A Study for the Treatment of Alcohol Dependence

Study Overview
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Brief Summary
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The Primary objective of this study is to test whether LY2196044 can reduce the number of heavy drinking days per month in people with alcohol dependence. Each subject will undergo a screening and assessment period (including medication washout) prior to randomization into a 16 week double blind treatment period.

Official Title
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A Phase 2 Study of LY2196044 Compared With Placebo in the Treatment of Alcohol Dependence

Conditions
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Alcohol Dependence

Intervention / Treatment
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* Drug: LY2196044
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have Alcohol Dependence. Subjects must manifest at least the following 3 requirements for their diagnosis of Alcohol Dependence: Be tolerant, as defined by either of the following: A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. Markedly diminished effect with continued use of the same amount of alcohol. Consume alcohol, often in larger amounts or over a longer period than was intended. Have a persistent desire or unsuccessful effort(s) to reduce or control alcohol use. Drink on average more than 14 drinks (women) or 21 drinks (men) per week with at least 2 heavy drinking days per week (≥4 drinks/day for women and ≥5 drinks/day for men) during the consecutive 30 day period prior to Screening and maintained through Randomization. Endorse abstinence or reduction in drinking. Female subjects of childbearing potential must have a negative urine pregnancy test and agree to use a reliable method of birth control during the study and for 2 months following the last dose of study drug. Exclusion Criteria: Have experienced an acute alcohol withdrawal syndrome within the past 6 months or are currently at significant risk of suffering an acute alcohol withdrawal syndrome. Have a history of serious head injury, intracranial neoplasm or hemorrhage, prior seizure (other than remote history of childhood febrile seizure), or other condition that would place the subject at increased risk of seizure. Have ever taken anticonvulsants for seizure control. Are diagnosed with substance dependence or abuse (other than alcohol, cannabis, nicotine, or caffeine) within 6 months prior to Screening. Are receiving intensive behavioral or psychological therapy, delivered by a licensed or certified alcohol treatment specialist, for alcohol dependence. Meet criteria for a lifetime diagnosis of Schizophrenia, Schizoaffective Disorder, Bipolar I Disorder, or other psychoses. Have signs and symptoms of an active illness within the past 6 months of Screening for a diagnosis of Major Depressive Disorder (MDD) or Anxiety Disorder, or have a Cognitive Disorder diagnosed by clinical assessment. Subjects who were diagnosed with MDD in the more distant past, but have had a recent diagnosis of an active Major Depressive Episode, will not be eligible. Are actively suicidal, in the opinion of the investigator. Have taken any opiate or opioid analgesic (for example, codeine, hydrocodone) or an opiate receptor antagonist (for example, naltrexone) within 14 days prior to Screening. Are currently taking any medication excluded by the protocol. Note: Subjects who discontinue/washout excluded medications prior to Randomization are not excluded from participation. Have evidence of significant active cardiac, respiratory, renal, gastrointestinal, or hematologic disease. Have acute or active hepatitis or hepatic inflammation. Have a history of cirrhosis or laboratory evidence of significant hepatocellular injury. Have plasma levels of sodium, potassium, calcium, magnesium, or phosphorous that fall outside of established reference ranges of the central laboratory for those analytes [that is, below lower limit of normal (LLN) or above upper limit of normal (ULN)] unless corrected prior to randomization. Have electrocardiogram (ECG) abnormalities obtained at Screening that are clinically significant with regard to the subject's participation in the study. Are women who are either pregnant or breast feeding. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. Have previously completed or withdrawn from this study or any other study investigating LY2196044. Are unable, unreliable, and/or unwilling to provide informed consent, make themselves available for the duration of the study or abide by study procedures and restrictions.

Ages Eligible for Study
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Minimum Age: 21 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: LY2196044<br> | Drug: LY2196044<br>* 250 milligram (mg) (titrate via 1 week at 50 mg and 1 week at 125 mg), once daily, orally, 16 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* once daily, orally, 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Heavy Drinking Days at Week 16 Endpoint | The Timeline Followback Method assesses the subject's daily drinking by means of a calendar that covers a specific time period and was used to assess the number of heavy drinking days. Heavy drinking is defined as ≥4 drinks/day for women and ≥5 drinks/day for men. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, treatment*visit, gender*family history, baseline, and baseline*visit. An unstructured covariance structure was used. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Drinks Per Day at Week 16 Endpoint | The Timeline Followback Method assesses the subject's daily drinking by means of a calendar that covers a specific time period and was used to assess the number of drinks consumed per day. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, treatment*visit, gender*family history, baseline, and baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Percentage of Days Abstinent at Week 16 Endpoint | The Timeline Followback Method assesses the subject's daily drinking by means of a calendar that covers a specific time period and was used to assess the percentage of days abstinent. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, treatment*visit, gender*family history, baseline, and baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Drinks Per Drinking Day at Week 16 Endpoint | The Timeline Followback Method assesses the subject's daily drinking by means of a calendar that covers a specific time period and was used to assess the number of drinks consumed on the days the participant drank. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, treatment*visit, gender*family history, baseline, and baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Drinks Per Heavy Drinking Day at Week 16 Endpoint | The Timeline Followback Method assesses the subject's daily drinking by means of a calendar that covers a specific time period and was used to assess the number of drinks consumed on heavy drinking days. Heavy drinking is defined as ≥4 drinks/day for women and ≥5 drinks/day for men. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, treatment*visit, gender*family history, baseline, and baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Obsessive Compulsive Drinking Scale (OCDS) Total Score at Week 16 Endpoint | Cravings will be assessed using the OCDS. The OCDS is a 14-item self-rating instrument. Total scores range from 0-40. Higher scores indicate more obsessive and craving. Least Squares (LS) Mean value was controlled for treatment, site, visit, gender, history, baseline, gender*history, treatment*visit, baseline*visit, gender*treatment, gender*treatment*visit. Subject was treated as a random effect. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Drinker Inventory of Consequences (DrInC) - Recent Consequences (DrInC-2R) Total Score at Week 16 Endpoint | DrInC is a self-administered, 50-item questionnaire designed to measure adverse consequences of alcohol abuse in 5 areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. DrInC-2R provides a measurement since the last interview. Total scores range from 0-150, and higher scores indicate greater severity of symptoms. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, baseline, gender*family history, treatment*visit, baseline*visit. Subject was treated as a random effect. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Ratio of Geometric Means Over Baseline in Gamma-Glutamyltransferase (GGT) Level at Week 16 Endpoint | GGT and carbohydrate-deficient transferrin (%CDT) will be used as biochemical markers of alcohol consumption. A combination of GGT and %CDT improves the sensitivity of detecting excessive alcohol consumption as compared to either marker alone, or other traditional markers. Elevated levels indicate heavy alcoholism. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Week 16 | 
| Ratio of Geometric Means Over Baseline in Percent Carbohydrate-Deficient Transferrin (%CDT) Level at Week 16 Endpoint | Gamma-Glutamyltransferase (GGT) and %CDT will be used as biochemical markers of alcohol consumption. A combination of GGT and %CDT improves the sensitivity of detecting excessive alcohol consumption as compared to either marker alone, or other traditional markers. Elevated levels indicate heavy alcoholism. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Week 16 | 
| Ratio of Geometric Means Over Baseline in Aspartate Transaminase (AST) Level at Week 16 Endpoint | AST is a potential biomarker for LY2196044 efficacy as decreases reflect decreased alcohol consumption. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, gender, family history, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Week 16 | 
| Change From Baseline in Beck Depression Inventory II (BDI-II) Total Score at Week 16 Endpoint | The BDI-II contains 21 items that characterize how the subject was feeling in the past 2 weeks. There is a 4-point scale for each item ranging from 0 to 3 (0=no depression; 3=very depressed). Total scores range from 0-63. Higher scores indicate greater severity of depression. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, gender, family history, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Beck Anxiety Inventory (BAI) Total Score at Week 16 Endpoint | BAI is a 21-item patient-completed questionnaire designed to assess the characteristics of anxiety. Participant was asked to rate how much he or she has been bothered by each symptom over the past week. Each item is rated on a 4-point scale (0=not present; 3=present in the extreme). Total scores range from 0 to 63. The higher the score, the more severe the anxiety symptoms. LS Mean value was controlled for treatment, pooled investigator, gender, family history, visit, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Barratt Impulsivity Scale-11 (BIS-11) Total Score at Week 16 Endpoint | The BIS-11 is a 30-item, self-administered impulsivity scale. Motor, cognitive, and non-planning domains are assessed and a total score is computed. This scale has previously been used in substance-abusing populations. Total scores range from 30-120. Higher scores indicate greater severity of symptoms. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, gender, family history, baseline, gender*family history. | Baseline, Week 16 | 
| Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Thoughts About Abstinence Scale was to measure participant's commitment to abstinence. It includes 3 items on a scale of 1-10: own desire to stop drinking (1=no desire to quit); own expectation of success in quitting (1=lowest expectation of success); how difficult to quit and remain abstinent (1=lowest amount of difficulty); and their goal related to alcohol use (scale of 1-7: 1=having no goal, up to total abstinence at 6 [7 was none of 6 above]). Least Squares (LS) Mean value was controlled for treatment, pooled investigator, gender, family history, baseline, gender*family history. | Baseline, Week 16 | 
| Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 16 Endpoint | Q-LES-Q-SF is a self-report instrument that assesses the degree of enjoyment and satisfaction in daily life activities. The domains include: social relationships, living or house situation, and physical health. Total scores range from 14-70. Higher scores indicate better quality of life. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, gender, family history, visit, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Endicott Work Productivity Scale (EWPS) Total Score at Week 16 Endpoint | EWPS is a self-rated work productivity scale that assesses such topics as work hours, work missed, and behaviors and feelings related to the workplace. The EWPS will be completed only by subjects who work outside the home. There are 25 items and total scores range from 0-100. Higher scores indicate poorer productivity. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, gender, family history, visit, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Population Pharmacokinetic (PK) - Apparent Clearance | Plasma concentrations were analyzed using population PK methodology with non-linear mixed effect modeling (NONMEM) software. | Over 16 weeks | 
| Population Pharmacokinetic (PK) - Apparent Volume of Distribution | Plasma concentrations were analyzed using population PK methodology with non-linear mixed effect modeling (NONMEM) software. | Over 16 weeks | 
| Change From Baseline in Supine Blood Pressure (BP) at Week 16 Endpoint | Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Supine Pulse Rate at Week 16 Endpoint | Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in QTc Fridericia's Correction Interval (QTcF) Measured by Electrocardiograms at Week 16 Endpoint | Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Percentage of Participants Discontinuation Due to Adverse Events (AEs) | Percentage of participants discontinued study due to one or more AEs. | Baseline through Week 16 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Percentage of participants had one or more TEAEs during treatment period. TEAE is a worsening or new occurrence of adverse event during treatment compared to baseline. | Baseline through Week 16 | 
| Change From Baseline in Orthostatic Blood Pressure (BP) at Week 16 Endpoint | Orthostatic BP is the BP measured within 3 minutes of standing. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Change From Baseline in Orthostatic Pulse Rate at Week 16 Endpoint | Orthostatic pulse rate is the pulse rate measured within 3 minutes of standing. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment*visit. An unstructured covariance structure was used. | Baseline, Week 16 | 
| Number of Participants With Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar)≥10 at Any Time From Baseline Through Week 16 Endpoint | The revised CIWA-Ar scale measured the severity of alcohol withdrawal by rating 10 signs and symptoms: nausea; tremor; autonomic hyperactivity; anxiety; agitation; tactile, visual, and auditory disturbances; headache; and disorientation. Total scores range from 0-67. Higher scores indicate greater severity of withdrawal. | Baseline through Week 16 | 
| Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Total Score at Week 16 Endpoint | The GSRS is a clinician-administered scale used to assess upper and lower gastrointestinal physical symptoms. 15 items covering domains of abdominal pain, reflux syndrome, indigestion syndrome, diarrhea syndrome, and constipation syndrome were assessed with a 1-week recall period. Total scores range from 0-45. Higher scores indicate greater severity of symptoms. Least Squares (LS) Mean value was controlled for treatment, pooled investigator, gender, family history, visit, baseline, gender*family history, treatment*visit, baseline*visit. An unstructured covariance structure was used. | Baseline, Week 16 |