Clinical trial NCT03158025: 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
Official title: A Randomized, Double-Blind, 6-Way Crossover 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Insomnia Disorders
Keywords: Recreational sedatives
Healthy participants
Lemborexant
E2006
Zolpidem
Suvorexant
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Purdue Pharma LP
First posted: 2017-05-17
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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).

Detailed 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.

Eligibility 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

Primary outcomes:
measure: Mean peak Maximum Effect (Emax) score for Drug Liking on a Visual Analog Scale (VAS)
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
Secondary outcomes:
measure: Mean time to peak effect (TEmax) score for Drug Liking on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean peak minimum effect (Emin) score for Drug Liking on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean time to peak minimum effect (TEmin) score for Drug Liking on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean time-averaged area under the effects curve (TA_AUE) score for Drug Liking on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Overall Drug Liking (Overall, my liking for this drug is) on a VAS
timeFrame: 12 (Day 1), 24 (Day 2), and 48 hours (Day 3) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for taking the drug again on a VAS
timeFrame: 12 (Day 1), 24 (Day 2), and 48 hours (Day 3) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Subjective Drug Value (SDV)
timeFrame: 12 (Day 1), 24 (Day 2), and 48 hours (Day 3) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Good Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax score for Good Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for Good Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Feeling Stoned on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax score for Feeling Stoned on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for Feeling Stoned on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Feeling High on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax score for Feeling High on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for Feeling High on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Bad Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax score for Bad Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for Bad Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Sedative Effect on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax score for Sedative Effect on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for Sedative Effect on a VAS
timeFrame: Pre-dose; 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax for Addiction Research Center Inventory (ARCI) Pentobarbital-Chlorpromazine-Alcohol Group (PCAG) subscale score
timeFrame: 1, 2, 4, and 8 hours (all Day 1) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax for ARCI PCAG subscale score
timeFrame: 1, 2, 4, and 8 hours (all Day 1) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA-AUE for ARCI PCAG subscale score
timeFrame: 1, 2, 4, and 8 hours (all Day 1) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Any Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TEmax score for Any Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for Any Effects on a VAS
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean Emax score for Observer's Assessment of Alertness/Sedation (OAA/S): composite and sum scores
timeFrame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE score for OAA/S: composite and sum scores
timeFrame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Maximum change from baseline (CFBmax) in Choice Reaction Time (CRT) score (Motor Reaction Time [MRT] subscale score, Recognition Reaction Time [RRT] subscale score, and Total Reaction Time [TRT] subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE of CRT score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Minimum change from baseline (CFBmin) of percentage correct response relative to CRT score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE of percentage correct response relative to CRT score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: CFBmax in Divided Attention (DA) score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE of DA score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: CFBmin of percentage correct response relative to CRT score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Mean TA_AUE of percentage correct response relative to DA score (MRT subscale score, RRT subscale score, and TRT subscale score)
timeFrame: Pre-dose; 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 (all Day 1), and 24 hours (Day 2) post-dose of each treatment cycle (up to 11 weeks)
measure: Number of participants with any treatment-emergent adverse event (TEAE)
timeFrame: Up to 20 weeks
measure: Number of participants with any treatment-emergent serious adverse event (SAE)
timeFrame: up to 20 weeks
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: INC Research Toronto, Inc.
Study officials:
References:
citation: Landry I, Hall N, Alur J, Filippov G, Reyderman L, Setnik B, Henningfield J, Moline M. Acute Cognitive Effects of the Dual Orexin Receptor Antagonist Lemborexant Compared With Suvorexant and Zolpidem in Recreational Sedative Users. J Clin Psychopharmacol. 2022 Jul-Aug 01;42(4):374-382. doi: 10.1097/JCP.0000000000001562. Epub 2022 Jun 24.