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

Study Overview
=================
Brief 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.

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)

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

Conditions
-----------------
Posttraumatic Stress Disorder

Intervention / Treatment
-----------------
* Drug: Nepicastat
* Drug: Placebo


Participation Criteria
=================
Eligibility 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 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

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Arm 1 | Drug: Placebo<br>* 100-800mg placebo<br>|
| Active Comparator: Nepicastat<br>Arm 2 | Drug: Nepicastat<br>* 100-800mg<br>* Other names: Dopamine beta hydroxylase (DBH) inhibitor;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 (κ=0.78). | Baseline, week 2, 4 and 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 (κ=0.78). | Baseline, week 2,4, and 6 | 
| 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 (κ=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 | 
| 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 (κ=0.78). | Baseline, week 2, 4, and 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PTSD, Veterans, Nepicastat, OIF/OEF