Major Depressive Disorder
Conditions
Brief summary
LY2216684 is being studied as adjunctive treatment for major depressive disorder (MDD) in participants who are partial responders to selective serotonin reuptake inhibitors (SSRIs). Sertraline is a medication that is widely used to treat MDD and is a known substrate of cytochrome P450s (CYP450s), including CYP450 2D6 (CYP2D6), CYP450 2C19 (CYP2C19), CYPP450 3A4 (CYP3A4), and a modest inhibitor of CYP2D6. Based on the diversity of hepatic metabolic clearance pathways for LY2216684 and its elimination by the kidney, it is expected that CYP2D6 inhibition by sertraline will not result in a substantial change in the pharmacokinetic (PK) profile of LY2216684. LY2216684 is only known to be a moderate inhibitor of CYP2C19, so it is unlikely that coadministration of sertraline with LY2216684 will result in a clinically meaningful change in the PK of sertraline. This study is being conducted to test these hypotheses.
Interventions
DRUGLY2216684
po administration
DRUGSertraline
po administration
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Are overtly healthy as determined by medical history and physical examination. * Male participants - Agree to use a reliable method of birth control during the study and for 3 months following the last dose of study drug. * Female participants - 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 + 1 month following the last dose of study drug; or are women not of child-bearing potential due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation) or menopause (at least 1 year without menses or 6 months without menses and a follicle stimulating hormone (FSH) level ≥40 mass International Units per milliliter (mIU/mL). * Body mass index (BMI) up to 32.0 kilograms per square meter (kg/m\^2). * 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 according to the protocol. * Have normal blood pressure and pulse rate (supine position and standing) as determined by the investigator. * Are reliable and willing to be available for the duration of the study and willing to follow study procedures. * Provided 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/intolerance to LY2216684, sertraline, or related compounds. * Are persons who previously completed or discontinued from this study, or any other study investigating LY2216684 within 6 months prior to screening. * Have a clinically significant abnormality in the 12-lead electrocardiogram (ECG) as determined by the investigator. * Have significant history of or current cardiovascular (including dysrhythmias), respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders 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 of seizure disorders. * Have a history or presence of the signs and/or symptoms of hyponatremia. * Have a history or presence of the signs and/or symptoms of hyperthyroidism as determined by an abnormal thyroid stimulating hormone (TSH) at screening. * Have a history or presence of the signs and/or symptoms of urinary retention or benign prostatic hypertrophy. * Show evidence of significant active neuropsychiatric disease or a history of suicidal thoughts or suicide attempt. * 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. * Intend to use over-the-counter or prescription medication within 14 days prior to dosing unless deemed acceptable by the investigator and sponsor's medical monitor. * Have donated blood of more than 500 milliliters (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 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 participants unwilling to adhere to study caffeine restrictions. * Have used any tobacco-containing or nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to enrollment. * Have consumed grapefruit or grapefruit-containing products 7 days prior to enrollment and during the study. * Have a documented or suspected history of glaucoma. * Participants determined to be unsuitable by the investigator for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of LY2216684 | 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 3 and Day 13 | The Least Squares (LS) geometric mean AUCτ of LY2216684 was calculated based on the LY2216684 plasma concentration time curve from time 0 hour (hr) to time 24 hr (tau \[τ\]) when LY221684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The Day 13-to-Day 3 ratio of the LY2216684 LS geometric mean of AUCτ and the associated 90% confidence interval (CI) of the ratio were calculated. |
| Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of LY2216684 | 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 3 and Day 13 | The Least Squares (LS) geometric mean Cmax of LY2216684 was determined when LY2216684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The Day 13-to-Day 3 ratio of the LY2216684 LS geometric mean of Cmax and the associated 90% confidence interval (CI) of the ratio were calculated. |
| Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of LY2216684 | 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 3 and Day 13 | Tmax of LY2216684 was determined using the median of paired differences between the 2 treatment groups when LY2216684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The 90% confidence interval (CI) for the median of differences was calculated. |
| Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of Sertraline | 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 10 and Day 13 | The Least Squares (LS) geometric mean AUCτ of sertraline was calculated based on the sertraline plasma concentration time curve from time 0 hour (hr) to time 24 hr (tau \[τ\]) when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The Day 13-to-Day 10 ratio of the sertraline LS geometric mean of AUCτ and the associated 90% confidence interval (CI) of the ratio were calculated. |
| Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Sertraline | 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 10 and Day 13 | The Least Squares (LS) geometric mean Cmax of sertraline was determined when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The Day 13-to-Day 10 ratio of the sertraline LS geometric mean of Cmax and the associated 90% confidence interval (CI) of the ratio were calculated. |
| Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of Sertraline | 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 10 and Day 13 | Tmax of sertraline was determined using the median of paired differences between the 2 treatment groups when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The 90% confidence interval (CI) for the median of differences was calculated. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline Period 1: LY2216684 18 milligram (mg) oral (po) dose on Days 1-3; Period 2: Sertraline 50 mg po dose on Day 4 followed by sertraline 100 mg po dose on Days 5-10; Period 3: LY2216684 18 mg po dose + sertraline 100 mg po dose on Days 11-13. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 1: LY2216684 (Days 1-3) | Adverse Event | 2 |
| Period 3:LY2216684+Sertraline(Days11-13) | Adverse Event | 1 |
Baseline characteristics
| Characteristic | LY2216684/Sertraline/LY2216684 + Sertraline |
|---|---|
| Age, Continuous | 37.8 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 20 | 6 / 18 | 13 / 18 |
| serious Total, serious adverse events | 0 / 20 | 0 / 18 | 0 / 18 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of LY2216684
The Least Squares (LS) geometric mean AUCτ of LY2216684 was calculated based on the LY2216684 plasma concentration time curve from time 0 hour (hr) to time 24 hr (tau \[τ\]) when LY221684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The Day 13-to-Day 3 ratio of the LY2216684 LS geometric mean of AUCτ and the associated 90% confidence interval (CI) of the ratio were calculated.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 3 and Day 13
Population: The safety population included participants who were randomized, received study drug, and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of LY2216684 | LY2216684 alone | 675 hour*nanogram per milliliter (h*ng/mL) |
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of LY2216684 | LY2216684 + sertraline | 792 hour*nanogram per milliliter (h*ng/mL) |
90% CI: [1.06, 1.3]ANOVA
Primary
Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of Sertraline
The Least Squares (LS) geometric mean AUCτ of sertraline was calculated based on the sertraline plasma concentration time curve from time 0 hour (hr) to time 24 hr (tau \[τ\]) when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The Day 13-to-Day 10 ratio of the sertraline LS geometric mean of AUCτ and the associated 90% confidence interval (CI) of the ratio were calculated.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 10 and Day 13
Population: The safety population included participants who were randomized, received study drug, and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of Sertraline | sertraline alone | 1240 hour*nanogram per milliliter (h*ng/mL) |
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-Time Curve Over a 24-Hour Dosing Interval (AUCτ) of Sertraline | sertraline + LY2216684 | 1570 hour*nanogram per milliliter (h*ng/mL) |
90% CI: [1.17, 1.39]ANOVA
Primary
Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of LY2216684
The Least Squares (LS) geometric mean Cmax of LY2216684 was determined when LY2216684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The Day 13-to-Day 3 ratio of the LY2216684 LS geometric mean of Cmax and the associated 90% confidence interval (CI) of the ratio were calculated.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 3 and Day 13
Population: The safety population included participants who were randomized, received study drug, and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of LY2216684 | LY2216684 alone | 65.9 nanogram per milliliter (ng/mL) |
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of LY2216684 | LY2216684 + sertraline | 74.9 nanogram per milliliter (ng/mL) |
90% CI: [1.01, 1.28]ANOVA
Primary
Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Sertraline
The Least Squares (LS) geometric mean Cmax of sertraline was determined when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The Day 13-to-Day 10 ratio of the sertraline LS geometric mean of Cmax and the associated 90% confidence interval (CI) of the ratio were calculated.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 10 and Day 13
Population: The safety population included participants who were randomized, received study drug, and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Sertraline | sertraline alone | 70.7 nanogram per milliliter (ng/mL) |
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Sertraline | sertraline + LY2216684 | 86.4 nanogram per milliliter (ng/mL) |
90% CI: [1.1, 1.36]ANOVA
Primary
Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of LY2216684
Tmax of LY2216684 was determined using the median of paired differences between the 2 treatment groups when LY2216684 was administered alone (Day 3) and when LY2216684 was coadministered with sertraline (Day 13). The 90% confidence interval (CI) for the median of differences was calculated.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 3 and Day 13
Population: The safety population included participants who were randomized, received study drug, and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of LY2216684 | LY2216684 alone | 2.00 hours |
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of LY2216684 | LY2216684 + sertraline | 3.00 hours |
p-value: 0.828190% CI: [-0.5, 1]Wilcoxon (Mann-Whitney)
Primary
Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of Sertraline
Tmax of sertraline was determined using the median of paired differences between the 2 treatment groups when sertraline was administered alone (Day 10) and when sertraline was coadministered with LY2216684 (Day 13). The 90% confidence interval (CI) for the median of differences was calculated.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 10 and Day 13
Population: The safety population included participants who were randomized, received study drug, and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of Sertraline | sertraline alone | 6.00 hours |
| LY2216684/Sertraline/LY2216684 + Sertraline | Pharmacokinetic (PK) Parameter: Time to Maximum Plasma Concentration (Tmax) of Sertraline | sertraline + LY2216684 | 8.00 hours |
p-value: 0.312590% CI: [0, 2]Wilcoxon (Mann-Whitney)