A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder
A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder
This is a 6-week, randomised, multicenter, double-blind, placebo controlled, fixed dose
 parallel group study to assess the efficacy and safety of orvepitant (30 and 60 mg/day)
 versus placebo in subjects with a diagnosis of a Major Depressive Disorder, whose symptoms
 are considered moderate or severe.

 Following an initial screening visit, subjects fulfilling the study inclusion and exclusion
 criteria will enter a pre-treatment screening phase to permit evaluation of the laboratory
 and ECG assessments and to confirm eligibility for inclusion into the study. This screening
 phase will be a minimum of 7 days, but no longer than 21 days. At the completion of the
 screening period, eligible subjects will be randomised at the baseline visit to receive
 either orvepitant 30mg/day, orvepitant 60mg/day or placebo (equal chance of receiving any of
 the three possible treatments, i.e., a 1:1:1 ratio) for a six-week double-blind treatment
 phase. Those subjects randomised to receive placebo will receive study medication identical
 in appearance to that received by subjects assigned to receive orvepitant 30 or 60mg/day.

 Efficacy will be assessed via standard depression symptom and severity rating scales or
 questionaires. The Hamilton Depression Rating Scale (HAM-D) will be used as the primary
 measure. Secondary efficacy endpoints include the Quick Inventory of Depressive
 Symptomatology (QIDS-SR) and the Clinical Global Impression- Global Improvement and Severity
 of Illness Scale (CGI-I and CGI-S, respectively).

 Safety will be assessed by monitoring for adverse events (side effects) and through periodic
 laboratory evaluations (blood tests), vital signs assessments (e.g., blood pressure, heart
 rate, temperature) and heart function measurements (electrocardiograms, or ECGs).
The purpose of the current study is to test the safety and the anti-depressant effects of
 orvepitant, an investigational antidepressant. Efficacy will be assessed using standard
 depression symptom and severity rating scales (questionaires). The Hamilton Depression Rating
 Scale (HAM-D) will serve as the primary measure of efficacy, and . Secondary efficacy
 endpoints include the Bech Melancholia Scale (sum of items 1, 2, 7, 8, 10, and 13 of the
 17-item HAM-D scale), the Quick Inventory of Depressive Symptomatology (QIDS-SR), the
 Clinical Global Impression- Global Improvement and Severity of Illness Scale (CGI-I and
 CGI-S, respectively), the HAM-D anxiety factor score (sum of items 10, 11, 12, 13, 15 and
 17), the Cognitive and Physical Function Questionnaire (CPFQ) and a morning sleep
 questionnaire.

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

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

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

 Following an initial screening visit, subjects fulfilling the study entrance criteria will
 enter a pre-treatment screening phase to permit evaluation of the laboratory and
 electrocardiogram assessments and to confirm eligibility for inclusion into the study. This
 screening phase will be a minimum of 7 days, but no longer than 21 days. During the screening
 period, subjects may undergo up to three different assessments of their depressive symptoms,
 this may occur via a face-to-face interview or via an interview over the telephone. Upon
 completion of the screening period, eligible subjects will be randomly assigned at the
 baseline visit to one of three treatment regimens: orvepitant 30mg/day, orvepitant 60mg/day
 or placebo for a six-week treatment phase. The chances of receiving each of the three
 possible treatments will be equal. Orvepitant will be administered as tablets. Those subjects
 randomised to receive placebo will receive study medication identical in appearance to that
 received by subjects assigned to receive orvepitant.

 During the treatment phase, subjects will be required to return to the clinic at the end of
 Weeks 1, 2, 4 and 6. In addition, all subjects will be required to return for a follow-up
 visit 14 days after the last dose of study medication. In addition, all subjects with ongoing
 adverse events at the 14-day follow-up visit will be required to return for a further
 follow-up visit 28 days after the last dose of study medication.

 Male and female outpatients between the ages of 18 to 64 years inclusive with a primary
 diagnosis of Major Depressive Disorder will be enrolled into this study. A total of
 approximately 350 subjects are expected to be enrolled at approximately 20 different study
 sites in the U.S. and Canada.
Inclusion Criteria:

 -  Subjects must have the ability to comprehend the Informed Consent Form.

 -  Male or female outpatients, aged 18-64, inclusive.

 -  A primary diagnosis of major depressive disorder, single episode or recurrent

 -  Subjects must, in the investigator's opinion and based on the subject's history, have
 met depression criteria for at least 8 weeks prior to the Screening Visit.

 -  Subjects with symptom severity considered to be at least moderate to severe by the
 investigator.

 -  Women of childbearing potential are only eligible IF they commit to consistent and
 correct use of an acceptable method of birth control that must be documentation at
 each visit

 Exclusion Criteria:

 -  Subjects whose mood-related symptoms are better accounted for by a diagnosis other
 than depression; subjects diagnosed with Alzheimer's Disease or other form of
 dementia; subjects diagnosed with a current/recent eating disorder such as anorexia
 nervosa or bulimia; subjects with a diagnosed history of schizophrenia,
 schizoaffective disorder, or Bipolar Disorder.

 -  Subjects with any history of a significant abnormality of the neurological system
 (including dementia and other cognitive disorders or significant head injury) or any
 history of seizures (convulsions).

 -  Subjects have a positive urine test at screening for illegal drug use and/or who have
 a history of substance abuse or dependence (alcohol or drugs) within the past 12
 months.

 -  Subjects who are currently receiving regularly scheduled psychotherapy (individual or
 group), plan to start psychotherapy during the trial or have received regularly
 scheduled psychotherapy during the 12 week period prior to the Screening Visit.

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

 -  Subjects who, in the investigator's judgement, pose a homicidal or serious suicidal
 risk, have made a suicide attempt within the 6 months preceding screening or who have
 ever been homicidal.

 -  Subjects who have received the following treatments for depression in the past:
 electroconvulsive therapy (ECT), vagal stimulation, or transcranial magnetic
 stimulation (TMS) within the 6 months prior to the Screening Visit.

 -  Subjects with an unstable medical disorder; or with a disorder that otherwise would
 likely interfere with the activity of the study medication (orvepitant).

 -  Subjects have any screening laboratory abnormality that in the investigator's
 judgement is considered to be clinically significant.

 -  Subjects with an abnormal thyroid test at the Screening Visit. Subjects maintained on
 thyroid medication must have normal thyroid levels for a period of at least six months
 prior to the Screening Visit.

 -  Subjects have any screening electrocardiography (ECG) finding that in the
 investigator's judgement is considered to be clinically significant.

 -  Women who have a positive pregnancy test at the Screening Visit, a positive urine
 dipstick test at the Baseline (Randomization) Visit, or who are lactating or planning
 to become pregnant within the 4 months following the Screen Visit.

 -  Subjects who have taken other psychoactive drugs within two weeks prior to the
 Baseline Visit i.e. at any time during the Screening period. This includes
 "over-the-counter" psychoactive medications such as St. John's Wort and SAM-e.

 -  Subjects who have taken other drugs within 2 weeks prior to the Baseline visit which
 the investigator feels may interact with the study medication.

 -  Subjects who are currently participating in another clinical trial in which the
 subject is or will be exposed to an investigational or non-investigational drug or
 device, or has done so within the preceding month for studies unrelated to depression,
 or 6 months for studies related to depression.

 -  Subjects who have no contact with an adult on a daily basis. This would exclude
 subjects who are not living with at least one other adult or subjects who do not have
 an adult who contacts them on a daily basis.