@article{3041011994614a0f854479ddfe8ff143,
title = "Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: Study protocol for a randomized controlled trial",
abstract = "Background: Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD.Methods/design: Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects.Discussion: Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD.Trial registration: Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010.",
keywords = "Anxiety disorders, Clinical Research Protocol, CRH, Drugs, Fear conditioning, Fear-potentiated startle, HPA Axis, Investigational, Neuropsychological tests, Placebo, Psychophysiology",
author = "Dunlop, {Boadie W.} and Rothbaum, {Barbara O.} and Binder, {Elisabeth B.} and Erica Duncan and Harvey, {Philip D.} and Tanja Jovanovic and Kelley, {Mary E.} and Becky Kinkead and Michael Kutner and Iosifescu, {Dan V.} and Mathew, {Sanjay J.} and Neylan, {Thomas C.} and Kilts, {Clinton D.} and Nemeroff, {Charles B.} and Mayberg, {Helen S.}",
note = "Funding Information: In the past five years, the authors report the following: BWD has received research support from AstraZeneca, Bristol-Myers Squibb, Evotec, Forest, GlaxoSmithKline, NIMH, Novartis, Ono Pharmaceuticals, Pfizer, Takeda, and Transcept. He has also received honoraria for consulting work with Bristol-Myers Squibb, Imedex LLC, Medavante, Pfizer and Roche. BOR has funding from the Department of Defense, NIMH, Brain and Behavior Research Foundation (NARSAD), and McCormick Foundation and recent previous support from Transcept Pharmaceuticals. Dr. Rothbaum receives royalties from Oxford University Press, Guilford, APPI, and Emory University and received one advisory board payment from Genentech. EBB has received grant support from Pharma-Neuroboost and is co-inventors on the following patent applications: {\textquoteleft}Means and methods for diagnosing predisposition for treatment emergent suicidal ideation (TESI){\textquoteright}. European application number: 08016477.5 International application number: PCT/ EP2009/061575; {\textquoteleft}FKBP5: a novel target for antidepressant therapy{\textquoteright}. International publication number: WO 2005/054500 and {\textquoteleft}Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments{\textquoteright}. International application number: PCT/EP2005/005194. ED is a salaried Attending Psychiatrist in the Mental Health Service at the Atlanta Veterans Affairs Medical Center in Decatur, GA. She has received grant support from Posit Science Corporation, Bristol-Myers Squibb Company, and Ortho-McNeil Janssen Scientific Affairs. PDH has served as a consultant to Abbvie, Boeheringer-Ingelheim, En Vivo, Forest, Genentech, Otsuka-America, Roche, Sunovion, and Takeda. He has received contract research support from Genentech. MK has served as a consultant for St. Jude Medical Neuromodulation Division and served on the Clinical Research Advisory Committee for the Shriners Hospitals for Children. DVI has received funding (through Icahn School of Medicine at Mount Sinai) from AstraZeneca, Brainsway, Euthymics, Neosync, Roche and Shire; and consulting fees from Avanir, CNS Response, Lundbeck, Otsuka, Servier and Sunovion. SJM has received research funding or salary support from the Banner Family Fund, Brain and Behavior Research Foundation (NARSAD), The Brown Foundation, Inc., Bristol-Myers Squibb, Department of Veterans Affairs, Evotec, Johnson & Johnson, the Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Chair for Research in Psychiatry, and the National Institute of Mental Health. He has received consulting fees or honoraria from Allergan, AstraZeneca, Bristol-Myers Squibb, Cephalon, Corcept, Genentech, Noven, Roche, and Takeda, and has received medication from Sanofi-Aventis for a NIH sponsored study. TCN has received research medications from Actelion and GlaxoSmithKline for studies funded by the Department of Defense and Department of Veterans Affairs and has consulted for Genentech. CDK served on a scientific advisory meeting for Allergan, co-holds a patent on the method and devices for transdermal delivery of lithium (US 6,375,990 B1), and serves on the National Advisory Board for Skyland Trail. CBN has received research support from the NIMH and Agency for Healthcare Research and Quality. He has served as a consultant to Xhale, Takeda and SK Pharma. He has been a stockholder in CeNeRx Biopharma, NovaDel Pharma Inc., PharmaNeuroboost, Revaax Pharma and Xhale. He has had additional financial interests in Corcept, CeNeRx BioPharma, PharmaNeuroboost, Novadel Pharma Inc., and Revaax. He has served on the scientific advisory boards of American Foundation for Suicide Prevention (AFSP); AstraZeneca, CeNeRx Biopharma, Forest Labs, Janssen/Ortho-McNeil, Mt. Cook Pharma Inc., NARSAD, NovaDel Pharma Inc., Pharma-Neuroboost, Quintiles, and the Anxiety Disorders Association of America. He has served on the Board of Directors for the AFSP, George West Mental Health Foundation, NovaDel Pharma Inc., and Mt. Cook Pharma Inc. Dr Nemeroff holds a patent on the method and devices for transdermal delivery of lithium (US 6,375,990 B1) and the method to estimate drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). BK, TJ, and MEK report no competing interests. Funding Information: Funding for the study is provided from a grant from the National Institute of Mental Health, U19 MH069056 (BWD, HM). Additional support was received from K23 MH086690 (BWD) and VA CSRD Project ID 09S-NIMH-002 (TCN). GlaxoSmithKline contributed the study medication and matching placebo, as well as funds to support subject recruitment and laboratory testing. GSK is uninvolved in the data collection, data analysis (excepting some pharmacokinetic analysis), or interpretation of findings. The GSK561679 compound is currently licensed by Neurocrine Biosciences, which will also perform pharmacokinetic analyses. This work was supported with resources and the use of facilities at the Michael E DeBakey VA Medical Center, Houston, TX. Disclaimer: the views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Funding Information: This clinical investigation is part of a translational collaborative effort supported by the National Institute of Mental Health (NIMH) National Cooperative Drug Discovery/Development Groups (NCDDG) program. The NCDDG program encourages collaborations between clinical and preclinical academic researchers and industry with the goals of developing novel tools for drug development and {\textquoteleft}first in human, first in patient testing,{\textquoteright} as well as facilitating partnerships between academia and industry.",
year = "2014",
month = jun,
day = "21",
doi = "10.1186/1745-6215-15-240",
language = "English (US)",
volume = "15",
journal = "Trials",
issn = "1745-6215",
publisher = "BioMed Central",
number = "1",
}
