Alcohol Dependence
Conditions
Brief summary
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.
Interventions
DRUGLY2196044
250 milligram (mg) (titrate via 1 week at 50 mg and 1 week at 125 mg), once daily, orally, 16 weeks
DRUGplacebo
once daily, orally, 16 weeks
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Have Alcohol Dependence. Subjects must manifest at least the following 3 requirements for their diagnosis of Alcohol Dependence: 1. Be tolerant, as defined by either of the following: 1. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. 2. Markedly diminished effect with continued use of the same amount of alcohol. 2. Consume alcohol, often in larger amounts or over a longer period than was intended. 3. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Heavy Drinking Days at Week 16 Endpoint | Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percentage of Days Abstinent at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Drinks Per Drinking Day at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Drinks Per Heavy Drinking Day at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Obsessive Compulsive Drinking Scale (OCDS) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Drinker Inventory of Consequences (DrInC) - Recent Consequences (DrInC-2R) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Ratio of Geometric Means Over Baseline in Gamma-Glutamyltransferase (GGT) Level at Week 16 Endpoint | Week 16 | 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. |
| Ratio of Geometric Means Over Baseline in Percent Carbohydrate-Deficient Transferrin (%CDT) Level at Week 16 Endpoint | Week 16 | 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. |
| Ratio of Geometric Means Over Baseline in Aspartate Transaminase (AST) Level at Week 16 Endpoint | Week 16 | 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. |
| Change From Baseline in Beck Depression Inventory II (BDI-II) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Beck Anxiety Inventory (BAI) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Barratt Impulsivity Scale-11 (BIS-11) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Drinks Per Day at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Endicott Work Productivity Scale (EWPS) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Population Pharmacokinetic (PK) - Apparent Clearance | Over 16 weeks | Plasma concentrations were analyzed using population PK methodology with non-linear mixed effect modeling (NONMEM) software. |
| Population Pharmacokinetic (PK) - Apparent Volume of Distribution | Over 16 weeks | Plasma concentrations were analyzed using population PK methodology with non-linear mixed effect modeling (NONMEM) software. |
| Change From Baseline in Supine Blood Pressure (BP) at Week 16 Endpoint | Baseline, Week 16 | Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment\*visit. An unstructured covariance structure was used. |
| Change From Baseline in Supine Pulse Rate at Week 16 Endpoint | Baseline, Week 16 | Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment\*visit. An unstructured covariance structure was used. |
| Change From Baseline in QTc Fridericia's Correction Interval (QTcF) Measured by Electrocardiograms at Week 16 Endpoint | Baseline, Week 16 | Least Squares (LS) Mean value was controlled for treatment, pooled investigator, visit, baseline, treatment\*visit. An unstructured covariance structure was used. |
| Percentage of Participants Discontinuation Due to Adverse Events (AEs) | Baseline through Week 16 | Percentage of participants discontinued study due to one or more AEs. |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Baseline through Week 16 | 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. |
| Change From Baseline in Orthostatic Blood Pressure (BP) at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Orthostatic Pulse Rate at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Number of Participants With Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar)≥10 at Any Time From Baseline Through Week 16 Endpoint | Baseline through Week 16 | 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. |
| Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
| Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 16 Endpoint | Baseline, Week 16 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LY2196044 250 milligram (mg) (titrate via 1 week at 50 mg and 1 week at 125 mg), once daily, orally, 16 weeks | 187 |
| Placebo once daily, orally, 16 weeks | 188 |
| Total | 375 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 7 |
| Overall Study | Entry criteria not met | 5 | 5 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 18 | 21 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol Violation | 12 | 16 |
| Overall Study | Sponsor decision | 1 | 4 |
| Overall Study | Withdrawal by Subject | 21 | 38 |
Baseline characteristics
| Characteristic | LY2196044 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.92 years STANDARD_DEVIATION 10.62 | 44.79 years STANDARD_DEVIATION 10.08 | 44.85 years STANDARD_DEVIATION 10.34 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 26 participants | 43 participants | 69 participants |
| Race/Ethnicity, Customized Multiple races | 7 participants | 7 participants | 14 participants |
| Race/Ethnicity, Customized Unknown/Missing | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 152 participants | 134 participants | 286 participants |
| Region of Enrollment United States | 187 participants | 188 participants | 375 participants |
| Sex: Female, Male Female | 66 Participants | 66 Participants | 132 Participants |
| Sex: Female, Male Male | 121 Participants | 122 Participants | 243 Participants |
| Years of Alcohol Use | 30.64 years STANDARD_DEVIATION 9.5 | 28.60 years STANDARD_DEVIATION 10.44 | 29.53 years STANDARD_DEVIATION 10.02 |
| Years of Heavy Drinking | 25.06 years STANDARD_DEVIATION 13.2 | 24.83 years STANDARD_DEVIATION 11 | 24.94 years STANDARD_DEVIATION 12.05 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 143 / 187 | 116 / 188 |
| serious Total, serious adverse events | 4 / 187 | 5 / 188 |
Outcome results
Primary
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.
Time frame: Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Percentage of Heavy Drinking Days at Week 16 Endpoint | -43.02 percentage of days | Standard Error 2.09 |
| Placebo | Percentage of Heavy Drinking Days at Week 16 Endpoint | -38.72 percentage of days | Standard Error 2.12 |
p-value: 0.1295% CI: [-9.72, 1.13]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Barratt Impulsivity Scale-11 (BIS-11) Total Score at Week 16 Endpoint | -1.70 units on a scale | Standard Error 0.65 |
| Placebo | Change From Baseline in Barratt Impulsivity Scale-11 (BIS-11) Total Score at Week 16 Endpoint | -2.95 units on a scale | Standard Error 0.69 |
p-value: 0.14295% CI: [-0.42, 2.92]ANCOVA
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Beck Anxiety Inventory (BAI) Total Score at Week 16 Endpoint | -1.98 units on a scale | Standard Error 0.25 |
| Placebo | Change From Baseline in Beck Anxiety Inventory (BAI) Total Score at Week 16 Endpoint | -1.54 units on a scale | Standard Error 0.26 |
p-value: 0.18595% CI: [-1.1, 0.21]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Beck Depression Inventory II (BDI-II) Total Score at Week 16 Endpoint | -3.10 units on a scale | Standard Error 0.28 |
| Placebo | Change From Baseline in Beck Depression Inventory II (BDI-II) Total Score at Week 16 Endpoint | -2.78 units on a scale | Standard Error 0.28 |
p-value: 0.39295% CI: [-1.05, 0.41]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Drinker Inventory of Consequences (DrInC) - Recent Consequences (DrInC-2R) Total Score at Week 16 Endpoint | -16.54 units on a scale | Standard Error 1.09 |
| Placebo | Change From Baseline in Drinker Inventory of Consequences (DrInC) - Recent Consequences (DrInC-2R) Total Score at Week 16 Endpoint | -13.53 units on a scale | Standard Error 1.11 |
p-value: 0.03495% CI: [-5.8, -0.22]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Drinks Per Day at Week 16 Endpoint | -5.37 number of drinks/day | Standard Error 0.22 |
| Placebo | Change From Baseline in Drinks Per Day at Week 16 Endpoint | -4.66 number of drinks/day | Standard Error 0.22 |
p-value: 0.01395% CI: [-1.27, -0.15]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Drinks Per Drinking Day at Week 16 Endpoint | -3.77 number of drinks/drinking day | Standard Error 0.26 |
| Placebo | Change From Baseline in Drinks Per Drinking Day at Week 16 Endpoint | -3.38 number of drinks/drinking day | Standard Error 0.26 |
p-value: 0.24995% CI: [-1.07, 0.28]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Drinks Per Heavy Drinking Day at Week 16 Endpoint | -2.61 number of drinks/heavy drinking day | Standard Error 0.26 |
| Placebo | Change From Baseline in Drinks Per Heavy Drinking Day at Week 16 Endpoint | -2.17 number of drinks/heavy drinking day | Standard Error 0.26 |
p-value: 0.19995% CI: [-1.12, 0.23]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Endicott Work Productivity Scale (EWPS) Total Score at Week 16 Endpoint | -5.67 units on a scale | Standard Error 0.76 |
| Placebo | Change From Baseline in Endicott Work Productivity Scale (EWPS) Total Score at Week 16 Endpoint | -6.13 units on a scale | Standard Error 0.79 |
p-value: 0.63395% CI: [-1.44, 2.36]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Total Score at Week 16 Endpoint | 0.03 units on a scale | Standard Error 0.13 |
| Placebo | Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Total Score at Week 16 Endpoint | -0.54 units on a scale | Standard Error 0.13 |
p-value: <0.00195% CI: [0.24, 0.9]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Obsessive Compulsive Drinking Scale (OCDS) Total Score at Week 16 Endpoint | -8.64 units on a scale | Standard Error 0.51 |
| Placebo | Change From Baseline in Obsessive Compulsive Drinking Scale (OCDS) Total Score at Week 16 Endpoint | -7.96 units on a scale | Standard Error 0.53 |
p-value: 0.31895% CI: [-2.03, 0.66]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2196044 | Change From Baseline in Orthostatic Blood Pressure (BP) at Week 16 Endpoint | Orthostatic Systolic BP | -1.23 mmHg | Standard Error 0.42 |
| LY2196044 | Change From Baseline in Orthostatic Blood Pressure (BP) at Week 16 Endpoint | Orthostatic Diastolic BP | -0.07 mmHg | Standard Error 0.27 |
| Placebo | Change From Baseline in Orthostatic Blood Pressure (BP) at Week 16 Endpoint | Orthostatic Systolic BP | -0.55 mmHg | Standard Error 0.43 |
| Placebo | Change From Baseline in Orthostatic Blood Pressure (BP) at Week 16 Endpoint | Orthostatic Diastolic BP | 0.25 mmHg | Standard Error 0.28 |
p-value: 0.23595% CI: [-1.82, 0.45]Mixed Models Analysis
p-value: 0.495% CI: [-1.05, 0.42]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Orthostatic Pulse Rate at Week 16 Endpoint | 0.65 beats per minute | Standard Error 0.3 |
| Placebo | Change From Baseline in Orthostatic Pulse Rate at Week 16 Endpoint | -0.09 beats per minute | Standard Error 0.31 |
p-value: 0.07795% CI: [-0.08, 1.57]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Percentage of Days Abstinent at Week 16 Endpoint | 33.49 percentage of days | Standard Error 2.05 |
| Placebo | Change From Baseline in Percentage of Days Abstinent at Week 16 Endpoint | 28.12 percentage of days | Standard Error 2.09 |
p-value: 0.05195% CI: [-0.02, 10.77]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in QTc Fridericia's Correction Interval (QTcF) Measured by Electrocardiograms at Week 16 Endpoint | -1.90 milliseconds | Standard Error 0.86 |
| Placebo | Change From Baseline in QTc Fridericia's Correction Interval (QTcF) Measured by Electrocardiograms at Week 16 Endpoint | 0.18 milliseconds | Standard Error 0.9 |
p-value: 0.08195% CI: [-4.41, 0.26]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 16 Endpoint | 2.85 units on a scale | Standard Error 0.56 |
| Placebo | Change From Baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) Total Score at Week 16 Endpoint | 2.08 units on a scale | Standard Error 0.59 |
p-value: 0.29795% CI: [-0.68, 2.22]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2196044 | Change From Baseline in Supine Blood Pressure (BP) at Week 16 Endpoint | Supine Systolic BP | -1.22 millimeters of mercury (mmHg) | Standard Error 0.68 |
| LY2196044 | Change From Baseline in Supine Blood Pressure (BP) at Week 16 Endpoint | Supine Diastolic BP | -1.53 millimeters of mercury (mmHg) | Standard Error 0.43 |
| Placebo | Change From Baseline in Supine Blood Pressure (BP) at Week 16 Endpoint | Supine Systolic BP | -0.45 millimeters of mercury (mmHg) | Standard Error 0.69 |
| Placebo | Change From Baseline in Supine Blood Pressure (BP) at Week 16 Endpoint | Supine Diastolic BP | -1.08 millimeters of mercury (mmHg) | Standard Error 0.44 |
p-value: 0.40995% CI: [-2.62, 1.07]Mixed Models Analysis
p-value: 0.45295% CI: [-1.63, 0.73]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Change From Baseline in Supine Pulse Rate at Week 16 Endpoint | -0.16 beats per minute (bpm) | Standard Error 0.51 |
| Placebo | Change From Baseline in Supine Pulse Rate at Week 16 Endpoint | 0.37 beats per minute (bpm) | Standard Error 0.53 |
p-value: 0.45695% CI: [-1.93, 0.87]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2196044 | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Difficulty to quit and remain abstinent | -1.11 units on a scale | Standard Error 0.28 |
| LY2196044 | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Expectation of success in quitting alcohol | -0.20 units on a scale | Standard Error 0.25 |
| LY2196044 | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Goal related to alcohol use | 0.00 units on a scale | Standard Error 0.17 |
| LY2196044 | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Desire to stop drinking at this time | -0.60 units on a scale | Standard Error 0.2 |
| Placebo | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Goal related to alcohol use | 0.04 units on a scale | Standard Error 0.18 |
| Placebo | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Expectation of success in quitting alcohol | -0.00 units on a scale | Standard Error 0.27 |
| Placebo | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Difficulty to quit and remain abstinent | -0.63 units on a scale | Standard Error 0.3 |
| Placebo | Change From Baseline in Thoughts About Abstinence Scale at Week 16 Endpoint | Desire to stop drinking at this time | -0.11 units on a scale | Standard Error 0.21 |
p-value: 0.6995% CI: [-1.01, 0.04]ANCOVA
p-value: 0.54595% CI: [-0.85, 0.45]ANCOVA
p-value: 0.1995% CI: [-1.2, 0.24]ANCOVA
p-value: 0.85695% CI: [-0.49, 0.4]ANCOVA
Secondary
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.
Time frame: Baseline through Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2196044 | Number of Participants With Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar)≥10 at Any Time From Baseline Through Week 16 Endpoint | 0 participants |
| Placebo | Number of Participants With Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar)≥10 at Any Time From Baseline Through Week 16 Endpoint | 0 participants |
Secondary
Percentage of Participants Discontinuation Due to Adverse Events (AEs)
Percentage of participants discontinued study due to one or more AEs.
Time frame: Baseline through Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2196044 | Percentage of Participants Discontinuation Due to Adverse Events (AEs) | 7.5 percentage of participants |
| Placebo | Percentage of Participants Discontinuation Due to Adverse Events (AEs) | 3.7 percentage of participants |
p-value: 0.122Fisher Exact
Secondary
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.
Time frame: Baseline through Week 16
Population: Participants who took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2196044 | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | 76.5 percentage of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | 61.7 percentage of participants |
p-value: 0.002Fisher Exact
Secondary
Population Pharmacokinetic (PK) - Apparent Clearance
Plasma concentrations were analyzed using population PK methodology with non-linear mixed effect modeling (NONMEM) software.
Time frame: Over 16 weeks
Population: Participants who took study drug and contributed PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Population Pharmacokinetic (PK) - Apparent Clearance | 36.5 Liter/hour (L/hr) | Standard Error 3.97 |
Secondary
Population Pharmacokinetic (PK) - Apparent Volume of Distribution
Plasma concentrations were analyzed using population PK methodology with non-linear mixed effect modeling (NONMEM) software.
Time frame: Over 16 weeks
Population: Participants who took study drug and contributed PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Population Pharmacokinetic (PK) - Apparent Volume of Distribution | 587 Liter (L) | Standard Error 8.38 |
Secondary
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.
Time frame: Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Ratio of Geometric Means Over Baseline in Aspartate Transaminase (AST) Level at Week 16 Endpoint | 0.88 ratio | Standard Error 0.02 |
| Placebo | Ratio of Geometric Means Over Baseline in Aspartate Transaminase (AST) Level at Week 16 Endpoint | 0.94 ratio | Standard Error 0.02 |
p-value: 0.01295% CI: [0.89, 0.99]Mixed Models Analysis
Secondary
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.
Time frame: Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Ratio of Geometric Means Over Baseline in Gamma-Glutamyltransferase (GGT) Level at Week 16 Endpoint | 0.85 ratio | Standard Error 0.02 |
| Placebo | Ratio of Geometric Means Over Baseline in Gamma-Glutamyltransferase (GGT) Level at Week 16 Endpoint | 0.94 ratio | Standard Error 0.02 |
p-value: 0.00195% CI: [0.85, 0.96]Mixed Models Analysis
Secondary
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.
Time frame: Week 16
Population: Participants with a baseline and post-baseline value.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2196044 | Ratio of Geometric Means Over Baseline in Percent Carbohydrate-Deficient Transferrin (%CDT) Level at Week 16 Endpoint | 0.90 ratio | Standard Error 0.02 |
| Placebo | Ratio of Geometric Means Over Baseline in Percent Carbohydrate-Deficient Transferrin (%CDT) Level at Week 16 Endpoint | 0.94 ratio | Standard Error 0.02 |
p-value: 0.10395% CI: [0.91, 1.01]Mixed Models Analysis