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To allow assessment of isolated events of seizure during program
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| orvepitant 30 mg | Experimental | orvepitant 30 mg (low dose) |
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| orvepitant 60 mg | Experimental | orvepitant 60 mg (high dose) |
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| Placebo | Placebo Comparator | inactive placebo to match orvepitant 30 mg and 60 mg dosage forms |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| orvepitant | Drug | neurokinin-1 antagonist |
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| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Phoenix | Arizona | 85020 | United States | ||
| GSK Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23539641 | Background | Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013 May;27(5):424-34. doi: 10.1177/0269881113480990. Epub 2013 Mar 28. |
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A total of 339 participants were included in Intent-to-treat (ITT) population. ITT population comprised of all participants who gave informed consent, were randomized, received at least one dose of double blind medication and for whom at least one post-randomization assessment was available.
The study was conducted at 31 centers across the North America (27 centers in United States of America and 4 centers in Canada) during the period 06 April 2009 to 21 June 2010. Total of 1604 participants were screened for study eligibility, of which 343 participants were randomized into the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Participants received one tablet of matching placebo, once daily, in the evening for a period of 6 weeks. |
| FG001 | GW823296 30 mg | Participants received one tablet of GW823296 (orvepitant) 30 milligrams (mg), once daily, in the evening for a period of 6 weeks. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Placebo | Other | Placebo to match orvepitant 30 mg and 60 mg |
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| 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 |
| Little Rock |
| Arkansas |
| 72223 |
| United States |
| GSK Investigational Site | Orange | California | 92868 | United States |
| GSK Investigational Site | Denver | Colorado | 80239 | United States |
| GSK Investigational Site | Norwich | Connecticut | 06360 | United States |
| GSK Investigational Site | Jacksonville | Florida | 32216 | United States |
| GSK Investigational Site | Orlando | Florida | 32806 | United States |
| GSK Investigational Site | Winter Park | Florida | 32789 | United States |
| GSK Investigational Site | Springfield | Illinois | 62711 | United States |
| GSK Investigational Site | Rockville | Maryland | 20852 | United States |
| GSK Investigational Site | Weymouth | Massachusetts | 02190 | United States |
| GSK Investigational Site | Saint Charles | Missouri | 63301 | United States |
| GSK Investigational Site | Willingboro | New Jersey | 08046 | United States |
| GSK Investigational Site | Brooklyn | New York | 11235 | United States |
| GSK Investigational Site | Dayton | Ohio | 45408 | United States |
| GSK Investigational Site | Garfield Heights | Ohio | 44125 | United States |
| GSK Investigational Site | Portland | Oregon | 97210 | United States |
| GSK Investigational Site | Salem | Oregon | 97301 | United States |
| GSK Investigational Site | Emmaus | Pennsylvania | 18049 | United States |
| GSK Investigational Site | Philadelphia | Pennsylvania | 19131 | United States |
| GSK Investigational Site | Philadelphia | Pennsylvania | 19139 | United States |
| GSK Investigational Site | Columbia | South Carolina | 29201 | United States |
| GSK Investigational Site | Austin | Texas | 78756 | United States |
| GSK Investigational Site | Dallas | Texas | 75231 | United States |
| GSK Investigational Site | San Antonio | Texas | 78229-3815 | United States |
| GSK Investigational Site | Charlottesville | Virginia | 22903 | United States |
| GSK Investigational Site | Milwaukee | Wisconsin | 53226 | United States |
| GSK Investigational Site | Penticton | British Columbia | V2A 4M4 | Canada |
| GSK Investigational Site | Miramichi | New Brunswick | E1V 6X3 | Canada |
| GSK Investigational Site | Sydney | Nova Scotia | B1S 2E8 | Canada |
| GSK Investigational Site | Mississauga | Ontario | L5M 4N4 | Canada |
| GSK Investigational Site | Gatineau | Quebec | J9A 1K7 | Canada |
| FG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants received one tablet of matching placebo, once daily, in the evening for a period of 6 weeks. |
| BG001 | GW823296 30 mg | Participants received one tablet of GW823296 (orvepitant) 30 milligrams (mg), once daily, in the evening for a period of 6 weeks. |
| BG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Number | Percentage of participants | Up to Week 6 |
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| Secondary | 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. | ITT Population. | Posted | Number | Participants | Up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Number | Percentage of participants | Up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | minutes (min) | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Number of awakenings | Baseline and upto Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | ITT Population. Only those participants available at the specified time points were analyzed. | Posted | Count of Participants | Participants | Up to Week 6 |
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| Secondary | 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. | The All Subjects Population was defined as all participants who received at least one dose of study medication. Only those participants with data available at the indicated time points were analyzed. | Posted | Count of Participants | Participants | Up to 17 days post-treatment |
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| Secondary | 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. | All subjects Population. Only those participants available at the specified time points were analyzed. | Posted | Mean | Standard Deviation | Number of Incidences | Up to 17 days post-treatment |
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| Secondary | 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. | All subjects Population (males). Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | Scores on a scale | Baseline and up to Week 6 |
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| Secondary | 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. | All Subject Population (female). Only those participants available at the specified time points were analyzed. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline and up to Week 6 |
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AEs were reported up to follow up (28 day) post-treatment (Week 6)
AEs were reported for the All subjects Population which was defined as all participants who received at least one dose of study medication.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants received one tablet of matching placebo, once daily, in the evening for a period of 6 weeks. | 1 | 116 | 1 | 116 | 52 | 116 |
| EG001 | GW823296 30 mg | Participants received one tablet of GW823296 (orvepitant) 30 milligrams (mg), once daily, in the evening for a period of 6 weeks. | 0 | 115 | 1 | 115 | 61 | 115 |
| EG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. | 0 | 112 | 3 | 112 | 62 | 112 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Convulsion | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| Acute myocardial infarction | Cardiac disorders | MedDRA 13.0 | Systematic Assessment |
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| Road traffic accident | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| Abortion spontaneous | Pregnancy, puerperium and perinatal conditions | MedDRA 13.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry mouth | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 13.0 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 13.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 13.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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The study was terminated early upon the recommendation of an Independent Data Monitoring Committee. At the time the trial was terminated 343 participants had been randomized, compared to a target of 348 participants.
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| GSK Response Center | GlaxoSmithKline | 866-435-7343 |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D003863 | Depression |
| ID | Term |
|---|---|
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
Not provided
Not provided
| ID | Term |
|---|---|
| C584555 | orvepitant |
Not provided
Not provided
Not provided
| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Week 2 |
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| Week 4 |
|
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| Week 6 |
|
|
| 0.0006 |
| Mean Difference (Net) |
| -2.26 |
| 2-Sided |
| 95 |
| -3.54 |
| -0.98 |
| Superiority |
| Placebo vs GW823296 30 mg: Week 2 | Mixed Models Repeated Measures | 0.0394 | Mean Difference (Net) | -1.57 | 2-Sided | 95 | -3.06 | -0.08 | Superiority |
| Placebo vs GW823296 60mg: Week 2 | Mixed Models Repeated Measures | 0.0332 | Mean Difference (Net) | -1.65 | 2-Sided | 95 | -3.16 | -0.13 | Superiority |
| Placebo vs GW823296 30mg: Week 4 | Mixed Models Repeated Measures | 0.0601 | Mean Difference (Net) | -1.82 | 2-Sided | 95 | -3.71 | 0.08 | Superiority |
| Placebo vs GW823296 60mg: Week 4 | Mixed Models Repeated Measures | 0.0369 | Mean Difference (Net) | -2.03 | 2-Sided | 95 | -3.94 | -0.12 | Superiority |
| Placebo vs GW823296 30mg: Week 6 | Mixed Models Repeated Measures | 0.1122 | Mean Difference (Net) | -1.67 | 2-Sided | 95 | -3.73 | 0.39 | Superiority |
| Placebo vs GW823296 60mg: Week 6 | Mixed Models Repeated Measures | 0.4713 | Mean Difference (Net) | -0.76 | 2-Sided | 95 | -2.85 | 1.32 | Superiority or Other |
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| GW823296 60 mg |
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| GW823296 60 mg |
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| OG002 |
| GW823296 60 mg |
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
| Participants |
|
|
|
Participants received one tablet of GW823296 (orvepitant) 30 milligrams (mg), once daily, in the evening for a period of 6 weeks. |
| OG002 | GW823296 60 mg | Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks.
|
|
| GW823296 60 mg |
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|
Participants received one tablet of GW823296 (orvepitant) 60 mg, once daily, in the evening for a period of 6 weeks. |
|
|
|