A Randomised, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder

Study Overview
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Brief Summary
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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).

Detailed Description
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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 and the treatment phase if the study, if the subject is selected for study entry, subjects will undergo assessments of their depressive symptoms via a face-to-face interview as well as via a video-based system (i.e., live subject interview conducted by an off-site interviewer using a web-based video camera). 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 30 different study sites in the U.S. and Canada.

Official Title
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A Randomised, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: orvepitant
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: orvepitant 30 mg<br>orvepitant 30 mg (low dose) | Drug: orvepitant<br>* neurokinin-1 antagonist<br>* Other names: GW823296;|
| Experimental: orvepitant 60 mg<br>orvepitant 60 mg (high dose) | Drug: orvepitant<br>* neurokinin-1 antagonist<br>* Other names: GW823296;|
| Placebo Comparator: Placebo<br>inactive placebo to match orvepitant 30 mg and 60 mg dosage forms | Other: Placebo<br>* Placebo to match orvepitant 30 mg and 60 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) Total Score | HAM-D was use to measure the severity of depressive symptoms in participants with primary depressive illness. It was a checklist of items that were ranked on a scale of 0-4 or 0-2. Items with quantifiable severity were scored 0 (lowest severity) to 4 (greatest severity); The HAM-D total score was calculated by summing the individual response scores. The lowest possible score was 0 (absence of depression) and the highest possible score was 52 (most severe measure of depression). For the last observation carried forward analyses, the most recent post randomization total score (as opposed to individual responses) was carried forward and used in the calculation of the change from randomization (Baseline) value. If the responses to more than 1 question were missing for a participant at a particular time point, the total score was not calculated. Change from Baseline in total score was the difference between HAM-D total score at the time point being analyzed and randomization. | Baseline and up to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a >=50% Reduction From Baseline in HAM-D Total Score | HAM-D was use to measure the severity of depressive symptoms in participants with primary depressive illness. It was a checklist of items that were ranked on a scale of 0-4 or 0-2. The HAM-D Total Score was calculated by summing the individual response scores. The lowest possible score was 0 (absence of depression) and the highest possible score was 52 (most severe measure of depression). For the last observation carried forward analyses, the most recent post randomization total score (as opposed to individual responses) was carried forward and used in the calculation of the change from randomization value. If the responses to more than 1 question were missing for a participant at a particular time point, the total score was not calculated. Data was presented as percent of HAM-D responders which was defined as participants who has a >=50% reduction from randomization in HAM-D total score. | Up to Week 6 | 
| Number of Participants Who Maintained Clinical Response by Week 6 | The start of the 'maintained antidepressant response' was the time at which a participant demonstrates a 50% reduction from randomization in their HAM-D total score and where this response was maintained until the end of the treatment phase (week 6). Participants who met the 50% reduction at week 6 without having met it at week 4 were considered to have reached a maintained response, and therefore were censored at week 6. Where a participant met the criteria for maintained antidepressant response, the time (in days) to maintained antidepressant response was calculated as: (Date of assessment at which the maintained response commences minus Date of randomization) plus 1. Where a participant did not met the criteria for maintained antidepressant response, their time to response was censored at the last on-treatment assessment they undertake, up to and including the week 6 assessment. | Up to Week 6 | 
| Change From Baseline in the Bech Melancholia Scale Total Score (Sum of Items 1, 2, 7, 8, 10, and 13 of the 17-item HAM-D Scale) | The BECH scale was extracted from the HAMD-17 and comprised the 6 items (sum of items 1, 2, 7, 8, 10, and 13 of the 17-item HAM-D scale): Depressed Mood, Feelings of Guilt, Work and Activities, Retardation, Anxiety Psychic and Somatic Symptoms General. The BECH Total Score was calculated by summing the individual response scores. It was a checklist of items that were ranked on a scale of 0-4 or 0-2. The lowest possible score was 0 (absence of depression) and the highest possible score was 22 (most severe measure of depression). Due to the small number of items , missing data was not imputed for the BECH Total Score. If any of the 6 items above were missing, the total score was not calculated at that visit. Value at randomization was the Baseline value. Change from Baseline in BECH Total Score was the difference between BECH Total Score at the time point being analyzed to randomization. | Baseline and up to Week 6 | 
| Change From Baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) Total Score | QIDS-SR assessed symptoms severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criterion for major depressive disorder. It consisted of 16 separate items, defining 9 DSM-IV symptom criterion domains. A total score was obtained by summing scores on each domain. The lowest possible score was 0, which represented an absence of depression; the highest possible score was 27, which represented the most severe measure of depression. Due to the small number of items, missing data was not imputed for the QIDS-SR total score. If any of the 9 domains above were missing, the total score was not calculated at that visit. Value at randomization was the Baseline value. Change from Baseline in total score was the difference between QIDS total score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and up to Week 6 | 
| Change From Baseline in the HAM-D Anxiety Factor Score (Sum of Items 10, 11, 12, 13, 15 and 17) | The anxiety score was extracted from the HAM-D-17 and comprises of items 10, 11, 12, 13 and 15 from the HAM-D scale. The anxiety score was calculated by summing the individual response scores to these questions. It was a checklist of items that were ranked on a scale of 0-4 or 0-2. The lowest possible score was 0 (absence of depression) and the highest possible score was 18 (most severe measure of depression). Due to the small number of items, missing data was not imputed for the anxiety score. If either of the anxiety items was missing, the total score was not calculated at that visit. Value at randomization was the Baseline value. Change from Baseline in anxiety score was the difference between the anxiety score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and up to Week 6 | 
| Percentage of Participants With Clinical Global Impression- Global Improvement (CGI-I) Score | The CGI-I assessed scores range from 1 - Very much Improved to 7 - Very much worse, with 0 representing a participant that was not assessed. The assessed scores were dichotomized. Scores of 1 or 2 was in the first category, scoring 1. All other scores (except zero which was regarded as missing) was in the second category, scoring 0. The percentage of participants in the first category was calculated for each assessment. | Up to Week 6 | 
| Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score | The CGI-S assessed scores range from 1 - Very much Improved to 7 - Very much worse, with 0 representing a participant that was not assessed. For the CGI-S, remote, blinded MedAvante, raters assessed the participant's severity of illness considering their total clinical experience with the particular population being studied and information obtained during the Baseline HAMD interview with the participant. Value at randomization was the Baseline value. Change from Baseline in total score was the difference between CGI-S Score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and up to Week 6 | 
| Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score | CPFQ was a brief self-report scale which was designed to measure cognitive and executive dysfunction in mood and anxiety disorders. The CPFQ comprised of 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 indicating greater than normal functioning, 2, indicating normal functioning, and with higher numbers indicating poorer functioning. Two versions of the CPFQ were utilized during the study. The Baseline CPFQ requested the participant reflect back over the past month. For the treatment period, the CPFQ requested the participant reflect back over the past week. Value at randomization was the Baseline value. Change from Baseline in Total Score was the difference between CPFQ Score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and up to Week 6 | 
| Change From Baseline in Morning Sleep Questionnaire (MSQ) Total Sleep Time, Sleep Onset Latency and Wake Time After Sleep Onset | The MSQ was a self-rated scale designed to assess effects on sleep and effects on next day functioning. The following variables were assessed in order to determine effects on sleep: total sleep time, sleep onset latency, number of nocturnal awakenings, wake time after sleep onset and sleep quality (from poor, assigned a score of 1, to excellent, assigned a score of 10). The refreshing value of the sleep was also determined (poor assigned a score of 1, to excellent, assigned a score of 10). Value at randomization was the Baseline value. Change from Baseline was calculated for each domain separately. Change from Baseline was the difference between score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and up to Week 6 | 
| Change From Baseline in the MSQ Number of Nocturnal Awakenings | The MSQ was a self-rated scale designed to assess effects on sleep and effects on next day functioning. The following variables were assessed in order to determine effects on sleep: total sleep time, sleep onset latency, number of nocturnal awakenings, wake time after sleep onset and sleep quality (from poor, assigned a score of 1, to excellent, assigned a score of 10). The refreshing value of the sleep was also determined (poor assigned a score of 1, to excellent, assigned a score of 10). Value at randomization was the Baseline value. Change from Baseline was calculated for each domain separately. Change from Baseline was the difference between score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and upto Week 6 | 
| Change From Baseline in the MSQ Sleep Quality and Refreshing Value of Sleep | The MSQ was a self-rated scale designed to assess effects on sleep and effects on next day functioning. The following variables were assessed in order to determine effects on sleep: total sleep time, sleep onset latency, number of nocturnal awakenings, wake time after sleep onset and sleep quality (from poor, assigned a score of 1, to excellent, assigned a score of 10). The refreshing value of the sleep was also determined (poor assigned a score of 1, to excellent, assigned a score of 10). Value at randomization was the Baseline value. Change from Baseline was calculated for each domain separately. Change from Baseline was the difference between score at the time point being analyzed to randomization. If no post- randomization scores were available, change from Baseline was set to missing. | Baseline and up to Week 6 | 
| Number of HAM-D Remitters | A HAMD remitter was defined as a participant who had a HAMD Total Score <=7. The HAMD total score was calculated for each participant at each time point. Those participants with no missing value for HAMD total score were categorized as having a HAMD total score of <=7 or >7. | Up to Week 6 | 
| Number of Participants With Suicide-Related Events Based on the Columbia Suicidality Severity Rating Scale (CSSRS) | Assessment of suicidality were done through use of the CSSRS for suicidal ideation and suicidal behavior. For suicidal ideation ratings were 1 to 5, where 1. Wish to be dead, 2. Non-specific active suicidal thoughts, 3. Active suicidal ideation without intent to act, 4. Active suicidal ideation with any methods (not plan) without intent to act, 5. Active suicidal ideation with specific plan and intent and for suicidal behavior ratings were 6 to 12, Where 6. Actual attempt, 7. Engaged in non-suicidal self-injurious behavior, 8. Interrupted attempt, 9. Aborted attempt, 10. Preparatory acts or behavior, 11. Suicidal behavior, 12. Completed suicide. n= number participants with at least one CSSRS assessment after the first dose of study medication (i.e. on treatment or post treatment). Only those categories from CSSRS (1-12) are presented for which symptoms were actually observed in the participants. Categories with null values for all the arms have not been presented. | Up to 17 days post-treatment | 
| Number of Incidences of Discontinuation Emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS) | The DESS scale consisted 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'. 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 were calculated for each treatment and visit. n = number of subjects who had at least one of the 43 symptoms in the specified category. The summary for a specified category are of the number of symptoms the n subjects had in that category. Treatment period was up to Week 6. | Up to 17 days post-treatment | 
| Change From Baseline in the Massachusetts Sexual Function Questionnaire (MSFQ) Total Score in Males | MSFQ included five items with a score ranging from 1 to 6 (1 = greater than normal; 2 = normal; 3 = minimally diminished; 5 = markedly diminished; and 6 = totally absent). The following areas of sexual functioning were included: diminished/absent libido; arousal difficulties; orgasm difficulties/anorgasmia; erectile dysfunction (males only) and degree of sexual satisfaction. A total score was used as a global measure of sexual dysfunction. The Baseline MSFQ requested the participant reflect back over the past month. For the treatment period, the follow-up MSFQ requested the participant reflect back over the past week. Change from Baseline was the value at post-Baseline visit minus Baseline value. | Baseline and up to Week 6 | 
| Change From Baseline in the MSFQ Total Score in Females | MSFQ included five items with a score ranging from 1 to 6 (1 = greater than normal; 2 = normal; 3 = minimally diminished; 5 = markedly diminished; and 6 = totally absent). The following areas of sexual functioning were included: diminished/absent libido; arousal difficulties; orgasm difficulties/anorgasmia; erectile dysfunction (males only) and degree of sexual satisfaction. A total score was used as a global measure of sexual dysfunction. The Baseline MSFQ requested the participant reflect back over the past month. For the treatment period, the follow-up MSFQ requested the participant reflect back over the past week. Change from Baseline was the value at post-Baseline visit minus Baseline value. | Baseline and up to Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, safety, HAMD, QIDS-SR, NK-1 antagonist, efficacy, orvepitant, placebo, MDD, video-rating