Assess the Effect of Zolpidem, Silenor & Placebo on Arousability, Ataxia/Balance & Cognition in Healthy Volunteers

Study Overview
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Brief Summary
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This is a Phase IV, randomized, double-blind, placebo-controlled, four-arm crossover study. The study will assess the effects of a single dose of Silenor 6 mg compared with matching placebo and a single dose of zolpidem 10 mg compared to its matching placebo at the respective T-max in normal healthy adult male volunteers. The study will be conducted in approximately 52 male subjects

Detailed Description
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Subjects will be screened and asked to complete sleep disorders questionnaires and a sleep diary to establish normal sleep patterns and to rule out any sleep disorder. Eligible subjects will be scheduled for a Screening PSG to rule out PLMS, sleep apnea and other sleep disorders. Subjects who meet the screening PSG criteria will be randomly assigned to a treatment sequence order that involves both the study drug and the time subjects are awakened in the middle-of-the-night using a crossover study design. These four sequences include Silenor 6 mg with a middle-of-the-night awakening at 4 hours (DXP-4H), zolpidem 10 mg with a middle-of-the-night awakening at 1.5 hours (ZOL-1.5H), placebo with a middle-of-the-night awakening at 4 hours (PBO-4H), and placebo with a middle-of-the-night awakening at 1.5 hours (PBO-1.5H). Study drug will be administered under fasted conditions (at least 4 hours) as a single dose at bedtime (approximately 2300 hours), and each subject will receive one dose of each active drug (Silenor 6 mg and zolpidem 10 mg), and two doses of placebo during the treatment period. Safety assessments will be performed throughout the study. During the night of assessment, subjects will be awoken at the estimated T-max of the active drugs, with a matching placebo group awakened at each of these time points with the same arousability protocol. Arousability will be assessed using the Auditory Awakening Threshold test (AAT) . Once the Auditory Awakening Threshold has been determined, subjects will perform a Tandem Walk assessment followed by the Berg Balance Scale (BBS) and finally by Free Recall Memory testing. Subjects will be discharged from the sleep center once all assessments have been completed. A final study visit will be performed for subjects either after they have completed all four Treatment Periods or they have prematurely discontinued the study.

Official Title
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Phase IV 4 Way Crossover Study to Assess and Compare the Effect of a Single Nighttime Administration of Zolpidem, Silenor and Placebo on Arousability, Ataxia/Balance and Cognitive Performance in Healthy Volunteers.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Silenor 6 mg
* Drug: zolpidem 10 mg
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be in good general health as determined by the investigator; Have a 3-month history of a normal nightly sleep pattern based on the subject's self report ; A usual time in bed A regular bedtime between 2200 and 2400 hours No habitual daytime napping; Epworth Sleepiness Scale score ≤ 10; Be able to read, understand, and provide written/dated informed consent before enrolling in the study, and must be willing and able to comply with all study procedures; Be able to follow verbal and written instructions provided in English Exclusion Criteria: Have a body mass index (BMI) >35 kg/m2 Have symptoms consistent with the diagnosis of any sleep disorder (e.g., insomnia, sleep apnea, narcolepsy, periodic leg movements, or restless leg syndrome); On screening PSG AHI > 10 or PLMAI >10; Have a known or suspected diagnosis of Acquired Immune Deficiency Syndrome (AIDS), or have tested seropositive for human immunodeficiency virus (HIV) antibody or antigen previously; Have any clinically significant abnormal finding in physical examination, neurological assessment, vital signs, elevated body temperature, or clinical laboratory tests, as determined by the Investigator; Have a known exaggerated pharmacological sensitivity, hypersensitivity, or history of a clinically significant adverse reaction to zolpidem; Have a known or exaggerated pharmacological sensitivity, hypersensitivity, or intolerance to doxepin HCl, any tricyclic antidepressant, or antihistamine; Currently taking cimetidine or a monoamine oxidase inhibitor (MAOI); Current diagnosis of severe urinary retention; Current diagnosis of untreated glaucoma; Intends to use any medication including over-the-counter (OTC) medications that would interfere with normal sleep architecture (such as systemic steroids, beta-adrenergic blockers, amphetamines, modafinil, etc.); Self-reports use of products containing nicotine of greater than 15 cigarettes daily, or cannot avoid products containing nicotine during the normal sleep periods; Self report consumption of more than five alcoholic beverages on any one day or greater than 14 alcoholic beverages weekly over the past week; Have a history of epilepsy or serious head injury; Used CYP450 2D6 inducers or inhibitors within 7 days before screening; Have used prescribed or OTC medications within 30 days of screening (Day 0) or intend to use any prescription or OTC medication during the study that may interfere with the evaluation of the study drug. Have used an investigational drug within 30 days or five half lives (whichever is longer) before screening, or plans to use an investigational drug during the study or have used doxepin or zolpidem previously. Score of < 40 on the BBS at screening

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Silenor 6 mg (DXP-4H)<br>Silenor 6 mg single nightime dose- 4 hour post dose arousability and cognitive assessments | Drug: Silenor 6 mg<br>* Silenor 6 mg single nighttime dose.<br>* Other names: doxepin;Drug: zolpidem 10 mg<br>* Zolpidem 10 mg single nighttime dose<br>* Other names: zolpidem;Drug: Placebo<br>* placebo single nighttime dose-1.5 hours<br>Drug: Placebo<br>* placebo single nighttime dose-4 hours<br>|
| Placebo Comparator: Placebo (PBO-4H)<br>placebo single nightime dose -4 hour post dose arousability and cognitive assessments | Drug: Silenor 6 mg<br>* Silenor 6 mg single nighttime dose.<br>* Other names: doxepin;Drug: zolpidem 10 mg<br>* Zolpidem 10 mg single nighttime dose<br>* Other names: zolpidem;Drug: Placebo<br>* placebo single nighttime dose-1.5 hours<br>Drug: Placebo<br>* placebo single nighttime dose-4 hours<br>|
| Active Comparator: Zolpidem 10 mg (ZOL-1.5H)<br>zolpidem 10 mg single nightime dose - 1.5 hour arousability and cognitive assessments | Drug: Silenor 6 mg<br>* Silenor 6 mg single nighttime dose.<br>* Other names: doxepin;Drug: zolpidem 10 mg<br>* Zolpidem 10 mg single nighttime dose<br>* Other names: zolpidem;Drug: Placebo<br>* placebo single nighttime dose-1.5 hours<br>Drug: Placebo<br>* placebo single nighttime dose-4 hours<br>|
| Placebo Comparator: Placebo (PBO-1.5H)<br>placebo single nightime dose -1.5 hour arousability and cognitive assessments | Drug: Silenor 6 mg<br>* Silenor 6 mg single nighttime dose.<br>* Other names: doxepin;Drug: zolpidem 10 mg<br>* Zolpidem 10 mg single nighttime dose<br>* Other names: zolpidem;Drug: Placebo<br>* placebo single nighttime dose-1.5 hours<br>Drug: Placebo<br>* placebo single nighttime dose-4 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Auditory Arousal Threshold (AAT) at T-max | AAT will performed at T-max for Silenor and matching placebo at 4 hours post dose. Assessments performed at t max for zolpidem and placebo at 1.5 hours post dose. An acoustic stimulus (1000 Hz tone) was presented through audiometric earphones (E-A-RTone 3A Insert Earphones). Tones began at 30 dB and increased by 5 dB until the participant woke up or the maximum dB-level (110 dB) was reached. | at either 1.5 or 4 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tandem Walk Step-Offs | Tandem walk will be performed at T-max for Silenor and matching placebo at 4 hours post dose and at 1.5 hours post dose for zolpidem 10 mg and matching placebo. Fall risk as impacted by balance was measured using the Tandem Walk Test (TWT), which assesses balance via a method of walking in which the toes of the back foot must touch the heel of the front foot at each step; this elicits postural control by reducing the base of support compared to normal walking. Endpoints were the number of step-offs from the beam. | at either 1.5 or 4 hours post dose | 
| Tandem Walk Duration Over Five Trials | Tandem walk will be performed at T-max for Silenor and matching placebo at 4 hours post dose and at 1.5 hours post dose for zolpidem 10 mg and matching placebo. Fall risk as impacted by balance was measured using the Tandem Walk Test (TWT), which assesses balance via a method of walking in which the toes of the back foot must touch the heel of the front foot at each step; this elicits postural control by reducing the base of support compared to normal walking. Endpoint: mean completion duration over five trials. | at either 1.5 or 4 hours post dose | 
| Berg Balance Test | Berg Balance will be performed at T-max for silenor and matching placebo at 4 hours post dose and at 1.5 hours post dose for zolpidem 10 mg and matching placebo. Fall risk as impacted by gait was measured using the Berg Balance Scale (BBS). The BBS is a widely used clinical test of static and dynamic balance abilities. Comprising of 14 simple balance-related tasks, ranging from standing up from a sitting position to standing on one foot, the BBS takes 15-20 minutes to complete. Each component task is scored on a Likert scale: 0 (unable to perform) to 4 (performed independently). The sum of component scores yields the final BBS score (0-20: high fall risk; 21-40: medium fall risk; 41-56: low fall risk). | at either 1.5 or 4 hours post dose | 
| Immediate Free Recall Task | Immediate Free Recall will be performed at T-max for silenor and matching placebo at 4 hours post dose and at 1.5 hours post dose for zolpidem 10 mg and matching placebo. Free Recall is a basic paradigm in the psychological study of memory. In this paradigm, participants were presented with a total of 16 words serially. They were informed prior to the task that memory for the presented words would be tested later in the session. | directly after the encoding task | 
| Delayed Free Recall Task | Delayed Free Recall Task was performed 15 minutes after final awakening the morning Free Recall is a basic paradigm in the psychological study of memory. In this paradigm, participants were presented with a total of 16 words serially. They were informed prior to the task that memory for the presented words would be tested later in the session. Participants were asked to recall as many words as they can 15 minutes after final awakening in the morning | 15 minutes after final awakening the morning | 
| Number of Participants With Adverse Events | Adverse events were defined by any negative event experienced by a participant during the study (assessed in the morning prior to participants leaving the lab) and included the washout period following each treatment. | throughout the study until the final study visit, up to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, Balance