Enhancing Self Regulation Among Smokers

Study Overview
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Brief Summary
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The purpose of this study is to examine the effects of rapamycin (sirolimus) versus a placebo, an inactive substance, on responses to smoking cues in individuals with nicotine dependence. Rapamycin (sirolimus) is a FDA-approved antibiotic and immunosuppressive drug that is currently used to (a) prevent organ transplant recipients from rejecting their transplants (b) treat cardiovascular diseases, and (c) treat some forms of cancer. Rapamycin (sirolimus) is not FDA-approved for smoking cessation. The use of rapamycin (sirolimus) in this study is investigational, meaning that the study medication is not a proven treatment for nicotine dependence, however this study will examine the medication's use as a potential future treatment for nicotine dependence.

Detailed Description
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The proposed study will employ 58 ND treatment-seeking smokers who will be randomly assigned to receive either 15-mg of sirolimus or placebo (group n's=29) immediately after the first of two smoking cue exposure sessions scheduled to occur on consecutive days. The first session will serve as a Retrieval session during which smoking (e.g., handling and lighting of a cigarette) cue exposure will elicit retrieval and reconsolidation of smoking-related memories; the second session will be a Test session to examine the potential modulatory role of sirolimus on the reconsolidation of memories putatively elicited during the retrieval session. Participants will be required to refrain from smoking the night before (bedtime) their first laboratory (i.e., Retrieval) session and will remain abstinent from smoking until the completion of the second laboratory (i.e., Test) session. It is posited that changes in reactivity during the test session will reflect medication effects on memory reconsolidation that occurred following the retrieval session. Measures of subjective responses (i.e., craving) and physiological reactivity (i.e., heart rate & skin conductance) will be obtained before, during and after cue presentations in both sessions. The durability of any observed treatment effects will be assessed in a Follow-up session performed 7-days following completion of the test session. Treatment effects on self-report measures of smoking behavior during the 7-days preceding the Follow-up session will also be assessed.

Official Title
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Enhancing Self-regulation by Altering Memories That Increase Risk of Relapse Among Smokers: A Translational Clinical Neuroscience Study of a Novel Medication

Conditions
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Smoking Cessation, Smoking, Cigarette, Nicotine Dependence

Intervention / Treatment
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* Drug: sirolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must smoke 10+ cigarettes/day for three or more years Have a Fagerström Test for Nicotine Dependence score greater than or equal to 4 Be willing to make a cessation attempt Willing to comply with reinforced abstinence requirements for the three laboratory sessions Willing to use appropriate birth control methods during study participation including oral contraceptives, barrier methods (diaphragm or condoms with spermicide or both), surgical sterilization, use of an intra-uterine contraceptive device, or complete abstinence from sexual intercourse Remain abstinent from alcohol and all non-prescription drugs prior to medication administration and testing sessions Live with within a 50 mile radius of our research program and have reliable transportation Consent to fast for a two-hour period prior to medication administration Consent to random assignment to rapamycin (sirolimus) vs. placebo conditions Exclusion Criteria: Dependence on other substances (may meet criteria for abuse) Undergoing other smoking cessation treatment (e.g., nicotine replacement, Chantix) Taking medications that may interact with the study medication or alter responding on any study measure Are pregnant, nursing, or of childbearing potential and not using birth control Present evidence of or a history of significant endocrine, cardiovascular, pulmonary, renal or neurological disease, as these conditions may affect heart rate or skin conductance measurement Have significant liver impairment (as indicated by alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values that are three times the upper limit of normal) as rapamycin (sirolimus) is hepatically metabolized Have an existing infection or immune system disorder as rapamycin (sirolimus) has known immunosuppressive properties Have a history of or current psychotic disorder, severe major depression as evidenced by active and profound psychomotor retardation and/or persistent and intense suicidal ideation Currently taking anti-arrhythmic agents, psychostimulants or any other agents known to interfere with heart rate and skin conductance monitoring Have known or suspected hypersensitivity to macrolide compounds (such as rapamycin/sirolimus) Taking medications that could adversely interact with study medication including but not limited to significant inhibitors of CYP2D6 or CYP3A4 (voriconazole, fluconazole, itraconazole, erythromycin, clarithromycin, diltiazem, verapamil, etc.) or significant inducers of CYP3A4, such as anticonvulsants (carbamazepine, phenobarbital, phenytoin, etc.) and antibiotics (rifabutin, rifapentine, etc.) Have a history of thrombocytopenia, idiopathic thrombocytopenia purpura (ITP), or with a current platelet count of less than 100,000 cells per mm3, Have any unhealed wounds, including but not limited to oral ulcers, foot ulcers, or recent surgical or trauma wounds Have any planned surgeries within the next month, including surgical dental procedures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rapamycin 15mg (sirolimus)<br>Participants will receive three 5mg pills from a nurse in the Research Nexus, some participants will receive the study medication and others will be randomized to the placebo control group. | Drug: sirolimus<br>* Rapamycin (sirolimus) is administered in three 5mg oral capsules. This administration happens once during the first visit.<br>* Other names: rapamune;|
| Placebo Comparator: Placebo<br>Participants will receive three 5mg pills from a nurse in the Research Nexus, some participants will receive the study medication and others will be randomized to the placebo control group. | Drug: Placebo<br>* Placebo is administered in three 5mg oral capsules. This administration happens once during the first visit.<br>* Other names: Sugar Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Craving Levels in Response to Cue | Patients are asked about craving level on a scale of 0-100, 0 is least amount of craving and 100 is highest amount of craving | Study visit 1 (Baseline; day 0), visit 2 (day 7) and visit 3 (day 14) | 
| Heart Rate in Response to Cue | Heart rate is measured using a Biopac machine and Acqknowledge software at different timepoints throughout each visit while the participants are exposed to smoking cues. | Study visit 1 (Baseline; day 0), visit 2 (day 7) and visit 3 (day 14) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Cigarettes Smoked Per Day | Patients will be asked how many cigarettes per day they smoked 90 days prior to starting the study. Patients are then given a smoking and alcohol diary to complete during the course of the trial. | Visit 1 through Visit 3 (day 0-day 14) |