An Efficacy, Safety and Tolerability Study of JNJ-42165279 in Participants With Major Depressive Disorder With Anxious Distress

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety and tolerability of JNJ-42165279 in participants with major depressive disorder (MDD) with anxiety symptoms who have had inadequate response to treatment with a selective serotonin reuptake inhibitor (SSRI) or serotonergic/noradrenergic reuptake inhibitor (SNRI).

Detailed Description
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This is a multicenter, double-blind (neither physician nor participant knows the treatment that the participant receives), placebo-controlled, randomized, parallel-group study in participants with Major Depressive Disorder (MDD) with Anxious Distress. Participants who had treatment initiated with a SSRI/SNRI allowed by the protocol will be evaluated at the investigation site. The site assessment will be reviewed and validated by an independent central rater. The review will include the clinical history of MDD, SSRI/SNRI treatment of adequate dose and duration for the current episode of depression, and current symptom severity on the Hamilton Depression Rating Scale (HDRS17). Enrolled participants will be maintained on SSRI/SNRI treatment throughout the study to determine whether additional treatment with JNJ-4216579 can reduce the symptoms of MDD with anxious distress.The study will consist of 3 phases: a Screening Phase of up to 4 weeks, an 11-week double-blind Treatment Phase, and a 3-week post-treatment (follow up) Phase. The double-blind treatment Phase of the trial will consist of 3 periods. The first period is a placebo lead-in of double-blind duration, after which participants will enter the treatment period when they will be randomly assigned to JNJ-42165279 or continuation on placebo for 6 weeks. Participants who successfully complete the treatment period prior to the end of Week 11, will be treated with placebo for the remaining time of the double-blind phase of the study, which will vary depending on the duration of the placebo lead-in for the specific participant. The total study duration for each participant will be approximately 18 weeks. Efficacy and safety of JNJ-42165279 will be evaluated. Participants' safety will be monitored throughout the study.

Official Title
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A Phase 2a Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-center Study Investigating the Efficacy, Safety, and Tolerability of JNJ-42165279 in Subjects With Major Depressive Disorder With Anxious Distress

Conditions
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Depressive Disorder, Anxiety

Intervention / Treatment
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* Drug: JNJ-42165279
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must meet the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) or 5 diagnostic criteria for major depressive disorder (MDD) with Anxious Distress Participants with a diagnosis of comorbid Generalized Anxiety Disorder, Social Anxiety Disorder, or Panic Disorder may be included, if the investigator considers MDD with Anxious Distress to be the primary diagnosis (confirmed by an independent central rater at screening) Participants must have been treated with an approved SSRI/SNRI antidepressants for at least 6 continuous weeks, validated by an independent central rater contracted by the sponsor A 17-item Hamilton Depression Rating Scale (HDRS17) total score greater than or equal to (>=)18 and a HDRS17 anxiety/somatization factor score >=7 at screening, assessed by a site rater and reviewed by an independent central rater on Day 1 Participant must be willing and able to adhere to the prohibitions and restrictions Participant Body mass index (BMI = weight/height2) must be between 18 and 35 kilogram per square meter (kg/m^2) inclusive Exclusion Criteria: Has other psychiatric condition, including, but not limited to, MDD with psychotic features, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder, borderline personality disorder, eating disorder, or schizophrenia Has a length of current Major Depressive Episode (MDE) greater than (>) 6 months Has more than 1 failed antidepressant treatment of adequate dose and duration in the current MDE, Not including the inadequate response to the current selective serotonin reuptake inhibitor (SSRI) or serotonergic/noradrenergic reuptake inhibitor (SNRI) antidepressant Has initiated psychotherapy specific for MDD (such as cognitive behavioral, behavioral, or interpersonal therapy) for the current episode of depression within 6 weeks prior to Screening Has a current or recent history of clinically significant suicidal ideation within the past 6 months, or a history of suicidal behavior within the past year

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Responders-Placebo<br>Participants who responded in the placebo lead-in period will be administered with Matching Placebo orally. | Other: Placebo<br>* Matching Placebo will be administered orally.<br>|
| Experimental: Responders-JNJ-42165279<br>Participants who responded in the placebo lead-in period will be administered with JNJ-42165279 orally at a dose of 25 milligrams (mg) tablets once daily for 6 weeks. | Drug: JNJ-42165279<br>* JNJ-42165279 will be administered orally at a dose of 25 milligrams (mg) tablet once daily for 6 weeks.<br>|
| Placebo Comparator: Non Responders-Placebo<br>Participants who did not respond in the placebo lead-in period will be administered with Matching Placebo orally. | Other: Placebo<br>* Matching Placebo will be administered orally.<br>|
| Experimental: Non Responders-JNJ-42165279<br>Participants who did not respond in the placebo lead-in period will be administered with JNJ-42165279 orally at a dose of 25 mg tablets once daily for 6 weeks. | Drug: JNJ-42165279<br>* JNJ-42165279 will be administered orally at a dose of 25 milligrams (mg) tablet once daily for 6 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind Treatment Period: Change From Baseline in Hamilton Depression Rating Scale (HDRS17) Total Score at Week 6 (eITT Population) | HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants diagnosed with depression. Each of 17 items is rated by clinician on either 3-point (0-2) or 5-point (0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in HDRS17 Total Score at Week 6 (fITT Population) | HDRS17 is a clinician-administered rating scale designed to assess severity of symptoms in participants diagnosed with depression. Each of the 17 items is rated by clinician on either a 3-point (0 to 2) or a 5-point (0 to 4) scale which used a rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. HDRS17 total score is calculated as sum of 17 item scores and ranges from 0 to 52. For each item as well as the total score, higher scores indicate greater severity of depression. | Baseline and Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double-blind Treatment Period: Change From Baseline in Hamilton Anxiety Rating Subscale (HAM-A6) Score at Week 6 (eITT Population) | The HAM-A6 is a 6-item subscale derived from the original Hamilton Anxiety scale (HAM-A) which consists of 5 psychic anxiety symptoms (anxious mood, psychic tension, fears, intellectual disturbances, and anxious behavior observed at the interview), as well as one somatic item (muscular tension). Each of the 6 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree). The HAM-A6 score was calculated by summing the 6 item scores, and ranges from 0 to 24. Higher scores indicated greater severity of symptoms. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in HAM-A6 Score at Week 6 (fITT Population) | The HAM-A6 is a 6-item subscale derived from the original Hamilton Anxiety scale (HAM-A) which consists of 5 psychic anxiety symptoms (anxious mood, psychic tension, fears, intellectual disturbances, and anxious behavior observed at the interview), as well as one somatic item (muscular tension). Each of the 6 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum degree). The HAM-A6 score was calculated by summing the 6 item scores, and ranges from 0 to 24. Higher scores indicated greater severity of symptoms. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in Hamilton Depression Rating Subscale (HAM-D6) Score at Week 6 (eITT Population) | HAM-D6 is a 6-item subscale derived from HDRS17 and consists of depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and somatics symptoms (tiredness and pain), rated on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. Each of these items is rated by the clinician on either a 3-point (0 to 2) or a 5-point scale (0 to 4). The point scale used a rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). General somatic is scored 0 to 2 and all others are scored 0 to 4. The HAM-D6 is calculated from summing the 6 items and the score ranges from 0 (normal) to 22 (severe), with higher scores indicating greater severity of core symptoms. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in HAM-D6 Score at Week 6 (fITT Population) | HAM-D6 is a 6-item subscale derived from HDRS17 and consists of depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and somatic symptoms (tiredness and pain), rated on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. Each of these items is rated by the clinician on either a 3-point (0 to 2) or a 5-point scale (0 to 4). The point scale used a rating of 0 (absent), 1 (doubtful to mild), 2 (mild to moderate), 3 (moderate to severe), and 4 (very severe). General somatic is scored 0 to 2 and all others are scored 0 to 4. The HAM-D6 is calculated from summing the 6 items and the score ranges from 0 (normal) to 22 (severe), with higher scores indicating greater severity of core symptoms. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in Structured Interview Guide of the Hamilton Anxiety Scale (SIGH-A) Total Score at Week 6 (eITT Population) | The SIGH-A was included as a means to determine the frequency and severity of signs and symptoms of anxiety; and determine both their influence on treatment and their responsiveness to treatment. The SIGH-A scale consists of 14 items with a score of 0 to 4, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=incapacitating. The SIGH-A total score is calculated by summing the 14 item scores, and ranges from 0 to 56. For each individual item score and total score, higher scores indicate greater severity. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in SIGH-A Total Score at Week 6 (fITT Population | The SIGH-A was included as a means to determine the frequency and severity of signs and symptoms of anxiety; and determine both their influence on treatment and their responsiveness to treatment. The SIGH-A scale consists of 14 items with a score of 0 to 4, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=incapacitating. The SIGH-A total score is calculated by summing the 14 item scores, and ranges from 0 to 56. For each individual item score and total score, higher scores indicate greater severity. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in the HDRS17 Anxiety/Somatization Factor Total Score at Week 6 (eITT Population) | The HDRS17 anxiety/somatization factor derived from Cleary and Guy's factor analysis of the HDRS17 scale, includes six items from the original 17-item version: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. Each of 6 items is rated by clinician on either a 3-point (0 to 2) or a 5-point (0 to 4) scale with rating of 0:absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe and is calculated as sum of 6 item scores ranging from 0 to 18, with higher scores indicating greater severity of symptoms for each item as well as total score. | Baseline and Week 6 | 
| Double-blind Treatment Period: Change From Baseline in the HDRS17 Anxiety/Somatization Factor Total Score at Week 6 (fITT Population) | The HDRS17 anxiety/somatization factor derived from Cleary and Guy's factor analysis of the HDRS17 scale, includes six items from the original 17-item version: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. Each of 6 items is rated by clinician on either a 3-point (0 to 2) or a 5-point (0 to 4) scale with rating of 0:absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe and is calculated as sum of 6 item scores ranging from 0 to 18, with higher scores indicating greater severity of symptoms for each item as well as total score. | Baseline and Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With Greater Than or Equal to (>=) 30 Percent (%) Improvement on the HDRS17 Total Score at Week 6 (eITT Population) | Percentage of participants who had >=30% improvement (responders) on HDRS17 total score at Week 6 were reported. HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants diagnosed with depression. Each of 17 items is rated by clinician on either 3-point (0-2) or 5-point (0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 30 % Improvement on the HDRS17 Total Score at Week 6 (fITT Population) | Percentage of participants who had >=30% improvement (responders) on HDRS17 total score at Week 6 was reported. HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants diagnosed with depression. Each of 17 items is rated by clinician on either 3-point (0-2) or 5-point (0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 50% Improvement in the HDRS17 Total Score at Week 6 (eITT Population) | Percentage of participants who had >=50% improvement (responders) in HDRS17 total score at Week 6 were reported. HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants diagnosed with depression. Each of 17 items is rated by clinician on either 3-point (0-2) or 5-point (0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 50% Improvement in the HDRS17 Total Score at Week 6 (fITT Population) | Percentage of participants who had >=50% improvement (responders) in HDRS17 total score at Week 6 were reported. HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants diagnosed with depression. Each of 17 items is rated by clinician on either 3-point (0-2) or 5-point (0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 30% Improvement on SIGH-A Total Score at Week 6 (eITT Population) | The SIGH-A was included as a means to determine the frequency and severity of signs and symptoms of anxiety and determine both their influence on treatment and their responsiveness to treatment. The percentage of participants who had >= 30% improvement (responders) on SIGH-A total score at Week 6 was reported. The SIGH-A scale consists of 14 items with a score of 0 to 4, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=incapacitating. The SIGH-A total score is calculated by summing the 14 item scores, and ranges from 0 to 56. For each individual item score and total score, higher scores indicate greater severity. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 30% Improvement on SIGH-A Total Score at Week 6 (fITT Population) | The SIGH-A was included as a means to determine the frequency and severity of signs and symptoms of anxiety and determine both their influence on treatment and their responsiveness to treatment. The percentage of participants who had >= 30% improvement (responders) on SIGH-A total score at Week 6 was reported. The SIGH-A scale consists of 14 items with a score of 0 to 4, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=incapacitating. The SIGH-A total score is calculated by summing the 14 item scores, and ranges from 0 to 56. For each individual item score and total score, higher scores indicate greater severity. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 50% Improvement on SIGH-A Total Score at Week 6 (eITT Population) | The SIGH-A was included as a means to determine the frequency and severity of signs and symptoms of anxiety and determine both their influence on treatment and their responsiveness to treatment. The percentage of participants who had >= 50% improvement (responders) on SIGH-A total score at Week 6 was reported. The SIGH-A scale consists of 14 items with a score of 0 to 4, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=incapacitating. The SIGH-A total score is calculated by summing the 14 item scores, and ranges from 0 to 56. For each individual item score and total score, higher scores indicate greater severity. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With >= 50% Improvement on SIGH-A Total Score at Week 6 (fITT Population) | The SIGH-A was included as a means to determine the frequency and severity of signs and symptoms of anxiety and determine both their influence on treatment and their responsiveness to treatment. The percentage of participants who had >= 50% improvement (responders) on SIGH-A total score at Week 6 was reported. The SIGH-A scale consists of 14 items with a score of 0 to 4, where 0=absent, 1=mild, 2=moderate, 3=severe, 4=incapacitating. The SIGH-A total score is calculated by summing the 14 item scores, and ranges from 0 to 56. For each individual item score and total score, higher scores indicate greater severity. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With Remission as Assessed by HDRS17 Total Score Less Than or Equal to (<=) 7 at Week 6 (eITT Population) | Percentage of participants with HDRS17 total score <= 7 were considered as remitters. HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants with depression. Each of 17 items is rated by clinician on either 3-point(0-2) or 5-point(0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With Remission as Assessed by HDRS17 Total Score <= 7 at Week 6 (fITT Population) | Percentage of participants with HDRS17 total score <= 7 were considered as remitters. HDRS17 is clinician-administered rating scale designed to assess severity of symptoms in participants with depression. Each of 17 items is rated by clinician on either 3-point(0-2) or 5-point(0-4) scale with rating of 0: absent, 1: doubtful to mild, 2: mild to moderate, 3: moderate to severe, and 4: very severe. A total score (0 to 52) was calculated by adding scores of all 17 items. For each item as well as total score, higher score represents more severe condition. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With a Clinical Global Impression Improvement (CGI-I) Score of Very Much Improved or Much Improved at Week 6 (eITT Population) | The percentage of participants with a CGI-I score of very much improved or much improved at Week 6 was reported. CGI-I is a 7-point scale that required the clinician to assess how much the participant's illness had improved or worsened relative to a baseline state at the beginning of the intervention. The CGI-I is rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. For each individual item score and total score, higher scores indicate greater severity. | Week 6 | 
| Double-blind Treatment Period: Percentage of Participants With a Clinical Global Impression Improvement (CGI-I) Score of Very Much Improved or Much Improved at Week 6 (fITT Population) | The percentage of participants with a CGI-I score of very much improved or much improved at Week 6 was reported. CGI-I is a 7-point scale that required the clinician to assess how much the participant's illness had improved or worsened relative to a baseline state at the beginning of the intervention. The CGI-I is rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. For each individual item score and total score, higher scores indicate greater severity. | Week 6 | 
| Maximum Plasma Concentration (Cmax) of JNJ-42165279 | Cmax is defined as maximum plasma concentration of JNJ-42165279. The data was pooled across visits at different timepoints to calculate Cmax. | Pre-dose, 2 to 4 hours post-dose on Days 14, 35, 63, and 77 | 
| Area Under the Plasma Concentration-time Curve From Zero to Dosing Intervals (AUC[0-tau]) of JNJ-42165279 | AUC(0-tau) is defined as area under the plasma concentration-time curve from 0 to t hours post dosing (time t is the dosing interval). The data was pooled across visits at different timepoints to calculate AUC(0-tau). | Pre-dose, 2 to 4 hours post-dose on Days 14, 35, 63, and 77 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) of JNJ-42165279 | Tmax is defined as time to reach the maximum plasma concentration of JNJ-42165279. The data was pooled across visits at different timepoints to calculate Tmax. | Pre-dose, 2 to 4 hours post-dose on Days 14, 35, 63, and 77 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Major Depressive Disorder, Depression, Anxiety symptoms, JNJ-42165279