Clinical trial NCT01000493: Orvepitant (GW823296) in Adult Post Traumatic Stress Disorder
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Fixed-Dose Study Evaluating the Efficacy and Safety of the Neurokinin-1 Receptor Antagonist Orvepitant (GW823296) in Post Traumatic Stress Disorder (PTSD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Post-Traumatic Stress Disorder
Keywords: efficacy
double-blind
Clinician Administered PTSD Scale
placebo
Sleep
safety
CAPS
neurokinin-1 antagonist
orvepitant
PTSD
randomized
Post traumatic stress disorder
Phase II
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-10-23
Enrollment: 132
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 12-week, randomized, multicenter, double-blind, placebo controlled, fixed-dose parallel group study to assess the efficacy and safety of orvepitant (60 mg/day) versus placebo in subjects with a diagnosis of noncombat-related Posttraumatic Stress Disorder (PTSD), 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 randomized at the baseline visit to receive either orvepitant 60mg/day or placebo (1:1 ratio). Those subjects randomized to receive placebo will receive study medication identical in appearance to that received by subjects assigned to receive orvepitant.

Efficacy will be assessed using the Clinician Administered PTSD Scale (CAPS) as the primary efficacy measure. Key secondary efficacy endpoints will be based on the Davidson Trauma Scale (DTS), the Short PTSD Rating Interview (SPRINT), the Clinical Global Impression- Global Improvement and Severity of Illness Scales (CGI-I and CGI-S, respectively), the Hamilton Depression Rating Scale (HAM-D), the Cognitive and Physical Functioning Questionnaire (CPFQ) and the Pittsburgh Sleep Quality Index (PSQI).

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 effects of orvepitant, an investigational drug for the treatment of noncombat-related PTSD.

Efficacy will be assessed using standard symptom and severity rating scales (questionnaires). The Clinicain Adminstered PTSD Scale (CAPS) will serve as the primary measure of efficacy. Secondary efficacy endpoints include the CAPS subscale clusters (Re-Experiencing, Avoidance and Numbing, and Hyperarousal), the Davidson Trauma Scale (DTS), the Short PTSD Rating Interview (SPRINT), the Hamilton Depression Rating Scale (HAM-D), the Clinical Global Impression- Global Improvement and Severity of Illness Scale (CGI-I and CGI-S, respectively), the Cognitive and Physical Functioning Questionnaire (CPFQ) and the Pittsburgh Sleep Quality Index (PSQI).

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), Massachusetts Sexual Function Questionnaire (MSFQ), Discontinuation-Emergent Signs and Symptoms (DESS) scale 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 efficacy of orvepitant (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 CAPS 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. Upon completion of the screening period, eligible subjects will be randomly assigned at the baseline visit to one of two treatment regimens: orvepitant 60mg/day or placebo for a 12-week treatment phase. The chances of receiving each of the two 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, 6, 8, 10 and 12. 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. Women of child-bearing potential will also be required to attend the 28-Day follow-up visit for a pregnancy test. A further test will be performed 42 Days following the end of treatment.

Male and female outpatients between the ages of 18 to 64 years inclusive with a primary diagnosis of noncombat-related PTSD will be enrolled into this study. A total of approximately 240 subjects are expected to be enrolled at approximately 25 different study sites in North America.

Eligibility criteria: Inclusion Criteria:

* Aged 18-64 years, inclusive.
* A primary diagnosis of noncombat-related Post traumatic Stress Disorder (PTSD)
* Subjects with symptom severity considered to be at least moderate to severe.

Exclusion Criteria:

* Subjects whose symptoms are better accounted for by a diagnosis other than Post traumatic Stress Disorder (PTSD), subjects diagnosed with 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 who have a history of failing to respond to adequate treatment for PTSD with an antidepressant/anti-anxiety drug, i..e, failure to improve following administration of at least two other antidepressants/anti-anxiety drugs, each given for at least 4 weeks.

Primary outcomes:
measure: Change From Baseline in the 17-item Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) Total Severity Score at Week 12
timeFrame: Baseline (Day 1 pre-dose) and Week 12
Secondary outcomes:
measure: Percentage of Participants Responding, Based on More Than Equal to (>=) 30 Percent (%) Reduction From Baseline in CAPS Total Severity Score at Weeks 1, 4, 8 and 12
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: The Time to (Maintained) Clinical Response in Each Participants
timeFrame: Up to Week 12
measure: Change From Baseline in the 17-item CAPS Total Severity Score at Weeks 1, 4, and 8
timeFrame: Baseline (Day 1 pre-dose) and Week 1, 4, 8
measure: Percentage of Participants Remitting, Based on a CAPS Total Score < 20 at Weeks 1, 4, 8, and 12
timeFrame: Up to Week 12
measure: Change From Baseline in the CAPS Re-experiencing Subscale Cluster Score at Weeks 1, 4, 8 and 12
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the CAPS Avoidance/Numbing (A/N) Subscale Cluster Score at Weeks 1, 4, 8, and 12
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the CAPS Hyperarousal Subscale Cluster Score at Weeks 1, 4, 8, and 12
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Percentage of Participants Responding, Based on a Clinical Global Impression- Global Improvement (CGI-I) Score of 1 or 2, by Visit Week
timeFrame: Up to Week 12
measure: Change From Baseline in the CGI-S Score, by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the Short PTSD Rating Review (SPRINT), by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the Self-rated Davidson Trauma Scale (DTS), by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the DTS Cluster Sub Score
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the Pittsburgh Sleep Quality Index (PSQI) Global Score, by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the PSQI Addendum for PTSD (PSQI-A) Global Score, by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the CAPS Recurrent Distressing Dreams Item (B2) at Weeks 1, 4, 8, and 12
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in Hamilton Depression Rating Scale (HAM-D), by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in the Cognitive and Physical Function Questionnaire (CPFQ) Total Score, by Visit Week
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in Massachusetts Sexual Function Questionnaire (MSFQ) Total Score and Erectile Dysfunction Score in Males
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in MSFQ Total Score in Females
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Change From Baseline in MSFQ Items (Diminished/Absent Libido; Arousal Difficulties; Orgasm Difficulties/Anorgasmia and Degree of Sexual Satisfaction) Scores
timeFrame: Baseline (Day 1 pre-dose) and up to Week 12
measure: Number of Participant With Suicidal Behavior Based on the Columbia Suicide Severity Rating Scale (C-SSRS) During and Post Treatment
timeFrame: Baseline, Week 1, 2, 4, 6, 8, 10, 12 and Day 14 of follow-up (approximately 14 weeks)
measure: Number of Participant by Maximum Suicidal Ideation, Based on the C-SSRS During and Post Treatment
timeFrame: Baseline, Week 1, 2, 4, 6, 8, 10, 12 and Day 14 of follow-up (approximately 14 weeks)
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: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Marietta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Park Ridge
country: United States
facility: GSK Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Glen Burnie
country: United States
facility: GSK Investigational Site
state: Maryland
city: Weymouth
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Willingboro
country: United States
facility: GSK Investigational Site
state: New Jersey
city: The Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Dayton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Garfield Heights
country: United States
facility: GSK Investigational Site
state: Ohio
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Brown Deer
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Middleton
country: United States
facility: GSK Investigational Site
state: Wisconsin
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.