Depressive Disorder, Major
Conditions
Brief summary
This study involves a single dose of 18 milligrams (mg) LY2216684 taken as 1 or 2 tablets by mouth. The study will evaluate effect of LY2216684 on the pharmacokinetics of an oral contraceptive Ortho Cyclen®. This study will run approximately 93 days.
Interventions
DRUGLY2216684
Administered orally
DRUGOrtho Cyclen
35 micrograms (mcg) ethinyl estradiol and 250 mcg norgestimate administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Are overtly healthy females, as determined by medical history and physical examination * As it is possible that LY2216684 may cause the oral contraceptive tablet to be less effective than usual, participants will be required in addition to use double barrier methods of contraception from the Screening until 2 months after the post study follow-up. Additional barrier methods of contraception may include the following: a non-hormonal intrauterine device with spermicide; female condom with spermicide; contraceptive sponge with spermicide; diaphragm with spermicide; cervical cap with spermicide; a male sexual partner who agrees to use a male condom with spermicide; a sterile sexual partner; or abstinence (participants reporting abstinence who become sexually active while on the study must agree to use other additional barrier methods of contraception). The pregnancy test result must be negative at Screening and at each Check-in * Have a body weight of \>50 kilograms (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 as per the protocol * Have normal blood pressure and pulse rate (sitting position) as determined by the investigator * 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, have completed or discontinued within the last 30 days from, a clinical trial involving an investigational product other than the investigational product 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 Ortho Cyclen, LY2216684, or related compounds * Are participants who have previously 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 or presence of cardiovascular, 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 or show evidence of significant active neuropsychiatric disease or have a history or suicide attempt or ideation * Regular use of known drugs of abuse and/or show positive findings on urinary drug screening * Show evidence of human immunodeficiency virus infection (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 (other than the acceptable oral contraceptive allowed in this study and influenza vaccinations) within 14 days prior to dosing unless deemed acceptable by the investigator and sponsor's medical monitor * Have donated blood of more than 500 milliliter (mL) prior to lead-in phase Check-in (Day -1) * Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption for 48 hours prior to each Check-in to the clinical research unit (CRU) \[1 unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits\] * 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 * Use of any tobacco- 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 the lead-in phase Check-in (Day -1) and during the study * Have consumed grapefruit, starfruit, pomegranates, or products containing those items 7 days prior to enrollment or are unwilling to avoid them during the study * Have a documented or suspected history of glaucoma * Participants that have taken injectable contraceptives within 12 months of enrollment to this study or topical controlled delivery contraceptives (patch) for 3 months prior to enrollment into this study * The history or presence of any contraindications to the combined oral contraceptive tablet including thrombosis and the history of any thromboembolic disease, recurrent jaundice, acute or chronic liver disease, migraines, undiagnosed vaginal bleeding, significant hyperlipidemia, and mammary, endometrial, or hepatic carcinoma (known or suspected) * Participants determined to be unsuitable by the investigator for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norelgestromin | Predose up to 24 hours post dose on Day 21 | The results presented are Geometric Least Squares (LS) mean. LS mean values were adjusted for treatment, sequence, period and participant. |
| Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norelgestromin | Predose up to 24 hours post dose on Day 21 | — |
| Area Under the Concentration-Time Curve Over a Dosing Interval (AUCτ) of Ethinyl Estradiol and Norelgestromin | Predose up to 24 hours post dose on Day 21 | The results presented are Geometric Least Squares (LS) mean. LS mean values were adjusted for treatment, sequence, period and participant. |
Countries
United States
Participant flow
Pre-assignment details
This was a randomized, 2-period, 2-sequence crossover study with a lead-in period.
Participants by arm
| Arm | Count |
|---|---|
| OC + LY2216684 / OC + Placebo Lead-in Period: 28 days of Ortho Cyclen \[OC; 21 days of 35 micrograms (mcg) ethinyl estradiol and 250 mcg norgestimate and 7 days of OC placebo\]
Period 1: OC + 18 milligrams (mg) of LY2216684 administered concomitantly orally, once daily for 21 days and 7 days of OC placebo
Period 2: OC + LY2216684 placebo administered concomitantly orally, once daily for 21 days and 7 days of OC placebo | 10 |
| OC + Placebo / OC + LY2216684 Lead-in Period: 28 days of OC (21 days of 35 mcg ethinyl estradiol and 250 mcg norgestimate and 7 days of OC placebo)
Period 1: OC + LY2216684 placebo administered concomitantly orally, once daily for 21 days and 7 days of OC placebo
Period 2: OC + 18 mg of LY2216684 administered concomitantly orally, once daily for 21 days and 7 days of OC placebo | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Lead-in Period | Adverse Event | 2 | 0 |
| Period 1 | Adverse Event | 2 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | OC + LY2216684 / OC + Placebo | Total | OC + Placebo / OC + LY2216684 |
|---|---|---|---|
| Age, Continuous | 29.6 years STANDARD_DEVIATION 8.9 | 30.2 years STANDARD_DEVIATION 9.2 | 30.7 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 17 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 17 Participants | 8 Participants |
| Region of Enrollment United States | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Female | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 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 | 12 / 18 | 13 / 16 | 13 / 16 |
| serious Total, serious adverse events | 0 / 18 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Concentration-Time Curve Over a Dosing Interval (AUCτ) of Ethinyl Estradiol and Norelgestromin
The results presented are Geometric Least Squares (LS) mean. LS mean values were adjusted for treatment, sequence, period and participant.
Time frame: Predose up to 24 hours post dose on Day 21
Population: All randomized participants who received at least 1 dose of study drug and had pharmacokinetics data to analyze AUCτ. Participants were analyzed based on the treatment they received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| OC + LY2216684 | Area Under the Concentration-Time Curve Over a Dosing Interval (AUCτ) of Ethinyl Estradiol and Norelgestromin | Ethinyl Estradiol | 888 picograms*hour/milliliter (pg*hr/mL) |
| OC + LY2216684 | Area Under the Concentration-Time Curve Over a Dosing Interval (AUCτ) of Ethinyl Estradiol and Norelgestromin | Norelgestromin | 16156 picograms*hour/milliliter (pg*hr/mL) |
| OC + Placebo | Area Under the Concentration-Time Curve Over a Dosing Interval (AUCτ) of Ethinyl Estradiol and Norelgestromin | Ethinyl Estradiol | 827 picograms*hour/milliliter (pg*hr/mL) |
| OC + Placebo | Area Under the Concentration-Time Curve Over a Dosing Interval (AUCτ) of Ethinyl Estradiol and Norelgestromin | Norelgestromin | 16079 picograms*hour/milliliter (pg*hr/mL) |
90% CI: [1, 1.15]Mixed Models Analysis
90% CI: [0.944, 1.07]Mixed Models Analysis
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norelgestromin
The results presented are Geometric Least Squares (LS) mean. LS mean values were adjusted for treatment, sequence, period and participant.
Time frame: Predose up to 24 hours post dose on Day 21
Population: All randomized participants who received at least 1 dose of study drug and had pharmacokinetics data to analyze Cmax. Participants were analyzed based on the treatment they received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| OC + LY2216684 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norelgestromin | Ethinyl Estradiol | 79.0 picograms/milliliter (pg/mL) |
| OC + LY2216684 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norelgestromin | Norelgestromin | 1438 picograms/milliliter (pg/mL) |
| OC + Placebo | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norelgestromin | Ethinyl Estradiol | 80.9 picograms/milliliter (pg/mL) |
| OC + Placebo | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Ethinyl Estradiol and Norelgestromin | Norelgestromin | 1574 picograms/milliliter (pg/mL) |
90% CI: [0.907, 1.05]Mixed Models Analysis
90% CI: [0.842, 0.991]Mixed Models Analysis
Primary
Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norelgestromin
Time frame: Predose up to 24 hours post dose on Day 21
Population: All randomized participants who received at least 1 dose of study drug and had pharmacokinetics data to analyze tmax. Participants were analyzed based on the treatment they received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| OC + LY2216684 | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norelgestromin | Ethinyl Estradiol | 2.00 hour (h) |
| OC + LY2216684 | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norelgestromin | Norelgestromin | 3.00 hour (h) |
| OC + Placebo | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norelgestromin | Ethinyl Estradiol | 2.00 hour (h) |
| OC + Placebo | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of Ethinyl Estradiol and Norelgestromin | Norelgestromin | 2.03 hour (h) |
90% CI: [-0.73, 0.51]Wilcoxon Signed Rank Test
90% CI: [-0.5, 0.5]Wilcoxon Signed Rank Test