Orvepitant (GW823296) in Adult Post Traumatic Stress Disorder

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).

Time frame: Baseline (Day 1 pre-dose) and Week 12

Population: ITT population, consisted of all participants who gave informed consent, were randomized, received at least one dose of double blind medication and for whom at least one post-randomization assessment was available. Only those participants available at the indicated time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: Male participants from all subject population used. All subject population defined as participants who received at least one dose of study medication. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: All subject population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: Female participants from all subject population used. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and Week 1, 4, 8

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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.

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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).

Time frame: Baseline, Week 1, 2, 4, 6, 8, 10, 12 and Day 14 of follow-up (approximately 14 weeks)

Population: All subject population. Only those participants available at the time of indicated time points were analyzed.

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).

Time frame: Baseline, Week 1, 2, 4, 6, 8, 10, 12 and Day 14 of follow-up (approximately 14 weeks)

Population: All subject population. Only those participants available at the time of indicated time points were analyzed.

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.

Time frame: Up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed. The analysis method was logistic regression adjusted for Baseline CAPS total score. At a visit where there were no remitters, no analysis was performed.

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.

Time frame: Up to Week 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

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.

Time frame: Baseline (Day 1 pre-dose) and up to Week 12

Population: ITT Population. Only those participants available at the specified time points were analyzed.

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.

Time frame: Up to Week 12

Population: ITT Population. Only those participants available at the indicated time points were analyzed.