A Safety and Cognitive Function Study of EVP-6124 Versus Placebo in Subjects With Nicotine Dependence

Study Overview
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Brief Summary
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This study is designed to evaluate the initial evidence for efficacy of the investigational medicine, EVP-6124, to improve smoking cessation outcomes with and without a standard taper of nicotine replacement therapy (NRT) in healthy nicotine dependent smokers

Official Title
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Proof-of-Concept Study of EVP-6124, an Alpha-7 Nicotinic Acetylcholine Receptor Agonist, Versus Placebo in Subjects With Nicotine Dependence

Conditions
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Nicotine Dependence, Smoking Cessation

Intervention / Treatment
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* Drug: EVP-6124
* Drug: Placebo Capsule
* Drug: NicoDerm Patch (Active)
* Drug: NRT Patch (Placebo)
* Behavioral: Brief Supportive and Behavioral Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Self-report of smoking an average of ≥10 cigarettes/day for 6 months and expired carbon monoxide (CO) ≥10 parts per million (ppm) or urine cotinine ≥ 100 ng/mL at screening or self-report of smoking an average of 5-9 cigarettes/day for 6 months and a urine cotinine ≥30ng/ml at screening Have a negative urine drug screen at screening Fertile, sexually active subjects (males and females) must use an effective method of contraception from the first dose of study drug and for 3 months after the last dose of study drug If female and capable of conception, must have a negative urine Human chorionic gonadotrophin (hCG) pregnancy test at screening and Day 1 Exclusion Criteria: Have unstable medical illness with hospitalization for treatment likely within 6 months Have life-threatening arrhythmia, cerebrovascular or cardiovascular event within 6 months of enrollment Have liver function tests elevated >2.5 times the upper limit of normal range Have a tumor or a seizure disorder Currently using other tobacco- or nicotine-containing products and unwilling to try to quit Have a 6-month history of substance use disorder other than nicotine or caffeine or major depressive disorder Have a history of multiple adverse drug reactions Non-response (past 3 months) to nicotine replacement therapy (NRT) >20 mg/day, bupropion >150 mg/day, or varenicline 2 mg/day for ≥4 weeks Use of excluded concomitant medications Hospitalization for any reason within 30 days of screening Use of any investigational drug or device within 30 days of screening Have clinically significant abnormal serum electrolytes Have insufficiently controlled diabetes mellitus Have renal insufficiency (serum creatinine >1.8 mg/dL) Malignant tumor within the last 5 years, with the exception of squamous and basal cell carcinoma or cervical carcinoma in situ Have a clinically significant cardiovascular abnormality on the screening EKG Lifetime history of schizophrenia, bipolar disorder, post-traumatic stress disorder, bulimia, organic mental disorder, dementia, pervasive developmental disorder Have untreated, clinically significant hypothyroidism or hyperthyroidism Have a positive self-report of human immunodeficiency virus infection Females who are pregnant or nursing Any experimental drug currently or within 30 days before baseline Have a serious risk of suicide Have a screening electrocardiogram (ECG) with a corrected QT (QTc) interval using Bazett's formula >450 msec for males and >470 msec for females or the presence of any clinically significant cardiac abnormalities

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Experimental: EVP-6124 + NicoDerm (Active)<br>One EVP-6124 capsule ingested orally daily for 12 weeks (84 days) and one NicoDerm patch (Active) daily for first 6 weeks (42 days) | Drug: EVP-6124<br>* One EVP-6124 capsule ingested orally daily for 12 weeks (84 days)<br>Drug: NicoDerm Patch (Active)<br>* One NicoDerm patch once daily for first 6 weeks (42 days). Dosage will taper from 21 mg (Weeks 1-3) to 14 mg (Weeks 4-5) to 7 mg (Week 6).<br>Behavioral: Brief Supportive and Behavioral Treatment<br>* Brief, standard, manualized individual cognitive behavioral therapy intervention will be based on the Freedom from Smoking curriculum from the American Lung Association.<br>|
| Active Comparator: Placebo + NicoDerm (Active)<br>One placebo capsule ingested orally daily for 12 weeks (84 days) and one NicoDerm patch (Active) daily for first 6 weeks (42 days) | Drug: Placebo Capsule<br>* One placebo capsule ingested orally daily for 12 weeks (84 days)<br>Drug: NicoDerm Patch (Active)<br>* One NicoDerm patch once daily for first 6 weeks (42 days). Dosage will taper from 21 mg (Weeks 1-3) to 14 mg (Weeks 4-5) to 7 mg (Week 6).<br>Behavioral: Brief Supportive and Behavioral Treatment<br>* Brief, standard, manualized individual cognitive behavioral therapy intervention will be based on the Freedom from Smoking curriculum from the American Lung Association.<br>|
| Experimental: EVP-6124 + NRT Patch (Placebo)<br>One EVP-6124 capsule ingested orally daily for 12 weeks (84 days) and one NRT patch (Placebo) daily for first 6 weeks (42 days) | Drug: EVP-6124<br>* One EVP-6124 capsule ingested orally daily for 12 weeks (84 days)<br>Drug: NRT Patch (Placebo)<br>* One NRT patch (Placebo) daily for first 6 weeks (42 days).<br>Behavioral: Brief Supportive and Behavioral Treatment<br>* Brief, standard, manualized individual cognitive behavioral therapy intervention will be based on the Freedom from Smoking curriculum from the American Lung Association.<br>|
| Placebo Comparator: Placebo + NRT Patch (Placebo)<br>One placebo capsule ingested orally daily for 12 weeks (84 days) and one NRT patch (Placebo) daily for first 6 weeks (42 days) | Drug: Placebo Capsule<br>* One placebo capsule ingested orally daily for 12 weeks (84 days)<br>Drug: NRT Patch (Placebo)<br>* One NRT patch (Placebo) daily for first 6 weeks (42 days).<br>Behavioral: Brief Supportive and Behavioral Treatment<br>* Brief, standard, manualized individual cognitive behavioral therapy intervention will be based on the Freedom from Smoking curriculum from the American Lung Association.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of EVP-6124 on 7-day Point-prevalence Smoking Abstinence | Smoking abstinence is defined as a self-report of smoking no cigarettes for the past 7 days by time-line follow-back, confirmed by expired carbon monoxide (CO) <10 ppm and/or urine cotinine <50 ng/mL. | Week 1, 2, 4, 6, 8, 10, 12 | 
| Difference in Expired Carbon Monoxide (CO) Concentration From Baseline to End Point | CO concentration was measured at every visit. | Baseline, Weeks 1, 2, 4, 6, 8, 10, 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of EVP-6124 on Cognitive Performance as Measured by the Continuous Performance Test Hit Reaction Time | The Continuous Performance Test (CPT) is a measure of both vigilance/attentional control and response inhibition. During the task, subjects are required to press a button whenever a letter appears on the screen unless that letter is an 'X'. Measures of attentional control will serve as primary measure from this test. Baseline attentional impairment is associated with reduced odds of abstinence, abstinence differentially worsens performance on this measure in those with baseline attentional impairment, and NRT improves performance on a similar measure. | Baseline, week 1, week 12 | 
| Safety and Tolerability of EVP-6124 Alone or Combined With NRT | All AEs (adverse experiences) spontaneously reported by subjects and/or observed by investigator and evaluation of physical examinations, prior and concomitant medications, clinical laboratory tests, ECGs, and vital signs measurements. Data was collected at every visit and was analyzed as aggregate at the end of week 12 | Weeks 1-12 | 
| Effects of EVP-6124 on Working Memory as Measured by the N-Back Task Reaction Time | This task is a standard measure that can assess working memory performance under varying levels of task demand. Subjects are presented with a stream of stimuli, and the task is to decide for each stimulus whether it matches the one presented N items before. The processing load can be varied systematically by manipulating the value of N, which is expressed with changes in accuracy and reaction time. The number of errors as well as reaction times increase monotonically with increasing levels of N. The n-back task is sensitive to nicotine administration and abstinence effects. Here we present reaction time (RT) | Baseline, week 1, week 12 |