Sleep Initiation and Maintenance Disorders
Conditions
Brief summary
The aim of this study is to learn how different doses of LY2624803 affect sleep in healthy Japanese participants. The study has four treatment periods. Participants will receive a single dose of LY2624803 or placebo in each treatment period.
Interventions
DRUGLY2624803 - Solution
Administered orally as reconstituted solution
DRUGLY2624803 - Capsule
Administered orally as a capsule
Administered orally as solution
Administered orally as a capsule
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Overtly healthy males or female Japanese * Women of child-bearing potential, who test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control during the study and for 3 months following the last dose of study drug * Body mass index (BMI) of 17.6 to 26.4 kilogram per meter square (kg/m\^2), inclusive * Normal bedtime hours, with routine time spent in bed between 6.5 hours and 9 hours each night * Clinical laboratory test results within normal reference range * 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 and able to follow study procedures * Have given written informed consent approved by Lilly and the ethical review board governing the site
Exclusion criteria
* Within 4 months of the initial dose of study drug, have received treatment with a drug that has not received regulatory approval for any indication * Persons who have previously completed or withdrawn from this study or any other study investigating LY2624803 after receiving study drug * Known allergies to LY2624803 or related compounds * Women who are lactating * Shift workers \[those who shifted or plan to shift work within 7 days of any phase advance polysomnography (PSG) night\] or any person who has crossed (or will have crossed) more than one time zone by aircraft within 3 days prior to entry * Have an irregular or altered sleep/wake schedule that is likely to prevent from keeping a regular sleep/wake schedule during the study * Regular napping (≥ 2 daytime naps/week by history) * Extreme morning type or evening type * Rhinitis, conjunctivitis, urticaria or chronic pain severe enough to interfere with sleep * Nocturia that would interfere with sleep assessment * Symptoms consistent with a sleep disorder or history of same * Evidence of significant active neuropsychiatric disease and in particular evidence of significant medical or psychiatric illness within the past 12 months that could contribute to insomnia * History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neurocardiogenic 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 * History or presence of orthostatic signs and symptoms within 2 years * History of seizure or a close relative having a seizure disorder (such as epilepsy). History of a single febrile convulsion more than 10 years ago is acceptable. History of cranial trauma and loss of consciousness will be discussed prior to including any such participant * Abnormal movements observed outside of normal sleep time * Abnormal supine blood pressure and/or pulse rate * Participants with orthostatic hypotension at screening * An abnormality in the 12-lead electrocardiogram (ECG) that increases the risks associated with participating in the study * Regular use of known drugs of abuse and/or positive findings on urinary drug screening * Evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies * Evidence of hepatitis C and/or positive hepatitis C antibody * Evidence of hepatitis B and/or positive hepatitis B surface antigen * Evidence of syphilis infection and/or positive syphilis test * Use or intended use of prescription (except oral contraceptives), over-the-counter or herbal medication, specifically antihistamines, anticholinergic medications or any medications that affect sleepiness, within 28 days prior to Period 1 dosing and/or during the study * Participants who have donated more than 200 milliliters (mL) of blood or component blood within one month of screening, or those who have donated more than 400 mL of blood within 3 months of screening * History of smoking within the previous 6 months of screening * Participants who have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females), or participants unwilling to stop alcohol consumption for the period * Participants whose daily caffeine intake does not permit maintenance of usual sleep/wake schedule * No response to phase advance or a placebo responder * Sleep disorders detected during the PSG screening night * History or presence of breast cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo | 8 hours in Periods 1, 2 and 3 | WASO was calculated as total time in awake epochs between sleep onset time (first stage 2 epoch) and the end of the primary recording period (8 hours after lights -off). Data presented are Geometric Least Squares (LS) means. Geometric LS mean was calculated using mixed models analysis. The model included factors for treatment, treatment sequence, period and participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Latency to Persistent Sleep (LPS) | 8 hours in Periods 1, 2 and 3 | LPS is defined as the latency from the lights-off time to the first stage 2 sleep followed by at least 10 consecutive minutes of sleep epochs. Data presented are Geometric LS means. Geometric LS mean was calculated using mixed models analysis. The model included factors for treatment, treatment sequence, period and participants. |
| Total Sleep Time (TST) | 8 hours in Periods 1, 2 and 3 | TST is defined as the total time in sleep epochs from sleep onset time to the end of the primary recording period (8 hours after lights -off). LS mean was calculated using mixed models analysis. The model included factors for treatment, treatment sequence, period and participants. |
| PK: Maximum Plasma Concentration (Cmax) of LY2624803 After Single Oral Dose in Period 4 | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 10, 12, 18, and 42 hours post-dose in Period 4 | — |
| PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2624803 After Single Oral Dose in Period 4 | Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 10, 12, 18, and 42 hours post-dose in Period 4 | — |
Countries
Japan
Participant flow
Pre-assignment details
This was a double-blind, randomized, placebo-controlled, 4-period cross-over study. The first 3 of which were used for polysomnography (PSG) measurements, and the fourth period was used to determine plasma concentrations of LY2624803 to estimate pharmacokinetic (PK) parameters.
Participants by arm
| Arm | Count |
|---|---|
| Overall Single dose of 0.1 mg LY2624803 oral solution plus 1 placebo capsule, one 1.0, 3.0 or 6.0 mg LY2624803 capsule plus placebo solution administered orally in up to 2 of 4 periods or 1 placebo capsule plus placebo solution administered orally in up to 1 of 4 periods.
There was at least 7 days washout between each period. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 54.1 years STANDARD_DEVIATION 14.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 0 Participants |
| Region of Enrollment Japan | 24 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 9 | 3 / 17 | 3 / 17 | 0 / 8 | 3 / 18 | 0 / 6 | 2 / 5 | 1 / 6 | 3 / 5 |
| serious Total, serious adverse events | 0 / 9 | 0 / 17 | 0 / 17 | 0 / 8 | 0 / 18 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 5 |
Outcome results
Primary
Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo
WASO was calculated as total time in awake epochs between sleep onset time (first stage 2 epoch) and the end of the primary recording period (8 hours after lights -off). Data presented are Geometric Least Squares (LS) means. Geometric LS mean was calculated using mixed models analysis. The model included factors for treatment, treatment sequence, period and participants.
Time frame: 8 hours in Periods 1, 2 and 3
Population: All randomized participants who received at least 1 dose of study drug and had PSG measurements in Periods 1, 2 and 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 0.1 mg LY2624803 | Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo | 58.88 minutes (min) |
| 1.0 mg LY2624803 | Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo | 40.70 minutes (min) |
| 3.0 mg LY2624803 | Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo | 32.27 minutes (min) |
| 6.0 mg LY2624803 | Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo | 18.42 minutes (min) |
| Placebo | Wake After Sleep Onset (WASO) With LY2624803 Compared to Placebo | 61.10 minutes (min) |
p-value: 0.90890% CI: [0.56, 1.65]Mixed Models Analysis
p-value: 0.08390% CI: [0.45, 0.98]Mixed Models Analysis
p-value: 0.0190% CI: [0.36, 0.78]Mixed Models Analysis
p-value: <0.00190% CI: [0.18, 0.51]Mixed Models Analysis
Secondary
Latency to Persistent Sleep (LPS)
LPS is defined as the latency from the lights-off time to the first stage 2 sleep followed by at least 10 consecutive minutes of sleep epochs. Data presented are Geometric LS means. Geometric LS mean was calculated using mixed models analysis. The model included factors for treatment, treatment sequence, period and participants.
Time frame: 8 hours in Periods 1, 2 and 3
Population: All randomized participants who received at least 1 dose of study drug and had PSG measurements in Periods 1, 2 and 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 0.1 mg LY2624803 | Latency to Persistent Sleep (LPS) | 14.30 min |
| 1.0 mg LY2624803 | Latency to Persistent Sleep (LPS) | 8.39 min |
| 3.0 mg LY2624803 | Latency to Persistent Sleep (LPS) | 7.84 min |
| 6.0 mg LY2624803 | Latency to Persistent Sleep (LPS) | 7.27 min |
| Placebo | Latency to Persistent Sleep (LPS) | 10.40 min |
Secondary
PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2624803 After Single Oral Dose in Period 4
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 10, 12, 18, and 42 hours post-dose in Period 4
Population: All randomized participants who received a single oral dose of LY2624803 in Period 4 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.1 mg LY2624803 | PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2624803 After Single Oral Dose in Period 4 | 79.0 nanograms•hour/milliliter (ng•hr/mL) | Geometric Coefficient of Variation 39 |
| 1.0 mg LY2624803 | PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2624803 After Single Oral Dose in Period 4 | 714 nanograms•hour/milliliter (ng•hr/mL) | Geometric Coefficient of Variation 20 |
| 3.0 mg LY2624803 | PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2624803 After Single Oral Dose in Period 4 | 2240 nanograms•hour/milliliter (ng•hr/mL) | Geometric Coefficient of Variation 34 |
| 6.0 mg LY2624803 | PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of LY2624803 After Single Oral Dose in Period 4 | 4220 nanograms•hour/milliliter (ng•hr/mL) | Geometric Coefficient of Variation 24 |
Secondary
PK: Maximum Plasma Concentration (Cmax) of LY2624803 After Single Oral Dose in Period 4
Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 10, 12, 18, and 42 hours post-dose in Period 4
Population: All randomized participants who received a single oral dose of LY2624803 in Period 4 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.1 mg LY2624803 | PK: Maximum Plasma Concentration (Cmax) of LY2624803 After Single Oral Dose in Period 4 | 4.88 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 10 |
| 1.0 mg LY2624803 | PK: Maximum Plasma Concentration (Cmax) of LY2624803 After Single Oral Dose in Period 4 | 43.8 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 10 |
| 3.0 mg LY2624803 | PK: Maximum Plasma Concentration (Cmax) of LY2624803 After Single Oral Dose in Period 4 | 146 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 13 |
| 6.0 mg LY2624803 | PK: Maximum Plasma Concentration (Cmax) of LY2624803 After Single Oral Dose in Period 4 | 251 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 9 |
Secondary
Total Sleep Time (TST)
TST is defined as the total time in sleep epochs from sleep onset time to the end of the primary recording period (8 hours after lights -off). LS mean was calculated using mixed models analysis. The model included factors for treatment, treatment sequence, period and participants.
Time frame: 8 hours in Periods 1, 2 and 3
Population: All randomized participants who received at least 1 dose of study drug and had PSG measurements in Periods 1, 2 and 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 0.1 mg LY2624803 | Total Sleep Time (TST) | 374.37 min |
| 1.0 mg LY2624803 | Total Sleep Time (TST) | 404.35 min |
| 3.0 mg LY2624803 | Total Sleep Time (TST) | 420.65 min |
| 6.0 mg LY2624803 | Total Sleep Time (TST) | 452.09 min |
| Placebo | Total Sleep Time (TST) | 373.78 min |