Substance P Antagonist in the Treatment of Posttraumatic Stress Disorder
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: GR205171 selective neurokinin-1 receptor antagonist, fixed 5 mg dose every day, for 8 weeks. |
Drug: NK1 Antagoist (GR205171)
Procedure: Psychophysiology (Trauma Script)
Procedure: Psychophysiology (Verbal Threat)
Procedure: Psychophysiology (Fear Conditioning)
Procedure: Psychophysiology (Affective Modulation)
Procedure: Psychophysiology (Heart rate variability)
Procedure: Lumbar Puncture
Procedure: 24-hour plasma sampling
Procedure: MRI
|
| Placebo Comparator: placebo sugar pill |
Procedure: Psychophysiology (Trauma Script)
Procedure: Psychophysiology (Verbal Threat)
Procedure: Psychophysiology (Fear Conditioning)
Procedure: Psychophysiology (Affective Modulation)
Procedure: Psychophysiology (Heart rate variability)
Procedure: Lumbar Puncture
Procedure: 24-hour plasma sampling
Procedure: MRI
|
Outcome Measures
Primary Outcome Measures
- Changes in CAPS Scores. [Baseline, 8 weeks]
The Clinician-Administered PTSD Scale (CAPS) is the gold standard in PTSD assessment. The CAPS is a 30-item structured interview that corresponds to the DSM-IV criteria for PTSD. This is a 17-item core symptom scale, measuring both frequency and intensity of symptoms, with the most frequently used scoring rule is to count a symptom as present if it has a frequency of 1 or more and an intensity of 2 or more. A PTSD diagnosis is made if there is at least 1 "B" symptom, 3 "C" symptoms, and 2 "D" symptoms as well as meeting the other diagnostic criteria. Scores range from 0-136 0 (best possible outcome) to 136 (worst possible outcome). The relevant time-points for reporting change were at baseline and 8 weeks.
Other Outcome Measures
- Able to Identify Biological Markers That Predict Response to Treatment. [10 weeks]
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
Subjects may be included in the study only if they meet all of the following criteria:
-
Male or female subjects, 18 to 65 years.
-
Female subjects of childbearing potential must be using a medically accepted means of contraception.
-
Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
-
A negative urine toxicology.
-
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.
-
Duration of illness of PTSD for at least 3 months.
-
Subjects must have an initial score at Visit 1 and Visit 2 of at least 50 on the CAPS for PTSD Studies.
-
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:
-
Presence of psychotic features.
-
Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry (Visit 1).
-
Female subjects who are either pregnant or nursing.
-
Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
-
Subjects with uncorrected hypothyroidism or hyperthyroidism.
-
Previous treatment with NK1 receptor antagonist.
-
DSM-IV substance abuse or dependence within the past 90 days.
-
Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections prior to Visit 2.
-
Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week or with fluoxetine within 6 weeks prior to Visit 2.
-
Treatment with any other concomitant medication with primarily CNS activity.
-
Treatment with clozapine or ECT within 12 weeks prior to Visit 2.
-
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.
-
Patients who are currently at high risk for homicide or suicide, a score greater than 4 on item 10 of the MADRS.
-
Current or planned litigation regarding the traumatic event.
Patients will not be allowed to receive structured psychotherapy during the trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
| 2 | Mt. Sinai Medical Center | New York | New York | United States | 10029-0574 |
Sponsors and Collaborators
- Baylor College of Medicine
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Dennis S Charney, MD, Icahn School of Medicine at Mount Sinai
Study Documents (Full-Text)
None provided.More Information
Publications
- Agelink MW, Boz C, Ullrich H, Andrich J. Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment. Psychiatry Res. 2002 Dec 15;113(1-2):139-49.
- Ballard TM, Sänger S, Higgins GA. Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist. Eur J Pharmacol. 2001 Feb 2;412(3):255-64.
- Bernstein EM, Putnam FW. Development, reliability, and validity of a dissociation scale. J Nerv Ment Dis. 1986 Dec;174(12):727-35.
- 060253
- 06-M-0253
- NCT00211861
Study Results
Participant Flow
| Recruitment Details | Patients (aged 18-65) were recruited from media advertisement (86%) or clinician referral (14%). Diagnoses were made with the SCID-IV performed by an experienced research clinician, along with an independent interview by a psychiatrist. A primary diagnosis of chronic PTSD, signifying an illness duration. |
|---|---|
| Pre-assignment Detail | Of 235 potential participants screened for eligibility, 171 (73%) were excluded prior to placebo lead-in. 128 did not meet eligibility criteria, 24 were lost to follow-up, and 19 withdrew consent. Sixty-four patients began placebo lead-in, of whom 47 patients (73%) were randomized (11 were ineligible and 6 withdrew consent). |
| Arm/Group Title | GR205171 | Placebo |
|---|---|---|
| Arm/Group Description | selective neurokinin-1 receptor antagonist, 5mg/day for a period of 8 weeks | sugar pill administered daily for a period of 8 weeks |
| Period Title: Overall Study | ||
| STARTED | 22 | 25 |
| COMPLETED | 18 | 13 |
| NOT COMPLETED | 4 | 12 |
Baseline Characteristics
| Arm/Group Title | GR205171 | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | selective neurokinin-1 receptor antagonist | sugar pill | Total of all reporting groups |
| Overall Participants | 22 | 25 | 47 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
22
100%
|
25
100%
|
47
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
43.0
(11.5)
|
38.7
(12.3)
|
40.9
(11.9)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
12
54.5%
|
11
44%
|
23
48.9%
|
| Male |
10
45.5%
|
14
56%
|
24
51.1%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
22
100%
|
25
100%
|
47
100%
|
Outcome Measures
| Title | Changes in CAPS Scores. |
|---|---|
| Description | The Clinician-Administered PTSD Scale (CAPS) is the gold standard in PTSD assessment. The CAPS is a 30-item structured interview that corresponds to the DSM-IV criteria for PTSD. This is a 17-item core symptom scale, measuring both frequency and intensity of symptoms, with the most frequently used scoring rule is to count a symptom as present if it has a frequency of 1 or more and an intensity of 2 or more. A PTSD diagnosis is made if there is at least 1 "B" symptom, 3 "C" symptoms, and 2 "D" symptoms as well as meeting the other diagnostic criteria. Scores range from 0-136 0 (best possible outcome) to 136 (worst possible outcome). The relevant time-points for reporting change were at baseline and 8 weeks. |
| Time Frame | Baseline, 8 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| 20 patients randomized to drug were included in the primary analysis as 2 our of the 22 randomized were excluded because they did not receive a week 1 assessment. 19/25 randomized to placebo were included in the analysis after 6 were excluded due to not receiving week 1 assessments. |
| Arm/Group Title | GR205171 | Placebo |
|---|---|---|
| Arm/Group Description | ||
| Measure Participants | 20 | 19 |
| Mean (Standard Deviation) [scores on a scale] |
43.5
(5.1)
|
51.1
(5.7)
|
| Title | Able to Identify Biological Markers That Predict Response to Treatment. |
|---|---|
| Description | |
| Time Frame | 10 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | GR205171 | Placebo | ||
| Arm/Group Description | selective neurokinin-1 receptor antagonist | sugar pill | ||
All Cause Mortality |
||||
| GR205171 | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| GR205171 | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/22 (0%) | 0/25 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| GR205171 | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 13/22 (59.1%) | 6/25 (24%) | ||
| Nervous system disorders | ||||
| Headache | 13/22 (59.1%) | 6/25 (24%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Sanjay Mathew, MD/PI |
|---|---|
| Organization | Baylor College of Medicine |
| Phone | 7137985439 |
| sjmathew@bcm.edu |
- 060253
- 06-M-0253
- NCT00211861