Clinical trial NCT00880399: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder
Official title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Fixed Dose Study Evaluating the Efficacy and Safety of Orvepitant in Subjects With Major Depressive Disorder
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Depressive Disorder, Major
Keywords: depression
QIDS-SR
HAMD-17
orvepitant
MDD
neurokinin-1 antagonist
double-blind
Phase II
randomized
efficacy
placebo
safety
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-04-13
Enrollment: 328
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) Total Score
timeFrame: Baseline (Day 1) to Week 6
Secondary outcomes:
measure: Percentage of Participants With a >= 50 Percent (%) Reduction From Baseline in HAM-D Total Score
timeFrame: Baseline (Day 1) to Week 6
measure: Number of Participants With (Maintained) Clinical Response
timeFrame: Up to Week 6
measure: Change From Baseline in the Bech Melancholia Scale Total Score (Sum of Items 1, 2, 7, 8, 10, and 13 of the 17-item HAMD Scale)
timeFrame: Baseline (Day 1) to Week 6
measure: Change From Baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) Total Score
timeFrame: Baseline (Day 1) to Week 6
measure: Change From Baseline in the HAM-D Anxiety Factor Score (Sum of Items 10, 11, 12, 13, 15 and 17)
timeFrame: Baseline (Day 1) to Week 6
measure: Percentage of Participants With Clinical Global Impression- Global Improvement (CGI-I) Score of 1 (Very Much Improved) or 2 (Much Improved)
timeFrame: Up to Week 6
measure: Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score
timeFrame: Baseline (Day 1) to Week 6
measure: Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score
timeFrame: Baseline (Day 1) and Week 6
measure: Change From Baseline in Morning Sleep Questionnaire (MSQ) Values for Total Sleep Time (TST), Sleep Onset Latency (SOL) and Wake Time After Sleep Onset (WTSO)
timeFrame: Baseline (Day 1) to Week 6
measure: Change From Baseline in MSQ Values for Number of Nocturnal Awakenings
timeFrame: Baseline (Day 1) to Week 6
measure: Change From Baseline in MSQ Values for Sleep Quality (SQ) and Refreshing Value of Sleep (RVS)
timeFrame: Baseline (Day 1) to Week 6
measure: Number of Participants Who Remit (Have an Endpoint HAM-D Total Score <= 7) Who Continue to Show Symptoms on the HAM-D Sleep Items
timeFrame: Up to Week 6
measure: Number of Participants With Suicidal Behavior, Ideation, and Most Common Ideation Using the Columbia Suicidality Severity Rating Scale (C-SSRS)
timeFrame: Week 8
measure: Number of Discontinuation-emergent Signs and Symptoms Using the Discontinuation-Emergent Signs and Symptoms (DESS)
timeFrame: Week 1 to Week 8/Follow up 1
measure: Change From Baseline in the Massachusetts Sexual Function Questionnaire (MSFQ)-Males
timeFrame: Baseline (Day 1) to Week 6
measure: Change From Baseline in the MSFQ Total Score-Females
timeFrame: Baseline (Day 1) to Week 6
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Scottsdale
country: United States
facility: GSK Investigational Site
state: Arizona
city: Arcadia
country: United States
facility: GSK Investigational Site
state: California
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: National City
country: United States
facility: GSK Investigational Site
state: California
city: Upland
country: United States
facility: GSK Investigational Site
state: California
city: Bradenton
country: United States
facility: GSK Investigational Site
state: Florida
city: Maitland
country: United States
facility: GSK Investigational Site
state: Florida
city: North Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Overland Park
country: United States
facility: GSK Investigational Site
state: Kansas
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: The Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Toledo
country: United States
facility: GSK Investigational Site
state: Ohio
city: Lincoln
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Middleton
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Burlington
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.