Insomnia Disorder
Conditions
Keywords
Insomnia Disorder, E2006, Multiple Sleep Latency Test, Lemborexant
Brief summary
This is a single-dose, randomized, placebo-controlled, 3-way crossover study of 2 dosage strengths of lemborexant (5 mg and 10 mg) in participants with insomnia disorder.
Detailed description
The study will have 2 phases: Prerandomization and Randomization. The Prerandomization Phase will consist of 2 periods that taken together, will last up to a maximum of 21 days: a Screening Period and a Baseline Period. The Randomization Phase will comprise 4 treatment periods (Treatment 1, Treatment 2, Treatment 3, Treatment 4) with intervening washout periods between treatment periods (Washout 1, Washout 2, Washout 3). A single dose of study drug will be administered in a randomized, 3-way double-blind crossover manner at Treatment Periods 1-3; flurazepam 30 mg will be administered in an open-label manner at Treatment Period 4.
Interventions
DRUGLemborexant 5 mg
Lemborexant 5 mg tablet.
Lemborexant 10 mg tablet.
DRUGLemborexant-matched placebo.
Lemborexant-matched placebo tablet.
DRUGFlurazepam 30 mg
Flurazepam 30 mg capsule.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, age 18 or older, at the time of informed consent. 2. Meets the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Insomnia Disorder, as follows: 1. Complains of dissatisfaction with nighttime sleep despite adequate opportunity for sleep, with complaint being one or more of the following: difficulty getting to sleep, difficulty staying asleep, or awakening earlier in the morning than desired. 2. Frequency of complaint greater than or equal to 3 times per week. 3. Duration of complaint greater than or equal to 3 months. 4. Associated with complaint of daytime impairment. 3. Insomnia Severity Index score greater than or equal to 15 at Screening. 4. Regular time in bed between 7 and 9 hours as reported at Screening. 5. Regular bedtime, defined as the time the participant attempts to fall asleep, between 21:00 and 24:00 and regular wake time between 05:00 and 09:00 as reported at Screening. 6. Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed for 7 nights during Screening, such that participant Sleep Onset Latency (sSOL) greater than or equal to 30 minutes on at least 3 nights and subjective Wake After Sleep Onset (sWASO) greater than or equal to 60 minutes on at least 3 nights.
Exclusion criteria
1. Excessive morning sleepiness at Baseline as determined by average SOL at Baseline less than 10 minutes. 2. Females must not be lactating or pregnant at Screening or Baseline (documented by a negative beta-human chorionic gonadotropin \[beta-hCG\] or human chorionic gonadotropin \[hCG\] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG or hCG). (Note: A negative urine pregnancy test is required at check-in before each dose of study drug and flurazepam). 3. If females of childbearing potential: 1. Had unprotected sexual intercourse within 30 days before study entry and do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method \[such as condom plus diaphragm with spermicide\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation. 2. Are currently abstinent, and do not agree to use a double barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation. 3. Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and do not agree to use the same contraceptive during the study or for 28 days after study drug discontinuation. NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). 4. A current diagnosis of sleep-related breathing disorder, periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or narcolepsy, or an exclusionary score on screening instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia. 5. Reports experiencing within the past year confusional arousals, symptoms of REM Behavior Disorder, or sleep-related violent behavior on Munich Parasomnia Scale (MUPS), or a history of aberrant nocturnal behaviors including sleep-driving or sleep-eating. 6. Habitually naps more than 3 times per week. 7. History of drug or alcohol dependency or abuse within approximately the last 2 years. 8. Has a positive drug screen at Screening. 9. A prolonged QT/QTc interval (QTc greater than 450 ms) as demonstrated by a repeated ECG at Screening (repeated only if initial ECG indicates a QTc interval greater than 450 ms). 10. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of Screening or any lifetime suicidal behavior. 11. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal, psychiatric or neurological disease, or chronic pain) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments. 12. Used any prohibited prescription or over-the-counter concomitant medications within 2 weeks prior to Screening, or between Screening and Randomization. 13. Used any modality of treatment for insomnia, including cognitive behavioral therapy or marijuana within 2 weeks prior to Screening, or between Screening and Randomization. 14. Scheduled for surgery during the study. 15. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or between Screening and Baseline, or plans to travel more than 3 times zones during the study. 16. Hypersensitivity to flurazepam, the study drug, or any of the excipients. 17. Currently enrolled in another clinical trial or used any investigational drug or device within 28 days or 5 x the half-life, whichever is longer preceding informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Baseline, Day 2 of each of three treatment periods that were separated by approximately 2 weeks (for a total of up to 4 weeks) | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The multiple sleep latency test (MSLT) is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four Sleep Latency Tests (SLTs), with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Whose Treatment Difference (Under Either Dose of Lemborexant) Average SOL Score is More Than (>) 6.0 Minutes Shorter Than Placebo | Day 2 of each of three treatment periods that are separated by approximately 2 weeks (for a total of up to 6 weeks) | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. |
| Number of Participants Whose Average SOL is <8.0 Minutes and >6.0 Minutes Shorter Than Placebo | Day 2 of each of three treatment periods that are separated by approximately 2 weeks (for a total of up to 6 weeks) | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. |
| Mean Change From Baseline in the Average SOL From the M-MSLT in Treatment Period 4 | Baseline, Day 2 of Treatment Period 4 (Week 6) | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. |
| Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Days 2, 16 and 30 within 20 minutes after the end of 4th SLT (up to 155 minutes after wake time) | The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. |
| Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment | Day 2 of each of three treatment periods that were separated by approximately 2 weeks (for a total of up to 6 weeks) | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. |
| Number of Participants With Clinically Significant Abnormal Laboratory Values | From first dose of study drug up to Day 54 | — |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values | From first dose of study drug up to Day 54 | — |
| Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters | From first dose of study drug up to Day 54 | — |
| Relationship Between PK Concentrations of Lemborexant and Sleepiness as Measured by M-MSLT | Baseline up to Day 44 (Week 6) | Pearson correlation was used to calculate the relationship between PK concentration of lemborexant and sleepiness. The M-MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | From first dose of study drug up to Day 54 | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in the United Sates from 13 December 2014 to 21 April 2015.
Pre-assignment details
A total of 123 participants were screened, of which 54 participants were screen failures and 69 participants were randomized to receive study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo, Lemborexant 5 mg, Lemborexant 10 mg, Flurazepam 30 mg Participants received a single oral dose of lemborexant-matched placebo tablet, on Day 1 of Treatment Period 1, followed by a single oral dose of lemborexant 5 mg tablet, on Day 1 of Treatment Period 2, followed by a single oral dose of lemborexant 10 mg tablet, on Day 1 of Treatment Period 3, followed by a single oral dose of flurazepam 30 mg capsule on Day 1 of Treatment Period 4. All doses were administered within 5 minutes before bedtime. A washout period of 12 to 16 days was maintained between the 2 treatment periods. | 12 |
| Lemborexant 10 mg, Placebo, Lemborexant 5 mg, Flurazepam 30 mg Participants received a single oral dose of lemborexant 10 mg tablet, on Day 1 of Treatment Period 1, followed by a single oral dose of lemborexant-matched placebo tablet, on Day 1 of Treatment Period 2, followed by a single oral dose of lemborexant 5 mg tablet, on Day 1 of Treatment Period 3, followed by a single oral dose of flurazepam 30 mg capsule on Day 1 of Treatment Period 4. All doses were administered within 5 minutes before bedtime. A washout period of 12 to 16 days was maintained between the 2 treatment periods. | 11 |
| Lemborexant 5 mg, Lemborexant 10 mg, Placebo, Flurazepam 30 mg Participants received a single oral dose of lemborexant 5 mg tablet, on Day 1 of Treatment Period 1, followed by a single oral dose of lemborexant 10 mg tablet, on Day 1 of Treatment Period 2, followed by a single oral dose of lemborexant-matched placebo tablet, on Day 1 of Treatment Period 3, followed by a single oral dose of flurazepam 30 mg capsule on Day 1 of Treatment Period 4. All doses were administered within 5 minutes before bedtime. A washout period of 12 to 16 days was maintained between the 2 treatment periods. | 11 |
| Lemborexant 10 mg, Lemborexant 5 mg, Placebo, Flurazepam 30 mg Participants received a single oral dose of lemborexant 10 mg tablet, on Day 1 of Treatment Period 1, followed by a single oral dose of lemborexant 5 mg tablet, on Day 1 of Treatment Period 2, followed by a single oral dose of lemborexant-matched placebo tablet, on Day 1 of Treatment Period 3, followed by a single oral dose of flurazepam 30 mg capsule on Day 1 of Treatment Period 4. All doses were administered within 5 minutes before bedtime. A washout period of 12 to 16 days was maintained between the 2 treatment periods. | 11 |
| Lemborexant 5 mg, Placebo, Lemborexant 10 mg, Flurazepam 30 mg Participants received a single oral dose of lemborexant 5 mg tablet, on Day 1 of Treatment Period 1, followed by a single oral dose of lemborexant-matched placebo tablet, on Day 1 of Treatment Period 2, followed by a single oral dose of lemborexant 10 mg tablet, on Day 1 of Treatment Period 3, followed by a single oral dose of flurazepam 30 mg capsule on Day 1 of Treatment Period 4. All doses were administered within 5 minutes before bedtime. A washout period of 12 to 16 days was maintained between the 2 treatment periods. | 12 |
| Placebo, Lemborexant 10 mg, Lemborexant 5 mg, Flurazepam 30 mg Participants received a single oral dose of lemborexant-matched placebo tablet, on Day 1 of Treatment Period 1, followed by a single oral dose of lemborexant 10 mg tablet, on Day 1 of Treatment Period 2, followed by a single oral dose of lemborexant 5 mg tablet, on Day 1 of Treatment Period 3, followed by a single oral dose of flurazepam 30 mg capsule on Day 1 of Treatment Period 4. All doses were administered within 5 minutes before bedtime. A washout period of 12 to 16 days was maintained between the 2 treatment periods. | 12 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (2 Days) | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period 4 (2 Days) | Death in the Family | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo, Lemborexant 5 mg, Lemborexant 10 mg, Flurazepam 30 mg | Lemborexant 10 mg, Placebo, Lemborexant 5 mg, Flurazepam 30 mg | Lemborexant 5 mg, Lemborexant 10 mg, Placebo, Flurazepam 30 mg | Lemborexant 10 mg, Lemborexant 5 mg, Placebo, Flurazepam 30 mg | Lemborexant 5 mg, Placebo, Lemborexant 10 mg, Flurazepam 30 mg | Placebo, Lemborexant 10 mg, Lemborexant 5 mg, Flurazepam 30 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.5 years STANDARD_DEVIATION 15.73 | 50.2 years STANDARD_DEVIATION 12.54 | 49.0 years STANDARD_DEVIATION 12.32 | 52.5 years STANDARD_DEVIATION 15.91 | 48.1 years STANDARD_DEVIATION 13.9 | 52.2 years STANDARD_DEVIATION 7.86 | 50.2 years STANDARD_DEVIATION 12.91 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 11 Participants | 11 Participants | 11 Participants | 12 Participants | 12 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 7 Participants | 3 Participants | 6 Participants | 5 Participants | 33 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 4 Participants | 4 Participants | 8 Participants | 5 Participants | 7 Participants | 35 Participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 10 Participants | 9 Participants | 7 Participants | 8 Participants | 51 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 5 Participants | 4 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 69 | 0 / 68 | 0 / 68 |
| other Total, other adverse events | 2 / 68 | 5 / 69 | 8 / 68 | 5 / 68 |
| serious Total, serious adverse events | 0 / 68 | 0 / 69 | 0 / 68 | 0 / 68 |
Outcome results
Primary
Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3
SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The multiple sleep latency test (MSLT) is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four Sleep Latency Tests (SLTs), with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL.
Time frame: Baseline, Day 2 of each of three treatment periods that were separated by approximately 2 weeks (for a total of up to 4 weeks)
Population: The full analysis set (FAS) was the group of randomized participants who received at least 1 dose of study drug and had at least 1 postdose pharmacodynamics (PD) measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lemborexant-matched Placebo | Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Baseline | 18.25 minutes | Standard Deviation 2.621 |
| Lemborexant-matched Placebo | Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Change at Day 2 After Each Treatment | -3.43 minutes | Standard Deviation 4.424 |
| Lemborexant 5 mg | Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Baseline | 18.28 minutes | Standard Deviation 2.61 |
| Lemborexant 5 mg | Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Change at Day 2 After Each Treatment | -4.56 minutes | Standard Deviation 4.693 |
| Lemborexant 10 mg | Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Baseline | 18.25 minutes | Standard Deviation 2.621 |
| Lemborexant 10 mg | Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | Change at Day 2 After Each Treatment | -6.95 minutes | Standard Deviation 4.967 |
p-value: 0.0262Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
Secondary
Mean Change From Baseline in the Average SOL From the M-MSLT in Treatment Period 4
SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL.
Time frame: Baseline, Day 2 of Treatment Period 4 (Week 6)
Population: The FAS was the group of randomized participants who received at least 1 dose of study drug and had at least 1 postdose PD measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lemborexant-matched Placebo | Mean Change From Baseline in the Average SOL From the M-MSLT in Treatment Period 4 | Baseline | 18.25 minutes | Standard Deviation 2.621 |
| Lemborexant-matched Placebo | Mean Change From Baseline in the Average SOL From the M-MSLT in Treatment Period 4 | Change at Day 2 of Treatment Period 4 | -9.49 minutes | Standard Deviation 5.413 |
Secondary
Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT
The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT.
Time frame: Days 2, 16 and 30 within 20 minutes after the end of 4th SLT (up to 155 minutes after wake time)
Population: The pharmacokinetic (PK) analysis set was the group of participants who received at least one dose of lemborexant and had at least one quantifiable postdose drug concentration. The PK analysis set where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lemborexant-matched Placebo | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Metabolite M10: Day 30 | 0.994 nanogram per milliliter (ng/mL) | Standard Deviation 0.639 |
| Lemborexant-matched Placebo | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Metabolite M10: Day 2 | 1.246 nanogram per milliliter (ng/mL) | Standard Deviation 0.792 |
| Lemborexant-matched Placebo | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Lemborexant: Day 16 | 3.236 nanogram per milliliter (ng/mL) | Standard Deviation 1.895 |
| Lemborexant-matched Placebo | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Metabolite M10: Day 16 | 1.361 nanogram per milliliter (ng/mL) | Standard Deviation 0.634 |
| Lemborexant-matched Placebo | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Lemborexant: Day 30 | 2.020 nanogram per milliliter (ng/mL) | Standard Deviation 1.446 |
| Lemborexant-matched Placebo | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Lemborexant: Day 2 | 2.285 nanogram per milliliter (ng/mL) | Standard Deviation 1.426 |
| Lemborexant 5 mg | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Lemborexant: Day 30 | 5.293 nanogram per milliliter (ng/mL) | Standard Deviation 4.293 |
| Lemborexant 5 mg | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Lemborexant: Day 2 | 6.423 nanogram per milliliter (ng/mL) | Standard Deviation 3.262 |
| Lemborexant 5 mg | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Metabolite M10: Day 16 | 2.689 nanogram per milliliter (ng/mL) | Standard Deviation 1.592 |
| Lemborexant 5 mg | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Metabolite M10: Day 2 | 2.582 nanogram per milliliter (ng/mL) | Standard Deviation 0.959 |
| Lemborexant 5 mg | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Metabolite M10: Day 30 | 2.304 nanogram per milliliter (ng/mL) | Standard Deviation 1.534 |
| Lemborexant 5 mg | Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | Lemborexant: Day 16 | 5.306 nanogram per milliliter (ng/mL) | Standard Deviation 3.175 |
Secondary
Number of Participants Whose Average SOL is <8.0 Minutes and >6.0 Minutes Shorter Than Placebo
SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL.
Time frame: Day 2 of each of three treatment periods that are separated by approximately 2 weeks (for a total of up to 6 weeks)
Population: The FAS was the group of randomized participants who received at least 1 dose of study drug and had at least 1 postdose PD measurement. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lemborexant-matched Placebo | Number of Participants Whose Average SOL is <8.0 Minutes and >6.0 Minutes Shorter Than Placebo | 4 Participants |
| Lemborexant 5 mg | Number of Participants Whose Average SOL is <8.0 Minutes and >6.0 Minutes Shorter Than Placebo | 13 Participants |
| Lemborexant 10 mg | Number of Participants Whose Average SOL is <8.0 Minutes and >6.0 Minutes Shorter Than Placebo | 25 Participants |
Secondary
Number of Participants Whose Treatment Difference (Under Either Dose of Lemborexant) Average SOL Score is More Than (>) 6.0 Minutes Shorter Than Placebo
SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL.
Time frame: Day 2 of each of three treatment periods that are separated by approximately 2 weeks (for a total of up to 6 weeks)
Population: The FAS was the group of randomized participants who received at least 1 dose of study drug and had at least 1 postdose PD measurement. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lemborexant-matched Placebo | Number of Participants Whose Treatment Difference (Under Either Dose of Lemborexant) Average SOL Score is More Than (>) 6.0 Minutes Shorter Than Placebo | 9 Participants |
| Lemborexant 5 mg | Number of Participants Whose Treatment Difference (Under Either Dose of Lemborexant) Average SOL Score is More Than (>) 6.0 Minutes Shorter Than Placebo | 20 Participants |
| Lemborexant 10 mg | Number of Participants Whose Treatment Difference (Under Either Dose of Lemborexant) Average SOL Score is More Than (>) 6.0 Minutes Shorter Than Placebo | 35 Participants |
Secondary
Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment
SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL.
Time frame: Day 2 of each of three treatment periods that were separated by approximately 2 weeks (for a total of up to 6 weeks)
Population: The FAS was the group of randomized participants who received at least 1 dose of study drug and had at least 1 postdose PD measurement.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lemborexant-matched Placebo | Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment | 3 Participants |
| Lemborexant 5 mg | Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment | 11 Participants |
| Lemborexant 10 mg | Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment | 20 Participants |
| Flurazepam 30 mg | Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment | 36 Participants |
p-value: 0.0215McNemar
p-value: <0.0001McNemar
p-value: <0.0001McNemar
Secondary
Number of Participants With Clinically Significant Abnormal Laboratory Values
Time frame: From first dose of study drug up to Day 54
Population: The safety analysis set was the group of participants who received at least one dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lemborexant-matched Placebo | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| Lemborexant 5 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| Lemborexant 10 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values
Time frame: From first dose of study drug up to Day 54
Population: The safety analysis set was the group of participants who received at least one dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lemborexant-matched Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values | 0 Participants |
| Lemborexant 5 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values | 0 Participants |
| Lemborexant 10 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values | 0 Participants |
Secondary
Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters
Time frame: From first dose of study drug up to Day 54
Population: The safety analysis set was the group of participants who received at least one dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lemborexant-matched Placebo | Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters | 0 Participants |
| Lemborexant 5 mg | Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters | 0 Participants |
| Lemborexant 10 mg | Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation
Time frame: From first dose of study drug up to Day 54
Population: The safety analysis set was the group of participants who received at least one dose of study drug and had at least 1 postdose safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lemborexant-matched Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Lemborexant-matched Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Death | 0 Participants |
| Lemborexant-matched Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | TEAEs | 2 Participants |
| Lemborexant-matched Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | SAEs | 0 Participants |
| Lemborexant 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | TEAEs | 5 Participants |
| Lemborexant 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Lemborexant 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Death | 0 Participants |
| Lemborexant 5 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | SAEs | 0 Participants |
| Lemborexant 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Lemborexant 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | TEAEs | 8 Participants |
| Lemborexant 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | SAEs | 0 Participants |
| Lemborexant 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Death | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Death | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | SAEs | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Flurazepam 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation | TEAEs | 5 Participants |
Secondary
Relationship Between PK Concentrations of Lemborexant and Sleepiness as Measured by M-MSLT
Pearson correlation was used to calculate the relationship between PK concentration of lemborexant and sleepiness. The M-MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes.
Time frame: Baseline up to Day 44 (Week 6)
Population: The PK analysis set was the group of participants who received at least one dose of E2006 and had at least one quantifiable postdose drug concentration. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lemborexant-matched Placebo | Relationship Between PK Concentrations of Lemborexant and Sleepiness as Measured by M-MSLT | -0.2746 correlation coefficient |