A Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-64140284 in Healthy Participants

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03180762
• Other study ID #: CR108318
• Secondary ID: 2017-000283-1664
• Status: Terminated
• Phase: Phase 1
• Start date: May 30, 2017
• Est. completion date: September 25, 2017

Study information

• Verified date: October 2018
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 36
• Est. completion date: September 25, 2017
• Est. primary completion date: September 25, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Part 3:

• 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

Part 3:

• participants having a contraindication for spinal puncture including:

1. 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

2. Allergy to local anesthetics and/or iodine/disinfectants

3. Clinically significant abnormal values for coagulation at screening

4. Use of aspirin (even low dose) within 5 days prior to lumbar puncture

5. Use of low molecular weight heparin (LMWH) within 12 hours prior to lumbar puncture

6. Use of any anticoagulant treatment (besides LMWH described above) within 1 week prior to lumbar puncture

7. Has a topical infection or local dermatological condition at the puncture site prior to puncture

8. Has papilloedema or signs of increased intracranial pressure based on fundoscopy at screening

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• JNJ-64140284 0.1 mg
0.1 mg of JNJ-64140284 will be administered as an oral solution.
• JNJ-64140284 0.5 mg
0.5 mg of JNJ-64140284 will be administered as an oral solution.
• JNJ-64140284 2.5 mg
2.5 mg of JNJ-64140284 will be administered as an oral solution.
• JNJ-64140284 10 mg
10 mg of JNJ-64140284 will be administered as an oral solution.
• JNJ-64140284 50 mg
50 mg of JNJ-64140284 will be administered as an oral solution.
• JNJ-64140284 150 mg
150 mg of JNJ-64140284 will be administered as an oral solution.
• JNJ-64140284 (dose to be determined [TBD])
JNJ-64140284 (dose to be determined) will be administered as an oral solution.
• Placebo
Matching placebo will be administered.

Locations

Country	Name	City	State
Belgium	Clinical Pharmacology Unit	Merksem

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability: Part 1, Part 2, and Part 3	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.	Approximately 40 days
Primary	Maximum Plasma Concentration (Cmax) of JNJ-64140284: Part 1, Part 2, and Part 3	The Cmax is the maximum observed plasma concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Maximum Cerebrospinal Fluid (CSF) Concentration (Cmax) of JNJ-64140284: Part 3	The Cmax is the maximum observed CSF concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Primary	Last Quantifiable Plasma Concentration (Clast) of JNJ-64140284: Part 1, Part 2, and Part 3	The Clast is the last quantifiable plasma concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Last Quantifiable CSF Concentration (Clast) of JNJ-64140284: Part 3	The Clast is the last quantifiable CSF concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Primary	Time to Reach Maximum Plasma Concentration (Tmax) of JNJ-64140284: Part 1, Part 2, and Part 3	The Tmax is defined as actual sampling time to reach maximum observed plasma concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Time to Reach Maximum CSF Concentration (Tmax) of JNJ-64140284: Part 1, Part 2, and Part 3	The Tmax is defined as actual sampling time to reach maximum observed CSF concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Primary	Time of the Last Quantifiable Plasma Concentration (Tlast) of JNJ-64140284: Part 1, Part 2, and Part 3	The Tlast is defined as the time of the last quantifiable plasma concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Time of the Last Quantifiable CSF Concentration (Tlast) of JNJ-64140284: Part 3	The Tlast is defined as the time of the last quantifiable CSF concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Primary	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	The (AUC [0-last]) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	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	The (AUC [0-last]) is the area under the CSF concentration-time curve from time 0 to time of the last quantifiable concentration.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Primary	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	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.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Area Under the CSF Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of JNJ-64140284: Part 3	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.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours post dose
Primary	Elimination Rate Constant (Lambda[z]) of JNJ-64140284: Part 1, Part 2, and Part 3	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.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Elimination Half-life (t1/2) of JNJ-64140284: Part 1, Part 2, and Part 3	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).	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Primary	Total Clearance (CL/F) of JNJ-64140284: Part 1, Part 2, and Part 3	CL/F is the total clearance of drug after extravascular administration, uncorrected for absolute bioavailability.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Creatinine Clearance (CLcr) of JNJ-64140284: Part 1, Part 2, and Part 3	CLcr will be determined with the Cockcroft-Gault formula.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose
Primary	Amount of Drug Excreted in Urine From Time Zero to Infinite Time (Aeinf): Part 1	Aeinf is the cumulative amount of study drug excreted into urine from time of dosing extrapolated to time infinity.	0-1, 1-2, 2-4, 4-12, and 12-24 hours post dose
Primary	Renal Clearance (CLr): Part 1	The CLr is the renal clearance of the drug.	0-1, 1-2, 2-4, 4-12, and 12-24 hours post dose
Secondary	Bond & Lader Visual Analogue Scale (VAS) Score: Part 1 and Part 3	The VAS is a participant rated scale, made up of 16 (items) pairs of alternative descriptors of mood and attention at either end of a 10 cm line. The item score ranges from 0 to 100, with a high score reflecting a high level of anxiety, sedation or dysphoria.	Days -1, 1, 2 and 3
Secondary	Karolinska Sleepiness Scale (KSS) Score: Part 1 and Part 3	The KSS is a participant-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging from 'extremely alert' (1) to 'very sleepy, great effort to keep awake, fighting sleep' (9).	Days -1, 1, 2 and 3
Secondary	Profile of Mood States (POMS) Score: Part 1 and Part 3	The POMS is a self-administered scale that assesses individuals' mood states. This is a validated scale to measure positive and negative mood states. The POMS contains 30 items describing the feeling/mood state rated by participants on a 5-point scale (where, 0=not at all and 4=extremely). The greater the score, the greater the corresponding mood state.	Days -1, 1, 2 and 3
Secondary	Body Sway: Part 1	Body sway will be used to measure body movements, providing a measure of postural stability. The method has been used to demonstrate effects of sleep deprivation, alcohol, and benzodiazepines. It will be measured either using a stabilometric platform or a pot string meter based on the Wright ataxiameter.	Days -1, 1, 2 and 3
Secondary	Cognitive Test Battery: International Shopping List Test (ISLT): Part 1	The ISLT is a measure of Verbal Learning. The test measures total number of correct responses remembering the word list on 3 consecutive trials at a single assessment. Higher score indicates better performance.	Days -21 to -2, Day -1, and Day 1 (6 hours post dose)
Secondary	Cognitive Test Battery: Groton Maze Learning Test (GMLT): Part 1	GMLT is a measure of Executive Function and Spatial Learning. The test measures total number of errors made while locating and learning 28 step pathway hidden beneath a 10*10 grid on 5 consecutive trials during a single session. Lower score indicates better performance.	Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose)
Secondary	Cognitive Test Battery: Detection Task (DET): Part 1	DET is a measure of Psychomotor Function. The test measures speed of performance; mean of the log10 transformed reaction times for correct responses. Lower score indicates better performance.	Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose)
Secondary	Cognitive Test Battery: Identification Task (IDN): Part 1	IDN is a measure of Attention. The test measures speed of performance; mean of the log10 transformed reaction times for correct responses. Lower score indicates better performance.	Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose)
Secondary	Cognitive Test Battery: One Card Learning Task (OCL): Part 1	OCL is a measure of Visual Learning. The test measures accuracy of performance; arcsine transformation of the square root of the proportion of correct responses. Higher score indicates better performance.	Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose)
Secondary	Cognitive Test Battery: One Back Task (ONB): Part 1	ONB is a measure of Working Memory. The test measures speed of performance; mean of the log10 transformed reaction times for correct responses. Lower score indicates better performance.	Days -21 to -2, Day -1, Day 1 (2, 4, 6, and 12 hours post dose), and Day 2 (24 hours post dose)
Secondary	Cognitive Test Battery: Groton Maze Learning Test (GMLT) Delayed Recall: Part 1	GMLT delayed recall is a measure of Delayed Spatial Memory. The test measures number of errors made while locating 28 step pathway hidden beneath a 10*10 grid after a delay. Lower score indicates better performance.	Days -21 to -2, Day -1, and Day 1 (6 hours post dose)
Secondary	Cognitive Test Battery: International Shopping List Test Delayed (ISLT-D): Part 1	ISLT-D is a measure of Delayed Verbal Memory. The test measures total number of correct responses recalling the word list learned initially. Higher score indicates better performance.	Days -21 to -2, Day -1, Predose, Day 1 (6 hours post dose), and Day 2 (24 hours post dose)
Secondary	Sheehan Irritability Scale (SIS) Score: Part 1 and Part 3	The SIS is a 7-item self-report rating scale that assess symptoms of irritability, frustration, edginess/impatience, moodiness, anger with self, anger with others and temper during the past hour. Each item is assessed on an 11-point numeric rating scale ranging from 0 (not at all) to 10 (extremely). The SIS total score is calculated by summing of the scores for each of the 7 individual items and ranges from 0 to 70. A higher score indicates greater symptomatology.	Day -1, Day 1 (6 and 12 hours post dose), and Day 2 (24 hours post dose)
Secondary	Cerebrospinal Fluid (CSF) Biomarkers Level: Brain Derived Neurotrophic Factor (BDNF): Part 3	BDNF level in the CSF (a CSF biomarker) will be analyzed to evaluate the pharmacodynamic effect of JNJ-64140284.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours post dose
Secondary	Cerebrospinal Fluid (CSF) Biomarkers Level: Monoaminergic Neurotransmitters and Their Metabolites: Part 3	Monoaminergic neurotransmitters (such as dopamine, serotonine and [nor]adrenaline) and their metabolites (such as homovanillic acid [HVA], 3,4-dihydroxyphenyl glycol [DHPG], 5-hydroxyindoleacetic acid [5-HIAA], 3,4-dihydroxyphenylalanine [DOPA], and 3,4-dihydroxyphenylacetic acid [DOPAC]) in the CSF (CSF biomarkers) will be analyzed to evaluate the pharmacodynamic effect of JNJ-64140284.	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours post dose