Nepicastat for Posttraumatic Stress Disorder (PTSD) in OIF/OEF Veterans

Posttraumatic Stress Disorder Clinical Trial

— Nepicastat  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00659230
• Other study ID #: 08-06
• Secondary ID: PT074384/W81XWH-
• Status: Completed
• Phase: Phase 2
• First received: March 10, 2008
• Last updated: September 12, 2017
• Start date: July 1, 2009
• Est. completion date: August 30, 2012

Study information

• Verified date: September 2017
• Source: Tuscaloosa Research & Education Advancement Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)or other Southwest conditions since 19800. 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, our study in 120 outpatient veterans with PTSD will compare nepicastat 120 mg/day vs. placebo in a 6-week double-blind, randomized clinical trial (RCT). The veterans will be followed for an additional 8 weeks after the RCT, 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: August 30, 2012
• Est. primary completion date: July 5, 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 19 Years and older

Eligibility

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 or other Southwest Asia conditions

• 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 in the previous 2 weeks and no substance dependence disorders in the past 4 weeks (except for nicotine and caffeine)

• 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

Related Conditions & MeSH terms

• Posttraumatic Stress Disorder
• Stress Disorders, Post-Traumatic
• Stress Disorders, Traumatic

Intervention

Drug:
• Nepicastat
100-800mg
• Placebo
100-800mg placebo

Locations

Country	Name	City	State
United States	VA San Diego Healthcare System	San Diego	California
United States	James J.Peters VA Medical Center	The Bronx	New York
United States	Tuscaloosa VAMC	Tuscaloosa	Alabama

Sponsors (6)

Lead Sponsor	Collaborator
Tuscaloosa Research & Education Advancement Corporation	Acorda Therapeutics, Baylor College of Medicine, James J. Peters Veterans Affairs Medical Center, Ralph H. Johnson VA Medical Center, San Diego Veterans Healthcare System

Country where clinical trial is conducted

United States, 

References & Publications (2)

Graham DP, Nielsen DA, Kosten TR, Davis LL, Hamner MB, Makotkine I, Yehuda R. Examining the utility of using genotype and functional biology in a clinical pharmacology trial: pilot testing dopamine ß-hydroxylase, norepinephrine, and post-traumatic stress disorder. Psychiatr Genet. 2014 Aug;24(4):181-2. doi: 10.1097/YPG.0000000000000039. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinician Administered PTSD Scale Subscore D (Hyperarousal)	The Clinician Administered PTSD Scale subscore D (CAPS-D) measures the hyperarousal cluster for PTSD symptoms (5 items). Higher scores indicate greater severity. Range for CAPS-D is zero to 40. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (?=0.78).	Baseline, week 2, 4 and 6
Secondary	Clinician Administered PTSD Scale Total Score	The Clinician Administered PTSD Scale (CAPS) measures the full spectrum of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS is zero to 136. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (?=0.78).	Baseline, week 2,4, and 6
Secondary	Clinician Administered PTSD Scale Subscale B Score	The Clinician Administered PTSD Subscale B (CAPS-B) measures the re-experiencing cluster of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS-B is zero to 40. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (?=0.78). Blake, D.D., Weathers, F.W., Nagy, L.M., Kaloupek, D.G., Gusman, F.D., Charney, D.S., Kean, T.M., 1995, The development of a clinician-administered PTSD scale. Journal of Traumatic Stress, 8:75-90.	6 weeks
Secondary	Clinician Administered PTSD Scale Subscale C Score	The Clinician Administered PTSD Subscale C (CAPS-C) measures the Avoidance and emotional numbing cluster of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS-C is zero to 56. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (?=0.78).	Baseline, week 2, 4, and 6