Study to Evaluate the Effect of Lemborexant Versus Placebo on Driving Performance in Healthy Adult and Elderly Subjects

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo- and active-controlled, 4-period crossover study of lemborexant in healthy adult and elderly subjects to evaluate driving performance

Detailed Description
-----------------
The study will have 2 phases, Prerandomization and Randomization. The Prerandomization Phase will consist of 2 periods that will last up to a maximum of 21 days: Screening and Baseline. The Randomization Phase will comprise of four, 9-day treatment periods (Treatment Period 1 - Treatment Period 4) with a minimum 14-day washout between treatment periods, and a follow-up interval of at least 14 days after Treatment Period 4 before the end-of-study (EOS) visit. Participants will be randomized to 1 of 12 sequences in an incomplete blocks design.

Official Title
-----------------
A Randomized, Double-Blind, Placebo- and Active-Controlled, 4-Period Crossover Study to Evaluate the Effect of Lemborexant Versus Placebo on Driving Performance in Healthy Adult and Elderly Subjects

Conditions
-----------------
Healthy Participants

Intervention / Treatment
-----------------
* Drug: Placebo tablet matching lemborexant
* Drug: Placebo tablet matching zopiclone
* Drug: Zopiclone 7.5 mg
* Drug: Lemborexant 2.5 mg
* Drug: Lemborexant 5 mg
* Drug: Lemborexant 10 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy, male or female, aged 21 years or older at Screening Regular time spent in bed between 7.0 and 8.5 hours per night Regular bedtime, defined as the time the participant attempts to fall asleep, between 22:00 hours and 01:00 hours, and regular waketime, defined as the time the participant gets out of bed for the day, between 05:00 hours and 09:00 hours Body mass index (BMI) ≥18 and <31 kg/m2 at Screening Subjective sleep onset latency (sSOL) <30 minutes and subjective wake after sleep onset (sWASO) <60 minutes on the Sleep Diary At least 3 years of experience driving at least 3000 km per year Holds a valid license to drive a vehicle in the European Union (EU) as confirmed at the Screening visit Has driving ability during the practice driving test that is judged to be adequate by the driving instructor Able to communicate adequately (written and verbal) in either Dutch or English as determined by the investigator Exclusion Criteria: A current complaint or diagnosis of insomnia disorder (per either The Diagnostic and Statistical Manual of Mental Disorders Version IV [DSM-IV] or Version 5 [DSM-5] criteria), sleep-related breathing disorder, periodic limb movement disorder, restless legs or narcolepsy, or an exclusionary score on a subscale of the SLEEP50 Habitually naps more than 3 times per week Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of B-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. Females of childbearing potential who: Had unprotected sexual intercourse within 30 days before study entry and who 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. Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexually active during the study period or for 28 days after study drug discontinuation. 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 who 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]). Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period or for 28 days after study drug discontinuation). No sperm donation is allowed during the study period or for 28 days after study drug discontinuation. Clinically significant illness that requires medical treatment between Screening and Baseline Any clinically abnormal symptom or organ impairment found by medical history at Screening or Baseline and physical examinations, vital signs, ECG finding, or laboratory test results that require medical treatment Has a QT interval corrected using Fridericia's formula interval (QTcF interval) >450 ms demonstrated on repeated ECGs (repeated only if initial ECG showed corrected QT interval (QTc) >450 ms) at Screening or Baseline Has a history of or a family history of congenital QT prolongation or with a history of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT syndrome), or uses concomitant medications that prolong the QT/QT interval corrected for heart rate (QTc interval) Has systolic blood pressure (BP) >140 mmHg (age 21-59) or >150 mmHg (age ≥60) or diastolic BP >90 mmHg (all ages) at Screening or Baseline Has a resting heart rate <50 or ≥100 beats/min at Screening or Baseline Has a history of drug or alcohol dependency or abuse (as defined by DSM-5 criteria) within approximately 2 years before Screening Any suicidal ideation with intent with or without a plan within 6 months of the Screening Period (ie, answering Yes to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS) Habitually consumes more than 14 drinks per week (females) or more than 21 drinks per week (males) Has a positive alcohol breathalyzer test at Screening or Baseline check-in Smokes more than 6 cigarettes per day habitually and is unwilling to abstain from smoking cigarettes on evenings spent in the clinic until discharge after the driving test Habitually consumes more than 3 cups of caffeinated beverages per day Used any prohibited prescription or over-the-counter (OTC) concomitant medications within 1 week prior to starting the Sleep Diary during the Screening Period Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or between Screening and Baseline or plans for transmeridian travel across more than 3 time zones during the study A positive urine drug test at Screening or unwilling to refrain from use of illegal recreational drugs or marijuana during the study Hypersensitivity to the study drug or any of the excipients or to zopiclone Participated (received investigational product) in another clinical trial less than 1 month (or 5 elimination half-lives of the investigational product) before dosing or is currently enrolled in another clinical study

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Treatment A is a placebo tablet matching lemborexant and placebo tablet matching zopiclone on nights in the clinic; placebo tablet matching lemborexant on nights at home. | Drug: Placebo tablet matching lemborexant<br>* Tablet form taken orally at bedtime.<br>Drug: Placebo tablet matching zopiclone<br>* Tablet form taken orally at bedtime.<br>|
| Experimental: Treatment B<br>Treatment B is zopiclone 7.5 mg tablet and placebo tablet matching lemborexant on nights in the clinic; placebo tablet matching lemborexant on nights at home. | Drug: Placebo tablet matching lemborexant<br>* Tablet form taken orally at bedtime.<br>Drug: Zopiclone 7.5 mg<br>* 7.5 mg tablet taken orally at bedtime.<br>|
| Experimental: Treatment C<br>Treatment C is lemborexant 2.5 mg tablet and placebo tablet matching zopiclone on nights in the clinic; lemborexant 2.5 mg tablet on nights at home. | Drug: Placebo tablet matching zopiclone<br>* Tablet form taken orally at bedtime.<br>Drug: Lemborexant 2.5 mg<br>* 2.5 tablet taken orally at bedtime.<br>|
| Experimental: Treatment D<br>Treatment D is lemborexant 5 mg tablet and placebo tablet matching zopiclone on nights in the clinic; lemborexant 5 mg tablet on nights at home. | Drug: Placebo tablet matching zopiclone<br>* Tablet form taken orally at bedtime.<br>Drug: Lemborexant 5 mg<br>* 5 mg tablet taken orally at bedtime.<br>|
| Experimental: Treatment E<br>Treatment E is lemborexant 10 mg tablet and placebo tablet matching zopiclone on nights in the clinic; lemborexant 10 mg tablet on nights at home. | Drug: Placebo tablet matching zopiclone<br>* Tablet form taken orally at bedtime.<br>Drug: Lemborexant 10 mg<br>* 10 mg tablet taken orally at bedtime.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of standard deviation of lateral position (SDLP) during an on-road driving test |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of lapses on the driving test |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Outliers on SDLP |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Outliers on number of lapses |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Percentage of participants who never started a scheduled driving test or who stopped prematurely |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Standard deviation of lateral position (SDLP) during an on-road driving test, by age group |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Plasma concentration of lemborexant |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Number of lapses on the driving test, by age group |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 | 
| Plasma concentration of S-zopiclone |  | Day 2, Day 9, Day 23, Day 30, Day 44, Day 51, Day 65, and Day 72 |