A Study of LY2216684 in Major Depressive Disorder in Patients Taking Selective Serotonin Reuptake Inhibitors

Study Overview
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Brief Summary
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The purpose of this study is to determine the effect of LY2216684 on heart rate and blood pressure in research participants with MDD who are being treated with an SSRI (selective serotonin reuptake inhibitors). Information about any side effects that may occur will also be collected. The duration of participation in this study is approximately 24 days not including the screening visit. This study requires 1 clinic confinement of 17 days/16 nights and 1 Follow-up Outpatient Visit. A screening visit is required within 30 days prior to the start of the study. In both periods 1 and 2, the study involves 4 single daily doses of 18 mg LY2216684 or placebo taken as 2 tablets by mouth. In period 3, the study involves four single daily doses of 36 mg LY2216684 or placebo taken as 4 tablets by mouth.

Official Title
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Effect of LY2216684 on Ambulatory Heart Rate and Blood Pressure in Patients With Major Depressive Disorder Who Are Being Treated With Selective Serotonin Reuptake Inhibitors

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: LY2216684
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are patients that have been diagnosed with major depressive disorder (MDD) and are on a stable dose of an selective serotonin reuptake inhibitor (SSRI) for at least 4 weeks prior to enrollment, as determined by medical history and physical examination. Male patients: Agree to use a reliable method of birth control during the study and for 3 months following the last dose of study drug. Female patients: Are 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; or Women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause for at least 1 year without menses or 6 months without menses and a follicle stimulating hormone (FSH) >40 milli-international-units/milliliter (mIU/mL). Have a body mass index (BMI) of up to 32.0 kilogram/squaremeter (kg/m2). Have normal blood pressure (BP) and pulse rate (systolic BP <140, diastolic BP <90; supine position and standing) as determined by the investigator. Patients that have a diagnosis of hypertension but are well controlled on a stable dose (at least 4 weeks of diuretic, angiotensin converting enzyme [ACE]-inhibitor, or angiotensin 2 receptor inhibitor) are acceptable for inclusion in this study. Allowance of a specific anti-hypertensive is per the investigator's discretion. Have screening 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 blood sampling as per the protocol. 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. Exclusion Criteria: Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device 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 any compound related to LY2216684. Are persons who have previously completed or withdrawn from this study or any other study investigating LY2216684. Have a clinically significant 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 significant history of or presence of cardiovascular (including dysrhythmias), respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders, or any condition 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 unequal BP (> 20 millimeter of mercury [mm Hg]) in the left arm versus right arm (as measured with a BP cuff) or have absent or unequal radial pulses in either arm. Have a history of seizure disorders. Regularly use known drugs of abuse and/or show positive findings on urinary drug screening. Show evidence of human immunodeficiency virus (HIV) and/or positive human 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. Are women with a positive pregnancy test or women who are lactating. Use of over-the-counter or prescription medication (other than stable doses of SSRI as noted above) with a narrow therapeutic index (including, but not limited to warfarin or clopidogrel) or those that are known to have an effect on heart rate (e.g., beta-blockers) within 14 days prior to dosing. Use of any drugs or substances that are known to be a strong inducer or inhibitor of cytochrome P450 2D6 (CYP2D6) or cytochrome P450 3A4 (CYP3A4) within 30 days prior to check-in (study entry) and during the conduct of the study. Have donated blood of more than 500 milliliter (mL) within 4 weeks prior to screening. Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption 48 hours prior to check-in (study entry)until the completion of the study (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 any patients unwilling to adhere to study caffeine restrictions. Patients must adhere to the smoking restrictions of the Clinical Research Unit (CRU) while a resident of the CRU. Have consumed grapefruit or grapefruit-containing products 7 days prior to enrollment or are unwilling to avoid during the study. Have a documented or suspected history of glaucoma. Patients determined to be unsuitable by the investigator for any reason.

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2216684, placebo, LY or placebo<br>Period 1: 18 milligrams (mg) LY2216684 administered orally once daily on Days 1-4 Period 2: placebo administered orally once daily on Days 1-4 Period 3: 36 mg LY2216684 or placebo administered orally daily on Days 1-4 | Drug: LY2216684<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: Placebo, LY2216684, placebo or LY<br>Period 1: placebo administered orally once daily on Days 1-4 Period 2: 18 mg LY2216684 administered orally once daily on Days 1-4 Period 3: 36 mg LY2216684 or placebo administered orally daily on Days 1-4 | Drug: LY2216684<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum and Mean Change From Baseline in Ambulatory Heart Rate on Day 1 | Heart rate was determined during ambulatory blood pressure monitoring (ABPM). Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Maximum and mean changes in ABPM heart rate were determined from a 24-hour continuous ABPM monitoring for Day 1 (0 to 24 hours). Least Squares (LS) mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 1 | 
| Maximum and Mean Change From Baseline in Ambulatory Heart Rate on Day 4 | Heart rate was determined during ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Maximum and mean changes in ABPM heart rate were determined from 24 hour continuous ABPM monitoring for Day 4 (0 to 24 hours). LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum and Mean Change From Baseline in Ambulatory Systolic and Diastolic Blood Pressure During Treatment With 18-mg LY2216684 or Placebo on Day 1 | Blood pressure (BP) was determined with ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Changes in ABPM BP were determined from a 24-hour continuous ABPM monitoring for Day 1. LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 1 | 
| Maximum and Mean Change From Baseline in Ambulatory Systolic and Diastolic Blood Pressure During Treatment With 18-mg LY2216684 or Placebo on Day 4 | BP was determined with ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Changes in ABPM BP were determined from a 24-hour continuous ABPM monitoring for Day 4. LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 4 | 
| Maximum and Mean Change From Baseline in ABPM Heart Rate During Treatment With 36-mg LY2216684 or Placebo on Day 4 | Heart rate was determined with ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Changes in ABPM heart rate were determined from a 24-hour continuous ABPM monitoring for Day 4. LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 4 | 
| Maximum and Mean Change From Baseline in ABPM Systolic and Diastolic Blood Pressure During Treatment With 36-mg LY2216684 or Placebo on Day 4 | BP was determined with ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Changes in ABPM BP were determined from a 24-hour continuous ABPM monitoring for Day 4. LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 4 | 
| Maximum and Mean Change From Baseline in ABPM Heart Rate During Treatment With 18-mg LY2216684 or 36-mg LY2216684 on Day 4 | Heart rate was determined with ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Changes in ABPM heart rate were determined from a 24-hour continuous ABPM monitoring for Day 4. LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 4 | 
| Maximum and Mean Change From Baseline in ABPM Systolic and Diastolic Blood Pressure During Treatment With 18-mg LY2216684 or 36-mg LY2216684 on Day 4 | BP was determined with ABPM. Mean pre-dose ABPM values from Day 1 in Period 1 were used as baseline. Changes in ABPM BP were determined from a 24-hour continuous ABPM monitoring for Day 4. LS mean changes from baseline were calculated with a mixed effects model including sequence, period, study day, treatment groups, and interaction between treatment groups and study day as fixed effects, and subject as random effect. | Baseline through the 24-hour interval on Day 4 |