Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Healthy Subjects and Adult and Elderly Subjects With Mild Obstructive Sleep Apnea

Phase 1

Completed

Conditions: Obstructive Sleep Apnea
Healthy Subjects

Interventions: Drug: Placebo
Drug: Lemborexant 10 mg
Drug: Lemborexant 25 mg

Registration Number: NCT03471871

Lead Sponsor: Eisai Inc.

Brief Summary: This study will be conducted to determine whether lemborexant as compared to placebo decreases the peripheral oxygen saturation during total sleep time in healthy adult and elderly participants after a single dose of treatment and to determine whether it increases the apnea-hypopnea index after single and multiple doses of treatment in adult and elderly participants with mild obstructive sleep apnea (OSA).

Detailed Description: Healthy Volunteer (HV) Cohort:

The HV Cohort comprises a randomized, double-blind, placebo-controlled, 3-period crossover study. Eligible healthy adult and elderly participants will be randomized to treatment sequence A, B, or C, each consisting of 3 Treatment Periods, each of one night's duration, in which participants will receive a single dose of lemborexant 10 milligrams (mg), or lemborexant 25 mg, or placebo. Treatment Periods will be separated by a washout interval of at least 14 days. A sufficient number of participants will be randomized to ensure that 8 evaluable adult participants (\<65 years) and 4 evaluable elderly participants (≥65 years) complete the study.

OSA Cohort:

The OSA Cohort comprises a multiple-dose, randomized, double-blind, placebo-controlled, 2-period crossover study. Adult and elderly participants with mild OSA will be randomized to treatment sequence D or E, each consisting of 2 Treatment Periods, each of 8 nights' duration, in which participants will receive lemborexant 10 mg or placebo. The Treatment Periods will be separated by a washout interval of at least 14 days. A sufficient number of participants will be randomized to ensure that 20 evaluable adult participants (\<65 years) and 10 evaluable elderly participants (≥65 years) complete the study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 146

Inclusion Criteria

Participants must meet all of the following criteria to be included in this study:

Male or female, age ≥18 years and ≤90 years at the time of informed consent
Voluntary agreement and ability to provide written informed consent
Reports habitually sleeping for at least 5.5 hours per night
Agrees to stay in bed for 7 hours per night for the duration of treatment
Reports habitual bedtime between 21:00 and 01:00
Peripheral capillary oxygen saturation (SpO2) ≥94% assessed as part of vital signs at Screening Visit 1

Additional Inclusion Criteria (Healthy Volunteer [HV] Cohort):

Body mass index (BMI) less than or equal to 32 kilograms per meters squared (kg/m^2)
On screening polysomnography (PSG) (Screening Visit 2): apnea-hypopnea index (AHI) <5

Additional Inclusion Criteria (Obstructive Sleep Apnea [OSA] Cohort):

BMI ≤40 kg/m^2
OSA, diagnosed according to the criteria of the International Classification of Sleep Disorders, version 3
On Screening PSG: AHI ≥5 to <15 (mild severity)

Exclusion Criteria

A current diagnosis of restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, or narcolepsy
Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator indicate the need for referral for a diagnostic evaluation for the presence of narcolepsy
A history of a parasomnia or parasomnia observed on the Screening PSG that in the investigator's opinion makes the participant unsuitable for the study
Periodic Limb Movement with Arousal Index (PLMAI) as measured on the Screening PSG:
1. Age 18 to <65 years: PLMAI ≥10
2. Age ≥65 years: PLMAI >15
History of or suspected drug or alcohol use disorder within approximately 2 previous years
A positive urine drug test or breath alcohol test at Screening or Baseline, or unwilling to refrain from use of recreational drugs during the study
Known to be human immunodeficiency virus positive
Active viral hepatitis (B or C) as demonstrated by positive viral serology at Screening
A prolonged QT/corrected QT (QTc) interval (QT interval corrected for heart rate using Fridericia's formula [QTcF] >450 milliseconds [ms]) as demonstrated by a repeated electrocardiogram (ECG) at Screening (repeated if initial ECG indicates a QTcF interval >450 ms)
Comorbid nocturia resulting in the need to get out of bed to use the bathroom more than 3 times during the night
Any history of medical or psychiatric condition that in the opinion of the investigator could affect the participant's safety or interfere with the study assessments
Any suicidal ideation with intent to act with or without a plan, current or within 6 months before the Columbia - Suicide Severity Rating Scale (C-SSRS) administration during the Screening (e.g., answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS
Any suicidal behavior (per the Suicidal Behavior section of the C-SSRS) within 10 years of Screening
Scheduled for surgery during the study that requires general anesthesia or administration of prohibited medications
Used any prohibited prescription or over-the-counter medications within 1 week or 5 half-lives, whichever is longer, before the Screening PSG
Hypersensitivity to lemborexant or excipients
Currently enrolled in another interventional clinical trial or used any investigational drug or device within 30 days or 5 times the half-life, whichever is longer preceding informed consent
Previously participated in other clinical trial of lemborexant
Is unable to avoid working a night shift within 2 weeks before the Screening PSG, or between the Screening PSG and End-of-Study
Has travelled across 3 or more time zones in the week prior to Screening, or plans to travel across more than 3 time zones during the study
Clinically significant findings based on vital signs, physical examination, ECG, or clinical laboratory tests

Additional Exclusion Criteria (HV Cohort):

Any valid event of SpO2 <90% during the Screening PSG
Current evidence of a clinically significant, active respiratory disorder. This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease, or any other pulmonary disorder identified by review of medical history, physical examination, and which in the opinion of the investigator, could compromise the participant's safety or interfere with study assessments
Presence of significant illness (including insomnia) that requires treatment or may influence the study assessments (e.g., psychiatric disorders, disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, cardiovascular system, or a congenital abnormality), malignancy within the past 5 years (other than adequately treated basal cell carcinoma or in situ carcinoma of the cervix), or chronic pain that in the opinion of the investigator could interfere with the study assessments. Participants for whom a sedating drug would be contraindicated for safety reasons because of the participant's occupation or activities are also excluded

Additional Exclusion Criteria (OSA Cohort):

SpO2 less than 80% for ≥ 5% of total sleep time during the Screening PSG
Uses or plans to use of continuous positive airway pressure device or dental appliance within 2 weeks of the Screening PSG (Screening Visit 2) or during the study
Current evidence of a clinically significant, active respiratory disorder other than OSA. This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any other pulmonary disorder identified by review of medical history, physical examination, and which in the opinion of the investigator, could compromise the participant's safety or interfere with study assessments
Current evidence of other clinically significant disease (e.g., psychiatric disorders, disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, cardiovascular system, or a congenital abnormality), malignancy within the past 5 years (other than adequately treated basal cell carcinoma or in situ carcinoma of the cervix), or chronic pain that in the opinion of the investigator could affect the participant's safety or interfere with the study assessments. Participants for whom a sedating drug would be contraindicated for safety reasons because of the participant's occupation or activities are also excluded. Participants with insomnia disorder, who complain of difficulties with sleep onset and/or sleep maintenance, are eligible provided that they meet this criterion. Note that medications to treat insomnia are prohibited.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
HV Cohort,Sequence A:Placebo,Lemborexant 10mg,Lemborexant 25mg	Lemborexant 25 mg	Eligible healthy adult and elderly participants will receive lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence B:Lemborexant 10mg,Lemborexant 25mg,Placebo	Lemborexant 25 mg	Eligible healthy adult and elderly participants will receive lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 2, and then lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence C:Lemborexant 25mg,Placebo,Lemborexant 10mg	Lemborexant 25 mg	Eligible healthy adult and elderly participants will receive lemborexant 25 mg (2 lemborexant 10 mg tablet and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 1, followed by lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
OSA Cohort, Sequence D: Placebo, Lemborexant 10mg	Lemborexant 10 mg	Eligible adult and elderly participants with mild OSA will receive one lemborexant-matched placebo tablet on the night of Day 1 through Day 8 of Treatment Period 1, followed by one lemborexant 10 mg tablet on the night of Day 1 through Day 8 of Treatment Period 2. A washout period of 14 days was maintained between each Treatment Period.
OSA Cohort, Sequence E: Lemborexant 10mg, Placebo	Lemborexant 10 mg	Eligible adult and elderly participants with mild OSA will receive one lemborexant 10 mg tablet on the night of Day 1 through Day 8 of Treatment Period 1, followed by one lemborexant-matched placebo tablet on the night of Day 1 through Day 8 of Treatment Period 2. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence C:Lemborexant 25mg,Placebo,Lemborexant 10mg	Placebo	Eligible healthy adult and elderly participants will receive lemborexant 25 mg (2 lemborexant 10 mg tablet and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 1, followed by lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence C:Lemborexant 25mg,Placebo,Lemborexant 10mg	Lemborexant 10 mg	Eligible healthy adult and elderly participants will receive lemborexant 25 mg (2 lemborexant 10 mg tablet and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 1, followed by lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence B:Lemborexant 10mg,Lemborexant 25mg,Placebo	Lemborexant 10 mg	Eligible healthy adult and elderly participants will receive lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 2, and then lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence A:Placebo,Lemborexant 10mg,Lemborexant 25mg	Placebo	Eligible healthy adult and elderly participants will receive lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence A:Placebo,Lemborexant 10mg,Lemborexant 25mg	Lemborexant 10 mg	Eligible healthy adult and elderly participants will receive lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 2, and then lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
HV Cohort,Sequence B:Lemborexant 10mg,Lemborexant 25mg,Placebo	Placebo	Eligible healthy adult and elderly participants will receive lemborexant 10 mg (1 lemborexant 10 mg tablet and 2 matching placebo tablets) on the night of Day 1 of Treatment Period 1, followed by lemborexant 25 mg (2 lemborexant 10 mg tablets and 1 lemborexant 5 mg tablet) on the night of Day 1 of Treatment Period 2, and then lemborexant-matched placebo (3 matched tablets) on the night of Day 1 of Treatment Period 3. A washout period of 14 days was maintained between each Treatment Period.
OSA Cohort, Sequence D: Placebo, Lemborexant 10mg	Placebo	Eligible adult and elderly participants with mild OSA will receive one lemborexant-matched placebo tablet on the night of Day 1 through Day 8 of Treatment Period 1, followed by one lemborexant 10 mg tablet on the night of Day 1 through Day 8 of Treatment Period 2. A washout period of 14 days was maintained between each Treatment Period.
OSA Cohort, Sequence E: Lemborexant 10mg, Placebo	Placebo	Eligible adult and elderly participants with mild OSA will receive one lemborexant 10 mg tablet on the night of Day 1 through Day 8 of Treatment Period 1, followed by one lemborexant-matched placebo tablet on the night of Day 1 through Day 8 of Treatment Period 2. A washout period of 14 days was maintained between each Treatment Period.

Primary Outcome Measures

Name	Time	Method
HV Cohort: Peripheral Oxygen Saturation (SpO2) During Total Sleep Time (TST) on Day 1 of Treatment	Day 1	SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 was monitored by noninvasive method known as transmissive pulse oximetry. TST was defined as the total time asleep in minutes using polysomnography (PSG).
OSA Cohort: Apnea-Hypopnea Index (AHI) on Day 8 of Treatment	Day 8	The AHI is the number of apneas and hypopneas per hour of sleep. AHI less than 5 is considered normal. An AHI from 5 to 14 denotes mild sleep apnea, 15 to 30 is moderate, while a greater than 30 AHI is considered severe.

Secondary Outcome Measures

Name	Time	Method
HV Cohort: AHI on Day 1 of Treatment	Day 1	The AHI is the number of apneas and hypopneas per hour of sleep. AHI less than 5 is considered normal. An AHI from 5 to 14 denotes mild sleep apnea, 15 to 30 is moderate, while a greater than 30 AHI is considered severe.
OSA Cohort: AHI on Day 1 of Treatment	Day 1	The AHI is the number of apneas and hypopneas per hour of sleep. AHI less than 5 is considered normal. An AHI from 5 to 14 denotes mild sleep apnea, 15 to 30 is moderate, while a greater than 30 AHI is considered severe.
HV Cohort: Percentage of TST During Which SpO2 Was Less Than (<) 90 Percent (%), 85 % and 80 % on Day 1 of Treatment	Day 1	TST was defined as the total time asleep in minutes using PSG. SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 was monitored by noninvasive method known as transmissive pulse oximetry.
HV Cohort: Percentage of Participants With at Least One Incident of SpO2 <90% for at Least 30 Seconds During TST on Day 1 of Treatment	Day 1	SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 was monitored by noninvasive method known as transmissive pulse oximetry. TST was defined as the total time asleep in minutes using PSG.
OSA Cohort: SpO2 During TST on Day 1 and Day 8 of Treatment	Day 1 and Day 8	SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 was monitored by noninvasive method known as transmissive pulse oximetry. TST was defined as the total time asleep in minutes using PSG.
OSA Cohort: Percentage of TST During Which the SpO2 is <90%, 85% and 80 % on Day 1 and Day 8 of Treatment	Day 1 and Day 8	TST was defined as the total time asleep in minutes using PSG. SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 was monitored by noninvasive method known as transmissive pulse oximetry.
OSA Cohort: Percentage of Participants With at Least One Incident of SpO2 <90% for at Least 30 Seconds During TST on Day 1 and Day 8 of Treatment	Day 1 and Day 8	SpO2 is an estimate of the amount of oxygen in the blood. It is the percentage of hemoglobin containing oxygen compared to the total amount of hemoglobin in the blood (that is, oxygenated hemoglobin versus oxygenated and non-oxygenated hemoglobin). SpO2 was monitored by noninvasive method known as transmissive pulse oximetry. TST was defined as the total time asleep in minutes using PSG.

Trial Locations

Locations (11): The Center for Sleep & Wake Disorders
🇺🇸
Chevy Chase, Maryland, United States
PACT
🇺🇸
Glendale, Arizona, United States
Clinilabs Drug Development
🇺🇸
New York, New York, United States
PAB Clinical Research
🇺🇸
Brandon, Florida, United States
Pacific Research Network. LLC
🇺🇸
San Diego, California, United States
Research Centers of America
🇺🇸
Hollywood, Florida, United States
Pulmonary Associates, PA
🇺🇸
Phoenix, Arizona, United States
CTI Clinical Research Center
🇺🇸
Cincinnati, Ohio, United States
Neurotrials Research, Inc
🇺🇸
Atlanta, Georgia, United States
Advarra
🇺🇸
Columbia, Maryland, United States
Community Research
🇺🇸
Cincinnati, Ohio, United States