Orvepitant (GW823296) in Adult Post Traumatic Stress Disorder

Post-Traumatic Stress Disorder Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Fixed-Dose Study Evaluating the Efficacy and Safety of the Neurokinin-1 Receptor Antagonist Orvepitant (GW823296) in Post Traumatic Stress Disorder (PTSD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01000493
• Other study ID #: 113211
• Status: Completed
• Phase: Phase 2
• First received: October 15, 2009
• Last updated: August 31, 2017
• Start date: November 2, 2009
• Est. completion date: June 28, 2010

Study information

• Verified date: July 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a 12-week, randomized, multicenter, double-blind, placebo controlled, fixed-dose parallel group study to assess the efficacy and safety of orvepitant (60 mg/day) versus placebo in subjects with a diagnosis of noncombat-related Posttraumatic Stress Disorder (PTSD), whose symptoms are considered moderate or severe.

Following an initial screening visit, subjects fulfilling the study inclusion and exclusion criteria will enter a pre-treatment screening phase to permit evaluation of the laboratory and ECG assessments and to confirm eligibility for inclusion into the study. This screening phase will be a minimum of 7 days, but no longer than 21 days. At the completion of the screening period, eligible subjects will be randomized at the baseline visit to receive either orvepitant 60mg/day or placebo (1:1 ratio). Those subjects randomized to receive placebo will receive study medication identical in appearance to that received by subjects assigned to receive orvepitant.

Efficacy will be assessed using the Clinician Administered PTSD Scale (CAPS) as the primary efficacy measure. Key secondary efficacy endpoints will be based on the Davidson Trauma Scale (DTS), the Short PTSD Rating Interview (SPRINT), the Clinical Global Impression- Global Improvement and Severity of Illness Scales (CGI-I and CGI-S, respectively), the Hamilton Depression Rating Scale (HAM-D), the Cognitive and Physical Functioning Questionnaire (CPFQ) and the Pittsburgh Sleep Quality Index (PSQI).

Safety will be assessed by monitoring for adverse events (side effects) and through periodic laboratory evaluations (blood tests), vital signs assessments (e.g., blood pressure, heart rate, temperature) and heart function measurements (electrocardiograms, or ECGs).

Description:

The purpose of the current study is to test the safety and effects of orvepitant, an investigational drug for the treatment of noncombat-related PTSD.

Efficacy will be assessed using standard symptom and severity rating scales (questionnaires). The Clinicain Adminstered PTSD Scale (CAPS) will serve as the primary measure of efficacy. Secondary efficacy endpoints include the CAPS subscale clusters (Re-Experiencing, Avoidance and Numbing, and Hyperarousal), the Davidson Trauma Scale (DTS), the Short PTSD Rating Interview (SPRINT), the Hamilton Depression Rating Scale (HAM-D), the Clinical Global Impression- Global Improvement and Severity of Illness Scale (CGI-I and CGI-S, respectively), the Cognitive and Physical Functioning Questionnaire (CPFQ) and the Pittsburgh Sleep Quality Index (PSQI).

Safety and tolerability will be assessed by monitoring adverse events (AEs or side effects), physical examinations (including vital signs such as blood pressure and heart rate), clinical laboratory assessments (blood tests), electrical recordings of the heart (electrocardiograms or ECG's), the Columbia Suicidality Severity Rating Scale (CSSRS), Massachusetts Sexual Function Questionnaire (MSFQ), Discontinuation-Emergent Signs and Symptoms (DESS) scale and weight change.

Blood samples will be taken at different time points to assess blood levels of orvepitant in patients, allowing the relationship between amount of orvepitant in the body and efficacy to be studied.

The primary objective of the study is to evaluate the efficacy of orvepitant (60mg/day) versus placebo (a "sugar pill", with no active ingredients). The secondary objectives include assessing the safety and tolerability of orvepitant, assessing the profile of appearance and disappearance of orvepitant in the body (blood) following administration (i.e., assessing how long the drug remains in the body), and lastly to examine the relationship between blood levels of the drug and efficacy (i..e, the change in CAPS score relative to what it was before starting the study medication).

Following an initial screening visit, subjects fulfilling the study entrance criteria will enter a pre-treatment screening phase to permit evaluation of the laboratory and electrocardiogram assessments and to confirm eligibility for inclusion into the study. This screening phase will be a minimum of 7 days, but no longer than 21 days. Upon completion of the screening period, eligible subjects will be randomly assigned at the baseline visit to one of two treatment regimens: orvepitant 60mg/day or placebo for a 12-week treatment phase. The chances of receiving each of the two possible treatments will be equal. Orvepitant will be administered as tablets. Those subjects randomised to receive placebo will receive study medication identical in appearance to that received by subjects assigned to receive orvepitant.

During the treatment phase, subjects will be required to return to the clinic at the end of Weeks 1, 2, 4, 6, 8, 10 and 12. In addition, all subjects will be required to return for a follow-up visit 14 days after the last dose of study medication. In addition, all subjects with ongoing adverse events at the 14-day follow-up visit will be required to return for a further follow-up visit 28 days after the last dose of study medication. Women of child-bearing potential will also be required to attend the 28-Day follow-up visit for a pregnancy test. A further test will be performed 42 Days following the end of treatment.

Male and female outpatients between the ages of 18 to 64 years inclusive with a primary diagnosis of noncombat-related PTSD will be enrolled into this study. A total of approximately 240 subjects are expected to be enrolled at approximately 25 different study sites in North America.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 132
• Est. completion date: June 28, 2010
• Est. primary completion date: June 28, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

Inclusion Criteria:

• Aged 18-64 years, inclusive.

• A primary diagnosis of noncombat-related Post traumatic Stress Disorder (PTSD)

• Subjects with symptom severity considered to be at least moderate to severe.

Exclusion Criteria:

• Subjects whose symptoms are better accounted for by a diagnosis other than Post traumatic Stress Disorder (PTSD), subjects diagnosed with dementia; subjects diagnosed with a current/recent eating disorder such as anorexia nervosa or bulimia; subjects with a diagnosed history of schizophrenia, schizoaffective disorder, or Bipolar Disorder.

• Subjects who have a history of failing to respond to adequate treatment for PTSD with an antidepressant/anti-anxiety drug, i..e, failure to improve following administration of at least two other antidepressants/anti-anxiety drugs, each given for at least 4 weeks.

Related Conditions & MeSH terms

• Disease
• Post-Traumatic Stress Disorder
• Stress Disorders, Post-Traumatic
• Stress Disorders, Traumatic

Intervention

Drug:
• orvepitant
Neurokinin-1 (NK-1) antagonist

Other:
• Placebo
Inactive placebo to match orvepitant 60 mg dosage form

Locations

Country	Name	City	State
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Beverly Hills	California
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Brown Deer	Wisconsin
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dayton	Ohio
United States	GSK Investigational Site	Garfield Heights	Ohio
United States	GSK Investigational Site	Glen Burnie	Maryland
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Marietta	Georgia
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Middleton	Wisconsin
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Park Ridge	Illinois
United States	GSK Investigational Site	Raleigh	North Carolina
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	Scottsdale	Arizona
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	The Bronx	New York
United States	GSK Investigational Site	Torrance	California
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Weymouth	Massachusetts
United States	GSK Investigational Site	Willingboro	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (1)

Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013 May;27(5):424-34. doi: 10.1177/0269881113480990. Epub 2013 Mar 28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in the 17-item Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) Total Severity Score at Week 12	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS total severity score was based on the 17 items that assess the frequency and intensity of PTSD symptoms. There were 8 items assessing associated features (guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment). The total score 0-136, higher scores means more severity, < 20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and > 80: extreme PTSD symptoms. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and Week 12
Secondary	Percentage of Participants Responding, Based on More Than Equal to (>=) 30 Percent (%) Reduction From Baseline in CAPS Total Severity Score at Weeks 1, 4, 8 and 12	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS total severity score was based on the 17 items that assess the frequency and intensity of PTSD symptoms. There were 8 items assessing associated features (guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment). The total score 0-136, higher scores means more severity, < 20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and > 80: extreme PTSD symptoms. Percentage of participants were calculated by total number of responders divided by number of participants assessed multiplied by 100.	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	The Time to (Maintained) Clinical Response in Each Participants	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS total severity score was based on the 17 items that assess the frequency and intensity of PTSD symptoms. There were 8 items assessing associated features (guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment). The total score 0-136, higher scores means more severity, < 20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and > 80: extreme PTSD symptoms. The time required to maintain CAPS response has been summarized.	Up to Week 12
Secondary	Change From Baseline in the 17-item CAPS Total Severity Score at Weeks 1, 4, and 8	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS total severity score was based on the 17 items that assess the frequency and intensity of PTSD symptoms. There were 8 items assessing associated features (guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment). The total score 0-136, higher scores means more severity, < 20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and > 80: extreme PTSD symptoms. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and Week 1, 4, 8
Secondary	Percentage of Participants Remitting, Based on a CAPS Total Score < 20 at Weeks 1, 4, 8, and 12	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS total severity score was based on the 17 items that assess the frequency and intensity of PTSD symptoms. There were 8 items assessing associated features (guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment). The total score 0-136, higher scores means more severity, < 20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and > 80: extreme PTSD symptoms. Remitter defined as a participants who has a CAPS total score <20. Percentage of participants were calculated by total number of responders divided by number of participants assessed multiplied by 100.	Up to Week 12
Secondary	Change From Baseline in the CAPS Re-experiencing Subscale Cluster Score at Weeks 1, 4, 8 and 12	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS assessed Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria for PTSD, including criteria B-D (core symptom clusters of re-experiencing). The re-experiencing subscale cluster score was derived from the CAPS. The possible range was 5 to 25 with lower score indicates less severe symptoms and with a greater score indicating greater PTSD symptom severity. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the CAPS Avoidance/Numbing (A/N) Subscale Cluster Score at Weeks 1, 4, 8, and 12	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS assessed DSM-IV diagnostic criteria for PTSD, including criteria B-D (core symptom clusters of A/N). The re-experiencing subscale cluster score was derived from the CAPS. The possible range is 7 to 35 with lower score indicates less severe symptoms and with a greater score indicating greater PTSD symptom severity. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the CAPS Hyperarousal Subscale Cluster Score at Weeks 1, 4, 8, and 12	The CAPS was a 30-item clinical interview. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The CAPS assessed DSM-IV diagnostic criteria for PTSD, including criteria B-D (core symptom clusters of hyperarousal). The re-experiencing subscale cluster score was derived from the CAPS. The possible range is 5 to 25 with lower score indicates less severe symptoms and with a greater score indicating greater PTSD symptom severity. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Percentage of Participants Responding, Based on a Clinical Global Impression- Global Improvement (CGI-I) Score of 1 or 2, by Visit Week	The global improvement items were rated on a 1-7 scale with 0 means not assessed (1: very much improved, 2: much improved, 3: minimally improved, 4: no change, 5: minimally worse, 6: much worse, 7: very much worse). For the global improvement item, the clinician indicated their assessment of the participant's total improvement or worsening compared with that individual's condition at the start of the study (the Baseline visit) whether or not the change was judged to be due to drug treatment. Responder was defined as a participant who had a CGI-I score of 1 or 2 ('very much improved' or 'much improved'). It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. Percentage of participants were calculated by total number of responders divided by number of participants assessed multiplied by 100.	Up to Week 12
Secondary	Change From Baseline in the CGI-S Score, by Visit Week	The severity of illness items were rated on a 1-7 scale with 0 means not assessed (1: normal, not at all ill, 2: borderline mentally ill, 3: mildly ill, 4: moderately ill, 5: markedly ill, 6: severely ill, 7: among the most extremely ill participants). For the severity of illness item, the clinician indicated his/her assessment of the participant severity of illness considering their total clinical experience with the particular population being studied. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the Short PTSD Rating Review (SPRINT), by Visit Week	The SPRINT consists of 8 items that assess the core symptoms of PTSD, as well as related aspects of somatic malaise, stress vulnerability and functional impairment. Each item was rated on a 5 point scale (0: not at all, 1: a little bit, 2: moderately, 3: quiet a lot and 4: very much), total score 0-32; with higher scores means more severity. Also, it provided the information about how the participant feeling (as a percentage) and symptoms improved since beginning of treatment (rated on a 5 point scale [0: worse, 1: a no change, 2: minimally, 3: much and 4: very much]). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the Self-rated Davidson Trauma Scale (DTS), by Visit Week	This instrument consists of 17 items which parallel the DSM criteria for PTSD. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) rated using 5-point scale. There were 8 items assessing associated features (guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment). The DTS cluster includes intrusion (items 1-4, 17 [score 0-40]), avoidance/numbing (A/N; items 5-11 [score 0-56]) and hyperarousal (items 12-16 [score 0-40]). The total score (0-136) was added, lower score indicates less symptoms and higher scores means more severity, <20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and > 80: extreme PTSD symptoms. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values.	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the DTS Cluster Sub Score	This instrument consists of 17 items which parallel the DSM criteria for PTSD. Both frequency (0: never; 4: daily or all the time) and intensity (0: none or no problem; 4: extreme, incapacitating) rated using 5-point scale and added to get total score. There were 8 items including guilt, hopelessness, memory impairment, overall response validity, global PTSD severity, global improvement and social and occupational impairment. The DTS cluster includes intrusion (items 1-4, 17 [score 0-40]), A/N (items 5-11 [score 0-56]) and hyperarousal (items 12-16 [score 0-40]) with lower score indicates less symptoms and higher scores means more severity, <20: few symptoms or being asymptomatic, 20-39: mild or subthreshold PTSD, 40-59: threshold and moderate PTSD, 60-79: severe PTSD symptoms and >80: extreme PTSD symptoms. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the Pittsburgh Sleep Quality Index (PSQI) Global Score, by Visit Week	The PSQI was a self-rated questionnaire to assess sleep quality and disturbances. Individual items (19) generate 7-component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction. The global score generated by addition of individual score excluding use of sleeping medication component. It contains 15 objective (about frequency of sleep disturbances and subjective sleep quality) and 4 subjective (typical bedtime, wake-up time, sleep latency and sleep duration) items with score range from 0: no to 3: severe difficulty. The PSQI Global Score ranges from 0 to 21 and a global score > 5 was suggestive of significant sleep disturbance. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the PSQI Addendum for PTSD (PSQI-A) Global Score, by Visit Week	The PSQI-A was self-report instrument to assess disruptive nocturnal behavior (DNB) in PTSD participants with 7 types of DNB. These items include frequency of 1: hot flashes, 2: general nervousness, 3: memories or nightmares of traumatic experience, 4: severe anxiety or panic, not related to traumatic memories, 5: bad dreams, not related to traumatic memories, 6: episodes of terror or screaming during sleep without fully awakening and 7: episodes of acting out dreams, such as kicking, punching, running, or screaming. Each item was rated on a scale (0: not in the past month, 1: less than once a week, 2: once or twice a week and 3: three or more times a week) with global score range of 0-21. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the CAPS Recurrent Distressing Dreams Item (B2) at Weeks 1, 4, 8, and 12	The B2 asked participant about 'Have you ever had unpleasant dreams about the event(s)? How often in the past month?' Both frequency (0: never; 4: daily or all the time) and 'at their worst, how much distress or discomfort did these dreams cause you? Did these dreams wake you up? [If yes, ask:] What were you feeling or doing when you awoke? How long does it usually take to get back to sleep? [Listen for report of panic symptoms, yelling, posturing] intensity (0: none or no problem with symptoms; 4: extreme, incapacitating) ratings were made on a 5-point scale. The total score 0-8, higher scores means more severity. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in Hamilton Depression Rating Scale (HAM-D), by Visit Week	The HAM-D was observer-rated depressive symptom rating scale to measure the severity of depressive symptoms in participants with primary depressive illness. The items were ranked on a scale of 0-4 (0: absent; 4: greatest severity) or 0-2 (0: no difficulty; 2: difficulty falling asleep). In addition to the total score (0-66; with higher score indicates more depression), the HAM-D anxiety factor score (sum of items 10, 11, 12, 13, 15 and 17) and the melancholia subscore (sum of items 1, 2, 7, 8, 10, and 13) of the 17-item HAM-D scale was analyzed. The melancholia subscale was derived from three formal psychometric criteria (calibration, ascending monotonicity and dispersion). It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score, by Visit Week	The Massachusetts CPFQ was a brief self-report scale to measure cognitive and executive dysfunction in mood and anxiety disorders. The CPFQ comprises 7 questions assessing each of the most common complaints of depressed participants reporting fatigue or cognitive/executive problems. Each question was rated on a scale of 1 to 6, with 1: greater than normal, 2: normal, 3: minimally diminished, 4: moderately diminished, 5: markedly diminished and 6: totally absent functioning with total score 7-42; higher score indicating more dysfunction. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in Massachusetts Sexual Function Questionnaire (MSFQ) Total Score and Erectile Dysfunction Score in Males	The MSFQ was derived from the Guided Interview Questionnaire for males and from the Arizona Sexual Experience Scale. The questionnaire includes five items with a score ranging from 1-6 (1: greater than normal; 2: normal; 3: minimally diminished; 4: moderately diminished; 5: markedly diminished and 6: totally absent with total score 5-30; higher score indicating more dysfunction). The areas of sexual functioning included were total score and erectile dysfunction (males only). A total score was used as a global measure of sexual dysfunction. A follow-up version of the questionnaire includes an additional sixth item of the participant's global impression of improvement, with a score ranging from 1 to 6. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in MSFQ Total Score in Females	The MSFQ was derived from the Guided Interview Questionnaire for males and from the Arizona Sexual Experience Scale. The questionnaire includes five items with a score ranging from 1-6 (1: greater than normal; 2: normal; 3: minimally diminished; 4: moderately diminished; 5: markedly diminished and 6: totally absent with total score 5-30; higher score indicating more dysfunction). The areas of sexual functioning included were total score used as a global measure of sexual dysfunction. A follow-up version of the questionnaire includes an additional sixth item of the participant's global impression of improvement, with a score ranging from 1 to 6. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Change From Baseline in MSFQ Items (Diminished/Absent Libido; Arousal Difficulties; Orgasm Difficulties/Anorgasmia and Degree of Sexual Satisfaction) Scores	The MSFQ was derived from the Guided Interview Questionnaire for males and from the Arizona Sexual Experience Scale. The questionnaire includes five items with a score ranging from 1-6 (1: greater than normal; 2: normal; 3: minimally diminished; 4: moderately diminished; 5: markedly diminished and 6: totally absent). The areas of sexual functioning included were diminished/absent libido; arousal difficulties; orgasm difficulties/anorgasmia and degree of sexual satisfaction. A follow-up version of the questionnaire includes an additional sixth item of the participant's global impression of improvement, with a score ranging from 1 to 6. It was assessed at Baseline, Week 1, 2, 4, 6, 8, 10 and 12. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline was defined as value on Day 1 (pre-dose).	Baseline (Day 1 pre-dose) and up to Week 12
Secondary	Number of Participant With Suicidal Behavior Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During and Post Treatment	The C-SSRS used to assess severity and change of suicidality by integrating both behavior and ideation and to be completed by the participants. The SSRS track change in the severity/density of suicidality. The interview was initiated with 5 (yes/no) questions; rated on 1-5 point scale, presented in ascending order of severity, about suicidal ideation. If the answers to the first 2 ideation questions were "yes," the clinician asked questions 3-5. If the answers to ideation questions 1 and 2 were "no," then the clinician proceeded to 5 (yes/no) questions that addressed suicidal behavior, which was categorized as actual attempt, engaged in non-suicidal self-injurious behavior, interrupted attempt, aborted attempt and preparatory acts or behaviors. Participants analyzed were number of participants with at least one C-SSRS assessment after the first dose of study medication (that is on treatment or post treatment).	Baseline, Week 1, 2, 4, 6, 8, 10, 12 and Day 14 of follow-up (approximately 14 weeks)
Secondary	Number of Participant by Maximum Suicidal Ideation, Based on the C-SSRS During and Post Treatment	The C-SSRS used to assess severity and change of suicidality by integrating both behavior and ideation and to be completed by the participants. The SSRS track change in the severity/density of suicidality. It assessed intensity of ideation (a potentially important marker of severity), specifically asking about frequency, duration, intrusiveness, controllability, and deterrents. The interview was initiated with 5 (yes/no) questions; rated on 1-5 point scale, presented in ascending order of severity, about suicidal ideation. The clinician asked 5 questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation without intent to act, active suicidal ideation with any methods (not plan) without intent to act and active suicidal ideation with specific plan and intent. Participants analyzed were number of participants with at least one C-SSRS assessment after the first dose of study medication (that is on treatment or post treatment).	Baseline, Week 1, 2, 4, 6, 8, 10, 12 and Day 14 of follow-up (approximately 14 weeks)

External Links

•   Visit the study website at www.copestudy.com/gov or call 1-866-548-7425 toll-free to learn more and find out if you may qualify.