for male and less than 470 in females.
- •Clinical laboratory test result without clinically significant abnormalities at screening and at admission.
- •Negative tests for Hepatitis B surface antigen, hepatitis C virus antibodies and human immunodeficiency virus (HIV-1 or HIV-2) antibody at screening.
- •Nonsmokers (use of any nicotine containing product) or ex-smokers (have ceased smoking for at least 6 months and do not use any drug for smoking cessation).
- •Negative screen for drugs of abuse at screening and admission.
- •Negative screen for alcohol at admission.
- •For Women: Must have no child-bearing potential by reason of a sterilization procedure or at least 1 year post-menopausal (i.e. 12 months without menstrual period), or menopause confirmed with follicle-stimulating hormone level of > 30 IU/L at screening.
- •For Men: Must be infertile (at least 3-months post-vasectomy), or truly abstinent of heterosexual intercourse, or heterosexual partner is not of child-bearing potential or must agree to use an effective method of contraception (condom or occlusive cap with spermicidal foam/gel/film/cream/suppository) through the study and for 28 days after last dose of study drug.
- •Able and willing to be available for the duration of the study.
- •Willing and able to give written informed consent to participate.
- •Able to understand and comply with protocol instructions.
- •Agrees not to receive any vaccination within 21 days prior to admission and through Day 7 after final discharge.
- •Agrees not to use nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to admission and through 7 days after final discharge. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day.
- •Agrees not to use nicotine-containing products from screening through 48 hours after discharge.
- •Agrees not to consume alcohol for the 72 hours prior to admission and through 48 hours after discharge.
- •Agrees not to eat grapefruit or drink grapefruit juice within 7 days prior to admission and through 24 hours after discharge.
- •Agrees to not drink caffeinated drinks from 72 hours prior to admission through discharge.
- •Agrees not to eat or drink (except water) for 8 hours before and 4 hour after dosing for all MAD cohort subjects.
排除标准
- •Individuals with significant previous or ongoing disease or disorder, based on history, physical exam, ECG, and laboratory tests, including for example: Cardiovascular diseases; hypertension; cancer or neoplasia; diabetes; hepatic, endocrine, metabolic, respiratory, renal, gastrointestinal (except appendectomy), dermatological or hematological disorders, Axis I or II psychiatric, substance use, or cognitive disorders.
- •Clinically significant infection or inflammation at time of admission.
- •Clinically significant abnormalities upon physical/neurological exam at screening.
- •Acute gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea) at admission
- •History of treatment from a physician or counselor for abuse or misuse of alcohol, non-prescription drugs, medicinal drugs or other substance abuse.
- •Any current or previous use of Class A drugs such as illicit opiate use, cocaine, ecstasy, LSD, and amphetamines (Class B). Volunteers that admit to occasional past use of cannabis will not be excluded as long as they have a negative drugs-of-abuse test at screening and admission and have been abstinent for at least 3 months.
- •An alcoholic intake greater than 21 units per week or unwillingness to stop alcohol consumption for the duration of the study. Note: 1 unit = 8 g ethanol (250 mL of beer, 1 glass wine [100 mL], 1 measure spirits [30 mL]).
- •Use of medication (including OTC and oral contraceptive agents) within 14 days of admission that may affect the safety of the subject or any study assessment, in the opinion of the investigator.
- •Use of prescribed centrally active or psychoactive agents within 28 days prior to admission.
- •Requirement for any medication that would need to be continued during the study.
- •Use of any investigational medication within 3 months prior to the start of this study or scheduled to receive an investigational drug during the course of this study.
- •Have participated in more than 2 clinical trials involving research medication use within the 12 months prior to screening.
- •History of blood donation in the 2 months prior to admission.
- •History of severe allergies or multiple adverse drug reactions.
- •Any condition, which compromises ability to give informed consent or to communicate with the investigator as required for the completion of this study.
- •The subject has been previously enrolled in the MAD study.
研究组 & 干预措施
Dose Escalation of VU319 - Dose 3
干预措施: Dose Escalation of Placebo (Drug)
Dose Escalation of VU319 - Dose 1
干预措施: Dose Escalation of VU319 (Drug)
Dose Escalation of VU319 - Dose 1
干预措施: Dose Escalation of Placebo (Drug)
Dose Escalation of Placebo - Dose 1
干预措施: Dose Escalation of VU319 (Drug)
Dose Escalation of Placebo - Dose 1
干预措施: Dose Escalation of Placebo (Drug)
Dose Escalation of VU319 - Dose 2
干预措施: Dose Escalation of VU319 (Drug)
Dose Escalation of VU319 - Dose 2
干预措施: Dose Escalation of Placebo (Drug)
Dose Escalation of Placebo - Dose 2
干预措施: Dose Escalation of VU319 (Drug)
Dose Escalation of Placebo - Dose 2
干预措施: Dose Escalation of Placebo (Drug)
Dose Escalation of VU319 - Dose 3
干预措施: Dose Escalation of VU319 (Drug)
Dose Escalation of Placebo - Dose 3
干预措施: Dose Escalation of VU319 (Drug)
Dose Escalation of Placebo - Dose 3
干预措施: Dose Escalation of Placebo (Drug)
结局指标
主要结局
Safety and Tolerability
时间窗: Changes in adverse events frequency from Baseline to 144 hours post last drug administration
Incidence of Treatment-Emergent Adverse Events
次要结局
- Cognitive Battery - Critical Flicker Fusion (CFF)(Baseline, 1 hours post last drug administration)
- Cognitive Battery - Choice Reaction Time (CRT)(Baseline, 1 hours post last drug administration)
- Cognitive Battery - Spatial Selective Attention (Posner Task)(Baseline, 1 hours post last drug administration)
- Cognitive Battery - Continuous Performance Test (Conners)(Baseline, 1 hours post last drug administration)
- Cognitive Battery - Working Memory (N-Back Test)(Baseline, 1 hours post last drug administration)
- Cognitive Battery - The Selective Reminding Task (SRT)(Baseline, 1 hours post last drug administration)
- Cognitive Battery - Trail Making Task(Baseline, 1 hours post last drug administration)
- Event-Related Potentials- Incidental Memory Tasks(Baseline, 2.5 hours post last drug administration)
- Event-Related Potentials- Auditory and Visual Oddball Tasks(Baseline, 2.5 hours post last drug administration)
- Quantitative EEG(Baseline, 2.5 hours post last drug administration)
- Behavioral Measure - Profile of Mood State (POMS)(Baseline, 1 hours post last drug administration)
- Behavioral Measure - Brief Psychiatric Rating Scale (BPRS)(Baseline, 1 hours post last drug administration)
- Behavioral Measure - Subject Visual Analogue Scale (SVAS)(Baseline, 1 hours post last drug administration)
- Behavioral Measure - Stanford Sleepiness Scale(Baseline, 0.5 hour pre each drug administration and 23.5 hour post last drug administration)
- Behavioral Measure - Physical Symptom Checklist(Baseline, 0.5 hour pre each drug administration and 23.5 hour post last drug administration)
- Actigraphy(Day-1 (Baseline) to Day 8 (23.5 hour post last drug administration))
- Behavioral Measure-Suicide Behavior Questionnaire (SBQ-R)(Day 8 (23.5 hour post last drug administration), Day 12(144 hours post last drug administration))
研究者
Paul Newhouse
MD, Principal Investigator
Vanderbilt University Medical Center