Clinical trial NCT02353299: Assess the Effect of Zolpidem, Silenor & Placebo on Arousability, Ataxia/Balance & Cognition in Healthy Volunteers
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy
Keywords: Cognition
Balance
Lead sponsor: Currax Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Henry Ford Hospital
First posted: 2015-02-02
Enrollment: 52
Sex: MALE
Minimum age (years): 21
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Auditory Arousal Threshold (AAT) at T-max
timeFrame: at either 1.5 or 4 hours post dose
Secondary outcomes:
measure: Tandem Walk Step-Offs
timeFrame: at either 1.5 or 4 hours post dose
measure: Tandem Walk Duration Over Five Trials
timeFrame: at either 1.5 or 4 hours post dose
measure: Berg Balance Test
timeFrame: at either 1.5 or 4 hours post dose
measure: Immediate Free Recall Task
timeFrame: directly after the encoding task
measure: Delayed Free Recall Task
timeFrame: 15 minutes after final awakening the morning
measure: Number of Participants With Adverse Events
timeFrame: throughout the study until the final study visit, up to 6 weeks
Other outcomes:
Locations:
city: Novi
country: United States
facility: Henry Ford Hospital Sleep Disorders & Research Center
state: Michigan
Study officials:
affiliation: Henry Ford Hospital Sleep Disorder Research Center
name: Chris Drake, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Sanofi-Synthelabo. Ambien (zolpidem tartrate) complete prescribing information. 2002.
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citation: Rechtschaffen A, Kales A, eds. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, Calif; Brain Information Service/Brain Research Institute, UCLA; 1968
citation: Berg Balance Scale (BBS)
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citation: Drake CL, Durrence H, Cheng P, Roth T, Pillai V, Peterson EL, Singh M, Tran KM. Arousability and Fall Risk During Forced Awakenings From Nocturnal Sleep Among Healthy Males Following Administration of Zolpidem 10 mg and Doxepin 6 mg: A Randomized, Placebo-Controlled, Four-Way Crossover Trial. Sleep. 2017 Jul 1;40(7). doi: 10.1093/sleep/zsx086.