Clinical trial NCT04051801: Multiple Ascending Dose Putative Cognitive Enhancer VU319
Official title: Multiple Ascending Dose Phase I Study of the M1 Positive Allosteric Modulator VU0467319
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Cognitive Impairment
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2019-08-09
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a safety study of the molecule VU319 to ascertain pharmacokinetic and pharmacodynamic data and test cognitive enhancement in healthy volunteers.

Detailed description: 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).

Eligibility criteria: Inclusion Criteria:

1. Men and women aged 18 through 55 years, inclusive.
2. Body mass index 18 through 32 kg/m2
3. 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.
4. Clinical laboratory test result without clinically significant abnormalities at screening and at admission.
5. Negative tests for Hepatitis B surface antigen, hepatitis C virus antibodies and human immunodeficiency virus (HIV-1 or HIV-2) antibody at screening.
6. 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).
7. Negative screen for drugs of abuse at screening and admission.
8. Negative screen for alcohol at admission.
9. 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.
10. 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.
11. Able and willing to be available for the duration of the study.
12. Willing and able to give written informed consent to participate.
13. Able to understand and comply with protocol instructions.
14. Agrees not to receive any vaccination within 21 days prior to admission and through Day 7 after final discharge.
15. 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.
16. Agrees not to use nicotine-containing products from screening through 48 hours after discharge.
17. Agrees not to consume alcohol for the 72 hours prior to admission and through 48 hours after discharge.
18. Agrees not to eat grapefruit or drink grapefruit juice within 7 days prior to admission and through 24 hours after discharge.
19. Agrees to not drink caffeinated drinks from 72 hours prior to admission through discharge.
20. Agrees not to eat or drink (except water) for 8 hours before and 4 hour after dosing for all MAD cohort subjects.

Exclusion Criteria:

1. 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.
2. Clinically significant infection or inflammation at time of admission.
3. Clinically significant abnormalities upon physical/neurological exam at screening.
4. Acute gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea) at admission
5. History of treatment from a physician or counselor for abuse or misuse of alcohol, non-prescription drugs, medicinal drugs or other substance abuse.
6. 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.
7. 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 \[30 mL\]).
8. 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.
9. Use of prescribed centrally active or psychoactive agents within 28 days prior to admission.
10. Requirement for any medication that would need to be continued during the study.
11. 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.
12. Have participated in more than 2 clinical trials involving research medication use within the 12 months prior to screening.
13. History of blood donation in the 2 months prior to admission.
14. History of severe allergies or multiple adverse drug reactions.
15. Any condition, which compromises ability to give informed consent or to communicate with the investigator as required for the completion of this study.
16. The subject has been previously enrolled in the MAD study.

Primary outcomes:
measure: Safety and Tolerability
timeFrame: Changes in adverse events frequency from Baseline to 144 hours post last drug administration
Secondary outcomes:
measure: Cognitive Battery - Critical Flicker Fusion (CFF)
timeFrame: Baseline, 1 hours post last drug administration
measure: Cognitive Battery - Choice Reaction Time (CRT)
timeFrame: Baseline, 1 hours post last drug administration
measure: Cognitive Battery - Spatial Selective Attention (Posner Task)
timeFrame: Baseline, 1 hours post last drug administration
measure: Cognitive Battery - Continuous Performance Test (Conners)
timeFrame: Baseline, 1 hours post last drug administration
measure: Cognitive Battery - Working Memory (N-Back Test)
timeFrame: Baseline, 1 hours post last drug administration
measure: Cognitive Battery - The Selective Reminding Task (SRT)
timeFrame: Baseline, 1 hours post last drug administration
measure: Cognitive Battery - Trail Making Task
timeFrame: Baseline, 1 hours post last drug administration
measure: Event-Related Potentials- Incidental Memory Tasks
timeFrame: Baseline, 2.5 hours post last drug administration
measure: Event-Related Potentials- Auditory and Visual Oddball Tasks
timeFrame: Baseline, 2.5 hours post last drug administration
measure: Quantitative EEG
timeFrame: Baseline, 2.5 hours post last drug administration
measure: Behavioral Measure - Profile of Mood State (POMS)
timeFrame: Baseline, 1 hours post last drug administration
measure: Behavioral Measure - Brief Psychiatric Rating Scale (BPRS)
timeFrame: Baseline, 1 hours post last drug administration
measure: Behavioral Measure - Subject Visual Analogue Scale (SVAS)
timeFrame: Baseline, 1 hours post last drug administration
measure: Behavioral Measure - Stanford Sleepiness Scale
timeFrame: Baseline, 0.5 hour pre each drug administration and 23.5 hour post last drug administration
measure: Behavioral Measure - Physical Symptom Checklist
timeFrame: Baseline, 0.5 hour pre each drug administration and 23.5 hour post last drug administration
measure: Actigraphy
timeFrame: Day-1 (Baseline) to Day 8 (23.5 hour post last drug administration)
measure: Behavioral Measure-Suicide Behavior Questionnaire (SBQ-R)
timeFrame: Day 8 (23.5 hour post last drug administration), Day 12(144 hours post last drug administration)
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Paul A Newhouse, MD
role: PRINCIPAL_INVESTIGATOR
References: