NCT00659230: Nepicastat

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

Completed Phase 2 Results posted Last updated 13 October 2017

What this trial tests

Phase 2 trial testing Nepicastat in Posttraumatic Stress Disorder in 100 participants. Completed in 30 August 2012.

Timeline

1 July 2009

Primary endpoint
5 July 2012

30 August 2012

Quick facts

Lead sponsor	Tuscaloosa Research & Education Advancement Corporation
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	100
Start date	1 July 2009
Primary completion	5 July 2012
Estimated completion	30 August 2012
Sites	3 locations across United States

Drugs / interventions tested

• Nepicastat — full drug profile →
• Placebo

Conditions studied

• Posttraumatic Stress Disorder — all drugs for Posttraumatic Stress Disorder →

Sponsor

Tuscaloosa Research & Education Advancement Corporation

Who can join

19 and older, any sex, with Posttraumatic Stress Disorder. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Clinician Administered PTSD Scale Subscore D (Hyperarousal) Primary · Baseline, week 2, 4 and 6

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

Group	Value	95% CI
Placebo	25.59	± 6.17
Nepicastat	26.07	± 6.01

Week 2

Group	Value	95% CI
Placebo	21.20	± 7.59
Nepicastat	22.07	± 7.95

Week 4

Group	Value	95% CI
Placebo	19.78	± 8.27
Nepicastat	21.15	± 8.13

Week 6

Group	Value	95% CI
Placebo	19.57	± 8.55
Nepicastat	21.62	± 9.17

Clinician Administered PTSD Scale Total Score Secondary · Baseline, week 2,4, and 6

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

Group	Value	95% CI
Placebo	74.52	± 16.73
Nepicastat	77.18	± 16.55

Week 2

Group	Value	95% CI
Placebo	61.82	± 25.02
Nepicastat	60.17	± 24.72

Week 4

Group	Value	95% CI
Placebo	52.61	± 27.17
Nepicastat	60.26	± 27.59

Week 6

Group	Value	95% CI
Placebo	58.22	± 28.37
Nepicastat	52.95	± 25.81

Clinician Administered PTSD Scale Subscale B Score Secondary · 6 weeks

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.

Baseline

Group	Value	95% CI
Placebo	20.37	± 7.26
Nepicastat	20.41	± 8.46

Week 2

Group	Value	95% CI
Placebo	16.95	± 9.77
Nepicastat	14.14	± 8.97

Week 4

Group	Value	95% CI
Placebo	11.51	± 10.02
Nepicastat	14.59	± 9.75

Week 6

Group	Value	95% CI
Placebo	12.64	± 10.04
Nepicastat	15.27	± 10.27

Clinician Administered PTSD Scale Subscale C Score Secondary · Baseline, week 2, 4, and 6

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

Group	Value	95% CI
Placebo	29.02	± 8.03
Nepicastat	30.70	± 7.37

Week 2

Group	Value	95% CI
Placebo	23.66	± 12.18
Nepicastat	24.39	± 11.41

Week 4

Group	Value	95% CI
Placebo	21.32	± 12.82
Nepicastat	24.51	± 13.06

Week 6

Group	Value	95% CI
Placebo	20.74	± 12.21
Nepicastat	21.32	± 12.11

Adverse events — posted to ClinicalTrials.gov

Time frame: During six-week placebo-controlled phase.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 3/46 (7%)

Deaths: 0/46

Nepicastat

Serious: 2/45 (4%)

Deaths: 0/45

Serious adverse events (2 terms)

Reaction	System	Placebo	Nepicastat
Psychiatric Inpatient	Psychiatric disorders	—	—
Chest Pain	Cardiac disorders	—	—

Other adverse events (34 terms — click to expand)

Reaction	System	Placebo	Nepicastat
headache	Nervous system disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Flu-like	Infections and infestations	—	—
arthralgia	Musculoskeletal and connective tissue disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Dry Mouth	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Gastroesophageal Reflux	Gastrointestinal disorders	—	—
Stomach Pain	Gastrointestinal disorders	—	—
Dental Caries	Gastrointestinal disorders	—	—
Gastroenteritis	Infections and infestations	—	—
sinusitis	Infections and infestations	—	—
rash acneiform	Skin and subcutaneous tissue disorders	—	—
Ear Pain	Ear and labyrinth disorders	—	—
Eye Pain	Eye disorders	—	—
Dry Eye	Eye disorders	—	—
Vomitting	Gastrointestinal disorders	—	—
Edema Face	General disorders	—	—
MRSA staphylococcal infection	Infections and infestations	—	—
injury to extremity	Injury, poisoning and procedural complications	—	—
muscle twitch	Musculoskeletal and connective tissue disorders	—	—
muscle spasm	Musculoskeletal and connective tissue disorders	—	—
dysgeusia (taste changes)	Nervous system disorders	—	—
paraesthesia	Nervous system disorders	—	—
memory problems	Nervous system disorders	—	—
insomnia	Psychiatric disorders	—	—
shortness of breath	Respiratory, thoracic and mediastinal disorders	—	—
epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
rash	Skin and subcutaneous tissue disorders	—	—
pruritus	Skin and subcutaneous tissue disorders	—	—
tongue lesion removed	Surgical and medical procedures	—	—
superficial thrombophlebitis	Vascular disorders	—	—
hypertension	Vascular disorders	—	—
hot flash	Vascular disorders	—	—

Most-reported serious reactions: Psychiatric Inpatient, Chest Pain.

Data from ClinicalTrials.gov NCT00659230 adverse events section.

Sponsor's own description

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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Emerging drugs for the treatment of anxiety.
   Murrough JW, Yaqubi S, Sayed S, Charney DS. · · 2015 · cited 91× · PMID 26012843 · DOI 10.1517/14728214.2015.1049996
2. Pharmacotherapy for post traumatic stress disorder (PTSD).
   Williams T, Phillips NJ, Stein DJ, Ipser JC. · · 2022 · cited 62× · PMID 35234292 · DOI 10.1002/14651858.cd002795.pub3