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

NCT00659230 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: 08-06PT074384/W81XWH-08-2-0071PT074384/W81XWH-09-1-0287
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 3

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.

Conditions

Posttraumatic Stress Disorder

Keywords

PTSD; Veterans; Nepicastat; OIF/OEF

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Clinician Administered PTSD Scale Total Score

  Baseline, week 2,4, and 6

• Clinician Administered PTSD Scale Subscale B Score

  6 weeks

• Clinician Administered PTSD Scale Subscale C Score

  Baseline, week 2, 4, and 6

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Arm 1

Drug: Placebo

Nepicastat

ACTIVE COMPARATOR

Arm 2

Drug: Nepicastat

Interventions

Nepicastat DRUG

100-800mg

Also known as: SYN117, Dopamine beta hydroxylase (DBH) inhibitor

Nepicastat

Placebo DRUG

100-800mg placebo

Placebo

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Tuscaloosa Research & Education Advancement Corporation: lead
• Acorda Therapeutics: collaborator
• Ralph H. Johnson VA Medical Center: collaborator
• Baylor College of Medicine: collaborator
• San Diego Veterans Healthcare System: collaborator
• James J. Peters Veterans Affairs Medical Center: collaborator

Study Sites (3)

Tuscaloosa VAMC

Tuscaloosa, Alabama, 35404, United States

Location

VA San Diego Healthcare System

San Diego, California, 92161, United States

Location

James J.Peters VA Medical Center

The Bronx, New York, 10468, United States

Location

Related Publications (2)

• Kosten TR, Krystal J. Biological mechanisms in posttraumatic stress disorder. Relevance for substance abuse. Recent Dev Alcohol. 1988;6:49-68. doi: 10.1007/978-1-4615-7718-8_3.

  PMID: 3283864 BACKGROUND

• 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 beta-hydroxylase, norepinephrine, and post-traumatic stress disorder. Psychiatr Genet. 2014 Aug;24(4):181-2. doi: 10.1097/YPG.0000000000000039. No abstract available.

  PMID: 24983834 BACKGROUND

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic

Interventions

nepicastat; Dopamine beta-Hydroxylase

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Mixed Function Oxygenases; Oxygenases; Oxidoreductases; Enzymes; Enzymes and Coenzymes

Limitations and Caveats

Limitations: short duration of placebo-controlled phase (six-weeks).

Results Point of Contact

• Title: Lori L. Davis, MD
• Organization: Tuscaloosa VA Medical Center

lori.davis@va.gov

205-554-2000

Study Officials

• Carlos Berry, M.D.

  IRB Tuscaloosa VAMC

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Chief of Staff

Study Record Dates

• First Submitted: March 10, 2008
• First Posted: April 16, 2008
• Study Start: July 1, 2009
• Primary Completion: July 5, 2012
• Study Completion: August 30, 2012
• Last Updated: October 13, 2017
• Results First Posted: June 1, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)