Driving Simulation to Assess Non-Sedative Effects of Tolperisone

Driving Simulation Cross-Over Study of Sedative Effects of Tolperisone Compared to Cyclobenzaprine and Placebo

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.

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.

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).