A Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-55375515 in Healthy Male Participants

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess safety and tolerability of day-time and night-time dosing of JNJ-55375515 in healthy male participants.

Official Title
-----------------
A 2-Part, Randomized, Placebo-controlled, Double-blind, Single Ascending Dose Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-55375515 in Healthy Male Subjects

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: JNJ-55375515 Dose Level 1
* Drug: JNJ-55375515 Dose Level 2
* Drug: JNJ-55375515 Dose Level 3
* Drug: JNJ-55375515 Dose Level 4
* Drug: JNJ-55375515 Dose Level 5
* Drug: JNJ-55375515 Dose Level 6
* Drug: Placebo
* Drug: JNJ-55375515


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Body Mass Index (BMI) between 18 and 30 kilogram / square meter (kg/m^2) inclusive (BMI=weight/height^2) Participant must be healthy based on clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, coagulation 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. It is expected that laboratory values will generally be within the normal range for the laboratory, though minor deviations, which are not considered to be of clinical significance to the investigator, are acceptable Participant must be healthy based on physical and neurological examination, medical history, vital signs, and 12-lead Electrocardiography (ECG) [including QTcF less than or equal to (<=) 450 millisecond (msec)] performed at screening, admission to the clinical unit and pre dose on Day 1 of Period 1. Abnormalities, which are not considered to be of clinical significance by the investigator, are acceptable. The presence of Left Bundle Branch Block (LBBB), AV Block (second degree or higher), or a permanent pacemaker or implantable cardioverter defibrillator [ICD] will lead to exclusion Non-smoker (not smoked for 3 months prior to screening) During the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study drug, in addition to the highly effective method of contraception, a man who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (for example, condom with spermicidal foam/gel/film/cream/suppository); who is sexually active with a woman who is pregnant must use a condom; must agree not to donate sperm Exclusion Criteria: History of or current significant medical illness including (but not limited to psychotic, bipolar, major depressive, or anxiety disorder) Cardiac arrhythmias or other cardiac disease, hematological disease, lipid abnormalities, 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 Serology positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) antibodies Participant has a history of or current vestibular disease including (but not limited to) Meniere's disease, benign paroxysmal positional vertigo (BPPV), vestibular neuronitis, vestibular schwannoma or vestibular migraine Only for part 2: Has a current diagnosis or history of narcolepsy, central sleep apnea, sleep related hypoventilation, circadian rhythm sleep-wake disorders, substance/medication induced sleep disorder or parasomnias (non-rapid eye movement sleep arousal disorders, nightmare disorder, rapid eye movement sleep behavior disorder); obstructive sleep apnea/hypopnea (apnea/hypopnea index greater than (>)10) or restless legs syndrome (periodic leg movements with arousal index >15); night-shift worker or significantly shifted diurnal activity pattern (it is expected that eligible participant normally wake up between 6:00 am - 8:00 am and go to bed between 10:00 pm - 12:00 am); usual bedtime outside of 10:00 pm and 12:00 am and taking, on average, less than 6 hours or more than 9 hours of bed rest

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 54 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (Panel 1): JNJ-55375515 and placebo<br>Participants will receive dose level (DL) 1 of JNJ-55375515 (starting dose) or placebo on Day 1 of period 1 based on their randomization sequence 1, 2 or 3. Dose of the study medication will be escalated to DL 3 (period 2) and a maximum of DL 5 (period 3) based on the safety and tolerability profile and pharmacodynamic (PD) profile assessed at the preceding dose level. A wash-out period of at least 10 days will be maintained between study drug administrations. | Drug: JNJ-55375515 Dose Level 1<br>* Participants will receive JNJ-55375515 orally at a Dose level 1 in Part 1 of study.<br>Drug: JNJ-55375515 Dose Level 3<br>* Participants will receive JNJ-55375515 orally at a Dose level 3 in Part 1 of study.<br>Drug: JNJ-55375515 Dose Level 5<br>* Participants will receive JNJ-55375515 orally at a Dose level 5 in Part 1 of study.<br>Drug: Placebo<br>* All participants will receive matching placebo orally in Part 1 and Part 2 of the study.<br>|
| Experimental: Part 1 (Panel 2): JNJ-55375515 and placebo<br>Participants will receive DL 2 of JNJ-55375515 (starting dose) or placebo on Day 1 of period 1 based on their randomization sequence 1, 2 or 3. Dose of the study medication will be escalated to DL 4 (period 2) and a maximum of DL 6 (period 3) based on the safety and tolerability profile and PD profile assessed at the preceding dose level. A wash-out period of at least 10 days will be maintained between study drug administrations. | Drug: JNJ-55375515 Dose Level 2<br>* Participants will receive JNJ-55375515 orally at a Dose level 2 in Part 1 of study.<br>Drug: JNJ-55375515 Dose Level 4<br>* Participants will receive JNJ-55375515 orally at a Dose level 4 in Part 1 of study.<br>Drug: JNJ-55375515 Dose Level 6<br>* Participants will receive JNJ-55375515 orally at a Dose level 6 in Part 1 of study.<br>Drug: Placebo<br>* All participants will receive matching placebo orally in Part 1 and Part 2 of the study.<br>|
| Experimental: Part 2: JNJ-55375515 and placebo<br>Participants will randomly be assigned to one of four treatment sequences 1, 2, 3 or 4. In the first 3 sequences, participants will receive 2 doses of JNJ-55375515 and placebo. Participants assigned to sequence 4 will receive placebo only in all periods. 3 dose levels will be tested in Part 2 based on Part 1 and will not exceed those evaluated in Part 1. A wash-out period of at least 10 days will be maintained between study drug administrations in period 1, 2, 3 and 4. In period 4 (open-label pharmacokinetic (PK) assessment period) participants will be randomly assigned to one of two dose levels tested in periods 1 to 3. | Drug: Placebo<br>* All participants will receive matching placebo orally in Part 1 and Part 2 of the study.<br>Drug: JNJ-55375515<br>* Participants will receive JNJ-55375515 as per the assigned treatment in Part 2.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 (Day-Time Dosing): Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Up to Week 8 | 
| Part 2 (Night-Time Dosing): Number of Participants with AEs as a Measure of Safety and Tolerability | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Up to Week 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slow Wave Activity Recorded by the Electroencephalogram (EEG) | The Effect of JNJ-55375515 on slow wave activity recorded by the electroencephalogram (EEG) will be evaluated. EEG recordings are made using gold electrodes, fixed at Midline Frontal Electrode (Fz), Midline Central Electrode (Cz), Midline Parietal Electrode (Pz) and Midline Occipital Electrode (Oz), with the same common ground electrode as for the eye movement registration (international 10/20 system). Per session eight consecutive blocks of eight seconds are recorded. For each lead, fast Fourier transform analysis will be performed to obtain the sum of amplitudes in the very low (0.5-2 Hertz [Hz]), delta- (2-4 Hz), theta (4-7.5 Hz), alpha- (7.5-13.5 Hz), beta- (13.5-35 Hz), and gamma-(35-48.9 Hz) frequency ranges. The total test will last approximately 2 minutes. | Pre-dose, 1 hour (h), 2h, and 4h post dose on Day 1 | 
| Part 1: PD of JNJ-55375515 as Assessed by Heart Rate Variability (HRV) | Heart rate variability (HRV) is the physiological phenomenon of variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval. HRV will be derived from Holter recordings. Holter recordings will start pre dose on Day 1 of each period in Part 1 and continue for 24 hours. Measurements will be made at rest (during 5 minutes) and HRV parameters will be derived from these 5-minute recordings and from the 24-hour recordings. | Pre-dose (Day 1) up to 24 hours post dose | 
| Part 1: Saccadic Reaction Time (RT) as Measured by Saccadic Eye Movements | Saccadic eye movements will be recorded to measure saccadic reaction time (RT). The recording and analysis of saccadic eye movements is performed using a computer-based system for sampling and analysis of eye movements. In a typical test system, electrodes are applied on the forehead and beside the lateral canthi of both eyes of the participant for registration of the electro-oculographic signals. Head movements are restrained using a fixed head support. The target consists of a moving dot that is displayed on a computer screen. Fifteen saccades are recorded with inter-stimulus intervals varying randomly between 3 and 6 seconds. Average values of latency (reaction time) of all correct saccades will be assessed. | Pre-dose, 1 h, 2h, and 4h post dose on Day 1 | 
| Part 1: Saccadic Peak Velocity (SPV) as Measured by Saccadic Eye Movements | Saccadic eye movements will be recorded to measure saccadic peak velocity (SPV). The recording and analysis of saccadic eye movements is performed using a computer-based system for sampling and analysis of eye movements. In a typical test system, electrodes are applied on the forehead and beside the lateral canthi of both eyes of the participant for registration of the electro-oculographic signals. Head movements are restrained using a fixed head support. The target consists of a moving dot that is displayed on a computer screen. Fifteen saccades are recorded with inter-stimulus intervals varying randomly between 3 and 6 seconds. Average values of saccadic peak velocity of all correct saccades will be assessed. | Pre-dose, 1h, 2h, and 4h post dose on Day 1 | 
| Part 1: Change from Baseline in Body Sway | The body sway meter allows measurement of body movements in a single plane, providing a measure of postural stability. Body sway may be measured with a pot string meter (Celesco) based on the Wright ataxiameter or platform. Participants will be instructed to wear a pair of comfortable, low-heeled shoes on each session. The total period of body-sway measurement will be 2 minutes. | Baseline, 1h, 2h, and 4h post dose on Day 1 | 
| Part 1 and 2: PD as Assessed by Karolinska Sleepiness Scale (KSS) Score | The KSS is a patient reported assessment of drowsiness level at the time of scale administration. This scale is focused mainly on the propensity to fall asleep and has a high validity in assessing sleepiness. It consists of a 9-point Likert scale with response options from: 1=very alert, 3=alert, 5=neither alert nor sleepy, 7=sleepy (but not fighting sleep), 9=very sleepy (fighting sleep). | Part 1: Pre-dose, 1h, 3h, and 8h post dose on Day 1; Part 2: Pre-dose (Day 1) and 8h post dose (Day 2) | 
| Part 1: Change from Baseline in Bond and Lader Visual Analogue Scale (B&L VAS) Score | The Bond and Lader Visual Analogue Scale consists of sixteen 100 millimeter (mm) visual analog scales anchored by antonyms (example, Alert-Drowsy, Lethargic-Energetic, etc). Scores will be combined to form three mood factors: alertness, calmness, and contentedness. | Baseline, 1h, 2h, and 4h post dose on Day 1 | 
| Part 1 and 2: Change from Baseline in Cortisol Levels | To establish diurnal levels of cortisol levels, repeated serum samples will be obtained throughout the Day 1 of each period. The diurnal cortisol levels will be explored to further clarify the effect of the compound on the hypothalamic-pituitary-adrenal-axis. | Part 1: Baseline, 0.5h, 1h, 2h, 3h, 4h, 5h 45minutes (m), 6h, 6h 05m, 6h 25m, 6h 30m, 6h 50m, 6h 55m, 7h 15m, 7h 35m, 8h, 12h and 24h post dose on Day 1; Part 2: Baseline, 0.5h, 1h, 2h (Day 1 or 2), 3h, 4h, 6h, 8h, 12h and 24h post dose on Day 2 | 
| Part 1: PD as Assessed by Probabilistic Instrumental Learning Task (PILT) | In this motivational processing task, participants with depressive symptoms may show a lower response bias towards a reward compared to healthy participants. The PILT allows the objective assessment of participants propensity to modulate behavior as a function of reward. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: International Shopping List Test | The International Shopping List Test is a measure of Verbal Memory-Learning. The test measures total number of correct responses remembering the 16-word list on three consecutive learning trials. Higher score indicates better performance. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: Groton Maze Learning Task | Groton Maze Learning Task 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. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: Social Emotional Cognition Task | To evaluate social and emotional cognition, a series of tests will be used to quantify both the ability to empathize and understand the emotions of others, and the ability to interpret their thoughts and intentions. A classical test involves the presentation of facial expressions and is asked to choose which word best describes what the person in the image is thinking or trying. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: Detection Task | Detection task 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. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: Identification Task | Identification task 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. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: one Back Task | One back task 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. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: International Shopping List Test - Delayed Recall | International shopping list test - Delayed Recall is a measure of Delayed Verbal Memory. The test measures total number of correct responses recalling the 16 words learned previously after a delay. Higher score indicates better performance. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: PD as Assessed by Cognitive Test Battery: Groton Maze Learning - Delayed Recall | Groton Maze Learning - 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. | Pre-dose, 3h, and 8h post dose on Day 1 | 
| Part 1: Evoked Stress Response as Assessed by Induced Stress | The induced stress test consists of a highly demanding computer task that is performed for 20 minutes. | 6h 30m to 6h 50m post dose on Day 1 | 
| Part 2: Latency to Persistent Sleep (LPS) by 8-hour Overnight Polysomnography | LPS is the time in minutes from 'lights out' that marks the starting of total recording time to the first epoch scored as sleep. | 0 hour (Day 1) up to 8 Hour (Day 2) | 
| Part 2: Total Time Spent in Deep Sleep (Duration of Slow Wave Sleep) - Stage 3 Sleep by 8-Hour Overnight Polysomnography | Polysomnographic recordings will be used to determine the total time spent in deep sleep (duration of slow wave sleep) -stage 3 sleep by 8-hour overnight. | 0 hour (Day 1) up to 8 Hour (Day 2) | 
| Part 2: Time in bed by 8-hour Overnight Polysomnography | Polysomnographic recordings will be used to determine the time in bed by 8-hour overnight. | 0 hour (Day 1) up to 8 Hour (Day 2) | 
| Part 2: Cognitive Test Battery: Continuous Paired Associate Learning Task (CPAL) | The Continuous Paired Associate Learning (CPAL) test will be used to assess whether JNJ-55375515 will improve performance of complex cognitive tasks. CPAL assess Visual episodic memory (associate learning) cognitive domain. In this task, participants must learn a series of associations between a set of difficult to verbalize patterns (amoeba) and locations. In healthy adults, 14 pattern/location associations must be learned. In the presentation phase of the task the pattern appears at the location and the participant is required to acknowledge that they have seen the pattern by touching the location at which it appears. Patterns are presented in random order. In the learning phase of the task, participants must place each of the 14 patterns in their correct locations. They must do this in 10 rounds. Number of errors made in correctly placing each of the four patterns in their location four times. (Lower score = better performance). | -7 hour (Day 1), 17 hour (Day 2) | 
| Part 1 and 2: Maximum Observed Plasma Concentration (Cmax) | Cmax is the maximum observed plasma concentration. | Part 1: Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, and 96h post dose; Part 2: Pre dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 46h, 70h, and 94h post dose | 
| Part 1 and 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) | Tmax is defined as actual sampling time to reach maximum observed analyte concentration. | Part 1: Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, and 96h post dose; Part 2: Pre dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 46h, 70h, and 94h post dose | 
| Part 1 and 2: Area Under the Plasma Concentration-Time Curve from Time 0 to Time of the Last Quantifiable Concentrations (AUC[0-last]) | AUC(0-last) is area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentrations. | Part 1: Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h, and 96h post dose; Part 2: Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 46h, 70h, and 94h post dose |