Clinical trial NCT00383786: Substance P Antagonist in the Treatment of Posttraumatic Stress Disorder
Official title: Evaluation of the Efficacy of the NK1 Antagonist GR205171 in Posttraumatic Stress Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: PTSD
Keywords: PTSD
Substance P
Treatment Study
Placebo
Controlled
Post Traumatic Stress Disorder
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2006-10-04
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study, conducted at the NIH and the Mount Sinai School of Medicine, will examine the effectiveness of a substance P or NK1 antagonist study drug known as GR205171 in treating the symptoms of posttraumatic stress disorder (PTSD).

People between 18 and 65 years of age who have been diagnosed with PTSD may be eligible for this study. Participants undergo the following tests and procedures:

Treatment: Patients are tapered off current ineffective medications over 1 to 2 weeks. All participants receive placebo (sugar pill) at the start of the study. At some point within the first 3 weeks of the study, they are then randomly assigned either to take GR205171 or to continue with placebo for the remainder of the 10-week treatment period.

Clinic visits: Patients come to the clinic once a week during treatment. The following procedures are done at various visits.

* Interviews, self report questionnaires and psychiatric rating scales at every visit.
* Physical examination, blood and urine tests. Blood is drawn up to 10 times during the study.

Follow-up visits continue for up to 3 months after the end of the study, during which patients are offered standard clinical treatment.

Detailed description: Posttraumatic Stress Disorder (PTSD) is a common chronic anxiety disorder that is often debilitating and follows exposure to an overwhelming traumatic event. The burden of PTSD on individuals and society is significant. The majority of PTSD sufferers also meet the diagnostic criteria for several other psychiatric disorders and many attempt suicide. Despite the devastating impact of PTSD on the lives of millions worldwide, little is known about the etiology or pathophysiology of this disorder. Although disruptions in the hypothalamic-pituitary adrenal (HPA) Axis, noradrenergic, serotonergic systems have been proposed as neurobiological substrates in the development of PTSD, the exact underpinnings of the neurobiology of PTSD remain to be fully elucidated.

PTSD is responsive to treatment with selective serotonin reuptake inhibitors, but response rates rarely exceed 60%, and even fewer patients (20%-30%) experience improvement that could be characterized as remission. Thus, there is a clear need to develop novel and improved therapeutics for PTSD. A growing body of preclinical evidence suggests that activation of the Substance P (SP) and its receptor NK1 is anxiogenic and that NK1 antagonists, upon chronic administration, exert significant dampening (albeit complex) effects on the SP-NP system. Furthermore, several stress paradigms are believed to exert many of their deleterious effects on hippocampal structures via enhancement of SP-NK1 system. Overall, excess activity of the SP-NK1 system stands as a prime candidate for involvement in the pathophysiology of anxiety disorders such as PTSD.

In this study, we propose to investigate the potential antianxiety efficacy of the highly specific NK1 antagonist GR205171 in PTSD. Furthermore, we propose to, in a preliminary fashion, longitudinally investigate whether neuroendocrine surrogate markers are predictive of treatment response.

This is an 8-week double-blind placebo-controlled study that will examine the efficacy and safety of an NK1 antagonist in patients with PTSD.

Patients, ages 18 to 65 years with a diagnosis of PTSD, will in this pilot study be randomized to double-blind treatment to receive either the NK1 antagonist, GR205171 (5 mg/day) or placebo for a period of 8 weeks.

Approximately 52 patients will enter the study to obtain 40 subjects who complete the 8 weeks of acute NK1 antagonist treatment.

Eligibility criteria: * INCLUSION CRITERIA:

Subjects may be included in the study only if they meet all of the following criteria:

1. Male or female subjects, 18 to 65 years.
2. Female subjects of childbearing potential must be using a medically accepted means of contraception.
3. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
4. A negative urine toxicology.
5. Subjects must fulfill the criteria for PTSD as defined in DSM-IV (309.81), which should be the primary diagnosis. Diagnoses are based on clinical assessment and confirmed by structured diagnostic interview SCID-P.
6. Duration of illness of PTSD for at least 3 months.
7. Subjects must have an initial score at Visit 1 and Visit 2 of at least 50 on the CAPS for PTSD Studies.
8. Subjects must not have a decrease in the total score of CAPS of greater than 25% during washout (between Visits 1 and 2).

EXCLUSION CRITERIA:

Subjects will be excluded from the study for any of the following reasons:

1. Presence of psychotic features.
2. Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry (Visit 1).
3. Female subjects who are either pregnant or nursing.
4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
5. Subjects with uncorrected hypothyroidism or hyperthyroidism.
6. Previous treatment with NK1 receptor antagonist.
7. DSM-IV substance abuse or dependence within the past 90 days.
8. Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections prior to Visit 2.
9. Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week or with fluoxetine within 6 weeks prior to Visit 2.
10. Treatment with any other concomitant medication with primarily CNS activity.
11. Treatment with clozapine or ECT within 12 weeks prior to Visit 2.
12. Current diagnosis of schizophrenia or other psychotic disorder, bipolar disorder, other Axis I disorder (except for major depressive disorder, dysthymia and other anxiety disorders that followed exposure to the trauma) as defined in the DSM-IV.
13. Patients who are currently at high risk for homicide or suicide, a score greater than 4 on item 10 of the MADRS.
14. Current or planned litigation regarding the traumatic event.

Patients will not be allowed to receive structured psychotherapy during the trial.

Primary outcomes:
measure: Changes in CAPS Scores.
timeFrame: Baseline, 8 weeks
Secondary outcomes:
Other outcomes:
measure: Able to Identify Biological Markers That Predict Response to Treatment.
timeFrame: 10 weeks
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Dennis S Charney, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Mathew SJ, Vythilingam M, Murrough JW, Zarate CA Jr, Feder A, Luckenbaugh DA, Kinkead B, Parides MK, Trist DG, Bani MS, Bettica PU, Ratti EM, Charney DS. A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Eur Neuropsychopharmacol. 2011 Mar;21(3):221-9. doi: 10.1016/j.euroneuro.2010.11.012. Epub 2010 Dec 30.