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

Primary Purpose

Healthy

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Silenor 6 mg
zolpidem 10 mg
Placebo
Placebo
Sponsored by
Currax Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Healthy focused on measuring Cognition, Balance

Eligibility Criteria

21 Years - 50 Years (Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • Henry Ford Hospital Sleep Disorders & Research Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Silenor 6 mg (DXP-4H)

Placebo (PBO-4H)

Zolpidem 10 mg (ZOL-1.5H)

Placebo (PBO-1.5H)

Arm Description

Silenor 6 mg single nightime dose- 4 hour post dose arousability and cognitive assessments

placebo single nightime dose -4 hour post dose arousability and cognitive assessments

zolpidem 10 mg single nightime dose - 1.5 hour arousability and cognitive assessments

placebo single nightime dose -1.5 hour arousability and cognitive assessments

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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).
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.
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
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.

Full Information

First Posted
January 23, 2015
Last Updated
December 6, 2017
Sponsor
Currax Pharmaceuticals
Collaborators
Henry Ford Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02353299
Brief Title
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

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
January 2015 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Currax Pharmaceuticals
Collaborators
Henry Ford Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Healthy
Keywords
Cognition, Balance

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Silenor 6 mg (DXP-4H)
Arm Type
Active Comparator
Arm Description
Silenor 6 mg single nightime dose- 4 hour post dose arousability and cognitive assessments
Arm Title
Placebo (PBO-4H)
Arm Type
Placebo Comparator
Arm Description
placebo single nightime dose -4 hour post dose arousability and cognitive assessments
Arm Title
Zolpidem 10 mg (ZOL-1.5H)
Arm Type
Active Comparator
Arm Description
zolpidem 10 mg single nightime dose - 1.5 hour arousability and cognitive assessments
Arm Title
Placebo (PBO-1.5H)
Arm Type
Placebo Comparator
Arm Description
placebo single nightime dose -1.5 hour arousability and cognitive assessments
Intervention Type
Drug
Intervention Name(s)
Silenor 6 mg
Other Intervention Name(s)
doxepin
Intervention Description
Silenor 6 mg single nighttime dose.
Intervention Type
Drug
Intervention Name(s)
zolpidem 10 mg
Other Intervention Name(s)
zolpidem
Intervention Description
Zolpidem 10 mg single nighttime dose
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo single nighttime dose-1.5 hours
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
placebo single nighttime dose-4 hours
Primary Outcome Measure Information:
Title
Auditory Arousal Threshold (AAT) at T-max
Description
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.
Time Frame
at either 1.5 or 4 hours post dose
Secondary Outcome Measure Information:
Title
Tandem Walk Step-Offs
Description
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.
Time Frame
at either 1.5 or 4 hours post dose
Title
Tandem Walk Duration Over Five Trials
Description
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.
Time Frame
at either 1.5 or 4 hours post dose
Title
Berg Balance Test
Description
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).
Time Frame
at either 1.5 or 4 hours post dose
Title
Immediate Free Recall Task
Description
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.
Time Frame
directly after the encoding task
Title
Delayed Free Recall Task
Description
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
Time Frame
15 minutes after final awakening the morning
Title
Number of Participants With Adverse Events
Description
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.
Time Frame
throughout the study until the final study visit, up to 6 weeks

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chris Drake, PhD
Organizational Affiliation
Henry Ford Hospital Sleep Disorder Research Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Henry Ford Hospital Sleep Disorders & Research Center
City
Novi
State/Province
Michigan
ZIP/Postal Code
48377
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
Citation
Davis KL, Charey D, Cuyle JT, Nemeroff C. Neuropsychopharmacology, The Fifth Generation of Progress. 2002; Section 13: 1938-1939
Results Reference
background
Citation
Silenor [prescribing information]. Pernix Pharmaceuticals, Inc., San Diego, CA; March 2010.
Results Reference
background
Citation
Sanofi-Synthelabo. Ambien (zolpidem tartrate) complete prescribing information. 2002.
Results Reference
background
PubMed Identifier
1798888
Citation
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. doi: 10.1093/sleep/14.6.540.
Results Reference
background
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
Results Reference
result
Citation
Berg Balance Scale (BBS)
Results Reference
result
PubMed Identifier
10221356
Citation
Mintzer MZ, Griffiths RR. Selective effects of zolpidem on human memory functions. J Psychopharmacol. 1999;13(1):18-31. doi: 10.1177/026988119901300103.
Results Reference
result
PubMed Identifier
20625114
Citation
Gottlieb DJ, Yenokyan G, Newman AB, O'Connor GT, Punjabi NM, Quan SF, Redline S, Resnick HE, Tong EK, Diener-West M, Shahar E. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010 Jul 27;122(4):352-60. doi: 10.1161/CIRCULATIONAHA.109.901801. Epub 2010 Jul 12.
Results Reference
result
PubMed Identifier
18431116
Citation
Chung F, Yegneswaran B, Liao P, Chung SA, Vairavanathan S, Islam S, Khajehdehi A, Shapiro CM. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology. 2008 May;108(5):812-21. doi: 10.1097/ALN.0b013e31816d83e4.
Results Reference
result
PubMed Identifier
28575467
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.
Results Reference
derived

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

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