A Study of LY2216684 in Healthy Participants

Study Overview
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Brief Summary
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This study will evaluate the pharmacodynamic and pharmacokinetic interaction of LY2216684 with alcohol in healthy participants. This study will run approximately for 34 days.

Official Title
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A Study to Investigate the Pharmacodynamic and Pharmacokinetic Interaction of LY2216684 With Alcohol in Healthy Subjects

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: LY2216684
* Drug: Placebo-matching LY2216684
* Drug: Placebo-matching alcoholic beverage
* Drug: Alcoholic beverage


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overtly healthy male or female participants, as determined by medical history and physical examination Male participants: Agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug Female participants: Women of child-bearing potential who test negative for pregnancy at the time of enrollment, have used a reliable method of birth control for 6 weeks prior to administration of study drug, and agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug (hormonal methods of contraception, including oral and implantable contraceptives, are not allowed in this study) or women who are not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or due to menopause (at least 1 year without menses or 6 months without menses and a follicle stimulating hormone [FSH] >40 milli-international units/milliliter [mIU/mL]) Male and female participants: Examples of reliable methods of birth control include double-barrier methods (for example, condom and spermicide) alone or in combination with vasectomy, vasectomized partners, and abstinence. Have a body weight >50 kilogram (kg) Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator Have venous access sufficient to allow for blood sampling Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures Have given written informed consent approved by Lilly and the institutional review board (IRB) governing the site Have normal blood pressure and pulse rate (in sitting position) as determined by the investigator Exclusion Criteria: Are currently enrolled in or have completed or discontinued within the last 30 days from a clinical trial involving an investigational product other than the study drug used in this study; or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have known allergies to LY2216684, related compounds or any components of the formulation Are persons who have previously received the investigational product in this study or have completed or withdrawn from this study or any other study investigating LY2216684 within 6 months prior to Screening Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study. Have a history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders that are capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data Have a history or show evidence of significant active neuropsychiatric disease or have a history of suicide attempt or ideation Regularly use known drugs of abuse and/or show positive findings on urinary drug screening Participants with a past history of alcohol dependence/abuse Show evidence of human immunodeficiency virus (HIV) infection and/or positive HIV antibodies Show evidence of hepatitis C and/or positive hepatitis C antibody Show evidence of hepatitis B and/or positive hepatitis B surface antigen Women with a positive pregnancy test or women who are lactating Intend to use over-the-counter or prescription medication within 14 days prior to dosing or during the study unless deemed acceptable by the investigator and Sponsor's medical monitor, except for influenza vaccinations Have donated blood of more than 500 milliliter (mL) within the last month Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption 48 hours prior to each study period and while resident at the Clinical Research Unit (CRU) (except as required per this protocol); (1 unit = 12 ounces [oz] or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits) Consume 5 or more cups of coffee (or other beverages of comparable caffeine content) per day, on a habitual basis, or are unwilling to adhere to study caffeine restrictions Have consumed grapefruit or grapefruit-containing products 7 days prior to enrollment or are unwilling to abstain during the study Have a documented or suspected history of glaucoma Participants with known or suspected alcohol dehydrogenase deficiency Participants who do not drink alcohol and/or are not willing to drink 4 units of alcohol over a 15-minute period Participants determined to be unsuitable by the investigator for any reason

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY, Alc, Pl-Match Alc, Then Pl-Match LY, Alc, Pl-Match Alc<br>Period 1: 18 milligrams (mg) LY2216684 (LY) administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic (Alc) beverage (with an alcohol dose of 0.6 grams per kilograms [g/kg] for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching (Pl-Match) alcoholic beverage, taken orally, one time. Period 2: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. There was a 7-day washout period between Periods 1 and 2. | Drug: LY2216684<br>* Administered orally<br>* Other names: Edivoxetine;Drug: Placebo-matching LY2216684<br>* Administered orally<br>Drug: Placebo-matching alcoholic beverage<br>* Administered orally<br>Drug: Alcoholic beverage<br>* Administered orally<br>|
| Experimental: Pl-Match LY, Alc, Pl-Match Alc, Then LY, Alc, Pl-Match Alc<br>Period 1: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. Period 2: 18 mg LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. On Day 8, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. There was a 7-day washout period between Periods 1 and 2. | Drug: LY2216684<br>* Administered orally<br>* Other names: Edivoxetine;Drug: Placebo-matching LY2216684<br>* Administered orally<br>Drug: Placebo-matching alcoholic beverage<br>* Administered orally<br>Drug: Alcoholic beverage<br>* Administered orally<br>|
| Experimental: LY, Pl-Match Alc, Alc, Then Pl-Match LY, Pl-Match Alc, Alc<br>Period 1: 18 mg LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. Period 2: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. There was a 7-day washout period between Periods 1 and 2. | Drug: LY2216684<br>* Administered orally<br>* Other names: Edivoxetine;Drug: Placebo-matching LY2216684<br>* Administered orally<br>Drug: Placebo-matching alcoholic beverage<br>* Administered orally<br>Drug: Alcoholic beverage<br>* Administered orally<br>|
| Experimental: Pl-Match LY, Pl-Match Alc, Alc, Then LY, Pl-Match Alc, Alc<br>Period 1: Placebo-matching LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. Period 2: 18 mg LY2216684 administered orally, once daily for 8 days. On Day 6, participants were administered 2 cups of a placebo-matching alcoholic beverage, taken orally, one time. On Day 8, participants were administered 2 cups of an alcoholic beverage (with an alcohol dose of 0.6 g/kg for women and 0.7 g/kg for men), taken orally, one time. There was a 7-day washout period between Periods 1 and 2. | Drug: LY2216684<br>* Administered orally<br>* Other names: Edivoxetine;Drug: Placebo-matching LY2216684<br>* Administered orally<br>Drug: Placebo-matching alcoholic beverage<br>* Administered orally<br>Drug: Alcoholic beverage<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 10 Hours in Power of Attention Composite Score | Power of attention is a measure of focused attention and information processing speed; based on the summed reaction times from the simple reaction time, choice reaction time, and digit vigilance tasks. Scores are measured by response latencies, and smaller scores indicate better function. Least squares (LS) means were calculated using mixed model analysis of covariance (ANCOVA) adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 10 hours | 
| Change From Baseline to 10 Hours in Continuity of Attention Composite Score | Continuity of attention is a measure of sustained attention, combining (summed) accuracy and error measures from the choice reaction time and digit vigilance tasks. The number of correct responses (out of 50) for choice reaction time was added to the total number of targets correctly identified (out of 45) digit vigilance minus the number of false alarms (total score of -45 to 95). A high score reflects someone able to keep his/her mind on a single task for a prolonged period. A negative change from baseline reflects impairment compared to baseline. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 10 hours | 
| Change From Baseline to 10 Hours in Postural Stability | The ability to stand upright without moving was assessed using equipment modeled on the Wright Ataxia-meter. To measure movements, a cord was attached to the participant who was required to stand for one minute, as still as possible, with feet apart and eyes closed. The amount of sway is expressed as the total angular movement calibrated in units of one-third degree of angle of sway. The amount of sway is expressed as the total angular movement in the antero-posterior plane and calibrated in units of one-third degree of angle of sway. Higher result indicates better postural stability. A negative change from baseline reflects impairment compared to baseline. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 10 hours | 
| Change From Baseline to 10 Hours in Self-Rated Alertness | Assessed via the Bond and Lader Visual Analogue Scale (VAS), which utilizes a 16-point scale of 0 to 100 with 0 representing the worst rating and 100 representing the best rating. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 10 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Observed Maximum Plasma Concentration (Cmax) of LY2216684 |  | Predose through 24 hours postdose | 
| Pharmacokinetics: Observed Cmax of Alcohol |  | Predose through 24 hours postdose | 
| Pharmacokinetics: Observed Time to Maximum Plasma Concentration (Tmax) of LY2216684 |  | Predose through 24 hours postdose | 
| Pharmacokinetics: Observed Tmax of Alcohol |  | Predose through 24 hours postdose | 
| Pharmacokinetics: Area Under the Concentration Time Curve Over a Dosing Interval (AUCt) of LY2216684 |  | Predose through 24 hours postdose | 
| Pharmacokinetics: Area Under the Concentration Time Curve From Time Zero to the Last Time Point With a Measurable Concentration (AUC[0-tlast]) of Alcohol |  | Predose through 12 hours postdose | 
| Change From Baseline to 1, 2, 3, 4.5, 6, 8, and 10 Hours in Working Memory | Working memory is a sum of accuracy measures from the numeric and spatial working memory tasks known as the sensitivity index (SI). Working Memory SI is based on how fast the participant responds correctly and how many are correct responses. SI ranging from zero (chance performance) to one (perfect accuracy). A high score reflects someone able to hold in memory for a prolonged period. A negative change from baseline reflects impairment compared to baseline. A series of 5 digits were presented on a computer screen, every second, for the participant to hold in memory. Followed by 30 probe digits, the participant had to decide whether it appeared in the original series by responding with 'Yes' or 'No'. This was repeated 2 times using different series and probes. LS mean was calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 1, 2, 3, 4.5, 6, 8, and 10 hours | 
| Change From Baseline to 1, 2, 3, 4.5, 6, 8, and 10 Hours in Episodic Memory | Episodic memory is based on how accurate the participant responds using the measures from immediate word recall (range 0-15), delayed word recall (range 0-15), word recognition (range 0-15), and picture recognition (range 0-20) tasks. The sum of four the accuracy scores, are summed, and averaged to provide a composite score (range 0-37.5). This composite score reflects the ability to store, hold, and retrieve information of an episodic nature (such as an event, a name, an object, a scene, or an appointment). A high score reflects someone able to recall memory for a prolonged period. A negative change from baseline reflects impairment compared to baseline. LS mean was calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 1, 2, 3, 4.5, 6, 8, and 10 hours | 
| Change From Baseline to 1, 2, 3, 4.5, 6, 8, and 10 Hours in Speed of Retrieval of Information From Memory | Speed of retrieval is a measure of complex information processing speed, summing reaction times from the two working memory (numeric and spatial) tasks and the two episodic recognition (word recognition and picture recognition) tasks. This composite score reflects the time it takes to decide correctly whether an item is held in working memory or episodic secondary memory.Scores are measured by response latencies, and smaller scores indicate better function. A negative change from baseline reflects impairment compared to baseline. LS means calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 1, 2, 3, 4.5, 6, 8, and 10 hours | 
| Change From Baseline to 1, 2, 3, 4.5, 6, 8, and 10 Hours in Self-Ratings of Calmness and Contentment | Assessed via the Bond and Lader Visual Analogue Scale (VAS), which utilizes a 16-point scale of 0 to 100 with 0 representing the worst rating and 100 representing the best rating. LS means were calculated using mixed model ANCOVA adjusting for predose, sequence, period, day, time, treatment, and treatment*time as fixed effects and participant within sequence and treatment as random effect. | Baseline, 1, 2, 3, 4.5, 6, 8, and 10 hours |