A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder

Participants who had 50% or greater reduction from Baseline in their total HAMD score were termed as responders. The HAM-D was designed to measure the severity of depressive symptoms in participants with primary depressive illness. The scale is a checklist of items that are ranked on a scale of 0 to 4 or 0 to 2. Items with quantifiable severity are scored 0 to 4 (4 indicating the greatest severity) or 0 to 2 (2 indicating the greatest severity) with 0 indicating not present. The HAM-D Total Score is calculated by summing the individual response scores on the HAM-D questionnaire. The highest possible score is 52, which represents the most severe measure of depression; the lowest possible score is 0, which represents an absence of depression. The HAM-D is also useful for monitoring changes in depressive symptoms with treatment and in comparing the efficacy of various interventions if the participant requires more than one type of treatment. Baseline was Day 1.

Clinical response or antidepressant response was defined as >= 50% reduction from randomization in their HAMD total score, where this response was maintained until the end of the Treatment Phase (Week 6). Participants who met the >= 50% reduction at Week 6 without also having met it at Week 4 were not considered to have reached a maintained response, and therefore were censored at Week 6. Number of participants with maintained clinical response are reported.

The Bech Melancholia is sum of scores on 6 items/questions (item 1: depressed mood, item 2: feelings of guilt, item 7: work and activities, item 8: retardation, item 10: anxiety psychic and item 13: somatic symptoms general) pertaining to melancholia within HAM-D. The items are rated on a scale of 0 to 4 (items 1, 2, 7, 8 and 10) or 0 to 2 (item 13), higher scores reflecting greater severity. The highest possible score is 24, which represents the most severe measure of melancholy; the lowest possible score is 0, which represents an absence of melancholy. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The QIDS-SR is a self-report rating scale that assesses symptom severity of major depressive disorders. The QIDS-SR utilized during this study contained 16 separate items which correspond to 9 symptom criterion domains: (1) sad mood, (2) concentration, (3) self-criticism, (4) suicidal ideation,(5) interest, (6) energy/fatigue, (7) sleep disturbance (initial, middle, and late insomnia or hypersomnia), (8) decrease/increase in appetite/weight, and (9) psychomotor agitation/retardation. The QIDS-SR total score was calculated using the sum of the domain scores. The highest possible total QIDS-SR score is 27, which represents the most severe measure of depression. The lowest possible score is 0, which represents an absence of depression. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The HAMD anxiety factor score includes 6 items/questions (item 10: anxiety psychic, item 11: anxiety somatic, item 12: somatic symptoms gastrointestinal, item 13: somatic symptoms general, item 15: hypochondriasis and item 17: insight). The items are rated on a scale of 0 to 4 (items 10, 11 and 15) or 0 to 2 (items 12, 13 and 17), higher scores reflecting greater severity. The highest possible score is 18, which represents the most severe measure of anxiety; the lowest possible score is 0, which represents an absence of anxiety. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The CGI is a widely accepted measure of illness severity and clinical improvement in a variety of psychiatric disorders. Global improvement (CGI-I) item is rated on a 1-7 scale. The CGI-I assessed scores range from 1 - very much improved to 7 - very much worse. For the CGI-I, the investigator or delegated qualified clinician indicated their assessment of the participant's total improvement or worsening compared with the individual's condition at the start of the study whether or not the change was judged to be due to drug treatment. A participant with a CGI-I score of 1 'very much improved' or 2 'much improved' was considered a responder. Percentage of responders are reported.

The CGI is a widely accepted measure of illness severity and clinical improvement in a variety of psychiatric disorders. For the CGI-S, an independent site rater assessed the participant's severity of illness considering (1) their total clinical experience with the particular population being studied and (2) information obtained during the Baseline HAM-D interview with the participant. The severity of illness (CGI-S) item is rated on a 1 to 7 scale such that 1 (normal, not at all ill) and 7 (among the most extremely ill). Higher scores indicate worsening. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The CPFQ is a brief self-report scale which is designed to measure cognitive and executive dysfunction in mood and anxiety disorders. The scale comprises 7 questions assessing each of the most common complaints of depressed participants reporting fatigue or cognitive/executive problems. Each question is rated on a scale of 1 to 6, (1 = greater than normal; 2 = normal; 3 = minimally diminished; 4=moderately diminished; 5 = markedly diminished; and 6 = totally absent). The following five areas were included: motivation/interest/enthusiasm; wakefulness/alertness; energy; focus/sustain attention; remember/recall information; find words and sharpness/mental acuity. The total score (sum of individual question scores) ranged from 7 to 42. Lower score 7 represents greater than normal functioning and higher score 42 indicate poorer functioning (worst outcome). Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The MSQ is a self-rated scale designed to assess effects on sleep and effects on next day functioning. The following six variables were assessed in order to determine effects on sleep: (1) total sleep time, (2) sleep onset latency, (3) number of nocturnal awakenings, (4) wake time after sleep onset, (5) sleep quality (where poor=1 and excellent= 10) and (6) the refreshing value of the sleep (where poor=1 and excellent= 10). During the conduct of the study, participants self-administered the MSQ via an Interactive Voice Response System (IVRS) from their home the morning of each clinic visit. Participants were provided paper MSQ diary cards for note taking prior to completing the IVRS call. If a participant did not remember to place the IVRS MSQ call the morning of the clinic visit from home, they were allowed to place the call during in the clinic during their visit. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The MSQ is a self-rated scale designed to assess effects on sleep and effects on next day functioning. The following six variables were assessed in order to determine effects on sleep: (1) total sleep time, (2) sleep onset latency, (3) number of nocturnal awakenings, (4) wake time after sleep onset, (5) sleep quality (where poor=1 and excellent= 10) and (6) the refreshing value of the sleep (where poor=1 and excellent= 10). During the conduct of the study, participants self-administered the MSQ via an Interactive Voice Response System (IVRS) from their home the morning of each clinic visit. Participants were provided paper MSQ diary cards for note taking prior to completing the IVRS call. If a participant did not remember to place the IVRS MSQ call the morning of the clinic visit from home, they were allowed to place the call during in the clinic during their visit. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

The MSQ is a self-rated scale designed to assess effects on sleep and effects on next day functioning. The score relating to SQ and RVS was measured by items/questions 4 and 5 respectively of the MSQ. The following two variables SQ and RVS were assessed in order to determine effects on sleep. Participants were asked to rate their SQ and RVS on a scale of 1 to 10. This scale has no subscales. The total score for SQ and RVS, both, ranged from 1 to 10 where 1=poor and 10=excellent. Lower scores indicated poor SQ and RVS and higher scores indicated excellent SQ and excellent RVS. During the conduct of study, participants self-administered MSQ via an IVRS from their home the morning of each clinic visit. If a participant did not remember to place IVRS MSQ call the morning of the clinic visit from home, they were allowed to place call during in the clinic during their visit. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

A HAM-D remitter was defined as a participant with a HAM-D total score less than or equal to 7. The HAM-D was designed to measure the severity of depressive symptoms in participants with primary depressive illness. The scale is a checklist of items that are ranked on a scale of 0 to 4 or 0 to 2. Items with quantifiable severity are scored 0 to 4 (4 indicating the greatest severity) or 0 to 2 (2 indicating the greatest severity) with 0 indicating not present. The HAM-D Total Score is calculated by summing the individual response scores on the HAM-D questionnaire. The highest possible score is 52, which represents the most severe measure of depression; the lowest possible score is 0, which represents an absence of depression. The HAM-D is also useful for monitoring changes in depressive symptoms with treatment and in comparing the efficacy of various interventions if the participant requires more than one type of treatment.

The C-SSRS is a clinician-rated scale that evaluates severity and change of suicidality by integrating both behavior and ideation. It has 3 sections, Suicidal Behavior (SB), Suicidal Ideation (SI) and Intensity of Ideation (II). For SB, participants (par) were scored non-suicidal:0, preparatory acts or behavior communicating ideation:1, aborted attempt:2, interrupted attempt:3 or actual attempt:4 (most severe). For SI, par were scored non-suicidal:0, wish to be dead:1, non-specific active suicidal thoughts:2, active suicidal ideation with associated thoughts of methods without intent:3, active suicidal ideation with some intent to act on suicidal thoughts without clear plan:4, active suicidal ideation with plan and intent:5 (most severe). II scale made of 5 questions measuring frequency, duration, controllability, deterrent and reasons; par received a separate score on most common ideation and on most severe. Total II score is obtained by adding scores from all 5 questions.

The discontinuation signs and symptoms scale consists of 43 signs and symptoms, scored as 'new symptom', 'old symptom but worse', 'old symptom but improved' or ' symptom not present/old symptom but unchanged'. A frequency table for each symptom is reported by treatment and visit. The total number of new signs and symptoms, old symptoms but worse, old symptoms but improved and the total number of new or old-but-worse signs and symptoms are calculated for treatment and visit and reported.

The MSFQ is a self report rating scale derived from the Guided Interview Questionnaire for females and males. The questionnaire includes five questions with a score for each question ranging from 1 to 6 (1 = greater than normal; 2 = normal; 3 = minimally diminished; 4=moderately diminished; 5 = markedly diminished; and 6 = totally absent). The following five areas of sexual functioning were included: (1) diminished/absent libido; (2) arousal difficulties; (3) orgasm difficulties/anorgasmia; (4) erectile dysfunction (males only) and (5) degree of sexual satisfaction. A total score (sum of individual question score) was used as a global measure of sexual dysfunction which ranged from 5 to 30, where 5 represents greater than normal functioning and 30 represents poorer function (worst outcome). Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values. A negative change from Baseline was considered a positive outcome.

The MSFQ is a self report rating scale derived from the Guided Interview Questionnaire for females and males. The questionnaire includes five questions with a score for each question ranging from 1 to 6 (1 = greater than normal; 2 = normal; 3 = minimally diminished; 4=moderately diminished; 5 = markedly diminished; and 6 = totally absent). The following four areas of sexual functioning were included: (1) diminished/absent libido; (2) arousal difficulties; (3) orgasm difficulties/anorgasmia; and (4) degree of sexual satisfaction. A total score (sum of individual question score) was used as a global measure of sexual dysfunction which ranged from 4 to 24, where 5 represents greater than normal functioning and 24 represents poorer function (worst outcome). Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values. A negative change from Baseline was considered a positive outcome.