Substance P Antagonist in the Treatment of Posttraumatic Stress Disorder

NCT ID: NCT00383786

Last Updated: 2019-07-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-09-30
• Study Completion Date: 2009-06-30

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.

Conditions

PTSD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

GR205171

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

Group Type: EXPERIMENTAL

NK1 Antagoist (GR205171)

Intervention Type: DRUG

Psychophysiology (Trauma Script)

Intervention Type: PROCEDURE

Psychophysiology (Verbal Threat)

Intervention Type: PROCEDURE

Psychophysiology (Fear Conditioning)

Intervention Type: PROCEDURE

Psychophysiology (Affective Modulation)

Intervention Type: PROCEDURE

Psychophysiology (Heart rate variability)

Intervention Type: PROCEDURE

Lumbar Puncture

Intervention Type: PROCEDURE

24-hour plasma sampling

Intervention Type: PROCEDURE

MRI

Intervention Type: PROCEDURE

placebo

sugar pill

Group Type: PLACEBO_COMPARATOR

Psychophysiology (Trauma Script)

Intervention Type: PROCEDURE

Psychophysiology (Verbal Threat)

Intervention Type: PROCEDURE

Psychophysiology (Fear Conditioning)

Intervention Type: PROCEDURE

Psychophysiology (Affective Modulation)

Intervention Type: PROCEDURE

Psychophysiology (Heart rate variability)

Intervention Type: PROCEDURE

Lumbar Puncture

Intervention Type: PROCEDURE

24-hour plasma sampling

Intervention Type: PROCEDURE

MRI

Intervention Type: PROCEDURE

Interventions

NK1 Antagoist (GR205171)

Intervention Type: DRUG

Psychophysiology (Trauma Script)

Intervention Type: PROCEDURE

Psychophysiology (Verbal Threat)

Intervention Type: PROCEDURE

Psychophysiology (Fear Conditioning)

Intervention Type: PROCEDURE

Psychophysiology (Affective Modulation)

Intervention Type: PROCEDURE

Psychophysiology (Heart rate variability)

Intervention Type: PROCEDURE

Lumbar Puncture

Intervention Type: PROCEDURE

24-hour plasma sampling

Intervention Type: PROCEDURE

MRI

Intervention Type: PROCEDURE

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Sanjay Johan Mathew

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dennis S Charney, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Mt. Sinai Medical Center

New York, New York, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 12467953 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11166289 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 3783140 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 21194898 (View on PubMed)

Other Identifiers

06-M-0253

Identifier Type: -

Identifier Source: secondary_id

060253

Identifier Type: -

Identifier Source: org_study_id

NCT00211861

Identifier Type: -

Identifier Source: nct_alias