Trial Outcomes & Findings for A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder (NCT NCT00880399)

Last Updated: 2017-09-12

Results Overview

The HAM-D is designed to measure severity of depressive symptoms in participants with primary depressive illness. The scale is a checklist of items (1: depressed mood, 2: feelings of guilt, 3: suicide, insomnia early, 4: insomnia early, 5: insomnia middle, 6: insomnia late, 7: work and activities, 8: retardation, 9: agitation, 10: anxiety psychic item 10: anxiety psychic, item 11: anxiety somatic, item 12: somatic symptoms gastrointestinal, 13: somatic symptoms general, 14: genital symptoms, 15: hypochondriasis, 16: loss of weight and 17: insight) that are ranked on a scale of 0 to 4 or 0 to 2 (4 and 2: highly severe and 0: not present). The HAM-D total score is calculated by summing individual response scores on the HAM-D questionnaire. The highest possible score is 52, representing most severe measure of depression; lowest possible score is 0, representing no depression. Baseline was Day 1. Change from Baseline was calculated by subtracting Baseline values from post-Baseline values.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

328 participants

Primary outcome timeframe

Baseline (Day 1) to Week 6

Results posted on

2017-09-12

Participant Flow

This study was conducted at 20 centers across the United States of America (USA) (17 centers) and Canada (3 centers) from 04 March 2009 to 16 June 2010.

A total of 787 participants were screened for study eligibility, of which 331 participants were randomized. Out of 331 participants, 3 did not receive the study medication. All subjects population included all participants who had received at least one dose of the study medication and comprised of 328 participants.

Participant milestones

Participant milestones
Measure	Placebo Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Overall Study STARTED	108	113	107
Overall Study COMPLETED	77	84	81
Overall Study NOT COMPLETED	31	29	26

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Overall Study Adverse Event	4	6	5
Overall Study Lack of Efficacy	1	4	2
Overall Study Protocol Violation	4	4	6
Overall Study Study closed/terminated	3	7	4
Overall Study Lost to Follow-up	8	5	3
Overall Study Physician Decision	5	0	3
Overall Study Withdrawal by Subject	6	3	3

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=108 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=113 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Total n=328 Participants Total of all reporting groups
Age, Continuous	39.7 Years STANDARD_DEVIATION 11.67 • n=93 Participants	41.0 Years STANDARD_DEVIATION 11.45 • n=4 Participants	38.2 Years STANDARD_DEVIATION 11.15 • n=27 Participants	39.7 Years STANDARD_DEVIATION 11.45 • n=483 Participants
Sex: Female, Male Female	76 Participants n=93 Participants	68 Participants n=4 Participants	70 Participants n=27 Participants	214 Participants n=483 Participants
Sex: Female, Male Male	32 Participants n=93 Participants	45 Participants n=4 Participants	37 Participants n=27 Participants	114 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants	4 Participants n=483 Participants
Race (NIH/OMB) Asian	4 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants	9 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	16 Participants n=93 Participants	17 Participants n=4 Participants	21 Participants n=27 Participants	54 Participants n=483 Participants
Race (NIH/OMB) White	86 Participants n=93 Participants	92 Participants n=4 Participants	79 Participants n=27 Participants	257 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants	4 Participants n=483 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) to Week 6

Population: The Intent-to-Treat (ITT) population comprised of all participants who were randomized and 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 specified time points were analyzed.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) Total Score Week 1	-3.72 Scores on a Scale Standard Error 0.438	-4.19 Scores on a Scale Standard Error 0.417	-4.87 Scores on a Scale Standard Error 0.433
Change From Baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) Total Score Week 2	-5.32 Scores on a Scale Standard Error 0.540	-7.21 Scores on a Scale Standard Error 0.515	-7.16 Scores on a Scale Standard Error 0.525
Change From Baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) Total Score Week 4	-7.40 Scores on a Scale Standard Error 0.665	-9.61 Scores on a Scale Standard Error 0.627	-10.45 Scores on a Scale Standard Error 0.641
Change From Baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) Total Score Week 6	-9.08 Scores on a Scale Standard Error 0.777	-11.49 Scores on a Scale Standard Error 0.735	-11.93 Scores on a Scale Standard Error 0.749

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Percentage of Participants With a >= 50 Percent (%) Reduction From Baseline in HAM-D Total Score Week 1	5 Percentage of participants	5 Percentage of participants	4 Percentage of participants
Percentage of Participants With a >= 50 Percent (%) Reduction From Baseline in HAM-D Total Score Week 2	10 Percentage of participants	15 Percentage of participants	12 Percentage of participants
Percentage of Participants With a >= 50 Percent (%) Reduction From Baseline in HAM-D Total Score Week 4	19 Percentage of participants	27 Percentage of participants	33 Percentage of participants
Percentage of Participants With a >= 50 Percent (%) Reduction From Baseline in HAM-D Total Score Week 6	29 Percentage of participants	42 Percentage of participants	39 Percentage of participants

SECONDARY outcome

Timeframe: Up to Week 6

Population: ITT Population.

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Number of Participants With (Maintained) Clinical Response	13 Participants	21 Participants	22 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the Bech Melancholia Scale Total Score (Sum of Items 1, 2, 7, 8, 10, and 13 of the 17-item HAMD Scale) Week 1	-1.68 Scores on a Scale Standard Error 0.237	-1.77 Scores on a Scale Standard Error 0.225	-1.83 Scores on a Scale Standard Error 0.233
Change From Baseline in the Bech Melancholia Scale Total Score (Sum of Items 1, 2, 7, 8, 10, and 13 of the 17-item HAMD Scale) Week 2	-2.35 Scores on a Scale Standard Error 0.289	-3.39 Scores on a Scale Standard Error 0.276	-3.26 Scores on a Scale Standard Error 0.281
Change From Baseline in the Bech Melancholia Scale Total Score (Sum of Items 1, 2, 7, 8, 10, and 13 of the 17-item HAMD Scale) Week 4	-3.20 Scores on a Scale Standard Error 0.366	-4.49 Scores on a Scale Standard Error 0.345	-4.88 Scores on a Scale Standard Error 0.352
Change From Baseline in the Bech Melancholia Scale Total Score (Sum of Items 1, 2, 7, 8, 10, and 13 of the 17-item HAMD Scale) Week 6	-4.30 Scores on a Scale Standard Error 0.424	-5.53 Scores on a Scale Standard Error 0.402	-5.84 Scores on a Scale Standard Error 0.409

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) Total Score Week 1	-2.47 Scores on a Scale Standard Error 0.381	-3.19 Scores on a Scale Standard Error 0.364	-3.13 Scores on a Scale Standard Error 0.375
Change From Baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) Total Score Week 2	-3.48 Scores on a Scale Standard Error 0.428	-4.50 Scores on a Scale Standard Error 0.408	-4.03 Scores on a Scale Standard Error 0.415
Change From Baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) Total Score Week 4	-4.16 Scores on a Scale Standard Error 0.483	-5.85 Scores on a Scale Standard Error 0.457	-6.26 Scores on a Scale Standard Error 0.466
Change From Baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) Total Score Week 6	-5.05 Scores on a Scale Standard Error 0.551	-6.34 Scores on a Scale Standard Error 0.523	-6.73 Scores on a Scale Standard Error 0.532

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the HAM-D Anxiety Factor Score (Sum of Items 10, 11, 12, 13, 15 and 17) Week 1	-1.06 Scores on a Scale Standard Error 0.165	-1.07 Scores on a Scale Standard Error 0.157	-1.28 Scores on a Scale Standard Error 0.163
Change From Baseline in the HAM-D Anxiety Factor Score (Sum of Items 10, 11, 12, 13, 15 and 17) Week 2	-1.47 Scores on a Scale Standard Error 0.188	-1.90 Scores on a Scale Standard Error 0.179	-1.91 Scores on a Scale Standard Error 0.183
Change From Baseline in the HAM-D Anxiety Factor Score (Sum of Items 10, 11, 12, 13, 15 and 17) Week 4	-2.19 Scores on a Scale Standard Error 0.226	-2.51 Scores on a Scale Standard Error 0.212	-2.78 Scores on a Scale Standard Error 0.218
Change From Baseline in the HAM-D Anxiety Factor Score (Sum of Items 10, 11, 12, 13, 15 and 17) Week 6	-2.60 Scores on a Scale Standard Error 0.256	-3.06 Scores on a Scale Standard Error 0.242	-3.30 Scores on a Scale Standard Error 0.248

SECONDARY outcome

Timeframe: Up to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Percentage of Participants With Clinical Global Impression- Global Improvement (CGI-I) Score of 1 (Very Much Improved) or 2 (Much Improved) Week 1	5 Percentage of participants	10 Percentage of participants	4 Percentage of participants
Percentage of Participants With Clinical Global Impression- Global Improvement (CGI-I) Score of 1 (Very Much Improved) or 2 (Much Improved) Week 2	10 Percentage of participants	22 Percentage of participants	16 Percentage of participants
Percentage of Participants With Clinical Global Impression- Global Improvement (CGI-I) Score of 1 (Very Much Improved) or 2 (Much Improved) Week 4	22 Percentage of participants	35 Percentage of participants	32 Percentage of participants
Percentage of Participants With Clinical Global Impression- Global Improvement (CGI-I) Score of 1 (Very Much Improved) or 2 (Much Improved) Week 6	31 Percentage of participants	44 Percentage of participants	40 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score Week 1	-0.34 Scores on a Scale Standard Error 0.060	-0.43 Scores on a Scale Standard Error 0.057	-0.43 Scores on a Scale Standard Error 0.059
Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score Week 2	-0.51 Scores on a Scale Standard Error 0.077	-0.88 Scores on a Scale Standard Error 0.073	-0.73 Scores on a Scale Standard Error 0.074
Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score Week 4	-0.80 Scores on a Scale Standard Error 0.104	-1.14 Scores on a Scale Standard Error 0.098	-1.26 Scores on a Scale Standard Error 0.100
Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score Week 6	-1.07 Scores on a Scale Standard Error 0.127	-1.52 Scores on a Scale Standard Error 0.120	-1.56 Scores on a Scale Standard Error 0.122

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score Week 1	-3.24 Scores on a Scale Standard Error 0.582	-3.72 Scores on a Scale Standard Error 0.553	-3.22 Scores on a Scale Standard Error 0.572
Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score Week 2	-3.80 Scores on a Scale Standard Error 0.567	-5.31 Scores on a Scale Standard Error 0.541	-4.37 Scores on a Scale Standard Error 0.550
Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score Week 4	-5.12 Scores on a Scale Standard Error 0.659	-6.34 Scores on a Scale Standard Error 0.623	-6.27 Scores on a Scale Standard Error 0.637
Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score Week 6	-5.51 Scores on a Scale Standard Error 0.729	-7.67 Scores on a Scale Standard Error 0.693	-7.85 Scores on a Scale Standard Error 0.704

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) TST; Week 1	36.09 Minutes (mins) Standard Error 9.204	40.54 Minutes (mins) Standard Error 8.834	63.46 Minutes (mins) Standard Error 9.148
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) TST; Week 2	34.62 Minutes (mins) Standard Error 9.728	42.74 Minutes (mins) Standard Error 9.371	48.14 Minutes (mins) Standard Error 9.440
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) TST; Week 4	49.57 Minutes (mins) Standard Error 10.991	32.07 Minutes (mins) Standard Error 10.309	70.68 Minutes (mins) Standard Error 10.472
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) TST; Week 6	39.79 Minutes (mins) Standard Error 9.930	44.26 Minutes (mins) Standard Error 9.443	51.26 Minutes (mins) Standard Error 9.523
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) SOL; Week 1	-7.16 Minutes (mins) Standard Error 5.658	-18.68 Minutes (mins) Standard Error 5.440	-31.06 Minutes (mins) Standard Error 5.620
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) SOL; Week 2	-14.60 Minutes (mins) Standard Error 5.609	-22.27 Minutes (mins) Standard Error 5.405	-39.28 Minutes (mins) Standard Error 5.444
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) SOL; Week 4	-21.75 Minutes (mins) Standard Error 6.354	-32.46 Minutes (mins) Standard Error 5.949	-37.06 Minutes (mins) Standard Error 6.041
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) SOL; Week 6	-34.50 Minutes (mins) Standard Error 5.212	-27.66 Minutes (mins) Standard Error 4.940	-37.75 Minutes (mins) Standard Error 4.998
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) WTSO; Week 1	-12.09 Minutes (mins) Standard Error 7.248	-9.69 Minutes (mins) Standard Error 6.799	-21.38 Minutes (mins) Standard Error 7.252
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) WTSO; Week 2	-2.12 Minutes (mins) Standard Error 7.397	-17.99 Minutes (mins) Standard Error 7.196	-24.38 Minutes (mins) Standard Error 7.343
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) WTSO; Week 4	-15.76 Minutes (mins) Standard Error 11.019	-13.60 Minutes (mins) Standard Error 10.306	-17.43 Minutes (mins) Standard Error 10.819
Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO) WTSO; Week 6	-16.99 Minutes (mins) Standard Error 10.713	-21.08 Minutes (mins) Standard Error 10.428	-14.08 Minutes (mins) Standard Error 11.198

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in MSQ Values for Number of Nocturnal Awakenings Week 1	-0.07 Awakenings Standard Error 0.225	-0.29 Awakenings Standard Error 0.214	0.09 Awakenings Standard Error 0.227
Change From Baseline in MSQ Values for Number of Nocturnal Awakenings Week 2	-0.42 Awakenings Standard Error 0.120	-0.53 Awakenings Standard Error 0.116	-0.66 Awakenings Standard Error 0.119
Change From Baseline in MSQ Values for Number of Nocturnal Awakenings Week 4	-0.42 Awakenings Standard Error 0.140	-0.41 Awakenings Standard Error 0.130	-0.71 Awakenings Standard Error 0.137
Change From Baseline in MSQ Values for Number of Nocturnal Awakenings Week 6	-0.36 Awakenings Standard Error 0.152	-0.67 Awakenings Standard Error 0.147	-0.84 Awakenings Standard Error 0.157

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) SQ; Week 1	0.79 Scores on a Scale Standard Error 0.201	1.30 Scores on a Scale Standard Error 0.192	1.48 Scores on a Scale Standard Error 0.199
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) SQ; Week 2	0.81 Scores on a Scale Standard Error 0.207	1.75 Scores on a Scale Standard Error 0.199	1.65 Scores on a Scale Standard Error 0.201
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) SQ; Week 4	1.45 Scores on a Scale Standard Error 0.224	1.58 Scores on a Scale Standard Error 0.209	2.27 Scores on a Scale Standard Error 0.214
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) SQ; Week 6	1.53 Scores on a Scale Standard Error 0.238	2.19 Scores on a Scale Standard Error 0.226	2.30 Scores on a Scale Standard Error 0.228
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) RVS; Week 1	0.75 Scores on a Scale Standard Error 0.198	1.14 Scores on a Scale Standard Error 0.190	1.45 Scores on a Scale Standard Error 0.196
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) RVS; Week 2	1.10 Scores on a Scale Standard Error 0.208	1.70 Scores on a Scale Standard Error 0.200	1.69 Scores on a Scale Standard Error 0.202
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) RVS; Week 4	1.55 Scores on a Scale Standard Error 0.230	1.52 Scores on a Scale Standard Error 0.215	2.32 Scores on a Scale Standard Error 0.219
Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS) RVS; Week 6	1.67 Scores on a Scale Standard Error 0.246	2.31 Scores on a Scale Standard Error 0.234	2.41 Scores on a Scale Standard Error 0.236

SECONDARY outcome

Timeframe: Up to Week 6

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Number of Participants Who Remit (Have an Endpoint HAM-D Total Score <= 7) Who Continue to Show Symptoms on the HAM-D Sleep Items Week 1	1 Participants	2 Participants	0 Participants
Number of Participants Who Remit (Have an Endpoint HAM-D Total Score <= 7) Who Continue to Show Symptoms on the HAM-D Sleep Items Week 2	2 Participants	2 Participants	4 Participants
Number of Participants Who Remit (Have an Endpoint HAM-D Total Score <= 7) Who Continue to Show Symptoms on the HAM-D Sleep Items Week 4	5 Participants	10 Participants	10 Participants
Number of Participants Who Remit (Have an Endpoint HAM-D Total Score <= 7) Who Continue to Show Symptoms on the HAM-D Sleep Items Week 6	8 Participants	16 Participants	15 Participants

SECONDARY outcome

Timeframe: Week 8

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=110 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Number of Participants With Suicidal Behavior, Ideation, and Most Common Ideation Using the Columbia Suicidality Severity Rating Scale (C-SSRS) Suicidal Ideation score 1	27 Participants	26 Participants	27 Participants
Number of Participants With Suicidal Behavior, Ideation, and Most Common Ideation Using the Columbia Suicidality Severity Rating Scale (C-SSRS) Suicidal Ideation score 2	5 Participants	7 Participants	6 Participants
Number of Participants With Suicidal Behavior, Ideation, and Most Common Ideation Using the Columbia Suicidality Severity Rating Scale (C-SSRS) Suicidal Ideation score 3	1 Participants	3 Participants	4 Participants
Number of Participants With Suicidal Behavior, Ideation, and Most Common Ideation Using the Columbia Suicidality Severity Rating Scale (C-SSRS) Suicidal Ideation score 4	0 Participants	1 Participants	0 Participants
Number of Participants With Suicidal Behavior, Ideation, and Most Common Ideation Using the Columbia Suicidality Severity Rating Scale (C-SSRS) Suicidal Ideation score 5	1 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 1 to Week 8/Follow up 1

Population: All subjects population comprised of all participants who received at least one dose of study medication. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

Population: Only males from all subjects population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Outcome measures
Measure	Placebo n=32 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=45 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=37 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the Massachusetts Sexual Function Questionnaire (MSFQ)-Males Week 1	-1.61 Scores on a Scale Standard Error 0.961	0.58 Scores on a Scale Standard Error 0.835	-0.27 Scores on a Scale Standard Error 0.894
Change From Baseline in the Massachusetts Sexual Function Questionnaire (MSFQ)-Males Week 2	-2.22 Scores on a Scale Standard Error 1.050	-1.16 Scores on a Scale Standard Error 0.906	-1.20 Scores on a Scale Standard Error 0.952
Change From Baseline in the Massachusetts Sexual Function Questionnaire (MSFQ)-Males Week 4	-2.98 Scores on a Scale Standard Error 1.080	-1.49 Scores on a Scale Standard Error 0.938	-2.22 Scores on a Scale Standard Error 0.983
Change From Baseline in the Massachusetts Sexual Function Questionnaire (MSFQ)-Males Week 6	-3.46 Scores on a Scale Standard Error 1.168	-2.25 Scores on a Scale Standard Error 1.007	-2.82 Scores on a Scale Standard Error 1.046

SECONDARY outcome

Timeframe: Baseline (Day 1) to Week 6

Population: Only females from all subjects population. Only those participants available at the specified time points were analyzed.

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.

Outcome measures

Outcome measures
Measure	Placebo n=76 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=68 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=70 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Change From Baseline in the MSFQ Total Score-Females Week 4	-2.31 Scores on a Scale Standard Error 0.643	-2.24 Scores on a Scale Standard Error 0.641	-2.89 Scores on a Scale Standard Error 0.648
Change From Baseline in the MSFQ Total Score-Females Week 6	-2.13 Scores on a Scale Standard Error 0.702	-2.49 Scores on a Scale Standard Error 0.697	-4.40 Scores on a Scale Standard Error 0.711
Change From Baseline in the MSFQ Total Score-Females Week 1	-0.76 Scores on a Scale Standard Error 0.451	-0.76 Scores on a Scale Standard Error 0.455	-0.67 Scores on a Scale Standard Error 0.467
Change From Baseline in the MSFQ Total Score-Females Week 2	-1.30 Scores on a Scale Standard Error 0.520	-1.47 Scores on a Scale Standard Error 0.526	-0.70 Scores on a Scale Standard Error 0.533

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 27 other events

Deaths: 0 deaths

Orvepitant 30 mg

Serious events: 0 serious events

Other events: 40 other events

Deaths: 0 deaths

Orvepitant 60 mg

Serious events: 1 serious events

Other events: 34 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=108 participants at risk Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=113 participants at risk Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 participants at risk Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	0.00% 0/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	0.93% 1/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Injury, poisoning and procedural complications Pelvic fracture	0.93% 1/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	0.00% 0/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	0.00% 0/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.

Other adverse events

Other adverse events
Measure	Placebo n=108 participants at risk Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=113 participants at risk Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 participants at risk Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Nervous system disorders Headache	9.3% 10/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	9.7% 11/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	4.7% 5/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Nervous system disorders Somnolence	1.9% 2/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	8.0% 9/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	8.4% 9/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Nervous system disorders Dizziness	2.8% 3/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	6.2% 7/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	1.9% 2/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	6.5% 7/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	8.0% 9/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	6.5% 7/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Gastrointestinal disorders Nausea	5.6% 6/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	8.0% 9/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	4.7% 5/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Gastrointestinal disorders Dry mouth	5.6% 6/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	7.1% 8/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	3.7% 4/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
General disorders Fatigue	1.9% 2/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	0.00% 0/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	8.4% 9/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.
Infections and infestations Upper respiratory tract infection	5.6% 6/108 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	2.7% 3/113 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.	4.7% 5/107 • Serious adverse events (SAE) and non-serious adverse events (nSAE) were collected from Screening (Visit1), at Baseline (Day 1, Visit 2) until follow-up (Day 28, Visit 5). SAEs and nSAE are reported for all subjects population which comprised of all participants who received at least one dose of study medication.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=108 Participants Participants received Orvepitant matching placebo tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 30 mg n=113 Participants Participants received Orvepitant 30 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.	Orvepitant 60 mg n=107 Participants Participants received Orvepitant 60 mg tablets via oral route, once daily in the evening, for a total of 6 weeks.
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New symptom; Week 1	1.5 Signs and symptoms Standard Deviation 0.71	2.0 Signs and symptoms Standard Deviation NA Single participant analyzed	2.0 Signs and symptoms Standard Deviation NA Single participant analyzed
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Improved; Week 1	1.0 Signs and symptoms Standard Deviation NA Single participant	—	3.0 Signs and symptoms Standard Deviation NA Single participant
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Worsened; Week 1	5.7 Signs and symptoms Standard Deviation 4.04	—	1.0 Signs and symptoms Standard Deviation 0.00
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Unchanged/ Not present; Week 1	39.5 Signs and symptoms Standard Deviation 5.09	42.6 Signs and symptoms Standard Deviation 0.89	41.0 Signs and symptoms Standard Deviation 2.71
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New or Old but Worsened; Week 1	6.7 Signs and symptoms Standard Deviation 4.93	2.0 Signs and symptoms Standard Deviation NA Single participant analyzed	1.7 Signs and symptoms Standard Deviation 1.15
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New symptom; Week 2	—	1.0 Signs and symptoms Standard Deviation NA Single participant analyzed	—
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Improved; Week 2	—	3.0 Signs and symptoms Standard Deviation 3.46	—
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Worsened; Week 2	—	—	6.0 Signs and symptoms Standard Deviation 1.41
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Unchanged/ Not present; Week 2	43.0 Signs and symptoms Standard Deviation 0.00	39.7 Signs and symptoms Standard Deviation 3.21	41.0 Signs and symptoms Standard Deviation 3.16
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New or Old but Worsened; Week 2	—	1.0 Signs and symptoms Standard Deviation NA Single participant analyzed	6.0 Signs and symptoms Standard Deviation 1.41
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New symptom; Week 4	8.0 Signs and symptoms Standard Deviation NA Single participant analyzed	1.5 Signs and symptoms Standard Deviation 0.71	6.0 Signs and symptoms Standard Deviation 5.66
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Improved; Week 4	2.5 Signs and symptoms Standard Deviation 0.71	4.7 Signs and symptoms Standard Deviation 1.53	2.0 Signs and symptoms Standard Deviation 1.41
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Worsened; Week 4	6.0 Signs and symptoms Standard Deviation 4.36	11.7 Signs and symptoms Standard Deviation 8.50	4.5 Signs and symptoms Standard Deviation 0.71
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Unchanged/ Not present; Week 4	39.6 Signs and symptoms Standard Deviation 4.98	37.8 Signs and symptoms Standard Deviation 9.31	38.8 Signs and symptoms Standard Deviation 6.82
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New or Old but Worsened; Week 4	8.7 Signs and symptoms Standard Deviation 4.93	12.7 Signs and symptoms Standard Deviation 7.77	10.5 Signs and symptoms Standard Deviation 6.36
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New symptom; Week 6	2.8 Signs and symptoms Standard Deviation 3.45	2.1 Signs and symptoms Standard Deviation 1.98	5.2 Signs and symptoms Standard Deviation 7.74
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Improved; Week 6	4.1 Signs and symptoms Standard Deviation 2.98	4.0 Signs and symptoms Standard Deviation 3.46	5.7 Signs and symptoms Standard Deviation 7.41
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Worsened; Week 6	3.9 Signs and symptoms Standard Deviation 3.75	2.7 Signs and symptoms Standard Deviation 2.49	3.2 Signs and symptoms Standard Deviation 3.15
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Unchanged/ Not present; Week 6	40.4 Signs and symptoms Standard Deviation 3.82	40.0 Signs and symptoms Standard Deviation 4.01	39.0 Signs and symptoms Standard Deviation 6.48
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New or Old but Worsened; Week 6	4.0 Signs and symptoms Standard Deviation 3.82	3.0 Signs and symptoms Standard Deviation 3.31	5.2 Signs and symptoms Standard Deviation 7.01
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New symptom; Follow-up 1	3.0 Signs and symptoms Standard Deviation 3.37	1.8 Signs and symptoms Standard Deviation 1.09	2.4 Signs and symptoms Standard Deviation 1.86
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Improved; Follow-up 1	3.3 Signs and symptoms Standard Deviation 2.43	2.6 Signs and symptoms Standard Deviation 2.28	4.0 Signs and symptoms Standard Deviation 2.58
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Old Symptom But Worsened; Follow-up 1	2.6 Signs and symptoms Standard Deviation 1.82	3.9 Signs and symptoms Standard Deviation 4.07	4.1 Signs and symptoms Standard Deviation 3.72
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) Unchanged/ Not present; Follow-up 1	41.1 Signs and symptoms Standard Deviation 3.65	40.6 Signs and symptoms Standard Deviation 3.87	40.0 Signs and symptoms Standard Deviation 4.25
Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) New or Old but Worsened; Follow-up 1	4.5 Signs and symptoms Standard Deviation 4.22	4.0 Signs and symptoms Standard Deviation 3.96	4.8 Signs and symptoms Standard Deviation 4.01