To investigate effect of tizanidine ER 12 mg on simulated driving performance, cognitive and psychomotor functions compared with placebo, tizanidine IR 8 mg (two 4 mg doses given 6.5 hours apart) and active-control in healthy subjects
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
gezonde proefpersonen; slaperigheid bij rijden na inname medicatie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Driving simulator measurement at baseline and at four scheduled time points
post dose of standard deviation lateral position (SDLP) in centimeters
Secondary outcome
* Psychomotor and cognitive function- at baseline and at four scheduled time
points post dose. Reaction time to:
o Visual stimulus on psychomotor vigilance task (PVT) in milliseconds
o Visual stimulus on vigilance and tracking (VigTrack) task in milliseconds
o Light emitting diode (LED) in milliseconds
* Driving simulator measurement at baseline and at four scheduled time points
post dose of:
o Lateral position in centimeters
o Standard deviation of speed (SDSP) in miles per hour
o Distance headway (DHW) in kilometers
o Time-to-collision (TTC) in seconds
o Time headway (THW) in seconds
* Subjective assessment of sleepiness:
A subjective rating with scores 1 to 9 for alertness using Karolinska
Sleepiness Scale (KSS)
Background summary
Sun Pharma Advanced Research Company (SPARC) Limited has developed a new
formulation of tizanidine hydrochloride. It is an extended release (ER) tablet
(Tizanidine ER), 12 mg strength, in development for the treatment of acute
musculoskeletal pain. The new formulation is developed with the purpose to
provide patients with the benefit of less frequent dosing and, more
importantly, to minimize adverse effects of central nervous system as a result
of lower peak plasma concentrations of drug.
The hypothesis of lower effect on cognition and psychomotor function with
tizanidine ER will be evaluated in the proposed clinical study. Tizanidine ER
tablets will be evaluated and compared with Zanaflex® (tizanidine IR tablets),
diphenhydramine, and placebo on simulated driving and cognitive tests.
Driving a vehicle is a complex task that requires sufficient cognitive, visual,
and motor skills. Simulated driving is a valid tool for the assessment of
cognitive and psychomotor performance in a setting that is almost similar to
actual driving.18,19 The clinical facility (TNO), in the Netherlands, conducts
a wide variety of driving simulator studies ranging from a focus on fundamental
perceptual questions to cognitive research questions.18,19,20
SPARC plans to conduct the proposed study in the TNO*s high-fidelity
moving-base driving simulator settings. This study will be conducted in
well-controlled testing conditions. TNO*s simulator has previously shown
sensitivity to drug-induced impairment.21-26
Study objective
To investigate effect of tizanidine ER 12 mg on simulated driving performance,
cognitive and psychomotor functions compared with placebo, tizanidine IR 8 mg
(two 4 mg doses given 6.5 hours apart) and active-control in healthy subjects
Study design
This is a randomized, double blind, active and placebo-controlled, four
treatment, four period, crossover study
Intervention
In a crossover design all subjects will receive :
- Tizanidine extended release (ER) tablet, (single 12 mg dose) followed by
placebo dose after 6.5 hours
- Placebo tablet (two doses separated by 6.5 hours)
- Diphenhydramine 50 mg tablet (single dose) followed by placebo after 6.5
hours
- Tizanidine immediate release tablet (IR), 8 mg (two 4 mg doses separated by
6.5 hours)
all test sessions are one week apart
Study burden and risks
Volunteers have to visit the institute for screening, training on the tasks,
and have to undergo the assessments on 4 separate test trial days. Each trail
day lasts 11 hours. Before and after the test sessions there is a physical
examination, clinical laboratory assessments, a 12-lead ECG, and urine samples
at each visit. A measurement of systolic and diastolic blood pressure, to
assess orthostatic hypotension, will be scheduled pre-dose, 1, 2.5, 4, and 7
hours post dose.
In clinical studies, most frequently reported adverse effects with tizanidine
were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or
tiredness) and dizziness. In the controlled clinical studies, adverse events
that caused discontinuation treatment were asthenia [(weakness, fatigue and/or
tiredness) (3%)], somnolence (3%), dry mouth (3%), increased spasm or tone
(2%), and dizziness (2%). The detailed description for safety profile of
tizanidine is available on lablel information for Zanaflex®.
Several clinical studies studies were conducted in Indian population, to
evaluate pharmacokinetics of tizanidine ER product. To date, 84 subjects were
treated with tizanidine ER product. The medication was tolerated well and
reported side effects were similar to those reported for Zanaflex® and no new
adverse effects were reported.
Most frequently reported adverse event for diphenhydramine were somnolence,
dizziness, sedation. The rare adverse effects reported were irritability,
impaired performance (impaired driving performance, poor work performance,
incoordination, reduced motor skills and impaired information processing),
dryness of nose, tightness of chest, constipation, diarrhoea, dry mouth,
hypotension, palpitations, tachycardia, headache and photosensitivity. The
detailed description for safety profile of tizanidine is available on lablel
information for Sleepeaze or one a night nightcalm.
Due to the spatial limitations of the driving simulator, perceived
discrepancies between the motion of the simulator and that of the virtual
vehicle can occur and lead to simulator sickness. Symptoms of simulator
sickness include discomfort, apathy, drowsiness, disorientation, fatigue, and
vomiting. Occurrence of driving simulator sickness occurs in 5-10% of the
population and is reduced by selecting non-urban scenarios with a limited
amount of turning/braking events in the scenario.
It is anticipated that all reported adverse effects recover spontaneously after
termination of the treatment. It is considered that the possible adverse
effects of the study medication and/or simulator conditions are non-health
threatening and acceptable. The new medication will allow for less frequent
dosing and will lead to lower peak plasma concentrations thereby minimizing
adverse effects on the central nervous system.
Mahakali Caves Rd Andheri (E); Mahal Industrial Estate 17 B
Mumbai 400 093
IN
Mahakali Caves Rd Andheri (E); Mahal Industrial Estate 17 B
Mumbai 400 093
IN
Listed location countries
Age
Inclusion criteria
-The potential participant has given informed and written consent and is able to comply with all study assessments scheduled in the protocol
-Healthy males or females aged 21 to 45 years (both inclusive) with body mass index between 18 and 30 kg/m2 and having normal vision
-Possession of a valid Netherlands driver*s license * 3 years with a reported average annual mileage * 5,000 km during the last 3 years
-Any female surgically sterile (bilateral tubal ligation at least 6 months prior, bilateral oophorectomy, or hysterectomy performed) or any female of child bearing potential should be willing to practice an acceptable method of birth control following screening to completion of study of the study. The acceptable contraceptive methods are condoms, diaphragm, intrauterine device (IUD), same sex partner or partner with vasectomy, (note: hormonal contraception is not permitted as it affects tizanidine pharmacokinetics)
-Potential subjects considered healthy based on medical evaluation, electrocardiogram and laboratory values at screening, all lab values are within normal limits or any value out of normal limits considered by the Investigator to be of no clinical significance. lab tests:(Hematology: hemoglobin [Hb] and leukocytes; Biochemistry: C-reactive protein [CRP], creatinine, gamma-glutamyl transpeptidase [Gamma-GT], aspartate aminotransferase [ASAT], alanine aminotransferase [ALAT], bilirubin
Exclusion criteria
1. History of allergies or hypersensitivity or intolerance to tizanidine or diphenhydramine
2. History or presence of clinically significant or uncontrolled cardiovascular, neurological, psychiatric, hepatic, renal, gastrointestinal, hematological, musculoskeletal or sleep disorder
3. History of surgery within 4 weeks of screening
4. Clinical lab results suggestive of hepatic impairment (ALT or AST or bilirubin > 2 times of ULN) or renal impairment (creatinine > 2 mg/dL)
5. Clinically significant history of alcohol intake (> 21 drinks per week).
6. History of drug abuse with drugs used for recreational purpose within one year of the screening visit
7. Use of any drug known to induce or inhibit hepatic drug metabolism (specifically CPY1A2 inhibitors, fluoroquinolones, zileuton, antiarrythmics, anti-histamines, ticlopidine, anti-virals, oral contraceptives, anti-depressants and any drugs known to cause change in neurological function) within 14 days of screening to end of study
8. Signs or symptoms of narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction
9. History of participation in an investigational drug study within the past 30 days
10. History of excessive caffeine consumption (> 5 cups/day) or smoking (*10 cigarettes per day) during the last six months prior to screening
11. At admission for each period: evidence of pregnancy (urine pregnancy test positive on urine drug screen for women), or demonstrable blood-alcohol concentration (alcohol breath test)
12. Pregnant or lactating females
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003770-32-NL |
| CCMO | NL54219.028.15 |