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Substance P Antagonist in the Treatment of Posttraumatic Stress Disorder

Primary Purpose

PTSD

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

NK1 Antagoist (GR205171)

Psychophysiology (Trauma Script)

Psychophysiology (Verbal Threat)

Psychophysiology (Fear Conditioning)

Psychophysiology (Affective Modulation)

Psychophysiology (Heart rate variability)

Lumbar Puncture

24-hour plasma sampling

MRI

About this trial

This is an interventional treatment trial for PTSD focused on measuring PTSD, Substance P, Treatment Study, Placebo, Controlled, Post Traumatic Stress Disorder

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike
Mt. Sinai Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

GR205171

placebo

Arm Description

selective neurokinin-1 receptor antagonist, fixed 5 mg dose every day, for 8 weeks.

sugar pill

Outcomes

Primary Outcome Measures

Changes in CAPS Scores.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT00383786

First Posted

October 3, 2006

Last Updated

July 16, 2019

Sponsor

Baylor College of Medicine

Collaborators

National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT00383786

Brief Title

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

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

September 2006 (undefined)

Primary Completion Date

June 2009 (Actual)

Study Completion Date

June 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Baylor College of Medicine

Collaborators

National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

PTSD

Keywords

PTSD, Substance P, Treatment Study, Placebo, Controlled, Post Traumatic Stress Disorder

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

47 (Actual)

8. Arms, Groups, and Interventions

Arm Title

GR205171

Arm Type

Experimental

Arm Description

selective neurokinin-1 receptor antagonist, fixed 5 mg dose every day, for 8 weeks.

Arm Title

placebo

Arm Type

Placebo Comparator

Arm Description

sugar pill

Intervention Type

Drug

Intervention Name(s)

NK1 Antagoist (GR205171)

Intervention Type

Procedure

Intervention Name(s)

Psychophysiology (Trauma Script)

Intervention Type

Procedure

Intervention Name(s)

Psychophysiology (Verbal Threat)

Intervention Type

Procedure

Intervention Name(s)

Psychophysiology (Fear Conditioning)

Intervention Type

Procedure

Intervention Name(s)

Psychophysiology (Affective Modulation)

Intervention Type

Procedure

Intervention Name(s)

Psychophysiology (Heart rate variability)

Intervention Type

Procedure

Intervention Name(s)

Lumbar Puncture

Intervention Type

Procedure

Intervention Name(s)

24-hour plasma sampling

Intervention Type

Procedure

Intervention Name(s)

MRI

Primary Outcome Measure Information:

Title

Changes in CAPS Scores.

Description

Time Frame

Baseline, 8 weeks

Other Pre-specified Outcome Measures:

Title

Able to Identify Biological Markers That Predict Response to Treatment.

Time Frame

10 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dennis S Charney, MD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

Facility Name

Mt. Sinai Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10029-0574

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

12467953

Citation

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. doi: 10.1016/s0165-1781(02)00225-1.

Results Reference

background

PubMed Identifier

11166289

Citation

Ballard TM, Sanger 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. doi: 10.1016/s0014-2999(01)00724-5.

Results Reference

background

PubMed Identifier

3783140

Citation

Bernstein EM, Putnam FW. Development, reliability, and validity of a dissociation scale. J Nerv Ment Dis. 1986 Dec;174(12):727-35. doi: 10.1097/00005053-198612000-00004.

Results Reference

background

PubMed Identifier

21194898

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.

Results Reference

derived

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Substance P Antagonist in the Treatment of Posttraumatic Stress Disorder

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