A Study to Determine the Abuse Potential of Single Oral Doses of Lemborexant Compared to Zolpidem, Suvorexant and Placebo in Healthy, Non-Dependent, Recreational Sedative Users

Eisai

Status and phase: Completed; Phase 1

Conditions: Insomnia Disorders

Treatments: Drug: Placebo zolpidem; Drug: Zolpidem tablets; Drug: Placebo suvorexant; Drug: Lemborexant tablets; Drug: Suvorexant tablets, over-encapsulated; Drug: Placebo lemborexant

Study type: Interventional

Funder types: Industry

Identifiers

NCT03158025

E2006-A001-103

Details and patient eligibility

About

The primary purpose of this study is to evaluate the abuse potential of lemborexant (E2006) in comparison to placebo and 2 controls with known abuse potential (ie, zolpidem and suvorexant) with similar indications (zolpidem and suvorexant) or mechanisms of action (suvorexant).

Full description

This is a single-center, single oral dose, randomized, double-blind, placebo-controlled, 6-way crossover study in healthy, non-dependent recreational sedative users.

Enrollment: 39 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

• Healthy, male or female, 18 to 55 years of age, inclusive, at the time of informed consent

• Current sedative users who have used sedatives (e.g., zolpidem, benzodiazepines) for recreational (non-therapeutic) purposes (i.e., for psychoactive effects) at least five times in the past year and used sedatives for recreational (non-therapeutic) purposes (i.e., for psychoactive effects) at least once in the 12 weeks before Screening.

• A body mass index (BMI) of 18.0 to 33.0 kilograms per meters squared (kg/m^2), inclusive, and a minimum weight of 50.0 kg at Screening

• Female participants of childbearing potential with male sexual partners must be using and willing to continue using highly effective contraception for at least 1 month prior to Screening and for at least 1 month after the last study drug administration

• Female participants of non-childbearing potential must meet specified criteria.

• Male participants with female sexual partners of childbearing potential must be using and willing to continue using highly effective contraception from Screening and for at least 1 month after the last study drug administration.

• Participants who are using hormonal contraceptives must be on a stable dose of the same hormonal contraceptive product for at least 1 month before dosing and agree to use the same contraceptive during the study and for at least 1 month after the last study drug discontinuation

• Demonstrate the following in the Qualification Period:

  1. Ability to distinguish orally administered zolpidem 30 mg and suvorexant 40 mg from placebo on the bipolar Drug Liking (at this moment) Visual analog scale (VAS), defined as a ≥15 point peak increase for Drug Liking in response to zolpidem and suvorexant relative to placebo following drug administration. A peak score of ≥65 must be indicated on the bipolar measure of Drug Liking (at this moment) in response to zolpidem and suvorexant
  2. Display an acceptable placebo response, defined as a VAS response between 40 to 60 inclusive, for peak (Emax) Drug Liking (at this moment)
  3. Demonstrate responses to zolpidem and suvorexant that are consistent with discrimination relative to placebo on other subjective measures, as judged by the study center staff
  4. Tolerate study treatment (eg, no episodes of vomiting within the first 3 hours postdose) and demonstrate ability to complete the pharmacodynamic assessments (eg, no unarousable sedation within 4 hours postdose)
  5. Demonstrate general behavior suggestive that the participant could successfully complete the study, as judged by the study center staff.

• Able to speak, read, and understand English sufficiently to allow completion of all study assessments

• Must provide written informed consent prior to the initiation of any protocol-specific procedures

Exclusion Criteria

• Substance or alcohol dependence (excluding nicotine and caffeine) within the past 2 years, as defined by the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition Text Revision (DSM IV-TR), and/or have ever been in a substance or alcohol rehabilitation program to treat their substance or alcohol dependence

• Female participants who are currently pregnant (have a positive pregnancy test) or lactating or who are planning to become pregnant within 1 month of the last study drug administration. No ovum donation is allowed during the study period and for 1 month after study drug discontinuation.

• Male participants who have not had a successful vasectomy (self-reported, confirmed azoospermia) or they and their female partners do not meet specified Inclusion Criteria (i.e., not practicing highly effective contraception throughout the study period and for 1 month after study drug discontinuation). No sperm donation is allowed during the study period and for 1 month after study drug discontinuation.

• Are currently abstinent and do not agree to use a highly effective form of contraception or refrain from sexual activity during the study period and for 1 month after study drug discontinuation

• Clinically significant illness that requires medical treatment within 8 weeks or a clinically significant infection that requires medical treatment within 4 weeks of dosing

• History of gastrointestinal surgery, or evidence of disease that may influence the outcome of the study, within 4 weeks before dosing (e.g., psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism)

• Participated in, is currently participating in, or is seeking treatment for substance- or alcohol-related disorders (excluding nicotine and caffeine)

• Heavy smokers (≥20 cigarettes or eCigarettes per day on average in the past 30 days before Screening), chews tobacco, uses a nicotine transdermal patch (including nicotine-containing products), or is unable to abstain from smoking for at least 8 hours during any day

• Participant is a habitual napper (i.e., habitually naps more than 3 times per week)

  a. Self-reported insomnia disorder, breathing-related sleep disorders, periodic limb movement disorder, restless legs syndrome, nightmare disorder, non-rapid eye movement (REM) sleep arousal disorders (sleep terror disorder or sleepwalking disorder), REM sleep behavior disorder, circadian rhythm sleep-wake disorders, or narcolepsy as defined by the DSM-Fifth Edition (DSM 5), or an exclusionary score (as detailed below) on any of the following subscales of the SLEEP50 Questionnaire:

  1. ≥15 on Apnea subscale
  2. ≥19 on Insomnia subscale if and only if also ≥15 on Impact subscale
  3. ≥7 on Narcolepsy subscale
  4. ≥7 on Restless Legs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) subscale
  5. ≥8 on Circadian Rhythm subscale
  6. ≥7 on Sleepwalking subscale
  7. ≥3 on Item 32 and ≥9 on Items 33 to 35 (i.e., on nightmare subscale)
  8. ≥15 on Impact subscale

• Has been diagnosed with cancer within 3 years before Screening (excluding treated squamous or basal cell carcinoma of the skin), or has an active malignancy of any type (including squamous or basal cell carcinoma of the skin)

• Any clinically abnormal symptom or organ impairment found by medical history at Screening, and physical examinations, vital signs, electrocardiogram (ECG) finding (i.e., QTcF >450 milliseconds [msec]), or laboratory test results that require medical treatment at Screening or that, in the opinion of the investigator, could affect the safety of the participant or the validity of the study

• Increased respiratory impairment risk, including those with sleep apnea or myasthenia gravis

• Participants with any history of suicidal ideation or suicidal behavior (lifetime and 12 months), as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS; Screening version)

• Known hypersensitivity or known allergy to zolpidem, suvorexant, or other sedative-hypnotics (eg, benzodiazepines) or study drug excipients (eg, lactose)

• Positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)

• Require concomitant treatment with moderate and strong cytochrome P450 (CYP) 3A4, 2C9, 2C19, 1A2, and 2D6 inhibitors or any inducer, or respiratory depressants, or cannot safely discontinue prohibited substances within the washout interval before receiving study drug, according to the Investigator or designee. Medications that may interact with study drugs include but are not limited to imipramine, chlorpromazine, sertraline, fluoxetine, rifampin, and ketoconazole. Use of prohibited medication within 30 days prior to screening; use of any other antihistamine, anticholinergic, melatonin, dehydroepiandrosterone (DHA), or herbal sleep or relaxation remedy within 7 days before screening will also be exclusionary at the discretion of the Investigator or designee.

• Received treatment with an investigational drug within 30 days, an investigational antibody treatment within 6 months, or 5-half-lives (if the half-life is known), whichever is longer, preceding the first dose of study

• Donated or had a loss of more than 500 milliliters (mL) of whole blood within 30 days before entry into the Treatment Phase

• Unwilling to be searched (including personal effects) for illicit substances before admission to the study center or during the participants' stay at the clinic

• In the opinion of the Principal Investigator (PI) or designee, are considered unsuitable or unlikely to comply with the study protocol for any reason, including compliance with the Study Restrictions and Prohibitions

• Do not abstain from alcohol for 24 hours before Screening as confirmed by a positive alcohol breath test (Note: Participants that do not meet this criterion may be re-screened at a later date).

• Difficulty with venous blood draws

• An employee of the sponsor or research site personnel directly affiliated with this study or their immediate family member defined as a spouse, parent, child, or sibling, whether biological or legally adopted

• Do not agree to abstain from recreational drug use throughout the study, from Screening until after the last visit

• A participant who, in the opinion of the PI or designee, is considered unsuitable or unlikely to comply with the study protocol for any reason

• Current pending legal charges or who are currently on probation

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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39 participants in 6 patient groups

Placebo, LEM 10 mg, SUV 40 mg, LEM 20 mg, ZOL 30 mg, LEM 30 mg

Experimental group

Description:

Participants will receive the following treatments (orally) in Treatments Periods 1 through 6, respectively: Placebo (3 × placebo lemborexant \[LEM\] tablets; 3 × placebo zolpidem \[ZOL\] tablets; 2 × placebo suvorexant \[SUV\], over-encapsulated); LEM 10 milligrams (mg) (1 × 10 mg LEM tablet; 2 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); SUV 40 mg (2 × 20 mg SUV tablets, over-encapsulated; 3 × placebo ZOL tablets; 3 × placebo LEM tablets); LEM 20 mg (2 × 10 mg LEM tablets; 1 × placebo LEM tablet; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); ZOL 30 mg (3 × 10 mg ZOL tablets; 3 × placebo LEM tablets; 2 × placebo SUV, over-encapsulated); LEM 30 mg (3 × 10 mg LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated). Each treatment period will be separated by a washout interval of at least 14 days.

Treatment:

Drug: Placebo zolpidem

Drug: Suvorexant tablets, over-encapsulated

Drug: Lemborexant tablets

Drug: Placebo suvorexant

Drug: Zolpidem tablets

Drug: Placebo lemborexant

LEM 10 mg, LEM 20 mg, Placebo, LEM 30 mg, SUV 40 mg, ZOL 30 mg

Experimental group

Description:

Participants will receive the following treatments (orally) in Treatments Periods 1 through 6, respectively: LEM 10 mg (1 × 10 mg LEM tablet; 2 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 20 mg (2 × 10 mg LEM tablets; 1 × placebo LEM tablet; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); placebo (3 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 30 mg (3 × 10 mg LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); SUV 40 mg (2 × 20 mg SUV tablets, over-encapsulated; 3 × placebo ZOL tablets; 3 × placebo LEM tablets); ZOL 30 mg (3 × 10 mg ZOL tablets; 3 × placebo LEM tablets; 2 × placebo SUV, over-encapsulated). Each treatment period will be separated by a washout interval of at least 14 days.

Treatment:

Drug: Placebo zolpidem

Drug: Suvorexant tablets, over-encapsulated

Drug: Lemborexant tablets

Drug: Placebo suvorexant

Drug: Zolpidem tablets

Drug: Placebo lemborexant

LEM 20 mg, LEM 30 mg, LEM 10 mg, ZOL 30 mg, Placebo, SUV 40 mg

Experimental group

Description:

Participants will receive the following treatments (orally) in Treatments Periods 1 through 6, respectively: LEM 20 mg (2 × 10 mg LEM tablets; 1 × placebo LEM tablet; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 30 mg (3 × 10 mg LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 10 mg (1 × 10 mg LEM tablet; 2 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); ZOL 30 mg (3 × 10 mg ZOL tablets; 3 × placebo LEM tablets; 2 × placebo SUV, over-encapsulated); placebo (3 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); SUV 40 mg (2 × 20 mg SUV tablets, over-encapsulated; 3 × placebo ZOL tablets; 3 × placebo LEM tablets). Each treatment period will be separated by a washout interval of at least 14 days.

Treatment:

Drug: Placebo zolpidem

Drug: Suvorexant tablets, over-encapsulated

Drug: Lemborexant tablets

Drug: Placebo suvorexant

Drug: Zolpidem tablets

Drug: Placebo lemborexant

LEM 30 mg, ZOL 30 mg, LEM 20 mg, SUV 40 mg, LEM 10 mg, Placebo

Experimental group

Description:

Participants will receive the following treatments (orally) in Treatments Periods 1 through 6, respectively: LEM 30 mg (3 × 10 mg LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); ZOL 30 mg (3 × 10 mg ZOL tablets; 3 × placebo LEM tablets; 2 × placebo SUV, over-encapsulated); LEM 20 mg (2 × 10 mg LEM tablets; 1 × placebo LEM tablet; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); SUV 40 mg (2 × 20 mg SUV tablets, over-encapsulated; 3 × placebo ZOL tablets; 3 × placebo LEM tablets); LEM 10 mg (1 × 10 mg LEM tablet; 2 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); placebo (3 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated). Each treatment period will be separated by a washout interval of at least 14 days.

Treatment:

Drug: Placebo zolpidem

Drug: Suvorexant tablets, over-encapsulated

Drug: Lemborexant tablets

Drug: Placebo suvorexant

Drug: Zolpidem tablets

Drug: Placebo lemborexant

ZOL 30 mg, SUV 40 mg, LEM 30 mg, Placebo, LEM 20 mg, LEM 10 mg

Experimental group

Description:

Participants will receive the following treatments (orally) in Treatments Periods 1 through 6, respectively: ZOL 30 mg (3 × 10 mg ZOL tablets; 3 × placebo LEM tablets; 2 × placebo SUV, over-encapsulated); SUV 40 mg (2 × 20 mg SUV tablets, over-encapsulated; 3 × placebo ZOL tablets; 3 × placebo LEM tablets); LEM 30 mg (3 × 10 mg LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); placebo (3 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 20 mg (2 × 10 mg LEM tablets; 1 × placebo LEM tablet; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 10 mg (1 × 10 mg LEM tablet; 2 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated). Each treatment period will be separated by a washout interval of at least 14 days.

Treatment:

Drug: Placebo zolpidem

Drug: Suvorexant tablets, over-encapsulated

Drug: Lemborexant tablets

Drug: Placebo suvorexant

Drug: Zolpidem tablets

Drug: Placebo lemborexant

SUV 40 mg, Placebo, ZOL 30 mg, LEM 10 mg, LEM 30 mg, LEM 20 mg

Experimental group

Description:

Participants will receive the following treatments (orally) in Treatments Periods 1 through 6, respectively: SUV 40 mg (2 × 20 mg SUV tablets, over-encapsulated; 3 × placebo ZOL tablets; 3 × placebo LEM tablets); placebo (3 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); ZOL 30 mg (3 × 10 mg ZOL tablets; 3 × placebo LEM tablets; 2 × placebo SUV, over-encapsulated); LEM 10 mg (1 × 10 mg LEM tablet; 2 × placebo LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 30 mg (3 × 10 mg LEM tablets; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated); LEM 20 mg (2 × 10 mg LEM tablets; 1 × placebo LEM tablet; 3 × placebo ZOL tablets; 2 × placebo SUV, over-encapsulated). Each treatment period will be separated by a washout interval of at least 14 days.

Treatment:

Drug: Placebo zolpidem

Drug: Suvorexant tablets, over-encapsulated

Drug: Lemborexant tablets

Drug: Placebo suvorexant

Drug: Zolpidem tablets

Drug: Placebo lemborexant