A Study to Investigate the Effect of JNJ-42847922 on Polysomnography Measures in Patients With Major Depressive Disorder With Insomnia Who Are Stably Treated With Antidepressants

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate effect of JNJ-42847922 on sleep latency (latency to persistent sleep) in participants with major depressive disorder who are stably treated with selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor who suffer from insomnia (inability to fall asleep).

Detailed Description
-----------------
This is a double-blind (neither physician nor participants knows the treatment that the participant receives), placebo-controlled (placebo is compared with the study medication to test whether the study medication has a real effect in clinical study), randomized (the study medication is assigned by chance) 4-way crossover (method used to switch participants to 4 different arms in a clinical study), and a single dose study. This study will consist of a screening phase (between 28 to 2 days prior to the study medication), a treatment phase of 4 double blind study periods (2 days), and a follow-up phase (within 7 to 14 days after last dose of the study medication). Approximately 20 participants with major depressive disorder will participate in this study. Participants will be randomly assigned to 1 of 4 cohorts (groups) (Cohorts A, B, C, and D) to receive JNJ-42847922 (10 mg, 20 mg, and 40 mg) and placebo. Each cohort consists of 4 treatment periods (Periods 1, 2, 3, and 4). Safety will be evaluated by the assessment vital signs, 12-lead electrocardiogram, clinical laboratory testing, physical examination, and neurological examination. The total duration of study participation for a participant will be approximately 9 to 10 weeks.

Official Title
-----------------
A Single Dose, 4-way Crossover, Placebo-controlled, Randomized Study to Investigate the Effect of JNJ-42847922 on Polysomnography (PSG) Measures in Subjects With Major Depressive Disorder With Insomnia Who Are Stably Treated With Antidepressants

Conditions
-----------------
Depressive Disorder, Major

Intervention / Treatment
-----------------
* Drug: JNJ-42847922
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants with a current/recurrent or past episode of Major Depressive Disorder (MDD) as established per mini international neuropsychiatric interview at screening or otherwise specified by the treating physician Stably treated with selective serotonin re-uptake inhibitor / serotonin-norepinephrine reuptake inhibitor monotherapy, with no change in dose in the last 30 days before screening Insomnia per polysomnography (a diagnostic test to measure and record physiologic variables like latency to persistent sleep, total sleep time, sleep efficiency, time spent awake, and total time spent in deep sleep, during sleep) Participants must be healthy / medically stable on the basis of clinical laboratory tests performed at screening Female participants should not be of child bearing potential due to either tubal ligation or hysterectomy or who are postmenopausal (no spontaneous menses for at least 2 years) Exclusion Criteria: Has a current diagnosis of a psychotic disorder, MDD with psychosis, bipolar disorder, mental retardation, or cluster B personality disorder (eg, borderline personality disorders, antisocial personality disorder) Has been diagnosed with sleep-related breathing disorder Has suicidal ideation with some intent to act, or has homicidal ideation/intent, per Principal Investigator's clinical judgment Abnormal day/night rhythm, eg, nightshift worker, or normal bed time past midnight Has uncontrolled hypertension at screening and Day 1 prior to randomization; or any past history of hypertensive crisis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>5 participants will be included in this cohort. Participants will receive the study medications in the sequence of placebo (Period 1), JNJ-42847922 10 mg (Period 2), JNJ-42847922 20 mg (Period 3), and JNJ-42847922 40 mg (Period 4). Each treatment period and each subsequent treatment period will be separated by 1 week. | Drug: JNJ-42847922<br>* Participants will receive suspension of JNJ-42847922 (10 mg, 20 mg, and 40 mg) orally on Day 1 of the appropriate treatment periods.<br>Other: Placebo<br>* Participants will receive placebo orally on Day 1 of the appropriate treatment periods.<br>|
| Experimental: Cohort B<br>5 participants will be included in this cohort. Participants will receive the study medications in the sequence of JNJ-42847922 10 mg (Period 1), JNJ-42847922 40 mg (Period 2), placebo (Period 3), and JNJ-42847922 20 mg (Period 4). Each subsequent treatment period will be separated by 1 week. | Drug: JNJ-42847922<br>* Participants will receive suspension of JNJ-42847922 (10 mg, 20 mg, and 40 mg) orally on Day 1 of the appropriate treatment periods.<br>Other: Placebo<br>* Participants will receive placebo orally on Day 1 of the appropriate treatment periods.<br>|
| Experimental: Cohort C<br>5 participants will be included in this cohort. Participants will receive the study medications in the sequence of JNJ-42847922 20 mg (Period 1), placebo (Period 2), JNJ-42847922 40 mg (Period 3), and JNJ-42847922 10 mg (Period 4). Each subsequent treatment period will be separated by 1 week. | Drug: JNJ-42847922<br>* Participants will receive suspension of JNJ-42847922 (10 mg, 20 mg, and 40 mg) orally on Day 1 of the appropriate treatment periods.<br>Other: Placebo<br>* Participants will receive placebo orally on Day 1 of the appropriate treatment periods.<br>|
| Experimental: Cohort D<br>5 participants will be included in this cohort. Participants will receive the study medications in the sequence of JNJ-42847922 40 mg (Period 1), JNJ-42847922 20 mg (Period 2), JNJ-42847922 10 mg (Period 3), and placebo (Period 4). Each subsequent treatment period will be separated by 1 week. | Drug: JNJ-42847922<br>* Participants will receive suspension of JNJ-42847922 (10 mg, 20 mg, and 40 mg) orally on Day 1 of the appropriate treatment periods.<br>Other: Placebo<br>* Participants will receive placebo orally on Day 1 of the appropriate treatment periods.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Latency to Persistent Sleep (LPS) on Day 1 | LPS is with lights off, appearance of first epoch of Stage 1 (light sleep), Stage 2 (light sleep), Stage 3 (deep sleep), and Stage 4 (rapid eye movement sleep) sleep followed by at least 20 consecutive epochs without any Stage 0 sleep (awake but sleepy). LPS will be accessed on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events |  | Up to Week 10 | 
| Maximum Observed Plasma Concentration (Cmax) of JNJ-42847922 | Cmax is defined as maximum observed analyte concentration. This will be measured on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Predose, and postdose Day 1 (20 minutes, 8 hours 20 minutes, and 12 hours) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42847922 | Tmax is defined as actual sampling time to reach maximum observed analyte concentration. This be measured on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Predose, and postdose Day 1 (20 minutes, 8 hours 20 minutes, and 12 hours) | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time 12 (AUC[12]) | Area Under the Plasma Concentration-Time Curve From Time Zero to Time 12 is area under the plasma concentration-time curve from 0 to 12 hours post dosing. This will be measured on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Predose, and postdose Day 1 (20 minutes, 8 hours 20 minutes, and 12 hours) | 
| Total amount of JNJ-42847922 excreted in urine (Ae12) | Total amount of JNJ-42847922 excreted in urine is expressed as a percentage of dose administered. This will be measured overnight after the administration of the study medication on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Predose and postdose Day 1 | 
| Renal clearance (CLR) | CLR will be measured overnight after the administration of the study medication on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Predose and postdose Day 1 | 
| Number of participants with suicidal ideation or behavior measured using Columbia Suicide Severity Rating Scale (C-SSRS) | C-SSRS is a clinician rated assessment of suicidal behavior and / or intent. Scale consists of 28 items in 4 sections: suicide behavior, actual attempts, suicidal ideation, and intensity of ideation. Suicidal ideation consists of 5 yes/no items: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with any methods (not plan) without intention to act, active suicidal ideation with some intent to act without specific plan, active suicidal ideation with specific plan and intent. Only items with yes responses are listed. Worsening of suicidal ideation was an increase in severity of suicidal ideation from baseline. This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Total sleep time in participants | This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Sleep efficiency in participants | This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Next-day residual effect of JNJ-42847922 measured using visual analogue scale (VAS) for sleepiness | VAS scale is ued to measure subjective characteristics or attitudes that cannot be measured directly for sleepiness. VAS will assess whether the participants were feeling sleepy during the first hour after wake-up by using a 10 cm line, having sleepy/tired and awake at either end. The scores ranged from 0 to 100, with a high score reflecting a high level of anxiety. This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Next-day residual effect of JNJ-42847922 measured using the Bond and Lader visual analogue scale (VAS) to rate subjective feelings | The Bond-Lader Visual Analogue Scale (VAS) is made up of 16 pairs of alternative descriptors of mood and attention at either end of a 10 cm line. Participants were asked to rate their feelings at the time of assessment by indicating the point on the line which best represent their mood. Each item was scored by measuring the position relative to the left hand end of the line and levels of anxiety, sedation, and dysphoria were then calculated from the combined scores of selected items. The scores ranged from 0 to 100, with a high score reflecting a high level of anxiety, sedation or dysphoria. This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Next-day residual effect of JNJ-42847922 on body movements measured using a pot string meter and a stabilometric platform | A pot string meter includes a string attached the waist of the participant and all body movements over a period of time are integrated and expressed as mm sway. In a stabilometric platform, the participant will be made to sleep on a firm surface for about 51.2 seconds each with first eyes open and then eyes closed. This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Next-day residual effect of JNJ-42847922 on saccadic eye movements | Saccadic eye movements will be assessed using a computer-based system connected to electrodes placed lateral of the eyes or using infra-red technology. This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Number of participants with depressive symptoms measured using Quick Inventory of Depressive Symptomatology - Self Report 14-item (QIDS-SR14) | The QIDS-SR14, s a version of the QIDS-SR16 with a shorter, 24-hour recall period that has been developed for this trial. The total score ranges from 0 to 27. Using a scale of severity of depression of none, mild, moderate, severe, and very severe, corresponding QIDS-SR16 total scores are none 1-5, mild 6-10, moderate 11-15, severe 16-20 and very severe 21-27. Higher scores indicate worsening. This will be assessed on Days 1 and 2 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2), Day 1, and Day 2 | 
| Concentration of cortisol in saliva | This will be measured on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Predose Day 1 (30 minutes and 90 minutes) and postdose Day 2 (at wake-up and 30 minutes after wake-up) | 
| Time spent awake by the participants | This will be assessed on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2) and Day 1 | 
| Total time spent deep sleep by the participants | This will be assessed on Day 1 of each treatment period (Periods 1, 2, 3, and 4). | Screening (Day -28 to Day -2) and Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Major Depressive Disorder, Insomnia, JNJ-42847922, Placebo, Depressive Disorder, Major