Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet

• Sponsor: Transcept Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01106859
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 4
• Duration (Months): 3
• Patients Per Site Per Month: 13.2

Study Details

Study Description

Brief Summary

A study in healthy volunteers of the next morning driving performance after middle-of-the-night dosing of 3.5 mg zolpidem tartrate sublingual tablet, a sleep aid. The next morning driving performance will be measured by taking a standardized driving test.

Condition or Disease	Intervention/Treatment	Phase
Insomnia	Drug: zopiclone; Drug: zolpidem tartrate sublingual tablet; Drug: Placebo (sublingual tablet); Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Assessment of Next-Morning Driving Performance After Middle of the Night Administration of Zolpidem Tartrate Sublingual Tablet 3.5 mg in Healthy Adult Volunteers: Single-center, Double-blind, Randomized, Placebo-controlled, Four-way Crossover Study
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: zopiclone Zopiclone is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	Drug: zopiclone; 7.5 mg tablet by mouth. Zopiclone is a commonly used hypnotic in Europe that is known to impair driving in the morning 9 hours after dosing.; Other Names: non-benzodiazepine hypnotic agent Zimovane Imovane ; Drug: Placebo (sublingual tablet); Placebo matching zolpidem tartrate sublingual tablet taken either 3 or 4 hours prior to driving. Participants placed the study drug under the tongue and allowed it to dissolve there for about 2 minutes, then swallowed after dissolved.
Experimental: zolpidem 3 hours prior A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Drug: zolpidem tartrate sublingual tablet; 3.5 mg zolpidem tartrate sublingual tablet taken either 3 or 4 hours prior to driving. Participants placed the study drug under the tongue and allowed it to dissolve there for about 2 minutes, then swallowed after dissolved.; Other Names: Intermezzo® ; Drug: Placebo; Placebo matching zopiclone
Experimental: zolpidem 4 hours prior A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	Drug: zolpidem tartrate sublingual tablet; 3.5 mg zolpidem tartrate sublingual tablet taken either 3 or 4 hours prior to driving. Participants placed the study drug under the tongue and allowed it to dissolve there for about 2 minutes, then swallowed after dissolved.; Other Names: Intermezzo® ; Drug: Placebo; Placebo matching zopiclone
Placebo Comparator: Placebo A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.	Drug: Placebo (sublingual tablet); Placebo matching zolpidem tartrate sublingual tablet taken either 3 or 4 hours prior to driving. Participants placed the study drug under the tongue and allowed it to dissolve there for about 2 minutes, then swallowed after dissolved.; Drug: Placebo; Placebo matching zopiclone

Outcome Measures

Primary Outcome Measures

1. Number of Participants Whose Standard Deviation of Lateral Position (SDLP) Following Active Treatment As Compared to Placebo In Relation To The 2.5 cm SDLP Threshold [3-9 hours post dose]

   SDLP was measured by an infrared camera mounted on the car's roof during a highway driving test. Lateral position of the car relative to the left lane boundary was recorded. The data summarizes the number of participants whose driving performance was worse, neutral or improved as compared to placebo at the 2.5 cm threshold. A neutral driving performance shows a difference of SDLP >= 2.5 cm and <= -2.5 cm when compared to placebo. A worse performance is when the difference of SDLP > 2.5 cm, and an improved performance is when the difference of SDLP < -2.5 cm.

2. Probability of Differences From Placebo Exceeding The 2.5 cm Threshold in Standard Deviation of Lateral Position (SDLP) Following Administration of Active Therapy [3-9 hours post dose]

   This table represents the probability of driving performance changes summarized in the previous table. It answers the question: What is the chance that # participants out of the total number of participants had better (or worse) driving performance? Probability values of <.001 are listed in the data table as 0.000. A symmetry analysis was conducted for the probability of difference in mean SDLP (treatment) - mean SDLP (placebo) exceeding thresholds. Statistically significant asymmetries indicate a decrement in driving performance.

Secondary Outcome Measures

1. Mean Standard Deviation of Lateral Position (SDLP) in the Highway Driving Test [3-9 hours post dose]

   Standard deviation of lateral position (SDLP) in a highway-driving lane is a surrogate measure for driving performance. It measures the driver's ability to stay in a constant position within the driving lane. Variations in the lateral position are recorded and analyzed.

2. Mean Standard Deviation of Speed (SDS) in the Highway Drive Test [3-9 hours post dose]

   Mean standard deviation of speed (SDS) is a common measure of the driver's ability to maintain a constant driving speed. Variations in driving speed are recorded and analyzed.

3. Summary of Participants With Treatment Emergent Adverse Experiences (TEAEs) [Day 1 -6 weeks]

   Adverse Events were graded by the investigator using the World Health Organization (WHO) Adverse Event Grading Scale and were assessed for severity (mild, moderate, severe) and relatedness (summarized as 'unrelated' and 'related') to study treatment. Also included are counts of participants with serious AEs, AEs leading to discontinuation of study treatment, and deaths.

4. Number of Participants Whose Standard Deviation of Lateral Position (SDLP) Following Active Treatment As Compared to Placebo In Relation To The 2.0 cm SDLP Threshold [3-9 hours post dose]

   SDLP was measured by an infrared camera mounted on the car's roof during a highway driving test. Lateral position of the car relative to the left lane boundary was recorded. The data summarizes the number of participants whose driving performance was worse, neutral or improved as compared to placebo at the 2.0 cm threshold. A neutral driving performance shows a difference of SDLP >= 2.0 cm and <= -2.0 cm when compared to placebo. A worse performance is when the difference of SDLP > 2.0 cm, and an improved performance is when the difference of SDLP < -2.0 cm.

5. Probability of Differences From Placebo Exceeding The 2.0 cm Threshold in Standard Deviation of Lateral Position (SDLP) Following Administration of Active Therapy [3-9 hours post dose]

   This table represents the probability of driving performance changes summarized in the previous table. It answers the question: What is the chance that # participants out of the total number of participants had better (or worse) driving performance? Probability values of <.001 are listed in the data table as 0.000. A symmetry analysis was conducted for the probability of difference in mean SDLP (treatment) - mean SDLP (placebo) exceeding thresholds. Statistically significant asymmetries indicate a decrement in driving performance.

6. Number of Participants Whose Standard Deviation of Lateral Position (SDLP) Following Active Treatment As Compared to Placebo In Relation To The 3.5 cm SDLP Threshold [3-9 hours post dose]

   SDLP was measured by an infrared camera mounted on the car's roof during a highway driving test. Lateral position of the car relative to the left lane boundary was recorded. The data summarizes the number of participants whose driving performance was worse, neutral or improved as compared to placebo at the 3.5 cm threshold. A neutral driving performance shows a difference of SDLP >= 3.5 cm and <= -3.5 cm when compared to placebo. A worse performance is when the difference of SDLP > 3.5 cm, and an improved performance is when the difference of SDLP < -3.5 cm.

7. Probability of Differences From Placebo Exceeding The 3.5 cm Threshold in Standard Deviation of Lateral Position (SDLP) Following Administration of Active Therapy [3-9 hours post dose]

   This table represents the probability of driving performance changes summarized in the previous table. It answers the question: What is the chance that # participants out of the total number of participants had better (or worse) driving performance? Probability values of <.001 are listed in the data table as 0.000. A symmetry analysis was conducted for the probability of difference in mean SDLP (treatment) - mean SDLP (placebo) exceeding thresholds. Statistically significant asymmetries indicate a decrement in driving performance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or female subjects between the ages of 21 and 64 inclusive. For female subjects only: Female subjects will be included if they are post-menopausal or sterilized, or if they are of childbearing potential, they are not breastfeeding, their pregnancy test is negative, they have no intention of becoming pregnant during the course of the study, and are using adequate contraceptive drugs or devices. Medically acceptable methods of contraception that may be used by the subject and/or her partner are: oral contraceptives, progestin injection or implants, condom with spermicide, diaphragm with spermicide, IUD, vaginal spermicidal suppository, surgical sterilization or abstinence. Females using oral contraception must have started using the medication at least 4 weeks prior to screening. Surgical sterilization must have occurred at least 6 weeks prior to screening.

• Good health on the basis of pre-study history and physical examination, vital signs and the results of blood chemistry, hematology, and urinalysis

• Good binocular visual acuity, corrected or uncorrected

• Possession of valid driver's license for 3 years or more

• Driving experience at least 3000 km/year

• Signed informed consent

Exclusion Criteria:

• A history of drug addiction or drug or substance abuse, including alcohol abuse, within the past 12 months

• Has a history of restless legs syndrome, sleep apnea, narcolepsy or other primary sleep disorder

• A known hypersensitivity to zolpidem or zopiclone

• Has undergone oral surgery, tooth extraction or piercing of the lip/tongue within 60 days prior to screening

• Has used any medication to promote sleep, including herbal medications, within 14 days (or 5 half-lives of the drug, whichever is longer) prior to screening

• Prescription medications for other health conditions are allowed as long as the subject has been on a stable dose at least 30 days prior to screening

• Has taken any drugs known to induce hepatic drug metabolism (i.e., rifampin) within 30 days prior to screening

• BMI > 29 Kg/M^2

• Current use of medication that affects driving performance

• Smokes more than 10 cigarettes/day

• Uses tobacco products during periods of nighttime awakening

• Consumes more than 6 cups of coffee/day

• Consumes more than 21 glasses of alcohol/week

• Has received an investigational drug within 60 days or 5 half-lives (whichever is longer) prior to screening

• Has any additional condition(s) that in the Investigator's opinion would:

• Affect sleep/wake function

• Prohibit the subject from completing the study

• Not be in the best interest of the subject to participate in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Maastricht University	Maastricht		Netherlands	6229 ER

Sponsors and Collaborators

• Transcept Pharmaceuticals

Investigators

• Principal Investigator: Annemiek Vermeeren, PhD, Maastricht University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Transcept Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01106859
• Other Study ID Numbers: ZI-18; 2010-019959-22
• First Posted: Apr 20, 2010
• Last Update Posted: Feb 14, 2012
• Last Verified: Feb 1, 2012

• Keywords provided by Transcept Pharmaceuticals: insomnia
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Zolpidem; Zopiclone

Study Results

Participant Flow

Pre-assignment Detail	Forty-four candidates were screened. Four screening failures: high blood pressure (2), positive drug test (1), personal reasons (1)

Arm/Group Title	Total Population
Arm/Group Description	All participants in this four-way cross-over study
Period Title: Overall Study
STARTED	40
COMPLETED	40
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Total Population
Arm/Group Description	All participants in this four-way cross-over study
Overall Participants	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37 (15)
Sex: Female, Male (Count of Participants)
Female	20 50%
Male	20 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	40 100%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	39 97.5%
Black	0 0%
Asian	0 0%
Other	1 2.5%
Region of Enrollment (participants) [Number]
Netherlands	40 100%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	176 (9)
Weight (kilograms) [Mean (Standard Deviation) ]
Male	79 (8)
Female	65 (8)
Body Mass Index (BMI) (kilograms/meter^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/meter^2]	23.2 (2.4)

Outcome Measures

1. Secondary Outcome

Title	Mean Standard Deviation of Lateral Position (SDLP) in the Highway Driving Test
Description	Standard deviation of lateral position (SDLP) in a highway-driving lane is a surrogate measure for driving performance. It measures the driver's ability to stay in a constant position within the driving lane. Variations in the lateral position are recorded and analyzed.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone	Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40	40
Least Squares Mean (Standard Error) [centimeters]	16.7 (0.60)	17.3 (0.60)	18.3 (0.60)	15.9 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 4 Hours Prior, Placebo
	Comments	P-value is based on ANOVA model with fixed effects for sequence, period and treatment, a random effect for subject within sequence, and assuming compound symmetry covariance structure; the p-value is reported from LS Mean difference between Treatment Groups: LS mean of SDLP (Zolpidem 4 Hours) - LS mean of SDLP (Placebo).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0174
	Comments	No p-value adjustment for multiple comparisons.
	Method	ANOVA
	Comments	The degrees of freedom are 114 for the p-value testing the difference between treatment groups.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.1 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 3 Hours Prior, Placebo
	Comments	P-value is based on ANOVA model with fixed effects for sequence, period and treatment, a random effect for subject within sequence, and assuming compound symmetry covariance structure; the p-value is reported from LS Mean difference between Treatment Groups: LS mean of SDLP (Zolpidem 3 Hours) - LS mean of SDLP (Placebo).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No p-value adjustment for multiple comparisons.
	Method	ANOVA
	Comments	The degrees of freedom are 114 for the p-value testing the difference between treatment groups
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; 0.8 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zopiclone, Placebo
	Comments	P-value is based on ANOVA model with fixed effects for sequence, period and treatment, a random effect for subject within sequence, and assuming compound symmetry covariance structure; the p-value is reported from LS Mean difference between Treatment Groups: LS mean of SDLP (Zopiclone) - LS mean of SDLP (Placebo).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No p-value adjustment for multiple comparisons
	Method	ANOVA
	Comments	The degrees of freedom are 114 for the p-value testing the difference between treatment groups
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 1.8 to 3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Standard Deviation of Speed (SDS) in the Highway Drive Test
Description	Mean standard deviation of speed (SDS) is a common measure of the driver's ability to maintain a constant driving speed. Variations in driving speed are recorded and analyzed.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population. In one Zopiclone case, the velocity of the car was not recorded due to technical problems, and therefore SDS could not be calculated in this drive.

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone	Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	39	40
Least Squares Mean (Standard Error) [kilometers/hour]	1.98 (0.08)	1.91 (0.08)	1.99 (0.08)	1.83 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 4 Hours Prior, Placebo
	Comments	P-value is based on ANOVA model with fixed effects for sequence, period and treatment, a random effect for subject within sequence, and assuming compound symmetry covariance structure; the p-value is reported from LS Mean difference between Treatment Groups: LS mean of SDS (Zolpidem 4 hours prior) - LS mean of SDS (Placebo).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0145
	Comments	No p-value adjustment for multiple comparisons
	Method	ANOVA
	Comments	The degrees of freedom are 113 for the p-value testing the difference between treatment groups
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 3 Hours Prior, Placebo
	Comments	P-value is based on ANOVA model with fixed effects for sequence, period and treatment, a random effect for subject within sequence, and assuming compound symmetry covariance structure; the p-value is reported from LS Mean difference between Treatment Groups: LS mean of SDS (Zolpidem 3 Hours) - LS mean of SDS (Placebo).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2179
	Comments	No p-value adjustment for multiple comparisons
	Method	ANOVA
	Comments	The degrees of freedom are 113 for the p-value testing the difference between treatment groups
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zopiclone, Placebo
	Comments	P-value is based on ANOVA model with fixed effects for sequence, period and treatment, a random effect for subject within sequence, and assuming compound symmetry covariance structure; the p-value is reported from LS Mean difference between Treatment Groups: LS mean of SDS (Zopiclone) - LS mean of SDS (Placebo).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0096
	Comments	No p-value adjustment for multiple comparisons
	Method	ANOVA
	Comments	The degrees of freedom are 113 for the p-value testing the difference between treatment groups
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Summary of Participants With Treatment Emergent Adverse Experiences (TEAEs)
Description	Adverse Events were graded by the investigator using the World Health Organization (WHO) Adverse Event Grading Scale and were assessed for severity (mild, moderate, severe) and relatedness (summarized as 'unrelated' and 'related') to study treatment. Also included are counts of participants with serious AEs, AEs leading to discontinuation of study treatment, and deaths.
Time Frame	Day 1 -6 weeks

Outcome Measure Data

Analysis Population Description

Safety population (participants who were randomized and received at least one dose of study drug)

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone	Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40	40
At least one TEAE	5 12.5%	5 NaN	6 NaN	4 NaN
TEAE graded as mild	4 10%	5 NaN	6 NaN	4 NaN
TEAE graded as moderate	1 2.5%	0 NaN	0 NaN	0 NaN
TEAE graded as severe	0 0%	0 NaN	0 NaN	0 NaN
Unrelated	3 7.5%	2 NaN	4 NaN	1 NaN
Related	2 5%	3 NaN	2 NaN	3 NaN
At least one serious AE	0 0%	0 NaN	0 NaN	0 NaN
Discontinued study medication due to AE	0 0%	0 NaN	0 NaN	0 NaN
Death	0 0%	0 NaN	0 NaN	0 NaN

4. Primary Outcome

Title	Number of Participants Whose Standard Deviation of Lateral Position (SDLP) Following Active Treatment As Compared to Placebo In Relation To The 2.5 cm SDLP Threshold
Description	SDLP was measured by an infrared camera mounted on the car's roof during a highway driving test. Lateral position of the car relative to the left lane boundary was recorded. The data summarizes the number of participants whose driving performance was worse, neutral or improved as compared to placebo at the 2.5 cm threshold. A neutral driving performance shows a difference of SDLP >= 2.5 cm and <= -2.5 cm when compared to placebo. A worse performance is when the difference of SDLP > 2.5 cm, and an improved performance is when the difference of SDLP < -2.5 cm.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40
Impaired	5 12.5%	10 NaN	18 NaN
Neutral	34 85%	29 NaN	22 NaN
Improved	1 2.5%	1 NaN	0 NaN

5. Primary Outcome

Title	Probability of Differences From Placebo Exceeding The 2.5 cm Threshold in Standard Deviation of Lateral Position (SDLP) Following Administration of Active Therapy
Description	This table represents the probability of driving performance changes summarized in the previous table. It answers the question: What is the chance that # participants out of the total number of participants had better (or worse) driving performance? Probability values of <.001 are listed in the data table as 0.000. A symmetry analysis was conducted for the probability of difference in mean SDLP (treatment) - mean SDLP (placebo) exceeding thresholds. Statistically significant asymmetries indicate a decrement in driving performance.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone	Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40	40
Probability - impaired	0.125	0.250	0.450	NA
Probability - improved	0.025	0.025	0.000	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 4 Hours Prior, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-2.5 cm in Standard Deviation of Lateral Position (SDLP) following administration of zolpidem tartrate sublingual tablet 4 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2188
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 3 Hours Prior, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-2.5 cm in Standard Deviation of Lateral Position (SDLP) following administration of zolpidem tartrate sublingual tablet 3 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0117
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zopiclone, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-2.5 cm in Standard Deviation of Lateral Position (SDLP) following administration of zopiclone 9 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

6. Secondary Outcome

Title	Number of Participants Whose Standard Deviation of Lateral Position (SDLP) Following Active Treatment As Compared to Placebo In Relation To The 2.0 cm SDLP Threshold
Description	SDLP was measured by an infrared camera mounted on the car's roof during a highway driving test. Lateral position of the car relative to the left lane boundary was recorded. The data summarizes the number of participants whose driving performance was worse, neutral or improved as compared to placebo at the 2.0 cm threshold. A neutral driving performance shows a difference of SDLP >= 2.0 cm and <= -2.0 cm when compared to placebo. A worse performance is when the difference of SDLP > 2.0 cm, and an improved performance is when the difference of SDLP < -2.0 cm.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40
Impaired	6 15%	13 NaN	19 NaN
Neutral	33 82.5%	25 NaN	21 NaN
Improved	1 2.5%	2 NaN	0 NaN

7. Secondary Outcome

Title	Probability of Differences From Placebo Exceeding The 2.0 cm Threshold in Standard Deviation of Lateral Position (SDLP) Following Administration of Active Therapy
Description	This table represents the probability of driving performance changes summarized in the previous table. It answers the question: What is the chance that # participants out of the total number of participants had better (or worse) driving performance? Probability values of <.001 are listed in the data table as 0.000. A symmetry analysis was conducted for the probability of difference in mean SDLP (treatment) - mean SDLP (placebo) exceeding thresholds. Statistically significant asymmetries indicate a decrement in driving performance.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone	Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40	40
Probability - impaired	0.150	0.325	0.475	NA
Probability - improved	0.025	0.050	0.000	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 4 Hours Prior, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-2.0 cm in Standard Deviation of Lateral Position (SDLP) following administration of zolpidem tartrate sublingual tablet 4 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1250
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 3 Hours Prior, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-2.0 cm in Standard Deviation of Lateral Position (SDLP) following administration of zolpidem tartrate sublingual tablet 3 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zopiclone, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-2.0 cm in Standard Deviation of Lateral Position (SDLP) following administration of Zopiclone 9 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

8. Secondary Outcome

Title	Number of Participants Whose Standard Deviation of Lateral Position (SDLP) Following Active Treatment As Compared to Placebo In Relation To The 3.5 cm SDLP Threshold
Description	SDLP was measured by an infrared camera mounted on the car's roof during a highway driving test. Lateral position of the car relative to the left lane boundary was recorded. The data summarizes the number of participants whose driving performance was worse, neutral or improved as compared to placebo at the 3.5 cm threshold. A neutral driving performance shows a difference of SDLP >= 3.5 cm and <= -3.5 cm when compared to placebo. A worse performance is when the difference of SDLP > 3.5 cm, and an improved performance is when the difference of SDLP < -3.5 cm.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40
Impaired	2 5%	7 NaN	14 NaN
Neutral	38 95%	33 NaN	26 NaN
Improved	0 0%	0 NaN	0 NaN

9. Secondary Outcome

Title	Probability of Differences From Placebo Exceeding The 3.5 cm Threshold in Standard Deviation of Lateral Position (SDLP) Following Administration of Active Therapy
Description	This table represents the probability of driving performance changes summarized in the previous table. It answers the question: What is the chance that # participants out of the total number of participants had better (or worse) driving performance? Probability values of <.001 are listed in the data table as 0.000. A symmetry analysis was conducted for the probability of difference in mean SDLP (treatment) - mean SDLP (placebo) exceeding thresholds. Statistically significant asymmetries indicate a decrement in driving performance.
Time Frame	3-9 hours post dose

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	Zolpidem 4 Hours Prior	Zolpidem 3 Hours Prior	Zopiclone	Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 3 hours prior to driving.	Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
Measure Participants	40	40	40	40
Probability - impaired	0.050	0.175	0.350	NA
Probability - improved	0.000	0.000	0.000	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 4 Hours Prior, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-3.5 cm in Standard Deviation of Lateral Position (SDLP) following administration of zolpidem tartrate sublingual tablet 4 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5000
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zolpidem 3 Hours Prior, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-3.5 cm in Standard Deviation of Lateral Position (SDLP) following administration of zolpidem tartrate sublingual tablet 3 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0156
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zopiclone, Placebo
	Comments	Symmetry analysis was performed for the probability of difference from placebo falling above and below the threshold of +/-3.5 cm in Standard Deviation of Lateral Position (SDLP) following administration of zopiclone 9 hours prior to driving. Statistically significant asymmetries indicate a decrement in driving performance. Lack of statistical significance indicates symmetry which shows a lack of treatment effect on driving performance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	No adjustments. The a priori threshold for statistical significance is 0.05.
	Method	McNemar
	Comments	McNemar's exact test with one degree of freedom is used.

Adverse Events

Time Frame	Treatment emergent AEs (Day 1 to Week 6)
Arm/Group Title	Zolpidem 4 Hours Prior		Zolpidem 3 Hours Prior		Zopiclone		Placebo
Arm/Group Description	A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is 3.5 mg zolpidem tartrate sublingual tablet taken 4 hours prior to driving.		A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is zolpidem tartrate sublingual tablet taken 3 hours prior to driving.		Zopiclone (7.5 mg tablet) is taken at bedtime 9 hours before driving. The middle-of-the-night medication is a placebo matching zolpidem tartrate sublingual tablet.		A placebo matching zopiclone is taken at bedtime. The middle-of-the-night treatment is a placebo matching zolpidem tartrate sublingual tablet.
All Cause Mortality
	Zolpidem 4 Hours Prior		Zolpidem 3 Hours Prior		Zopiclone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Zolpidem 4 Hours Prior		Zolpidem 3 Hours Prior		Zopiclone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)		0/40 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Zolpidem 4 Hours Prior		Zolpidem 3 Hours Prior		Zopiclone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/40 (12.5%)		5/40 (12.5%)		6/40 (15%)		4/40 (10%)
Eye disorders
Eye inflammation	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1
Gastrointestinal disorders
Diarrhoea	0/40 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0
Nausea	1/40 (2.5%)	1	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0
Vomiting	0/40 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0
General disorders
Fatigue	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0	2/40 (5%)	2
Musculoskeletal and connective tissue disorders
Myalgia	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Nervous system disorders
Headache	0/40 (0%)	0	3/40 (7.5%)	3	1/40 (2.5%)	1	1/40 (2.5%)	1
Somnolence	2/40 (5%)	2	2/40 (5%)	2	2/40 (5%)	2	1/40 (2.5%)	1
Reproductive system and breast disorders
Dysmenorrhoea	1/40 (2.5%)	1	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0

Limitations/Caveats

No studies directly connect SDLP thresholds with an increased risk of an accident for an individual. Nor has a SDLP threshold been adopted by a regulatory body. Based on published literature, an SDLP change of 2.5 cm was used in the primary outcome.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor agrees to review manuscripts within a reasonable period of time. If sponsor determines the publication included patentable subject matter, sponsor will be granted no less than 120 days to prepare patent applications.