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| Name | Class |
|---|---|
| Henry Ford Hospital | OTHER |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Silenor 6 mg (DXP-4H) | Active Comparator | Silenor 6 mg single nightime dose- 4 hour post dose arousability and cognitive assessments |
|
| Placebo (PBO-4H) | Placebo Comparator | placebo single nightime dose -4 hour post dose arousability and cognitive assessments |
|
| Zolpidem 10 mg (ZOL-1.5H) | Active Comparator | zolpidem 10 mg single nightime dose - 1.5 hour arousability and cognitive assessments |
|
| Placebo (PBO-1.5H) | Placebo Comparator | placebo single nightime dose -1.5 hour arousability and cognitive assessments |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Silenor 6 mg | Drug | Silenor 6 mg single nighttime dose. |
|
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Chris Drake, PhD | Henry Ford Hospital Sleep Disorder Research Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Henry Ford Hospital Sleep Disorders & Research Center | Novi | Michigan | 48377 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Davis KL, Charey D, Cuyle JT, Nemeroff C. Neuropsychopharmacology, The Fifth Generation of Progress. 2002; Section 13: 1938-1939 | ||
| Background | Silenor [prescribing information]. Pernix Pharmaceuticals, Inc., San Diego, CA; March 2010. | ||
| Background | Sanofi-Synthelabo. Ambien (zolpidem tartrate) complete prescribing information. 2002. | ||
| 1798888 | Background | 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. | |
| Result |
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| ID | Title | Description |
|---|---|---|
| FG000 | PBO-4H Then PBO-1.5H Then DXP-4H Then ZOL-1.5H | Period 1: Doxepin-matching placebo-single nighttime dose Period 2: Zolpidem-matching placebo-single nighttime dose Period 3: Doxepin 6mg-single nighttime dose Period 4: Zolpidem 10 mg-single nighttime dose |
| FG001 | PBO-1.5H Then ZOL-1.5H Then PBO-4H Then DXP-4H | Period 1: Zolpidem-matching placebo-single nighttime dose Period 2: Zolpidem 10 mg-single nighttime dose Period 3: Doxepin-matching placebo-single nighttime dose Period 4: Doxepin 6mg-single nighttime dose |
| FG002 | ZOL-1.5H Then DXP-4H Then PBO-1.5H Then PBO-4H | Period 1: Zolpidem 10mg-single nighttime dose Period 2: Doxepin 6mg-single nighttime dose Period 3: Zolpidem-matching placebo-single nighttime dose Period 4: Doxepin-matching placebo-single nighttime dose |
| FG003 | DXP-4H Then PBO-4H Then ZOL-1.5H Then PBO-1.5H | Period 1: Doxepin 6mg-single nighttime dose Period 2: Doxepin-matching placebo-single nighttime dose Period 3: Zolpidem 10mg-single nighttime dose Period 4: Zolpidem-matching placebo-single nighttime dose |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (1 Night) |
| |||||||||||||
| Second Intervention (1 Night) |
| |||||||||||||
| Third Intervention (1 Night) |
| |||||||||||||
| Fourth Intervention (1 Night) |
|
Subjects were healthy males
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | A single group of subjects were recruited and assigned all study treatments in random order |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | Decibels (dB) | at either 1.5 or 4 hours post dose |
|
Throughout the study period until the final study visit, up to 6 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Silenor 6 mg (DXP-4H) | Silenor 6 mg single nightime dose- 4 hour post dose arousability and cognitive assessments Silenor 6 mg: Silenor 6 mg single nighttime dose. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Memory Impairment | Nervous system disorders | MedDRA (7.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christopher L Drake | Sleep Disorders and Research Center Henry Ford Hospital | 248-344-6672 | cdrake1@hfhs.org |
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| ID | Term |
|---|---|
| D004316 | Doxepin |
| D000077334 | Zolpidem |
| ID | Term |
|---|---|
| D010082 | Oxepins |
| D004988 | Ethers, Cyclic |
| D004987 | Ethers |
| D009930 | Organic Chemicals |
| D003990 |
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|
| zolpidem 10 mg | Drug | Zolpidem 10 mg single nighttime dose |
|
|
| Placebo | Drug | placebo single nighttime dose-1.5 hours |
|
| Placebo | Drug | placebo single nighttime dose-4 hours |
|
| 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 |
| 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 |
| Result | Berg Balance Scale (BBS) |
| 10221356 | Result | Mintzer MZ, Griffiths RR. Selective effects of zolpidem on human memory functions. J Psychopharmacol. 1999;13(1):18-31. doi: 10.1177/026988119901300103. |
| 20625114 | Result | 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. |
| 18431116 | Result | 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. |
| 28575467 | Derived | 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. |
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| Participants |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
placebo single nightime dose -4 hour post dose arousability and cognitive assessments
Silenor 6 mg: Silenor 6 mg single nighttime dose.
| OG002 | Zolpidem 10 mg (ZOL-1.5H) | zolpidem 10 mg single nightime dose - 1.5 hour arousability and cognitive assessments zolpidem 10 mg: Zolpidem 10 mg single nighttime dose |
| OG003 | Placebo (PBO-1.5H) | placebo single nightime dose -1.5 hour arousability and cognitive assessments zolpidem 10 mg: Zolpidem 10 mg single nighttime dose |
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | number of step offs | at either 1.5 or 4 hours post dose |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | Seconds | at either 1.5 or 4 hours post dose |
|
|
|
| Secondary | 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). | Posted | Mean | Standard Deviation | sum of component scores | at either 1.5 or 4 hours post dose |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | Number of words | directly after the encoding task |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | Number of words | 15 minutes after final awakening the morning |
|
|
|
| Secondary | 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. | Posted | Number | Participants | throughout the study until the final study visit, up to 6 weeks |
|
|
|
| 0 |
| 51 |
| 0 |
| 51 |
| 13 |
| 51 |
| EG001 | Placebo (PBO-4H) | placebo single nightime dose -4 hour post dose arousability and cognitive assessments Silenor 6 mg: Silenor 6 mg single nighttime dose. | 0 | 52 | 0 | 52 | 11 | 52 |
| EG002 | Zolpidem 10 mg (ZOL-1.5H) | zolpidem 10 mg single nightime dose - 1.5 hour arousability and cognitive assessments zolpidem 10 mg: Zolpidem 10 mg single nighttime dose | 0 | 52 | 0 | 52 | 12 | 52 |
| EG003 | Placebo (PBO-1.5H) | placebo single nightime dose -1.5 hour arousability and cognitive assessments zolpidem 10 mg: Zolpidem 10 mg single nighttime dose | 0 | 52 | 0 | 52 | 10 | 52 |
| Somnolence | Nervous system disorders | MedDRA (7.0) | Systematic Assessment |
|
| Insomnia | Nervous system disorders | MedDRA (7.0) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (7.0) | Systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA (7.0) | Systematic Assessment |
|
| Fatigue/lethargy | General disorders | MedDRA (7.0) | Systematic Assessment |
|
| Xerostomia | Gastrointestinal disorders | MedDRA (7.0) | Systematic Assessment |
|
| Rigors | Nervous system disorders | MedDRA (7.0) | Systematic Assessment |
|
| Other | General disorders | MedDRA (7.0) | Systematic Assessment |
|
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| Dibenzoxepins |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |