Glucocorticoid Antagonist Treatment for Tobacco Use Disorder

The purpose of this protocol is to examine whether mifepristone, a medication with glucocorticoid receptor antagonist activity, may be a potential treatment for Tobacco Use Disorder (TUD). Mifepristone has already shown promise as a potential treatment for PTSD (1) and alcohol use disorder (AUD) (2), but no previous studies have examined the therapeutic potential of mifepristone for TUD. This will be a double-blind, placebo-controlled study on the effects of a 7-day treatment with 600 mg mifepristone, or placebo, on cognitive function, tobacco withdrawal severity, and smoking behavior.

Study Overview

• Status: Terminated
• Conditions: Nicotine Dependence
• Intervention / Treatment: Drug: Placebo; Drug: Mifepristone

Detailed Description

This will be a double-blind, placebo-controlled study that tests the effects of a 7-day treatment with 600 mg mifepristone, or placebo, on cognitive function, tobacco withdrawal severity and smoking behavior. Once the intake and physical examination is completed and eligibility is determined, subjects will participate in a baseline session to become familiar with the study procedures and to assess baseline measures of withdrawal, smoking urges, pain sensitivity, and cognitive performance. Subjects will be asked to refrain from consuming alcoholic beverages and drugs during their study participation. This will be verified by urine drug screening and breathalyzer before the session and during outpatient visits. If results indicate non-compliance with these study procedures, subjects will be discharged from the study.

Participants will be assessed for compliance with medication treatment, withdrawal severity, recent smoking behavior, and cognitive function during treatment visits on Days 1 and 4. On Day 7, following overnight abstinence from smoking, participants will attend a test session that models relapse to smoking. During this session, subjects will have the option to smoke, or to delay smoking in exchange for monetary compensation (45). To examine if mifepristone's proposed therapeutic effects last beyond the treatment duration (as observed in previous studies), there will be 1-week and 1-month follow-up assessments on smoking behavior, urges to smoke, endocrine biomarkers, and cognitive function.

Participants in each group will complete the laboratory-based, delayed smoking procedure in a designated, negative pressure room in Bldg. 36 of the West Haven VA just after assessing pain sensitivity with the cPT. This sequence allows the cPT to assess pain sensitivity, a potential biomarker of relapse behavior, and to also be used as a mild stressor prior to participation in the smoking relapse model. Participants will be instructed to abstain from smoking after 10 pm the night before Test Sessions. Abstinence will be confirmed the morning of the session by measuring a breath CO level of < 8 ppm.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Veterans Affairs Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male smokers aged 18 to 55 years;
• History of smoking at least 5 cigarettes daily for the past 12 months;
• In good health as verified by medical history, screening examination, and -screening laboratory tests

Exclusion Criteria:

• History of mifepristone allergy;
• Requirement of any form of regular psychotropic medication (antidepressants, antipsychotics, or anxiolytics) and recent psychiatric history (in the past 6 months);
• Medical illnesses including diabetes, cardiovascular, renal, endocrine, or hepatic disorders;
• Prolonged QTc interval >450 msec;
• History of adrenal insufficiency or a morning plasma cortisol level less than 5 mcg/dl at screening;
• Hypokalemia at screening (defined as potassium level < 3.5 mEq/L);
• Current use of clinically significant CYP 3A4 substrates including, simvastatin, lovastatin, cyclosporine, ergotamines, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, triazolam, midazolam.
• use of rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's Wort.
• Current use of strong 3A4 inhibitors including ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenivir, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole.
• Treatment with systemic corticosteroids
• Current use of clinically significant CYP 3A inducers (e.g., rifampin, rifabutin);
• Abuse of alcohol or any other illicit or prescription drugs;
• Inability to tolerate cold exposure due to conditions such as peripheral -vascular disease or Raynaud's phenomenon;
• Inability to fulfill all scheduled visits and examination procedures throughout the study period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: HEALTH_SERVICES_RESEARCH
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Mifepristone; Mifepristone 600 mg/day in 2 tablets	Drug: Placebo; Placebo sugar 2 tablets will be compared to mifepristone; Other Names: sugar pill
PLACEBO_COMPARATOR: Placebo; matching placebo in 2 tablets	Drug: Mifepristone; Mifepristone 600mg 2 tablets will be compared to the placebo; Other Names: korlym, mifeprex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minnesota Nicotine Withdrawal Symptom Checklist (M-NWSC)	Smokers will be asked to rate several nicotine withdrawal symptoms on a 100 mm scale, from "not at all" to "extremely."	one week

Collaborators and Investigators

• Sponsor: Yale University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 29, 2017
• Primary Completion (ACTUAL): May 20, 2019
• Study Completion (ACTUAL): May 20, 2019

Study Registration Dates

• First Submitted: August 4, 2017
• First Submitted That Met QC Criteria: August 11, 2017
• First Posted (ACTUAL): August 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 28, 2019
• Last Update Submitted That Met QC Criteria: May 23, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Abortifacient Agents; Luteolytic Agents; Abortifacient Agents, Steroidal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Menstruation-Inducing Agents; Mifepristone
• Other Study ID Numbers: MS053

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No