Driving Impaired
Conditions
Keywords
cognitive function
Brief summary
This is a randomized blinded study to assess the sedative effect of 150 mg TID tolperisone and 10 mg TID cyclobenzaprine compared to placebo on simulated driving performance and cognitive functioning in healthy adult volunteers.
Detailed description
This will be a randomized, placebo-controlled, multiple-dose 3-way cross-over study of the safety and cognitive effects of multiple doses of 150 mg tolperisone administered TID in 30 male and female healthy volunteers. Treatment groups include 450 mg tolperisone (i.e., 150 mg administered three times daily), 30 mg cyclobenzaprine (i.e., 10 mg administered three times daily), and placebo. Subjects will receive 3 days of each treatment. Subject participation will be approximately 3 weeks as outpatients with 3 days each week as overnight clinic participants. In this crossover study, treatment effects will be assessed following the second initial dose, the morning following nighttime dosing (to assess residual next day effects), and at steady state (i.e., following AM dosing on Day 3). Subjects will be dosed on the morning of Day 1. Approximately one hour after the second dose on Day 1, subjects will be administered the cognitive test, followed by the driving simulator examination. On the morning of Day 2, prior to dosing, subjects will be readministered the cognitive test and driving examination to assess residual next day effects. Subjects will repeat cognitive testing and the driving examination on the morning of Day 3, after administration of the AM study medication, to evaluate the cumulative effects of 3 days of dosing.
Interventions
DRUGCyclobenzaprine 10 Mg Oral Tablet
cyclobenzaprine 10 mg tablets
DRUGPlacebo Oral Tablet
sugar pill
Sponsors
Cognitive Research Corporation
Neurana Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
subjects are blindfolded to receive oral dose of treatment, matching placebo, or unblinded active control
Intervention model description
multiple-dose 3-way cross-over study
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. All healthy volunteer subjects must be in general good health based on screening physical examination (defined as the absence of any clinically relevant abnormalities), medical history, 12-lead ECG, and clinical laboratory values (hematology, serum chemistry and urinalysis). 2. All subjects must be capable of understanding and complying with the protocol and have signed the informed consent document. Female subjects of childbearing potential must sign the Women of Childbearing Potential Addendum to the informed consent form. 3. Subjects are required to have a body mass index (BMI) of 18 to 32 kg/m2, inclusive, at Screening. 4. Subject must be able to reliably perform study assessments (i.e., SDLP no higher than 1 standard deviation greater than the mean for normal healthy adults completing the CVDA practice scenario; and number correct on CogScreen Symbol Digit Coding no less than 1 standard deviation below the mean for healthy adults in the 21-55 year age range); demonstrates the ability to understand task instructions (in English), and be physically capable (e.g., adequate manual dexterity, vision, and hearing), cognitively capable and motivated to perform study tasks. 5. Subject must possess a valid driver's license and be an active driver, and have driven a minimum of 10,000 miles (about 16,000 km) per year for the previous 3 years. 6. Subject must also demonstrate simulator sickness questionnaire scores which are not indicative of simulator sickness as defined in the driving simulation operations manual. 7. Subject must have a regular sleep pattern, not be engaged in shift-work, and in general, have at least 7 hours of sleep each night (bedtime occurs between 21:00 and 24:00 hours). 8. Subject has a score \< 10 on the Epworth Sleepiness Scale (ESS). 9. Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion criteria
1. Subjects who have any clinically significant unstable medical abnormality, chronic disease or a history of a clinically significant abnormality of the cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems. 2. Subjects who test positive at screening for hepatitis B surface antigen, hepatitis C antibody or have a history of a positive result. 3. Subjects who are known to be seropositive or test positive at Screening for Human immunodeficiency virus (HIV). 4. Female subjects who are pregnant or lactating. 5. Subjects who have a disorder or history of a condition (e.g., malabsorption, gastrointestinal surgery) that may interfere with drug absorption, distribution, metabolism, or excretion. 6. A history within 2 years of, or current treatment for a sleeping disorder (including excessive snoring, obstructive sleep apnea), or a chronic painful condition that interferes with the subject's sleep. 7. A history of difficulty in falling asleep or staying asleep in the previous 3 months, that is considered clinically significant by the investigator. 8. Subjects who have a history or diagnosis of any of the following conditions: 1. Primary or secondary insomnia 2. Narcolepsy 3. Cataplexy (familial or idiopathic) 4. Circadian Rhythm Sleep Disorder 5. Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, and rapid eye movement behavior disorder 6. Sleep-related Breathing Disorder (obstructive or central sleep apnea syndrome, central alveolar hypoventilation syndrome) 7. Periodic Limb Movement Disorder 8. Restless Legs Syndrome 9. Primary Hypersomnia 10. Excessive Daytime Sleepiness (EDS) 11. Subject has visual or auditory impairment which in the opinion of the investigator would interfere with study related procedures or study conduct. 9. Subjects expected to use any other medication or dietary supplement to promote sleep including over-the-counter sleep medications, during their participation in the study. 10. Subjects who have participated in any investigational study within 30 days prior to screening or are currently participating in another clinical trial. 11. Subjects who have had a recent history (less than 2 years before entering the study) of drug or alcohol abuse, or current positive urine drug screen. Alcohol abuse is defined as current consumption of more than three alcoholic beverages per day. 12. Subjects who have a history of allergic reaction to tolperisone or cyclobenzaprine or any components of these study medications. 13. Use of psychoactive prescription or non-prescription medications, psychoactive nutritional supplements or herbal preparations within 2 weeks or 5 half-lives (whichever is longer) of admission to the Clinical Research Unit (CRU) on Day 1. 14. Presence of a medical or psychiatric condition which could jeopardize the safety of the subject or validity of study results 15. Subjects who consume excessive amounts of coffee, tea, cola, or other caffeinated beverages per day. Excessive amount is defined as greater than 6 servings per day (where 1 serving is approximately equivalent to 120 mg of caffeine). 16. Subjects who will be working a night shift within 1 week of a visit. 17. Subject who have traveled across 1 or more time zones (transmeridian travel) in the last 2 weeks prior to randomization or is expected to travel across 1 or more time zones during the study. 18. Current smoker (\>10 cigarettes or eCigarettes, 3 cigars, or 3 pipes per day) and unwilling to refrain from smoking while confined to the CRU for periods of 3 days. 19. Subjects who have an inability or unwillingness to abide by the study protocol or cooperate fully with the Investigator or designee. 20. Subjects who are a staff member or relative of a staff member. 21. Inability or unwillingness to use adequate contraception (as defined in item 10 of the Inclusion Criteria) during and for 1 month following completion of the study. 22. Has a positive screen for alcohol or other drugs of abuse (amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standard Deviation of Lateral Position (SDLP) | at time of peak concentration of drug (Tmax) on Day 1 | In this crossover study, treatment effects were assessed following initial dose, the morning following nighttime dosing (to assess residual next day effects), and at steady state (i.e., following AM dosing on Day 3). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Standard Deviation of Lateral Position (SDLP) in Simulated Driving Test of Tolperisone Compared to Placebo on Day 2 Next Day Residual Effect | in the morning predose on Day 2 following nighttime dosing | SDLP measured by simulated driving performance of tolperisone compared to placebo on Day 2 prior to morning dosing to determine the next day residual effect or hangover of treatment |
| Sleepiness Endpoint Karolinska Sleepiness Scale KSS | at Tmax on Day 1 | assessment of self-reported motivation for driving performance where 1 equals alert and 9 equals extremely sleepy |
| Steady State Standard Deviation of Lateral Position (SDLP) Day 3 | Day 3 | SDLP measured on Day 3 at steady state following 3 days of dosing three times per day to achieve steady state drug concentration and effect on outcomes |
Countries
United States
Participant flow
Pre-assignment details
Randomized 3-way cross-over of multiple doses of 150 mg tolperisone, 10 mg cyclobenzaprine, or placebo TID in 35 male & female healthy volunteers. Treatment groups A (Tolperisone), B (Cyclobenzaprine), and C (Placebo) randomized by 6 treatment sequences. Subjects serve as own positive control, data analyzed and reported based on treatment type.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All Study Participants; n=33 | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants |
| BMI | 25.012 kg/m2 STANDARD_DEVIATION 2.959 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 31 | 0 / 33 |
| other Total, other adverse events | 15 / 33 | 12 / 31 | 20 / 33 |
| serious Total, serious adverse events | 0 / 33 | 0 / 31 | 0 / 33 |
Outcome results
Primary
Standard Deviation of Lateral Position (SDLP)
In this crossover study, treatment effects were assessed following initial dose, the morning following nighttime dosing (to assess residual next day effects), and at steady state (i.e., following AM dosing on Day 3).
Time frame: at time of peak concentration of drug (Tmax) on Day 1
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolperisone HCl 150 mg | Standard Deviation of Lateral Position (SDLP) | 29.3 cm of deviation of lateral position | Standard Deviation 6.25 |
| Placebo Oral Tablet | Standard Deviation of Lateral Position (SDLP) | 29.7 cm of deviation of lateral position | Standard Deviation 6.37 |
| Cyclobenzaprine 10 mg Oral Tablet | Standard Deviation of Lateral Position (SDLP) | 38.6 cm of deviation of lateral position | Standard Deviation 12.35 |
Secondary
Sleepiness Endpoint Karolinska Sleepiness Scale KSS
assessment of self-reported motivation for driving performance where 1 equals alert and 9 equals extremely sleepy
Time frame: at Tmax on Day 1
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolperisone HCl 150 mg | Sleepiness Endpoint Karolinska Sleepiness Scale KSS | 3.3 units on a scale | Standard Deviation 1.96 |
| Placebo Oral Tablet | Sleepiness Endpoint Karolinska Sleepiness Scale KSS | 3.4 units on a scale | Standard Deviation 1.99 |
| Cyclobenzaprine 10 mg Oral Tablet | Sleepiness Endpoint Karolinska Sleepiness Scale KSS | 5.6 units on a scale | Standard Deviation 2.44 |
Secondary
Standard Deviation of Lateral Position (SDLP) in Simulated Driving Test of Tolperisone Compared to Placebo on Day 2 Next Day Residual Effect
SDLP measured by simulated driving performance of tolperisone compared to placebo on Day 2 prior to morning dosing to determine the next day residual effect or hangover of treatment
Time frame: in the morning predose on Day 2 following nighttime dosing
Population: Per protocol population was analyzed per treatment group, therefore all subjects completing a treatment were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolperisone HCl 150 mg | Standard Deviation of Lateral Position (SDLP) in Simulated Driving Test of Tolperisone Compared to Placebo on Day 2 Next Day Residual Effect | 29.6 cm of deviation from lateral position | Standard Deviation 7.08 |
| Placebo Oral Tablet | Standard Deviation of Lateral Position (SDLP) in Simulated Driving Test of Tolperisone Compared to Placebo on Day 2 Next Day Residual Effect | 29.9 cm of deviation from lateral position | Standard Deviation 7.71 |
| Cyclobenzaprine 10 mg Oral Tablet | Standard Deviation of Lateral Position (SDLP) in Simulated Driving Test of Tolperisone Compared to Placebo on Day 2 Next Day Residual Effect | 35.1 cm of deviation from lateral position | Standard Deviation 10.37 |
Secondary
Steady State Standard Deviation of Lateral Position (SDLP) Day 3
SDLP measured on Day 3 at steady state following 3 days of dosing three times per day to achieve steady state drug concentration and effect on outcomes
Time frame: Day 3
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolperisone HCl 150 mg | Steady State Standard Deviation of Lateral Position (SDLP) Day 3 | 29.8 cm deviation from lateral position | Standard Deviation 6.68 |
| Placebo Oral Tablet | Steady State Standard Deviation of Lateral Position (SDLP) Day 3 | 29.6 cm deviation from lateral position | Standard Deviation 7.46 |
| Cyclobenzaprine 10 mg Oral Tablet | Steady State Standard Deviation of Lateral Position (SDLP) Day 3 | 31.7 cm deviation from lateral position | Standard Deviation 7.9 |