title: A two-site, two-arm, 34-week, double-blind, parallel-group, randomized controlled trial of reduced nicotine cigarettes in smokers with mood and/or anxiety disorders: trial design and protocol.
abstract: The U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks.
  
  
  
  Adult smokers (N = 200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms).
  
  
  
  Results from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes.
  
  
  
  TRN: NCT01928758 , registered August 21, 2013.
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA. sallen@phs.psu.edu.
authors.forename: Sophia I
authors.initials: SI
authors.lastname: Allen
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Foulds
authors.affiliation: Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Gladys N
authors.initials: GN
authors.lastname: Pachas
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Veldheer
authors.affiliation: Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Cather
authors.affiliation: Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Nour
authors.initials: N
authors.lastname: Azzouz
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Shari
authors.initials: S
authors.lastname: Hrabovsky
authors.affiliation: Department of Psychiatry, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hameed
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Yingst
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Hammett
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Modesto
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Nicolle M
authors.initials: NM
authors.lastname: Krebs
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Junjia
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Muscat
authors.affiliation: Department of Public Health Sciences, Tobacco Center of Regulatory Science, Pennsylvania State University College of Medicine, MC CH69, 500 University Drive, P.O. Box 850, Hershey, PA, 17033, USA.
authors.forename: John
authors.initials: J
authors.lastname: Richie
authors.affiliation: Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: A Eden
authors.initials: AE
authors.lastname: Evins
mesh_terms: D000328:Adult; D001008:Anxiety Disorders / Q000150:complications* / Q000523:psychology; D015415:Biomarkers / Q000032:analysis; D002248:Carbon Monoxide / Q000032:analysis; D002985:Clinical Protocols; D003367:Cotinine / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008404:Massachusetts; D019964:Mood Disorders / Q000150:complications* / Q000523:psychology; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage; D009602:Nitrosamines / Q000652:urine; D018384:Oxidative Stress; D010414:Pennsylvania; D011721:Pyrenes / Q000652:urine; D011725:Pyridines / Q000652:urine; D012906:Smoke; D012907:Smoking / Q000523:psychology; D016540:Smoking Cessation / Q000379:methods* / Q000523:psychology; D062789:Tobacco Products / Q000032:analysis*; D014029:Tobacco Use Disorder / Q000523:psychology / Q000628:therapy*; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018722:Nicotinic Agonists; D009602:Nitrosamines; D011721:Pyrenes; D011725:Pyridines; D012906:Smoke; D009538:Nicotine; D002248:Carbon Monoxide; C099565:4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol; D003367:Cotinine; C033146:1-hydroxypyrene
keywords: Anxiety; Cigarettes; Cotinine; Mood; NNAL; RCT; Spectrum; Tobacco