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

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.

Study Type: Interventional

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

Study Primary Completion Date: September 2011

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.

Intervention(s) in this Clinical Trial

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

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: Placebo
  • Arm 1
• Active Comparator: Nepicastat
  • Arm 2

Primary Measures

• Primary Outcome is determined by the CAPS scores.
  • Time Frame: 3 years
    Safety Issue?: Yes

Secondary Measures

• the secondary outcome measures (DTS, Quality of Life Measures)
  • Time Frame: 3 years
    Safety Issue?: Yes

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 19 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Tuscaloosa Research & Education Advancement Corporation

Overall Clinical Trial Officials and Contacts

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

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

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00659230

Study ID Number: 08-06

ClinicalTrials.gov Identifier: NCT00659230

Health Authority: United States: Food and Drug Administration