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

Depressive Disorder, Major Clinical Trial

— orvepitant MDD  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00880399
• Other study ID #: 111733
• Status: Terminated
• Phase: Phase 2
• First received: April 9, 2009
• Last updated: September 12, 2013
• Start date: March 2009
• Est. completion date: June 2010

Study information

• Verified date: September 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaUnited States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 328
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 64 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major

Intervention

Drug:
• orvepitant
Neurokinin-1 (NK-1) antagonist

Other:
• placebo
inactive placebo to match orvepitant 30 and 60 mg dosage forms

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Burlington	Ontario
Canada	GSK Investigational Site	Ottawa	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
United States	GSK Investigational Site	Arcadia	California
United States	GSK Investigational Site	Beverly Hills	California
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Bradenton	Florida
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Lincoln	Rhode Island
United States	GSK Investigational Site	Maitland	Florida
United States	GSK Investigational Site	Middleton	Wisconsin
United States	GSK Investigational Site	National City	California
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	North Miami	Florida
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Overland Park	Kansas
United States	GSK Investigational Site	Scottsdale	Arizona
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Toledo	Ohio
United States	GSK Investigational Site	Upland	California

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) total score.		6 weeks	No
Secondary	Percentage of subjects with a = 50% reduction from baseline in HAM-D total score.		6 weeks	No
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).		6 weeks	No
Secondary	Change from baseline in the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR 16) total score.		6 weeks	No
Secondary	Change from baseline in the HAM-D anxiety factor score (sum of items 10, 11, 12, 13, 15 and 17).		6 weeks	No
Secondary	Percentage of subjects with Clinical Global Impression- Global Improvement (CGI-I) score of 1 or 2, 'very much improved' or 'much improved'.		6 weeks	No
Secondary	Change from baseline in the Clinical Global Impression-Severity of Illness (CGI-S) score.		6 weeks	No
Secondary	Change from baseline in the Cognitive and Physical Function Questionnaire (CPFQ) total score.		6 weeks	No
Secondary	Change from baseline in morning sleep questionnaire values for sleep onset latency, number of wakenings, wake time after sleep onset, and total sleep time, as well as sleep quality and refreshing value of sleep.		6 weeks	No
Secondary	Proportion of patients who remit (have an endpoint HAM-D Total score = 7)		6 weeks	No
Secondary	Columbia Suicidality Severity Rating Scale (CSSRS)		6 weeks	Yes
Secondary	Incidence of discontinuation-emergent signs and symptoms using the Discontinuation-Emergent Signs and Symptoms (DESS)		6 weeks	Yes
Secondary	Sexual Function Questionnaire (SFQ)		6 weeks	Yes
Secondary	The time to (maintained) clinical response in each patient.			No