A 3-Part, Randomized, Placebo-controlled, Double-blind, Single Ascending Dose Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-64140284 in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- JNJ-64140284 0.1 mg
- Conditions
- Healthy
- Sponsor
- Janssen Research & Development, LLC
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC [0-last]) of JNJ-64140284: Part 1, Part 2, and Part 3
- Status
- Terminated
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to investigate the safety and tolerability of JNJ-64140284 versus placebo after single oral dose administration (ascending dose levels) under fasted condition, to characterize the pharmacokinetics (PK) of JNJ-64140284 in plasma, cerebrospinal fluid (CSF) and urine after single oral dose administration and to investigate the effect of food (high fat/high calorie) on the PK of JNJ-64140284 following single oral dose administration.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Part 1 and 2:
- •Healthy male participants between 18 and 58 years of age, inclusive
- •Part 1, 2 and 3:
- •Participants must be healthy on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, retesting of an abnormal lab value(s) that may lead to exclusion will be allowed once during the screening phase. The participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study according to both the investigator and to the Janssen Safety Physician, are acceptable
- •Healthy male and female participants between 59 and 75 years of age, inclusive
- •Participants must be healthy and medically stable on the basis of clinical laboratory tests (at screening) and physical and neurological examination (at screening and at admission to the clinical unit). If the participant is medically stable with medication, inclusion can be allowed on a case by case basis with written agreement of the sponsor's responsible safety physician
- •Women must not be of childbearing potential (must be postmenopausal with amenorrhea for at least 12 months) or permanently sterilized (for example, tubal occlusion, hysterectomy, bilateral salpingectomy)
Exclusion Criteria
- •Part 1, 2 and 3:
- •Participants with a history of or current significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematological disease, lipid abnormalities, bronchospastic respiratory disease, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, Parkinson's disease, infection, or any other illness that the Investigator considers should exclude the participant
- •Participants with a serology positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) antibodies
- •Participants with a clinically significant acute illness within 7 days prior to study drug administration
- •Donation of 1 or more units (approximately 450 milliliter \[mL\]) of blood or acute loss of an equivalent amount of blood within 90 days prior to study drug administration
- •participants having a contraindication for spinal puncture including:
- •A relevant history of lower back pain or scoliosis or kyphosis and/or major (lumbar) back surgery (microdiscectomy is allowed) in the opinion of the investigator
- •Allergy to local anesthetics and/or iodine/disinfectants
- •Clinically significant abnormal values for coagulation at screening
- •Use of aspirin (even low dose) within 5 days prior to lumbar puncture
Arms & Interventions
Part 1: Cohort 1 (JNJ-64140284 or Placebo)
Participants will receive 0.1 milligram (mg) JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: JNJ-64140284 0.1 mg
Part 1: Cohort 1 (JNJ-64140284 or Placebo)
Participants will receive 0.1 milligram (mg) JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: Placebo
Part 1: Cohort 2 (JNJ-64140284 or Placebo)
Participants will receive 0.5 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: JNJ-64140284 0.5 mg
Part 1: Cohort 2 (JNJ-64140284 or Placebo)
Participants will receive 0.5 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: Placebo
Part 1: Cohort 3 (JNJ-64140284 or Placebo)
Participants will receive 2.5 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: JNJ-64140284 2.5 mg
Part 1: Cohort 3 (JNJ-64140284 or Placebo)
Participants will receive 2.5 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: Placebo
Part 1: Cohort 4 (JNJ-64140284 or Placebo)
Participants will receive 10 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: JNJ-64140284 10 mg
Part 1: Cohort 4 (JNJ-64140284 or Placebo)
Participants will receive 10 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: Placebo
Part 1: Cohort 5 (JNJ-64140284 or Placebo)
Participants will receive 50 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: JNJ-64140284 50 mg
Part 1: Cohort 5 (JNJ-64140284 or Placebo)
Participants will receive 50 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: Placebo
Part 1: Cohort 6 (JNJ-64140284 or Placebo)
Participants will receive 150 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: JNJ-64140284 150 mg
Part 1: Cohort 6 (JNJ-64140284 or Placebo)
Participants will receive 150 mg JNJ-64140284 or matching placebo under fasted condition on Day 1.
Intervention: Placebo
Part 2: Cohort 7 (JNJ-64140284)
Participants will receive JNJ-64140284 (dose to be determined - the dose of JNJ-64140284 will be determined on the basis of acceptable safety, tolerability and pharmacokinetics \[PK\] of preceding dose levels; no more than 50 percent (%) of the highest dose tested \[though as high as possible within this restriction\] and considered well tolerated in Part 1) under fed conditions on Day 1.
Intervention: JNJ-64140284 (dose to be determined [TBD])
Part 3: Cohort 8 (JNJ-64140284 or Placebo)
Participants will receive JNJ-64140284 or matching placebo (dose to be determined - dose will be determined based on PK data from previous cohorts and which will be well-tolerated in Part 1) under fasted condition on Day 1.
Intervention: JNJ-64140284 (dose to be determined [TBD])
Part 3: Cohort 8 (JNJ-64140284 or Placebo)
Participants will receive JNJ-64140284 or matching placebo (dose to be determined - dose will be determined based on PK data from previous cohorts and which will be well-tolerated in Part 1) under fasted condition on Day 1.
Intervention: Placebo
Outcomes
Primary Outcomes
Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC [0-last]) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
The (AUC \[0-last\]) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.
Time of the Last Quantifiable CSF Concentration (Tlast) of JNJ-64140284: Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
The Tlast is defined as the time of the last quantifiable CSF concentration.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(0-last) and C(0-last)/lambda(z), wherein AUC(0-last) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentrations; C(0-last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.
Total Clearance (CL/F) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
CL/F is the total clearance of drug after extravascular administration, uncorrected for absolute bioavailability.
Amount of Drug Excreted in Urine From Time Zero to Infinite Time (Aeinf): Part 1
Time Frame: 0-1, 1-2, 2-4, 4-12, and 12-24 hours post dose
Aeinf is the cumulative amount of study drug excreted into urine from time of dosing extrapolated to time infinity.
Maximum Plasma Concentration (Cmax) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
The Cmax is the maximum observed plasma concentration.
Time to Reach Maximum CSF Concentration (Tmax) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
The Tmax is defined as actual sampling time to reach maximum observed CSF concentration.
Time of the Last Quantifiable Plasma Concentration (Tlast) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
The Tlast is defined as the time of the last quantifiable plasma concentration.
Area Under the CSF Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC [0-last]) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
The (AUC \[0-last\]) is the area under the CSF concentration-time curve from time 0 to time of the last quantifiable concentration.
Elimination Half-life (t1/2) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
The t1/2 is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).
Creatinine Clearance (CLcr) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
CLcr will be determined with the Cockcroft-Gault formula.
Renal Clearance (CLr): Part 1
Time Frame: 0-1, 1-2, 2-4, 4-12, and 12-24 hours post dose
The CLr is the renal clearance of the drug.
Area Under the CSF Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of JNJ-64140284: Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
The AUC (0-infinity) is the area under the CSF concentration-time curve from time zero to infinite time, calculated as the sum of AUC(0-last) and C(0-last)/lambda(z), wherein AUC(0-last) is the area under the CSF concentration-time curve from time 0 to time of the last quantifiable concentrations; C(0-last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.
Last Quantifiable CSF Concentration (Clast) of JNJ-64140284: Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
The Clast is the last quantifiable CSF concentration.
Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability: Part 1, Part 2, and Part 3
Time Frame: Approximately 40 days
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study.
Maximum Cerebrospinal Fluid (CSF) Concentration (Cmax) of JNJ-64140284: Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
The Cmax is the maximum observed CSF concentration.
Last Quantifiable Plasma Concentration (Clast) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
The Clast is the last quantifiable plasma concentration.
Time to Reach Maximum Plasma Concentration (Tmax) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
The Tmax is defined as actual sampling time to reach maximum observed plasma concentration.
Elimination Rate Constant (Lambda[z]) of JNJ-64140284: Part 1, Part 2, and Part 3
Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Lambda(z) is first-order rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.
Secondary Outcomes
- Cerebrospinal Fluid (CSF) Biomarkers Level: Brain Derived Neurotrophic Factor (BDNF): Part 3(Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours post dose)
- Cognitive Test Battery: Identification Task (IDN): Part 1(Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose))
- Cognitive Test Battery: Groton Maze Learning Test (GMLT) Delayed Recall: Part 1(Days -21 to -2, Day -1, and Day 1 (6 hours post dose))
- Sheehan Irritability Scale (SIS) Score: Part 1 and Part 3(Day -1, Day 1 (6 and 12 hours post dose), and Day 2 (24 hours post dose))
- Bond & Lader Visual Analogue Scale (VAS) Score: Part 1 and Part 3(Days -1, 1, 2 and 3)
- Karolinska Sleepiness Scale (KSS) Score: Part 1 and Part 3(Days -1, 1, 2 and 3)
- Profile of Mood States (POMS) Score: Part 1 and Part 3(Days -1, 1, 2 and 3)
- Body Sway: Part 1(Days -1, 1, 2 and 3)
- Cognitive Test Battery: International Shopping List Test (ISLT): Part 1(Days -21 to -2, Day -1, and Day 1 (6 hours post dose))
- Cerebrospinal Fluid (CSF) Biomarkers Level: Monoaminergic Neurotransmitters and Their Metabolites: Part 3(Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours post dose)
- Cognitive Test Battery: Groton Maze Learning Test (GMLT): Part 1(Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose))
- Cognitive Test Battery: Detection Task (DET): Part 1(Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose))
- Cognitive Test Battery: International Shopping List Test Delayed (ISLT-D): Part 1(Days -21 to -2, Day -1, Predose, Day 1 (6 hours post dose), and Day 2 (24 hours post dose))
- Cognitive Test Battery: One Card Learning Task (OCL): Part 1(Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose))
- Cognitive Test Battery: One Back Task (ONB): Part 1(Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose))