| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment for insomnia disorder |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to placebo (PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in subjects with insomnia disorder |
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| E.2.2 | Secondary objectives of the trial |
Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective sleep efficiency (sSE) after 6 months of treatment in subjects with insomnia disorder
Determine the efficacy of LEM5 and LEM10 compared to PBO on subjective wake after sleep onset (sWASO) after 6 months of treatment in subjects with insomnia disorder
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, age 18 years or older at the time of informed consent
2. Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for Insomnia Disorder, as follows:
- Complains of dissatisfaction with nighttime sleep in the form of difficulty getting to sleep, 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
3. At Screening: History of sSOL ≥30 minutes on at least 3 nights per week in the previous 4 weeks AND/OR sWASO ≥60 minutes on at least 3 nights per week in the previous 4 weeks
4. At Screening: Reports regular time spent in bed, either sleeping or trying to sleep, between 7 and 9 hours
5. At 1st Screening Visit (Visit 1) and 2nd Screening Visit (Visit 2a): Reports regular bedtime, defined as the time the subject attempts to sleep, between 21:00 and 01:00 and regular waketime, defined as the time the subject gets out of bed for the day, between 05:00 and 10:00
6. At Screening and Study Baseline: ISI score ≥15
7. At the 2nd Screening Visit (Visit 2a): Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed on at least 7 consecutive mornings (minimum 5 of 7 for eligibility), such that sSOL ≥30 minutes on at least 3 of the 7 nights and/or sWASO ≥60 minutes on at least 3 of the 7 nights
8. At the 2nd Screening Visit (Visit 2a): Confirmation of regular bedtimes and waketimes, as determined from responses on the Sleep Diary completed on a minimum of 7 consecutive mornings between the 1st and 2nd screening visit, such that the subject has a regular time spend in bed, either sleeping or traying to slee, between 7 and 10 hours
9. At the 2nd Screening Visit (Visit 2a): Confirmation of sufficient duration of time spent in bed, as determined from responses on the Sleep Diary completed on 7 mornings between the 1st and 2nd screening visit, such that there are not more than 2 nights with duration of time spent in bed <7 hours or >10 hours
10. At Baseline (Visit 3a): Reconfirmation of insomnia symptoms, as determined from responses on the Sleep Diary for the final 7 nights of the Run-in Period, such that sSOL ≥30 minutes on at least 3 of the 7 nights and/or sWASO ≥60 minutes on at least 3 of the 7 nights
11. At Baseline (Visit 3a): Confirmation of regular bedtimes and waketimes, such that the subject has a regular time spent in bed, either sleeping or trying to sleep, between 7 and 10 hours for the final 7 nights of the Run-In Period
12. At Baseline (Visit 3a): Reconfirmation of regular bedtime, defined as the time the subject attempts to sleep, between 21:00 and 01:00 and regular waketime, defined as the time the subject gets out of bed for the day, between 05:00 and 10:00 for the final 7 nights of the Run-In period
13. Willing and able to comply with all aspects of the protocol, including staying in bed for at least 7 hours each night
14. Willing to not start a behavioral or other treatment program for insomnia during the subject’s participation in the study |
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| E.4 | Principal exclusion criteria |
1. A current diagnosis of sleep-related breathing disorder including obstructive sleep apnea (with or without continuous positive airway pressure [CPAP] treatment), periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or narcolepsy, or an exclusionary score on the SDSB as follows: STOPBang score ≥5, IRLS score ≥16, ESS score >15 (scores of 11-15 require excessive daytime sleepiness must be recorded in subject's Medical History)
2. 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
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 asleep)
4. For subjects who underwent diagnostic PSG within 1 year before informed consent: Age 18 to 64 years: Apnea-Hypopnea Index ≥10, or Periodic Limb Movements with Arousal Index ≥10; Age ≥65 years: Apnea-Hypopnea Index >15, or Periodic Limb Movements with Arousal Index >15
5. Beck Depression Inventory – II (BDI-II) score >19 at Screening
6. Beck Anxiety Inventory (BAI) score >15 at Screening
7. Habitually naps more than 3 times per week
8. Females who are breastfeeding or pregnant at Screening or Study Baseline (as documented by a positive serum beta-human chorionic gonadotropin [ß-hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the 1st dose of study drug.
9. Females of childbearing potential who:
-Had unprotected sexual intercourse within 30 days before study entry or who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a contraceptive implant, injectable contraceptives, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
10. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s insomnia, or habitually consumes caffeine-containing beverages after 18:00 and is unwilling to forego caffeine after 18:00 for the duration of his/her participation in the study
11. History of drug or alcohol dependency or abuse within approximately the previous 2 years.
16. Current evidence of clinically significant disease (eg, cardiac; respiratory including chronic obstructive pulmonary disease, acute and/or severe respiratory depression; severe hepatic insufficiency; gastrointestinal; renal including severe renal impairment; neurological [including subjects who lack capacity and/or whose cognitive decline indicates disorientation to person/place/ time and/or situation] or psychiatric disease or malignancy within the past 5 years [other than adequately treated basal cell carcinoma]) or chronic pain that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments. Subjects for whom a sedating drug would be contraindicated for safety reasons because of the subject’s occupation or activities are also excluded.
17. Comorbid nocturia resulting in frequent need to get out of bed to use the bathroom during the night
18. Any history of a medical or psychiatric condition that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments
19. Any suicidal ideation with intent with or without a plan at Screening or Study Baseline or within 6 months of Study Baseline (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the eC-SSRS)
21. Scheduled for major surgery during the study
22. Used any prohibited prescription or over-the-counter concomitant medications within 1 week or 5 half lives, whichever is longer, before the 1st dose of study medication (Run-In Period).
23. Used any modality of treatment for insomnia, including cognitive behavioral therapy or marijuana within 1 week or 5 half lives, whichever is longer, before the 1st dose of study medication (Run-In Period)
24. Failed treatment with suvorexant (efficacy or safety) following treatment with an appropriate dose and of adequate duration in the opinion of the investigator
26. A positive drug test at Screening, Run-In, or Baseline or unwilling to refrain from use of recreational drugs during the study
28. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days or 5 times the half-life, whichever is longer preceding informed consent |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean change from Study Baseline in sSOL at Month 6 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Month 6.
The sSOL change from Study Baseline to Month 6 will be analyzed using the mixed effect model repeated measurement (MMRM) analysis on the FAS. The model will include all data and will be adjusted for the corresponding Study Baseline value, region, age group (<65 years old; ≥65 years old), treatment, time (average of the first 7 nights, Month 1, Month 3, and Month 6) and the interaction of treatment by time. |
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| E.5.2 | Secondary end point(s) |
Key Secondary endpoints:
Mean change from Study Baseline in sSE at Month 6
Mean change from Study Baseline of sWASO at Month 6
Additional Secondary Endpoints:
Mean change from Study Baseline of sSOL, of sSE, of sWASO and of subjective total sleep time (sTST), at the beginning of treatment (mean of the 7 nights after the 1st dose in Period 1), at Month 1 and at Month 3
Mean change from Study Baseline of sTST at Month 6
Proportion of responders at Month 6 and Month 12, where sleep onset responder is defined as
follows: sSOL at Study Baseline is ≥30 minutes and mean sSOL at 6 months is ≤20 minutes, and sleep maintenance responder is defined as follows: sWASO at Study Baseline is ≥60 minutes and mean sWASO at 6 months is ≤60 minutes and shows a reduction of >10 minutes compared to Study Baseline.
Change from Study Baseline in daytime functioning, assessed as the total score from the 4 items on daytime functioning, on the ISI, at Months 1, 3, and 6
Change from Study Baseline on the FSS at Months 1, 3, and 6
Ratings on the morning sleepiness item of the Sleep Diary, for:
The mean change from Study Baseline of the 1st 7 mornings after the 1st dose in Period 1 and Period 2
The mean change from Study Baseline at: Month 1, Month 3, and Month 6
The mean change from Study Baseline and from Period 2 Baseline (as appropriate) for subjects with 1, 3, 6, 9, and 12 months exposure (revised per Amendment 06)
The mean change from Screening for the 1st 7 mornings and 2nd 7 mornings of the Follow-up Period
Rebound insomnia endpoints as assessed from the Sleep Dairy during the Follow-up Period
Change from Screening of sSOL on each of the 1st 3 nights, mean sSOL of the 1st 7 nights, and mean sSOL of the 2nd 7 nights of the Follow-up Period
Change from Screening of sWASO on each of the 1st 3 nights, mean sWASO of the 1st 7 nights and mean sWASO of the 2nd 7 nights of the Follow-up Period
Proportion of subjects whose sSOL is longer than at Screening for each of the 1st 3 nights, or whose mean sSOL is longer than at Screening for 1st 7 nights or 2nd 7 nights of the Follow-up Period
Proportion of subjects whose sWASO is higher than at Screening for each of the 1st 3 nights, or whose mean sWASO is higher than at Screening for the 1st 7 nights or 2nd 7 nights of the Follow-up Period
Persistence of Effect
Mean change from Study Baseline of sSOL, of sSE, of sWASO and of sTST at Months 3, 6, 9, and 12 compared to Month 1
Mean change from Treatment Period 2 Baseline (Month 6) of sSOL, sSE, sWASO, and sTST at Months 9 and 12 compared to Month 7 (the first month of treatment in Period 2) (revised per Amendment 06)
Mean change form Study Baseline and Treatment Period 2 Baseline (as appropriate) of sSOL, sSE, sWASO, and sTST at 3 and 6 months exposure compared to 1 months of exposure (revised per Amendment 06)
Safety and Tolerability of Lemborexant
During Period 1, compared to PBO
For subjects exposed to lemborexant for 3, 6, 9, and 12 months (revised per Amendment 06) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At Month 6 for the Key Secondary endpoints
For the other secondary efficacy endpoints (change from Study Baseline of the following for LEM5 and LEM10 compared to PBO; mean sSOL, mean sSE, mean sWASO and mean sTST at 1st 7 nights, Months 1 and 3; and mean sTST at Month 6; ISI total of 4 items of daytime functioning at Months 1, 3, and 6, and FSS score at Months 1, 3, and 6) will be
analyzed using MMRM, assuming MAR. The FSS will also be analyzed for responders, including only those subjects who endorsed clinically significant fatigue at Study Baseline. (revised per Amendments 03 and 06) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Part 2 of the protocol foresees no placebo anymore but comparison between dose levels of test drug |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Chile |
| Finland |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Poland |
| Romania |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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