A Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant (LEM) for the Treatment of Insomnia

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04009577
• Collaborator: (none)
• Enrollment: 53
• Locations: 17
• Arms: 3
• Actual Duration (Months): 11.4
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the proportion of adult [greater than or equal to (>=) 18 years] participants with insomnia disorder taking zolpidem tartrate immediate release (ZOL-IR) or zolpidem tartrate extended release (ZOL-ER), intermittently or frequently, who transition to lemborexant 5 milligram (mg) (LEM5) or 10 mg (LEM10) after 2 weeks of receiving LEM.

Condition or Disease	Intervention/Treatment	Phase
Insomnia	Drug: LEM 5 mg; Drug: LEM 10 mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Pilot Study to Evaluate Next-Dose Transition From Zolpidem to Lemborexant for the Treatment of Insomnia
• Actual Study Start Date: Jul 15, 2019
• Actual Primary Completion Date: Mar 17, 2020
• Actual Study Completion Date: Jun 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 (LEM 5 mg) Participants who were taking zolpidem tartrate (ZOL) at least 3 but fewer than 5 nights per week, for each of at least 2 weeks of the 3-week Screening Period, will initially receive LEM 5 mg administered as a tablet, orally for up to 2 weeks. Participants who meet both criteria for intermittent (Cohort 1) and frequent ZOL use (Cohort 2A and 2B) for 1 week each of the last 2 weeks of the 3-week Screening Period will be assigned to Cohort 1 and also will receive LEM 5mg.	Drug: LEM 5 mg; LEM tablet.; Other Names: E2006 Lemborexant
Experimental: Cohort 2A (LEM 5 mg) Participants who were taking ZOL at least 5 nights per week, during, at minimum, the last 2 weeks of the 3-week Screening Period, will initially receive LEM 5 mg administered as a tablet, orally for up to 2 weeks.	Drug: LEM 5 mg; LEM tablet.; Other Names: E2006 Lemborexant
Experimental: Cohort 2B (LEM 10 mg) Participants who were taking ZOL at least 5 nights per week, during, at minimum, the last 2 weeks of the 3-week Screening Period, will initially receive LEM 10 mg administered as a tablet, orally for up to 2 weeks.	Drug: LEM 10 mg; LEM tablet.; Other Names: E2006 Lemborexant

Outcome Measures

Primary Outcome Measures

1. Percentage of Overall Participants Who Transitioned to LEM at the End of the Titration Period of Core Study [Up to 2 Weeks]

   Transition to LEM was defined as participant who remained on LEM at the end of the 2-week titration period and either 1) entered the extension phase, or 2) chooses to not enter the extension phase for reasons not related to LEM (including, but not limited to, time commitment related to the study, study-related travel expenses or preference to continue insomnia management with another health care provider).

Secondary Outcome Measures

1. Percentage of Participants Who Transitioned to LEM at the End of the 2-Week Titration Period of Core Study Within Each Cohort [Up to 2 Weeks]

   Transition to LEM was defined as participant who remained on LEM at the end of the 2-week titration period and either 1) entered the extension phase, or 2) chooses to not enter the extension phase for reasons not related to LEM (including, but not limited to, time commitment related to the study, study-related travel expenses or preference to continue insomnia management with another health care provider).

2. Percentage of Participants in the LEM5 Treatment Groups With Dose Increasing to LEM10 at the End of the Titration Period of Core Study by Cohort and Overall [Up to 2 Weeks]

   This outcome measure was planned for Cohort 1A, 1B and 2A. As there was no dose increase happened in Cohort 2B, this Outcome Measure is not applicable for Cohort 2B.

3. Percentage of Participants in LEM10 Treatment Group With Dose Decreasing to LEM5 at the End of the Titration Period of Core Study in Cohort 2 [Up to 2 Weeks]

   This outcome measure was planned for Cohort 2B. As dose decrease happened in Cohort 2B only, this Outcome Measure is not applicable for Cohort 1A, 1B and 2A.

4. Percentage of Participants With Positive Medication Effect Rating on Each Patient Global Impression of Insomnia (PGI-I) Item at the End of the 2-Week Titration Period of Core Study by Cohort and Overall Using End of the Titration Period Treatment [Up to 2 Weeks]

   The PGI-I was a self-report assessment of participant perception of the effects of a medication on their sleep. The PGI-I had 3 items related to study medication effects (a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) increased/decreased total sleep time, and 1 item related to perceived appropriateness of study medication strength. The first 3 items were answered on a 3-point scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and the last item on a different 3 point scale (medication: 1=too strong, 2=just right, 3=too weak), only 'positive medication effects' and 'just right' are reported here.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Meets the Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5) criteria for Insomnia Disorder, either currently or prior to zolpidem use, as follows:

• Complains of dissatisfaction with nighttime sleep, in the form of difficulty staying asleep and/or awakening earlier in the morning than desired despite adequate opportunity for sleep

• Frequency of complaint >=3 times per week

• Duration of complaint >=3 months

• Associated with complaint of daytime impairment

1. Reports spending at least 7 hours in bed per night

2. History of intermittent [taking zolpidem at least 3 or 4 nights per week], or frequent use (at least 5 nights per week) of ZOL-IR or ZOL-ER, for at least 1 month

3. Confirmation of intermittent or frequent use of zolpidem (based on review of drug use data). Intermittent use is defined as taking zolpidem at least 3 but fewer than 5 nights per week, for at least 2 weeks each of the 3-week Screening Period. Frequent use is defined as taking zolpidem at least 5 nights per week, during, at minimum, the last 2 weeks of the 3-week Screening Period

4. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours each night

5. Willing not to start another pharmacologic treatment for the management of insomnia during the participant's participation in the study

Exclusion Criteria:

1. Females who are breastfeeding or pregnant at screening or baseline (as documented by a positive serum pregnancy test). 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

2. Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:

• total abstinence (if it is their preferred and usual lifestyle)

• an intrauterine device or intrauterine hormone-releasing system (IUS)

• a contraceptive implant

• an oral contraceptive (Participant must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation)

• have a vasectomized partner with confirmed azoospermia

• Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and 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)

1. Any history of moderate or severe obstructive sleep apnea (OSA)

2. Current evidence of a clinically significant, active respiratory disorder other than mild OSA. This includes bronchiectasis, emphysema, asthma, chronic obstructive pulmonary disease or any other pulmonary disorder identified by review of medical history or physical examination, and which in the opinion of the investigator, could compromise the participant's safety or interfere with study assessments

3. A current diagnosis of periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or an exclusionary score on screening instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia as follows:

• STOP-Bang score >=5 (participants previously diagnosed with mild OSA are not excluded)

• International Restless Legs Scale (IRLS) score >=16

1. Habitually naps during the day more than 3 times per week

2. Reports symptoms potentially related to narcolepsy, that in the clinical opinion of the investigator indicates the need for referral for a diagnostic evaluation for the presence of narcolepsy

3. Reports a history of sleep-related violent behavior, or sleep driving, or any other complex sleep-related behavior (eg, making phone calls or preparing and eating food while sleeping), whether spontaneous or associated with a pharmacological sleep agent

4. Takes a dose of ZOL-IR greater (>)10 mg per night, or ZOL-ER >12.5 mg per night

5. Takes a dose of zolpidem that is lower than what is prescribed

6. Reports having altered zolpidem tablets

7. Unwilling to forgo alcohol consumption within 3 hours of bedtime for the duration of participation in the study

8. Used any prohibited prescription or over-the-counter concomitant medications within 1-week or 5 half-lives, whichever is longer, before the first dose of study medication (A list of prohibited concomitant medications is presented in the protocol)

9. Used any pharmacologic modality of treatment for insomnia other than zolpidem, including marijuana, within 1-week or 5 half-lives, whichever is longer, before the Screening Period

10. A prolonged difference between QTc corrected by Fridericia's formulas (QTcF) interval [QTcF >450 millisecond (ms)] as demonstrated by a repeated electrocardiogram

11. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of Screening (ie, answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale [C-SSRS])

12. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS)

13. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, and renal disease) that in the opinion of the investigator(s) 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

14. Hypersensitivity to LEM or any of the excipients

15. Any history of or concomitant medical condition that in the opinion of the investigator(s) would compromise the participant's ability to safely complete the study

16. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the study. Planned surgery, which requires only local anesthesia and which can be undertaken as a day case without inpatient stay postoperatively, need not result in exclusion if in the opinion of the investigator this operation does not interfere with the study procedures and patient safety

17. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years

18. History of drug or alcohol dependency or abuse within approximately the last 2 years

19. Currently enrolled in another clinical study or used any investigational drug or device within 28 days or 5 times the half-life, whichever is longer, preceding informed consent

20. Previously participated in any clinical trial of LEM

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PACT	Glendale	Arizona	United States	85306
2	Northern California Research Corp	Sacramento	California	United States	95821
3	Artemis Institute For Clinical Research LLC - San Diego - ClinEdge - PPDS	San Diego	California	United States	92103
4	SDS Clinical Trials, Inc.	Santa Ana	California	United States	92705
5	Fleming Island Center For Clinical Research - ERN-PPDS	Fleming Island	Florida	United States	32003
6	MD Clinical	Hallandale Beach	Florida	United States	33009
7	Clinical Neuroscience Solutions Inc	Jacksonville	Florida	United States	32256
8	Clinical Neuroscience Solutions Inc	Orlando	Florida	United States	32801
9	NeuroTrials Research Inc. - BTC - PPDS	Atlanta	Georgia	United States	30342
10	SleepCare Research Institute Inc	Stockbridge	Georgia	United States	30281
11	Chicago Research Center Inc - ClinEdge - PPDS	Chicago	Illinois	United States	60634
12	Centennial Medical Group - Elkridge - Rx Trials	Elkridge	Maryland	United States	21075
13	Albuquerque Neurosciences Inc	Albuquerque	New Mexico	United States	87109
14	Clinilabs Drug Development Corporation	New York	New York	United States	10019
15	CTI Clinical Research Center - ClinEdge - PPDS	Cincinnati	Ohio	United States	45212
16	Clinical Neuroscience Solutions Inc	Memphis	Tennessee	United States	38119
17	FutureSearch Trials of Neurology	Austin	Texas	United States	78731

Sponsors and Collaborators

• Eisai Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 1, 2019
• Statistical Analysis Plan - May 21, 2020

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT04009577
• Other Study ID Numbers: E2006-A001-312
• First Posted: Jul 5, 2019
• Last Update Posted: Apr 12, 2021
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eisai Inc.: Insomnia; Sleep Initiation and Maintenance Disorders; Insomnia Disorder; Sleeplessness; E2006; Zolpidem; Lemborexant
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Lemborexant

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 17 investigative sites in the United States from 15 July 2019 to 26 June 2020. This study included 2 parts: Core study (Pretreatment phase and Treatment Phase) and Extension Phase.
Pre-assignment Detail	A total of 99 participants were screened, of which 46 were screen failures and 53 participants were enrolled and randomized into the Core study. Out of 53 randomized and treated participants in the Core Study, 43 participants entered Extension Phase and 41 participants received study drug.

Arm/Group Title	Cohort 1A: LEM 5 or LEM 10 (Intermittent ZOL Use)	Cohort 1B: LEM 5 or LEM 10 (Mixed ZOL Use)	Cohort 2A: LEM 5 or LEM 10 (Frequent ZOL Use)	Cohort 2B: LEM 10 or LEM 5 (Frequent ZOL Use)
Arm/Group Description	Participants who took zolpidem tartrate (ZOL) at least 3 nights but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received lemborexant 5 milligram (mg) (LEM5) or 10 mg (LEM10) tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 12 weeks in the Extension Phase.
Period Title: Core Study
STARTED	7	3	21	22
LEM5	7	3	21	5
LEM10	3	2	10	22
COMPLETED	6	3	17	17
NOT COMPLETED	1	0	4	5
Period Title: Core Study
STARTED	6	3	17	17
Treated	6	3	15	17
LEM5	6	3	15	8
LEM10	5	3	12	17
COMPLETED	6	3	13	16
NOT COMPLETED	0	0	4	1

Baseline Characteristics

Arm/Group Title	Cohort 1A: LEM 5 or LEM 10 (Intermittent ZOL Use)	Cohort 1B: LEM 5 or LEM 10 (Mixed ZOL Use)	Cohort 2A: LEM 5 or LEM 10 (Frequent ZOL Use)	Cohort 2B: LEM 10 or LEM 5 (Frequent ZOL Use)	Total
Arm/Group Description	Participants who took ZOL at least 3 nights but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 12 weeks in the Extension Phase.	Total of all reporting groups
Overall Participants	7	3	21	22	53
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.1 (6.12)	60.0 (8.72)	52.7 (13.57)	63.5 (10.44)	59.0 (12.21)
Sex: Female, Male (Count of Participants)
Female	4 57.1%	3 100%	14 66.7%	14 63.6%	35 66%
Male	3 42.9%	0 0%	7 33.3%	8 36.4%	18 34%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%	1 33.3%	6 28.6%	5 22.7%	13 24.5%
Not Hispanic or Latino	6 85.7%	2 66.7%	15 71.4%	17 77.3%	40 75.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	1 4.5%	1 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 14.3%	1 33.3%	5 23.8%	3 13.6%	10 18.9%
White	6 85.7%	2 66.7%	15 71.4%	18 81.8%	41 77.4%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 4.8%	0 0%	1 1.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Overall Participants Who Transitioned to LEM at the End of the Titration Period of Core Study
Description	Transition to LEM was defined as participant who remained on LEM at the end of the 2-week titration period and either 1) entered the extension phase, or 2) chooses to not enter the extension phase for reasons not related to LEM (including, but not limited to, time commitment related to the study, study-related travel expenses or preference to continue insomnia management with another health care provider).
Time Frame	Up to 2 Weeks

Outcome Measure Data

Analysis Population Description

The FAS included participants who received at least 1 dose of lemborexant.

Arm/Group Title	Overall Cohort
Arm/Group Description	Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period or who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening or who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 or LEM10 tablet (as per titration schedule), orally once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed 2 weeks in Titration Period of Core Study continued to receive LEM5 or LEM10 (as per titration schedule) tablet, orally, once at night for up to 12 weeks in the Extension Phase.
Measure Participants	53
Number [percentage of participants]	81.1 1158.6%

2. Secondary Outcome

Title	Percentage of Participants Who Transitioned to LEM at the End of the 2-Week Titration Period of Core Study Within Each Cohort
Description	Transition to LEM was defined as participant who remained on LEM at the end of the 2-week titration period and either 1) entered the extension phase, or 2) chooses to not enter the extension phase for reasons not related to LEM (including, but not limited to, time commitment related to the study, study-related travel expenses or preference to continue insomnia management with another health care provider).
Time Frame	Up to 2 Weeks

Outcome Measure Data

Analysis Population Description

The FAS included participants who received at least 1 dose of lemborexant.

Arm/Group Title	Cohort 1A: LEM 5 or LEM 10 (Intermittent ZOL Use)	Cohort 1B: LEM 5 or LEM 10 (Mixed ZOL Use)	Cohort 2A: LEM 5 or LEM 10 (Frequent ZOL Use)	Cohort 2B: LEM 10 or LEM 5 (Frequent ZOL Use)
Arm/Group Description	Participants who took ZOL at least 3 nights but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 12 weeks in the Extension Phase.
Measure Participants	7	3	21	22
Number [percentage of participants]	85.7 1224.3%	100 3333.3%	81.0 385.7%	77.3 351.4%

3. Secondary Outcome

Title	Percentage of Participants in the LEM5 Treatment Groups With Dose Increasing to LEM10 at the End of the Titration Period of Core Study by Cohort and Overall
Description	This outcome measure was planned for Cohort 1A, 1B and 2A. As there was no dose increase happened in Cohort 2B, this Outcome Measure is not applicable for Cohort 2B.
Time Frame	Up to 2 Weeks

Outcome Measure Data

Analysis Population Description

The safety analysis set was the group of participants who received at least 1 dose of study drug and had at least 1 postdose safety assessment.

Arm/Group Title	Cohort 1A: LEM 5 or LEM 10 (Intermittent ZOL Use)	Cohort 1B: LEM 5 or LEM 10 (Mixed ZOL Use)	Cohort 2A: LEM 5 or LEM 10 (Frequent ZOL Use)	Overall Cohort
Arm/Group Description	Participants who took ZOL at least 3 nights but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period or who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening or who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 or LEM10 tablet (as per titration schedule), orally once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed 2 weeks in Titration Period of Core Study continued to receive LEM5 or LEM10 (as per titration schedule) tablet, orally, once at night for up to 12 weeks in the Extension Phase.
Measure Participants	7	3	21	31
Number [percentage of participant]	42.9	66.7	47.6	48.4

4. Secondary Outcome

Title	Percentage of Participants in LEM10 Treatment Group With Dose Decreasing to LEM5 at the End of the Titration Period of Core Study in Cohort 2
Description	This outcome measure was planned for Cohort 2B. As dose decrease happened in Cohort 2B only, this Outcome Measure is not applicable for Cohort 1A, 1B and 2A.
Time Frame	Up to 2 Weeks

Outcome Measure Data

Analysis Population Description

The FAS included participants who received at least 1 dose of lemborexant.

Arm/Group Title	Cohort 2B: LEM 10 or LEM 5 (Frequent ZOL Use)
Arm/Group Description	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 12 weeks in the Extension Phase.
Measure Participants	22
Number [percentage of participants]	22.7 324.3%

5. Secondary Outcome

Title	Percentage of Participants With Positive Medication Effect Rating on Each Patient Global Impression of Insomnia (PGI-I) Item at the End of the 2-Week Titration Period of Core Study by Cohort and Overall Using End of the Titration Period Treatment
Description	The PGI-I was a self-report assessment of participant perception of the effects of a medication on their sleep. The PGI-I had 3 items related to study medication effects (a) helped/worsened sleep, (b) decreased/increased time to fall asleep, (c) increased/decreased total sleep time, and 1 item related to perceived appropriateness of study medication strength. The first 3 items were answered on a 3-point scale (1=positive medication effect, 2=neutral medication effect, 3=negative medication effect) and the last item on a different 3 point scale (medication: 1=too strong, 2=just right, 3=too weak), only 'positive medication effects' and 'just right' are reported here.
Time Frame	Up to 2 Weeks

Outcome Measure Data

Analysis Population Description

The FAS included participants who received at least 1 dose of lemborexant.

Arm/Group Title	Cohort 1A: LEM 5 or LEM 10 (Intermittent ZOL Use)	Cohort 1B: LEM 5 or LEM 10 (Mixed ZOL Use)	Cohort 2A: LEM 5 or LEM 10 (Frequent ZOL Use)	Cohort 2B: LEM 10 or LEM 5 (Frequent ZOL Use)	Overall Cohort
Arm/Group Description	Participants who took ZOL at least 3 nights but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM5 or LEM10 tablet up titrated (in case previous dose was ineffective), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 2 weeks in Titration Period of Core Study and continued to receive LEM10 or LEM5 tablet down titrated (due to tolerability), orally, once at night for up to 12 weeks in the Extension Phase.	Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period or who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening or who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 or LEM10 tablet (as per titration schedule), orally once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed 2 weeks in Titration Period of Core Study continued to receive LEM5 or LEM10 (as per titration schedule) tablet, orally, once at night for up to 12 weeks in the Extension Phase.
Measure Participants	7	3	21	22	53
Positive medication effect: on Sleep	42.9 612.9%	66.7 2223.3%	33.3 158.6%	54.5 247.7%	43.4 81.9%
Positive medication effect: Time to fall asleep	85.7 1224.3%	66.7 2223.3%	47.6 226.7%	54.5 247.7%	50.9 96%
Positive medication effect: Total sleep time	42.9 612.9%	66.7 2223.3%	28.6 136.2%	45.5 206.8%	39.6 74.7%
Appropriateness of Medication Strength: Just Right	71.4 1020%	100 3333.3%	38.1 181.4%	50.0 227.3%	54.7 103.2%

Adverse Events

Time Frame	From the first dose of study drug up to 22 weeks
Arm/Group Title	Cohort 1A (Core Study): LEM 5		Cohort 1A (Core Study): LEM 10		Cohort 1B (Core Study): LEM 5		Cohort 1B (Core Study): LEM 10		Cohort 2A (Core Study): LEM 5		Cohort 2A (Core Study): LEM 10		Cohort 2B (Core Study) : LEM 5		Cohort 2B (Core Study): LEM 10		Cohort 1A (Extension Phase): LEM 5		Cohort 1A (Extension Phase): LEM 10		Cohort 1B (Extension Phase): LEM 5		Cohort 1B (Extension Phase): LEM 10		Cohort 2A (Extension Phase): LEM 5		Cohort 2A (Extension Phase): LEM 10		Cohort 2B (Extension Phase): LEM 5		Cohort 2B (Extension Phase): LEM 10
Arm/Group Description	Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 and later up titrated to LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, received LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 and later up titrated to LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 and later up titrated to LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 and later down titrated to LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study.		Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM5 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who took ZOL at least 3 but fewer than 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 and later up titrated to LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM10 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, received LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM5 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who met both criteria for intermittent and frequent ZOL use for 1 week each of the last 2 weeks of the 3-week Screening Period, initially received LEM5 and later up titrated to LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM10 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM5 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM5 and later up titrated to LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM10 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, initially received LEM10 and later down titrated to LEM5 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive initially LEM10 and later down titrated to LEM5 tablet, orally, once at night for up to 12 weeks in the Extension Phase.		Participants who took ZOL at least 5 nights per week, for the last 2 weeks of the 3-week Screening Period, received LEM10 tablet, orally, once at night for up to 2 weeks in Titration Period of Core Study. Eligible participants who completed Titration Period of Core Study entered Extension Phase and continued to receive LEM10 tablet, orally, once at night for up to 12 weeks in the Extension Phase.
All Cause Mortality
	Cohort 1A (Core Study): LEM 5		Cohort 1A (Core Study): LEM 10		Cohort 1B (Core Study): LEM 5		Cohort 1B (Core Study): LEM 10		Cohort 2A (Core Study): LEM 5		Cohort 2A (Core Study): LEM 10		Cohort 2B (Core Study) : LEM 5		Cohort 2B (Core Study): LEM 10		Cohort 1A (Extension Phase): LEM 5		Cohort 1A (Extension Phase): LEM 10		Cohort 1B (Extension Phase): LEM 5		Cohort 1B (Extension Phase): LEM 10		Cohort 2A (Extension Phase): LEM 5		Cohort 2A (Extension Phase): LEM 10		Cohort 2B (Extension Phase): LEM 5		Cohort 2B (Extension Phase): LEM 10
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		0/21 (0%)		0/10 (0%)		0/5 (0%)		0/22 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		0/17 (0%)
Serious Adverse Events
	Cohort 1A (Core Study): LEM 5		Cohort 1A (Core Study): LEM 10		Cohort 1B (Core Study): LEM 5		Cohort 1B (Core Study): LEM 10		Cohort 2A (Core Study): LEM 5		Cohort 2A (Core Study): LEM 10		Cohort 2B (Core Study) : LEM 5		Cohort 2B (Core Study): LEM 10		Cohort 1A (Extension Phase): LEM 5		Cohort 1A (Extension Phase): LEM 10		Cohort 1B (Extension Phase): LEM 5		Cohort 1B (Extension Phase): LEM 10		Cohort 2A (Extension Phase): LEM 5		Cohort 2A (Extension Phase): LEM 10		Cohort 2B (Extension Phase): LEM 5		Cohort 2B (Extension Phase): LEM 10
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		0/21 (0%)		0/10 (0%)		0/5 (0%)		0/22 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		1/17 (5.9%)
Infections and infestations
Pneumonia	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		0/21 (0%)		0/10 (0%)		0/5 (0%)		0/22 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		0/21 (0%)		0/10 (0%)		0/5 (0%)		0/22 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	Cohort 1A (Core Study): LEM 5		Cohort 1A (Core Study): LEM 10		Cohort 1B (Core Study): LEM 5		Cohort 1B (Core Study): LEM 10		Cohort 2A (Core Study): LEM 5		Cohort 2A (Core Study): LEM 10		Cohort 2B (Core Study) : LEM 5		Cohort 2B (Core Study): LEM 10		Cohort 1A (Extension Phase): LEM 5		Cohort 1A (Extension Phase): LEM 10		Cohort 1B (Extension Phase): LEM 5		Cohort 1B (Extension Phase): LEM 10		Cohort 2A (Extension Phase): LEM 5		Cohort 2A (Extension Phase): LEM 10		Cohort 2B (Extension Phase): LEM 5		Cohort 2B (Extension Phase): LEM 10
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		2/21 (9.5%)		0/10 (0%)		0/5 (0%)		6/22 (27.3%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		5/17 (29.4%)
Injury, poisoning and procedural complications
Accidental overdose	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		2/21 (9.5%)		0/10 (0%)		0/5 (0%)		0/22 (0%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		0/17 (0%)
Nervous system disorders
Somnolence	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		1/21 (4.8%)		0/10 (0%)		0/5 (0%)		3/22 (13.6%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		3/17 (17.6%)
Psychiatric disorders
Abnormal dreams	0/7 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		0/21 (0%)		0/10 (0%)		0/5 (0%)		4/22 (18.2%)		0/6 (0%)		0/5 (0%)		0/3 (0%)		0/3 (0%)		0/15 (0%)		0/12 (0%)		0/8 (0%)		2/17 (11.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.