Nepicastat for Posttraumatic Stress Disorder (PTSD) in OIF/OEF Veterans - Full Text View

Purpose

This study proposes a multi-site, randomized, double-blind, placebo-controlled clinical trial of the dopamine-ß-hydroxylase (DBH) inhibitor, nepicastat, for the treatment of posttraumatic stress disorder (PTSD) in outpatients who have previously served in a combat zone during Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF). A DBH inhibitor's mechanism of action is to decrease neuronal noradrenaline (NA) release by inhibiting DBH conversion of dopamine (DA) to NA. Animal models of PTSD and human studies have found a substantial increase in NA activity for these animal models and for PTSD in humans. Furthermore, recent clinical studies have improved PTSD hyper-arousal symptoms by reducing the NA over-activity using agents like NA post-synaptic antagonists. Key support for the proposed study is based on a similar improvement in PTSD symptoms after treatment with the DBH inhibitor, disulfiram.

In the experience of the clinical investigators, the most common chief complaint of the OIF/OEF veterans with PTSD is hyperarousal (DSM-IV criterion D symptom cluster). These symptoms significantly interfere with social, occupational, and interpersonal function. Standard treatments with antidepressants are not fully effective in treating the symptoms of PTSD in veterans; thus, new treatments are needed. An intervention, such as nepicastat, aimed at reducing hyperarousal, as well as other PTSD symptoms, would have significant impact of restoring overall function and quality of life in OIF/OEF veterans with PTSD. Since hyperarousal symptoms responded relatively quickly to medications of this type (i.e. disulfiram), our study in 90 outpatient OIF/OEF veterans with PTSD will compare nepicastat 120 mg/day vs. placebo (1:1 monotherapy) in a 6-week double-blind, randomized clinical trial (RCT). The veterans will be followed for an additional 8 weeks after the RCT (weeks 7-14), during which, those who have a priori defined positive clinical response to the study medication, nepicastat vs. placebo, will be continued on the study medication, in order to assess further improvement and safety. Those patients who do not have a positive clinical response during the 6 week RCT will be offered the addition of the standard first-line PTSD pharmacotherapy, paroxetine, during the 8 weeks extension phase. Thus, weeks 7-14 offer an opportunity to evaluate longer-term nepicastat efficacy and to compare the treatment response of nonresponders after augmentation with paroxetine.

Condition	Intervention	Phase
Posttraumatic Stress Disorder	Drug: Nepicastat Drug: Placebo	Phase II

MedlinePlus related topics:

Post-Traumatic Stress Disorder Stress

ChemIDplus related topics:

Dopamine Dopamine hydrochloride Nepicastat

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Official Title:	A Randomized, Placebo-Controlled Trial of the Dopamine-B-Hydroxylase (DBH) Inhibitor, Nepicastat, for the Treatment of PTSD in OIF/OEF Veterans

Further study details as provided by Tuscaloosa Research & Education Advancement Corporation:

Primary Outcome Measures:

Primary Outcome is determined by the CAPS scores. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

the secondary outcome measures (DTS, Quality of Life Measures) [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	90
Study Start Date:	September 2008
Estimated Study Completion Date:	September 2012
Estimated Primary Completion Date:	September 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo: Placebo Comparator Arm 1	Drug: Placebo 100-800mg placebo
Nepicastat: Active Comparator Arm 2	Drug: Nepicastat 100-800mg

Detailed Description:

HYPOTHESES Primary Hypothesis: Compared to placebo treatment, nepicastat-treated OIF/OEF veterans with PTSD will have significantly reduced PTSD hyperarousal symptoms as defined by the Clinician Administered PTSD Scale [CAPS], subscale D (CAPS-D).

Secondary Hypotheses: Compared to placebo, nepicastat-treated OIF/OEF veterans with PTSD will have:

Significantly reduced PTSD symptoms (total CAPS)
Significantly reduced PTSD reexperiencing symptoms (CAPS-B)
Significantly reduced PTSD avoidance symptoms (CAPS-C)
Significantly higher rates of PTSD response and remission
Significantly improved quality of life

Biomarker Hypotheses:

The NE (norepinephrine) to DA ratios in nepicastat-treated subjects will be significantly lower at the end of study than at baseline assessment and lower at the end of study than the placebo-treated subjects.
Baseline NE to DA ratios and hyper-arousal symptom severity will be correlated.
Reduction from baseline in hyper-arousal symptoms and in NE to DA ratios of PTSD patients will be positively correlated. This correlation may be stronger for nepicastat-treated subjects than for the placebo-treated subjects.

Eligibility

Ages Eligible for Study:	19 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Signed informed consent
Patient understands the risks and benefits and agrees to visit frequency and procedures
Male or female
Any race or ethnic origin
Served in OIF/OEF or Afghanistan conflicts
Currently Active Duty, National Guard, Reservist, Veteran, and/or Retired Military
Diagnosis of PTSD (by MINI (Mini International Neuropsychiatric Interview) and CAPS-DX (Clinician Administered PTSD scale- Diagnostic Form) using Rule of Fours and total CAPS-DX score of 45)
No substance use disorders (except for nicotine and caffeine) in the previous 2 months
Free of psychotropic medication for 2 weeks prior to randomization
Physical and laboratory panel are within normal limits or not clinically significant
Women of childbearing potential must be using medically-approved methods of birth control
≥19 to 65 years of age

Exclusion Criteria:

Lifetime history of bipolar I, schizophrenia, schizoaffective or cognitive disorders
Actively considering plans of suicide or homicide
Psychotic symptoms that in the investigator's opinion impair the patient's ability to give informed consent or make it unsafe for patient to be maintained without a neuroleptic
Unstable general medical conditions or a contraindication to the use of nepicastat
Women planning to become pregnant or breastfeed during the study
Current or pending incarceration
Terminal Illness

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00659230

Contacts


Contact: Lori L Davis, M.D.	205-554-2000 ext 3819	lori.davis@va.gov

Contact: Jennifer A Biladeau, MS	205-554-2000 ext 3274	jennifer.biladeau@va.gov

Locations


United States, Alabama
	Tuscaloosa VAMC	Not yet recruiting
	Tuscaloosa, Alabama, United States, 35404
	Contact: Beatrix Haustein, MBA 205-554-2000 ext 2840 beatrix.haustein@va.gov
	Contact: Julie R Wakefield, MA 205-554-2000 ext 3674 julie.wakefield@va.gov
	Principal Investigator: Lori L Davis, M.D.

Sponsors and Collaborators

Tuscaloosa Research & Education Advancement Corporation

Synosia Therapeutics, Inc.

Ralph H. Johnson VA Medical Center

Baylor College of Medicine

Investigators


Study Chair:	Carlos Berry, M.D.	IRB Tuscaloosa VAMC

More Information

Publications of Results:

Kosten TR, Krystal J. Biological mechanisms in posttraumatic stress disorder. Relevance for substance abuse. Recent Dev Alcohol. 1988;6:49-68. Review.

Jacobsen LK, Southwick SM, Kosten TR. Substance use disorders in patients with posttraumatic stress disorder: a review of the literature. Am J Psychiatry. 2001 Aug;158(8):1184-90. Review.

Southwick SM, Vythilingam M, Charney DS. The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol. 2005;1:255-91. Review.

Responsible Party:	Tuscaloosa Research and Education Advancement Corporation ( Lori L. Davis, M.D. )
Study ID Numbers:	08-06, DOD PT074384
First Received:	March 10, 2008
Last Updated:	September 17, 2008
ClinicalTrials.gov Identifier:	NCT00659230
Health Authority:	United States: Food and Drug Administration

Keywords provided by Tuscaloosa Research & Education Advancement Corporation:

PTSD

Veterans

Nepicastat

OIF/OEF

Study placed in the following topic categories:

Dopamine

Anxiety Disorders

Mental Disorders

Stress Disorders, Post-Traumatic

Stress

Stress Disorders, Traumatic

Additional relevant MeSH terms:

Pathologic Processes

Disease

ClinicalTrials.gov processed this record on October 17, 2008

Sponsors and Collaborators:	Tuscaloosa Research & Education Advancement Corporation Synosia Therapeutics, Inc. Ralph H. Johnson VA Medical Center Baylor College of Medicine
Information provided by:	Tuscaloosa Research & Education Advancement Corporation
ClinicalTrials.gov Identifier:	NCT00659230