Clinical trial NCT03353922
Conditions: Driving Impaired
Keywords: cognitive function
Sponsor: Neurana Pharmaceuticals, Inc.
Start date: 2017-07-31; Completion date: 2018-01-30
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 150 mg tolperisone tablets or cyclobenzaprine 10 mg oral tablet administered by mouth every 8 hours for 3 days arm 2: sugar pills administered by mouth every 8 hours for 3 days arm 3: 10 mg cyclobenzapine tablets administered by mouth every 8 hours for 3 days
Interventions: intervention 1: Cyclobenzaprine 10 Mg Oral Tablet intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: cyclobenzaprine 10 mg tablets intervention 2: sugar pill

Protocol documents:
Prot_ICF_000.pdf: 
 
  
CLINICAL TRIAL PROTOCOL: 115 
Title: 
Driving Simulation Cross-Over Study of Sedative Effects of 
Tolperisone Compared to Cyclobenzaprine and Placebo   
Substance Identifier
Tolperisone hydrochloride, NR100 
IND number 
69,169 
Protocol Number 
115 
Sponsor 
Neurana Pharmaceuticals, Inc. 
3525 Del Mar Heights Rd, #609  
San Diego, CA 92130 
Principal 
Investigator 
Russell Rosenberg, Ph.D. 
NeuroTrials Research 
1100 Johnson Ferry Rd, Suite 420 
Atlanta, GA 30342 
(678) 651-2006 
Date of Protocol 
28 April 2017 
Sponsor 
Representative 
Judy Caron, Ph.D., Chief Operating Officer 
Neurana Pharmaceuticals, Inc. 
3525 Del Mar Heights Rd, #609  
San Diego, CA 92130 
(617) 640-5043   
Amendment # 
NA 
 
Confidentiality Statement 
The present protocol is property of Neurana Pharmaceuticals, Inc. and it may not in full or in part 
be passed on, reproduced, published or otherwise employed without the express permission of 
Neurana Pharmaceuticals, Inc. 
 




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1.2 
Investigator 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment. I agree to conduct the study in accordance with Good Clinical Practice guidelines. I 
also agree to report all information or data in accordance with the protocol and, in particular, I 
agree to report any serious adverse experiences as defined in this protocol. I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol. I understand that information that identifies me will be used and 
disclosed as described in the protocol.  
It is obligatory that the Investigator become familiar with all the sections of the tolperisone 
Investigator’s Brochure prior to initiation of the study. 
 
 
SIGNATURE 
 
DATE 
 
 
 
 
 
PRINTED NAME 
 
 
____________________________________________ 


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2 
 SYNOPSIS 
Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
Study Title: 
Driving Simulation Cross-Over Study of Sedative Effects of Tolperisone Compared to 
Cyclobenzaprine and Placebo 
Study Number: 115 
Study Phase: 
Phase 1  
Primary Objective: 
• 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.  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). 
Secondary Objectives: 
• To assess the safety of 150 mg TID tolperisone dosing for 3 days in healthy volunteers. 


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Endpoints: 
Primary Endpoint:  
• Standard Deviation of Lateral Position (SDLP), measured by simulated driving 
performance using CRCDS-MiniSim, of tolperisone compared to placebo 
Secondary Endpoints: 
• SDLP measured by simulated driving performance using CRCDS-MiniSim of 
tolperisone compared to cyclobenzaprine 
• Sleepiness Endpoint – Karolinska Sleepiness Scale (KSS) 
• Self-reported readiness to drive (Response to: “Right now do you feel safe to drive?”) 
• Visual Analog Scales (VAS) to assess self-reported motivation and appraisal of driving 
performance 
• Cognitive Performance Endpoints 
 CogScreen Symbol Digit Coding (SDC) test 
• Number of correct responses  
• Response Accuracy 
• Standard deviation of reaction time 
• Driving Performance Endpoints 
 Lane exceedance; including number, maximum, and duration 
 Speed related measures; including speed deviation, average speed, 
excessive speed count, and speedings ratio 
 Driving safety measures; including excessive Ay (cornering speed 
threshold -exceeded), and total collisions 
 Divided attention measures; including correct responses, omission 
errors, commission errors, reaction time, and standard deviation of 
reaction time 
• Plasma drug levels and driving performance  
• Safety Endpoints 
 Clinical Evaluations 
• Vital signs 
• Orthostatic effects 
• Physical examinations 
• 12-lead electrocardiograms (ECGs) 
 Laboratory safety tests (blood chemistry, hematology,  urinalysis, serum 
and urine pregnancy tests for women of childbearing potential) 
 Adverse events (AEs) 
Study Design: 
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 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
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.   
Subjects will be screened within 28 days prior to Treatment Period 1 (Visit 2) for eligibility for 
participation in the study. The Familiarization and Practice drives on the driving simulator 
must be completed no more than 21 days prior to Treatment Period 1.  
Subjects meeting all inclusion/exclusion criteria will then be admitted to the clinic on Day -1 
to be evaluated for continued eligibility. Subjects will perform a practice trial with the driving 
simulator and the cognitive function test.  
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.  
Subjects will be discharged on Day 3 with instructions to return to the clinic on Day 7 and Day 
14 to repeat the above procedure with the second and third treatments.  
A follow-up phone call will be conducted 1 week (±3 days) following discharge from the 
clinic on Day 17 to assess for continued safety. 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
 
 
 
 
 
Schematic of Design: 
Hour 
Day -1 
Day 1 
Day 2 
Day 3 
Days 4-7 
6:00(WASHOUT)
Breakfast 
Breakfast 
Breakfast   
7:00  
Driving 
Simulation 
WASHOUT 
8:00  
AM Dosing 
AM Dosing 
AM Dosing   
9:00
  
Driving 
Simulation   
10:00 
 
 
 
 
11:30  
Lunch 
Lunch 
Lunch 
  
12:00  
  
13:00  
  
14:00  
PM Dosing 
PM Dosing 
Discharge   
15:00
  
Driving 
Simulation 
  
16:00Check-in 
  
17:00 Dinner 
Dinner 
Dinner 
  
18:00  
  
19:00  
  
20:00
Practice Cog
& Driving 
Simulation 
  
21:00  
  
22:00Bedtime 
HS 
Dosing/Bedtime 
HS 
Dosing/Bedtime 
  
  
 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
Subject Population: 
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. Male and female subjects must be between 21 and 55 years of age, inclusive, at the 
time of consent. 
3. 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. 
4. Subjects are required to have a body mass index (BMI) of 18 to 32 kg/m2, inclusive, 
at Screening. 
5. 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. 
6. 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. 
7. Subject must also demonstrate simulator sickness questionnaire scores which are 
not indicative of simulator sickness as defined in the driving simulation operations 
manual.  
8. 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). 
9. Subject has a score < 10 on the Epworth Sleepiness Scale (ESS). 
10. Female subjects must have a negative serum pregnancy test at screening, must be 
postmenopausal (amenorrhea for at least 2 years), surgically sterile, or practicing or 
agree to practice an effective method of birth control if they are sexually active 
before study entry, during the study and one month after the end of the study by 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
using an acceptable method of contraception. Acceptable methods of birth control 
must be used for at least 14 days prior to the use of study drug. Acceptable methods 
of birth control include oral, injected, vaginal or patch contraceptives, IUD (copper 
intrauterine device), or double-barrier method (e.g., condom, diaphragm or cervical 
cap with spermicidal foam, cream, gel or suppository). 
11. 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: 
a. Primary or secondary insomnia 
b. Narcolepsy 
c. Cataplexy (familial or idiopathic) 
d. Circadian Rhythm Sleep Disorder 
e. Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking 
disorder, and rapid eye movement behavior disorder 
f. Sleep-related Breathing Disorder (obstructive or central sleep apnea 
syndrome, central alveolar hypoventilation syndrome) 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
g. Periodic Limb Movement Disorder 
h. Restless Legs Syndrome 
i. Primary Hypersomnia 
j. Excessive Daytime Sleepiness (EDS) 
k. 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. 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
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). 
Planned Number of Subjects:  
A sufficient number of subjects will be enrolled to ensure a total of 30 normal, healthy, male 
and female subjects between the ages of 21 and 55 years (at the time of informed consent) will 
complete all dosing periods, including the driving assessment. 
Test Product; Dose; and Mode of Administration: 
Tolperisone 150 mg tablets and matching placebo will be provided for the study by the 
Sponsor.  
Cyclobenzaprine 10 mg tablets will be procured by the individual sites or by the CRO on 
behalf of the sites.  
The subjects will be instructed to swallow the tablets whole, with approximately 4-6 ounces of 
water. Study drug will be administered by qualified unblinded CRU personnel and a mouth 
and hand check performed. 
Duration of Treatment: 
The total duration of study participation will be approximately 4 weeks (range 4-8 weeks), 
including Screening and Follow-up. 
Safety Assessments: 
Adverse Events (AEs): 
AEs will be captured from the time of obtaining informed consent until discharge from the 
study. 
Pregnancy Test: 
A serum pregnancy test will be performed at Screening and a urine pregnancy test will be 
performed upon each admission to the unit for females of childbearing potential. A positive 
pregnancy test at any time during the study will automatically disqualify the subject from 
further participation in the trial. 
Serum Chemistries, Hematology and Urinalysis: 
Blood will be collected for serum chemistries and hematology and urine will be collected for 
urinalysis at the Screening visit and end of study (EOS) (Day 17).  


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
Vital Signs: 
Vital signs, including supine and standing blood pressure and heart rate, temperature and 
respiration rate will be collected at the following visits/time points: 
• Screening,  
• Day -1, 7, and 14 upon clinic check-in, 
• Day 1, 2, 3, 8, 9, 10, 15, 16, and 17 prior to and 4 hours post AM dosing. 
• Weight and height will be measured at Screening only. 
Electrocardiogram 
Twelve-lead ECG recording will be collected at Screening and EOS (Day 17). 
Pharmacokinetic (PK) Blood Sampling: 
Blood samples for the determination of plasma tolperisone concentrations will be drawn prior 
to each AM dosing on Days 1-3 and post-driving test (15-30 minutes after the drive) on Days 
1 and 3.  
Statistical Plan and Methods:  
Doses of tolperisone will be considered non-inferior (NI) to placebo if the upper 95% 
confidence limit on the difference in SDLP between that dose and placebo is less than 4.4 cm 
(the NI margin). Cyclobenzaprine comparisons to placebo are to assess assay sensitivity and 
no adjustment to alpha levels will be made for either the comparison of cyclobenzaprine to 
placebo or tolperisone, or for secondary endpoints or analyses. Formal statistical tests (where 
performed) will be two-sided and testing at the alpha=0.05 level of significance.   
The sequence of testing to control for multiplicity associated with comparisons of tolperisone 
to placebo (to assess NI) on multiple days is  Day 1 (single-dose), followed by Day 3 (steady-
state), followed by Day 2 (residual effect). Tolperisone will be considered NI to placebo if 
prior comparisons (at time points in the sequence provided, above) also indicate non-
inferiorty.    
In general, categorical variables will be summarized by the count (N) and percentage of 
subjects (%). Continuous variables will be summarized by the number of non-missing 
observations (N), mean, standard deviation (SD), median, minimum, and maximum values. 
All study data will be displayed in the data listings. 
Safety: 
Safety measures will be summarized using descriptive statistics and listed for each subject. 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
Safety analysis will be based on all subjects enrolled who receive at least 1 dose of the study 
medication. The safety analysis will evaluate adverse events and additional safety parameters.  
The number and percentage of subjects experiencing at least one AE will be summarized by 
body system, preferred term, and treatment. If appropriate, AEs will also be summarized by 
intensity and relationship to study drug. SAEs, if any, will be tabulated. 
Additional safety parameters will be assessed from summaries of physical examinations, 
12-lead ECGs and vital signs. The 12-lead ECG results will be categorized as normal, 
clinically significant abnormal, and not clinically significant abnormal. Hematology, chemistry 
and urinalysis laboratory test results will be categorized relative to the normal ranges. The 
changes from baseline for each of these parameters from Screening to EOS will be presented.  
Complete listings and summary tables for all safety information including AEs, laboratory 
safety data, ECG, vital signs and physical examination will be included in the study report. 
Pharmacokinetics: 
The correlations between plasma drug concentrations and key secondary end points will be 
evaluated. 
The decision as to which plasma samples collected will be assayed for evaluation of 
pharmacokinetics/pharmacodynamics will be determined by Neurana Pharmaceuticals, Inc. 
The relationship between plasma drug levels and driving performance will be evaluated, data 
permitting. If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.  
Pharmacodynamics: 
The primary endpoint, SDLP, will be analyzed using a normal theory mixed effects model 
with fixed effects for sequence, period, and treatment, and a random effect for subject within 
sequence. An unstructured covariance structure and Kenward-Roger degrees of freedom will 
be used.   
Pair-wise comparisons (hypothesis tests) of differences in least squares means, and 95% 
confidence intervals on differences will be provided for: 
 
 
 
 
 
Initial dose effect 
1. cyclobenzaprine versus placebo following Day 1 PM dose 
2. tolperisone versus placebo following Day 1 PM dose 
3. tolperisone versus cyclobenzaprine following Day 1 PM dose 
 
Next day residual dose effect 
 


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Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride, NR100 
Name of Active Ingredient: 
Tolperisone hydrochloride 
4.  cyclobenzaprine versus placebo following Day 2 AM dose 
5. tolperisone versus placebo following Day 2 AM dose 
6. tolperisone versus cyclobenzaprine following Day 2 AM dose 
 
Steady-state dose effect 
 
7. cyclobenzaprine versus placebo following Day 3 AM dose 
8. tolperisone versus placebo following Day 3 AM dose 
9. tolperisone versus cyclobenzaprine following Day 3 AM dose 
 
In addition, pair-wise within-subject differences in SDLP greater than 4.4 cm in absolute value 
(equal to the previously found difference between placebo and 0.05% Blood Alcohol Content 
(BAC) for the CRCDS) will be compared using McNemar’s test. These pair-wise, within 
subject differences in SDLP will also be tested for symmetry about zero [6] using the 
maximally selected McNemar test. 
Summary statistics will be provided (mean, SD, median, minimum, maximum) for SDLP for 
each time point and treatment group. 
Additional details of analysis for secondary endpoints of VAS, SDC, KSS, and driving 
performance endpoints will be specificed in the Statistical Analysis Plan (SAP).  
The relationship between tolperisone plasma drug levels and driving performance (i.e., the 
primary endpoint of SDLP) will be assessed by correlational analyses.   
All pharmacodynamic results will be summarized in tabular format, with summary statistics 
(number [n], mean, SD, median, minimum, and maximum) and change from baseline, as 
appropriate by time point. 


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3 
TABLE OF CONTENTS 
1 
SIGNATURES ........................................................................................................................2 
1.1 
Sponsor’s Representative .......................................................................................................... 2 
1.2 
Investigator ................................................................................................................................ 3 
2 
SYNOPSIS ..............................................................................................................................4 
3 
TABLE OF CONTENTS ......................................................................................................15 
4 
ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................18 
5 
STUDY ADMINISTRATION SCHEDULE ........................................................................20 
5.1 
Principal Investigator .............................................................................................................. 20 
5.2 
Study Director ......................................................................................................................... 20 
5.3 
Medical Monitor ...................................................................................................................... 20 
5.4 
SAE Reporting Contact Information - Sponsor ....................................................................... 20 
6 
BACKGROUND AND RATIONALE FOR THE STUDY .................................................21 
6.1 
Introduction ............................................................................................................................. 21 
6.2 
Drug Profile ............................................................................................................................. 21 
6.2.1 
Tolperisone.............................................................................................................. 21 
6.2.2 
Cyclobenzaprine ...................................................................................................... 21 
6.3 
Rationale .................................................................................................................................. 21 
6.3.1 
Study Design ........................................................................................................... 21 
6.3.2 
Tolperisone Dose Level .......................................................................................... 22 
6.3.3 
Positive Control Dose Level ................................................................................... 22 
7 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................23 
7.1 
Primary Objective.................................................................................................................... 23 
7.2 
Secondary Objectives .............................................................................................................. 23 
7.3 
Primary Endpoint .................................................................................................................... 23 
7.4 
Secondary Endpoints ............................................................................................................... 23 
8 
SUBJECT DEFINITION ......................................................................................................25 
8.1 
Inclusion Criteria ..................................................................................................................... 25 
8.2 
Exclusion Criteria .................................................................................................................... 26 
9 
STUDY DESIGN..................................................................................................................29 
9.1 
Summary of Study Design ...................................................................................................... 29 
9.2 
Meals ....................................................................................................................................... 30 
9.3 
Subject Assignment ................................................................................................................. 30 
10 
DAILY STUDY ACTIVITIES .............................................................................................31 
10.1 Screening ................................................................................................................................. 31 
10.2 Study Periods ........................................................................................................................... 31 
10.2.1 
CRU Admission Days (Visits 2, 6, and 10: Days -1, 7, and 14) ............................. 31 
10.2.2 
CRU Inpatient Day 1 (Visits 3, 7, and 11: Days 1, 8, and 15) ................................ 32 
10.2.3 
CRU Inpatient Day 2 (Visits 4, 8, and 12: Days 2, 9, and 16) ................................ 32 
10.2.4 
Clinic Discharge Days (Visits 5, 9, and 13: Days 3, 10, and 17) ............................ 33 


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10.3 Day 24 ±3 Days (Visit 14: Follow-up Phone Call) ................................................................. 34 
11 
STUDY PROCEDURES ......................................................................................................34 
11.1 CVDA Driving Scenario on the CRCDS-MiniSim ................................................................. 34 
11.2 Karolinska Sleepiness Scale .................................................................................................... 34 
11.3 Self-perceived Safety to Drive Question ................................................................................. 35 
11.4 Digit Symbol Substitution Test (CogScreen Symbol Digit Coding; SDC) ............................. 35 
11.5 Visual Analog Scales (VAS) to Assess Subject’s Motivation and Self-Appraisal ................. 35 
11.6 Vital Signs ............................................................................................................................... 35 
11.7 Clinical Laboratory Assessments ............................................................................................ 35 
11.8 Blood Collection for Tolperisone Plasma Concentrations ...................................................... 36 
11.8.1 
Sample Storage and Shipment ................................................................................ 37 
11.9 Blood Collection Volume for the Study .................................................................................. 37 
11.10 Medical and Social History ..................................................................................................... 37 
11.11 Physical Examination .............................................................................................................. 37 
11.12 Epworth Sleepiness Scale ........................................................................................................ 37 
11.13 Pregnancy Test ........................................................................................................................ 38 
11.14 Study Drug Preparation and Dispensing ................................................................................. 38 
11.15 Study Drug Administration ..................................................................................................... 38 
11.16 Concurrent Medication ............................................................................................................ 39 
11.17 Fluid, Food, and Lifestyle Restrictions ................................................................................... 39 
11.18 Discontinuation Criteria and Procedures ................................................................................. 39 
11.18.1 
Premature Termination of Study/Closure of Study Sites ........................................ 40 
12 
EVALUATION AND REPORTING OF ADVERSE EVENTS..........................................41 
12.1 Adverse Event (AE) Definitions ............................................................................................. 41 
12.1.1 
Severity Assessment ............................................................................................... 41 
12.1.2 
Causality Assessment .............................................................................................. 42 
12.2 Routine Reporting ................................................................................................................... 42 
12.3 Serious Adverse Event Reporting ........................................................................................... 43 
13 
STATISTICAL METHODS .................................................................................................44 
13.1 Determination of Sample Size ................................................................................................. 44 
13.2 Analysis Populations ............................................................................................................... 44 
13.3 Statistical Analysis – General Considerations ......................................................................... 44 
13.4 Safety Analysis ........................................................................................................................ 45 
13.4.1 
Adverse Events ....................................................................................................... 45 
13.4.2 
Clinical Laboratory ................................................................................................. 45 
13.4.3 
Vital Signs ............................................................................................................... 46 
13.4.4 
Twelve-lead ECG .................................................................................................... 46 
13.4.5 
Physical Examination .............................................................................................. 46 
13.5 Pharmacokinetic Analysis ....................................................................................................... 46 
13.6 Pharmacodynamic Analyses .................................................................................................... 46 
14 
CLINICAL SUPPLIES .........................................................................................................47 


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14.1 Product Description ................................................................................................................. 47 
14.2 Storage Requirements .............................................................................................................. 48 
14.3 Accountability ......................................................................................................................... 48 
15 
BIOLOGICAL SPECIMENS ...............................................................................................49 
16 
CLINICAL AND LABORATORY DATA COLLECTION ................................................49 
16.1 Case Report Forms .................................................................................................................. 49 
16.2 Laboratory Results .................................................................................................................. 49 
17 
STUDY DOCUMENTATION .............................................................................................50 
17.1 Source Documents ................................................................................................................... 50 
17.2 Access to Records ................................................................................................................... 50 
17.3 Retention of Records ............................................................................................................... 50 
18 
INSTITUTIONAL REVIEW BOARD (IRB) ......................................................................50 
19 
ETHICAL CONDUCT OF THE STUDY ............................................................................51 
20 
INFORMED CONSENT ......................................................................................................51 
21 
CONFIDENTIALITY...........................................................................................................51 
21.1 Confidentiality of Data ............................................................................................................ 51 
21.2 Confidentiality of Subject Records ......................................................................................... 51 
22 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT ............................................52 
23 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................................53 
24 
PUBLICATIONS ..................................................................................................................53 
25 
REFERENCES .....................................................................................................................54 
26 
SCHEDULE OF ACTIVITIES.............................................................................................55 
 
 


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4 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE(s) 
Adverse event(s)                     
ALT 
Alaninie aminotransferase 
AST 
Aspartate aminotransferase 
BAC 
Blood Alcohol Content 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
 
degrees Celcius 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
CNS 
Central Nervous System 
CRCDS-MiniSim 
Cognitive Research Corporation Driving Simulator-MiniSim 
CRF 
Case report form 
CRU 
Clinical research unit 
CVDA 
Country Vigilance-Divided Attention 
DA 
Divided attention 
E 
number of events 
ECG 
Electrocardiogram 
EDS 
Excessive Daytime Sleepiness 
EOS 
End of study 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
HCl 
Hydrochloride 
HIV 
Human immunodeficiency virus 
HR 
Heart Rate 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonization  
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 


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kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
km 
Kilometer 
KSS 
Karolinska Sleepiness Scale 
LLC 
Limited Liability Company 
LOQ 
Limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter  
mm 
Millimeter 
N 
Number 
NI 
Non-inferiority 
pH 
Potential of hydrogen 
PK 
Pharmacokinetic 
PT 
Preferred term 
PT 
Prothrombin time 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDC 
Symbol Digit Coding 
SDLP 
Standard deviation of lateral position 
SOC 
System Organ Class 
SOPs 
Standard operating procedures 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three times a day 
TSH 
Thyroid stimulating hormone 
VAS 
Visual analog scale 
 


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5 
 STUDY ADMINISTRATION SCHEDULE 
5.1 
Principal Investigator 
Russell Rosenberg, Ph.D. 
NeuroTrials Research 
1100 Johnson Ferry Rd, Suite 420 
Atlanta, GA 30342 
(678) 651-2006 
5.2 
Study Director 
Gary Kay, Ph.D. 
President 
Cognitive Research Corporation 
200 Central Avenue, Suite 1230 
Saint Petersburg, FL 33701 
Office:  (727) 897-9000 
Mobile:  (202) 256-5617 
5.3 
Medical Monitor 
Gerald M. Penn, M.D. 
Medical Director 
Mary Rutan Hospital Dept. of Pathology 
205 Palmer Rd. 
Bellfontaine, OH 43311 
Email: gerald.penn@maryrutan.org 
Office: 937-651-6632 
Mobile: 614-563-7543 
5.4 
SAE Reporting Contact Information - Sponsor 
Serious adverse events (SAEs) should be reported to the Medical Monitor within 24 hours after 
Investigator or Investigator’s representative becomes aware of their occurrence. 


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6 
BACKGROUND AND RATIONALE FOR THE STUDY 
6.1 
Introduction 
Tolperisone hydrochloride (HCl), a centrally acting muscle relaxant, is widely used in Europe, 
Asia, and South America for the treatment of abnormally increased muscle tone. NR100, an oral 
formulation of tolperisone HCl as film-coated tablets, is being developed by Neurana 
Pharmaceuticals, Inc. as a novel muscle relaxant for the treatment of acute and painful symptoms 
associated with muscle spasms resulting from occupational and sports-related injury or 
myofascial pain. Future development of NR100 will be for the separate indication of treatment of 
spasticity associated with neurological conditions such as multiple sclerosis and spinal cord 
injury.  
 
While the mode of action of tolperisone HCl is not fully characterized, the most prominent effect 
of tolperisone HCl is its inhibitory action on pathways of spinal reflexes. It suppresses the mono 
and polysynaptic reflex transmission by both pre-synaptic and post-synaptic mechanisms. 
Tolperisone HCl has sodium (Na+) and, to a lesser extent, calcium (Ca2+) channel blocking 
activity. It inhibits, in a relatively selective manner, voltage-gated Na+ channels. However, even 
with high tolperisone HCl concentrations, channel blockade remains incomplete and reversible. 
Tolperisone has been shown to have unique analgesic effects and a lack of sedation effects. 
 
The centrally acting muscle relaxants reduce the increased muscle tonus and are typically 
sedative when used. The avoidance of drug-induced central depression, e.g., dizziness, 
drowsiness and excessive loss of muscle strength, is important in the medical care of patients. 
 
The Study 115 will explore the sedative effects of tolperisone HCl after single and multiple 
doses of NR100 compared to placebo, and to a widely prescribed agent for muscle relaxation 
used as  a positive control, cyclobenzaprine. 
 
6.2 
Drug Profile 
6.2.1 Tolperisone 
Full details of tolperisone pre-clinical and clinical safety and tolerability data are contained in the 
Investigator's Brochure. 
6.2.2 Cyclobenzaprine  
Full details of cyclobenzaprine pre-clinical and clinical safety and tolerability data are contained 
in the Package Insert.   
6.3 
Rationale  
6.3.1 Study Design 
This will be a randomized, placebo-controlled, multiple-dose 3-way cross-over study of the 
safety and cognitive effects of multiple doses of tolperisone administered TID in 30 male and 


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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 meeting all inclusion/exclusion criteria at Screening will be admitted to the clinic on 
Day -1 to be evaluated for continued eligibility. Subjects will perform a practice trial with the 
driving simulator and the cognitive function test.  
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.  
Subjects will be discharged on Day 3 with instructions to return to the clinic on Day 7 and 
Day 14 to repeat the above procedures with the second and third treatments.  
A follow-up phone call will be conducted 1 week (±3 days) following discharge from the clinic 
on Day 17 to assess for continued safety. 
6.3.2 Tolperisone Dose Level 
For the tolperisone treatment arm, tolperisone will be administered three times per day, with 
1 tablet administered at 8:00 AM (AM dose), 2:00 PM (PM dose), and 10:00 PM (HS dose) daily 
for 2 days and 1 tablet at 8:00 AM on Day 3. Depending upon randomization sequence 
tolperisone dosing will take place at Visit 1, 2, or 3. Each dose will be a 150 mg tablet of 
tolperisone, for a total daily dose of 450 mg on Days 1 and 2, and a total dose of 150 mg on 
Day 3.  
6.3.3 Positive Control Dose Level 
Cyclobenzaprine will serve as the positive control to demonstrate assay sensitivity. For the 
cyclobenzaprine treatment arm, cyclobenzaprine will be administered three times per day, with 
1 tablet administered at 8:00 AM (AM dose), 2:00 PM (PM dose), and 10:00 PM (HS dose) daily 
for 2 days and 1 tablet at 8:00 AM on Day 3. Depending upon randomization sequence, 
cyclobenzaprine dosing will take place at Visit 1, 2, or 3. Each dose will be a 10 mg tablet of 
cyclobenzaprine, for a total daily dose of 30 mg on Days 1 and 2, and a total dose of 10 mg on 
Day 3. 


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7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary Objective 
The primary objective of this study is 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. 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).  
7.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To assess the safety of 150 mg TID tolperisone dosing for 3 days in healthy volunteers. 
7.3 
Primary Endpoint 
The primary endpoint for this study is simulated driving performance, as measured by Standard 
Deviation of Lateral Position (SDLP) using the Cognitive Research Corporation Driving 
Simulator-MiniSim (CRCDS-MiniSim) CVDA (100 km) driving scenario, of tolperisone 
compared to placebo. 
7.4 
Secondary Endpoints 
The secondary endpoints for this study include: 
• SDLP measured by simulated driving performance using CRCDS-MiniSim of tolperisone 
compared to cyclobenzaprine 
• Sleepiness Endpoint – Karolinska Sleepiness Scale (KSS) 
• Self-reported readiness to drive (Response to: “Right now do you feel safe to drive?”) 
• Visual Analog Scales (VAS) to assess self-reported motivation and appraisal of driving 
performance 
• Cognitive Performance Endpoints 
 CogScreen Symbol Digit Coding (SDC) test 
o Number of correct responses  
o Response Accuracy 
o Standard deviation of reaction time 
• Driving Performance Endpoints 
 Lane exceedance; including number, maximum, and duration 
 Speed related measures; including speed deviation, average speed, excessive speed count, 
and speedings ratio 
 Driving safety measures; including excessive Ay (cornering speed threshold -exceeded), 
and total collisions 


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 Divided attention measures; including correct responses, omission errors, commission 
errors, reaction rime, and standard deviation of reaction time 
• Plasma drug levels and driving performance  
• Safety Endpoints 
 Clinical Evaluations 
o Vital signs 
o Orthostatic effects 
o Physical examinations 
o 12-lead electrocardiograms (ECGs) 
 Laboratory safety tests (blood chemistry, hematology,  urinalysis, serum and urine 
pregnancy tests for women of childbearing potential) 
 Adverse events (AEs) 


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8 
SUBJECT DEFINITION 
A sufficient number of subjects will be enrolled to ensure a total of 30 subjects will complete all 
dosing periods, including the driving assessment. Individuals are eligible for this study if they 
meet all inclusion and no exclusion criteria. The criteria below will be assessed at the Screening 
visit.  
8.1 
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. Male and female subjects must be between 21 and 55 years of age, inclusive, at the time of 
consent. 
3. 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. 
4. Subjects are required to have a body mass index (BMI) of 18 to 32 kg/m2, inclusive, at 
Screening. 
5. 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 is physically 
capable (e.g., adequate manual dexterity, vision, and hearing), cognitively capable and 
motivated to perform study tasks. 
6. 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. 
7. Subject must also demonstrate simulator sickness questionnaire scores which are not 
indicative of simulator sickness as defined in the driving simulation operations manual.  
8. 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). 
9. Subject has a score < 10 on the Epworth Sleepiness Scale (ESS). 
10. Female subjects must have a negative serum pregnancy test at screening, must be 
postmenopausal (amenorrhea for at least 2 years), surgically sterile, or practicing or agree to 
practice an effective method of birth control if they are sexually active before study entry, 
during the study and one month after the end of the study by using an acceptable method of 
contraception. Acceptable methods of birth control must be used for at least 14 days prior to 


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the use of study drug. Acceptable methods of birth control include oral, injected, vaginal or 
patch contraceptives, IUD (copper intrauterine device), or double barrier method (e.g., 
condom, diaphragm or cervical cap with spermicidal foam, cream, gel or suppository). 
11. Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
8.2 
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: 
a. Primary or secondary insomnia 
b. Narcolepsy 
c. Cataplexy (familial or idiopathic) 
d. Circadian Rhythm Sleep Disorder 
e. Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, 
and rapid eye movement behavior disorder 
f. Sleep-related Breathing Disorder (obstructive or central sleep apnea syndrome, central 
alveolar hypoventilation syndrome) 
g. Periodic Limb Movement Disorder 


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h. Restless Legs Syndrome 
i. Primary Hypersomnia 
j. Excessive Daytime Sleepiness (EDS) 
k. 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.   


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22. Has a positive screen for alcohol or other drugs of abuse (amphetamines, methamphetamines, 
barbiturates, benzodiazepines, cocaine, cannabinoids, opiates). 


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9 
STUDY DESIGN 
9.1 
Summary of Study Design 
This will be a randomized, placebo-controlled, multiple-dose 3-way cross-over study of the 
safety and cognitive effects of multiple doses of 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.  
Subject participation will be approximately 3 weeks as outpatients with 3 days each week as 
overnight clinic participants.   
Subjects will be screened within 28 days prior to Treatment Period 1 (Visit 2) for eligibility for 
participation in the study. The Familiarization and Practice drives on the driving simulator must 
be completed no more than 21 days prior to Treatment Period 1.  
Subjects meeting all inclusion/exclusion criteria will then be admitted to the clinic on Day -1 to 
be evaluated for continued eligibility. Subjects will perform a practice trial with the driving 
simulator and the cognitive function test.  
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.  
Subjects will be discharged on Day 3 with instructions to return to the clinic on Day 7 and 
Day 14 to repeat the above procedures with the second and third treatments.  
A follow-up phone call will be conducted 1 week (±3 days) following discharge from the clinic 
on Day 17 to assess for continued safety. 


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Schematic of Design: 
Hour 
Day -1 
Day 1 
Day 2 
Day 3 
Days 4-7 
6:00 (WASHOUT)
Breakfast 
Breakfast 
Breakfast   
7:00   
Driving 
Simulation 
WASHOUT 
8:00   
AM Dosing 
AM Dosing 
AM Dosing   
9:00 
  
Driving 
Simulation   
10:00  
 
 
 
 
11:30   
Lunch 
Lunch 
Lunch 
  
12:00   
  
13:00   
  
14:00   
PM Dosing 
PM Dosing 
Discharge   
15:00 
  
Driving 
Simulation 
  
16:00 Check-in 
  
17:00  Dinner 
Dinner 
Dinner 
  
18:00   
  
19:00   
  
20:00 
Practice Cog 
& Driving 
Simulation 
  
21:00   
  
22:00 Bedtime 
HS 
Dosing/Bedtime
HS 
Dosing/Bedtime 
  
  
 
9.2 
Meals 
During each confinement period, subjects will consume only food and beverages that are 
provided to them by the CRU staff. Standard meals (e.g. breakfast, lunch, dinner, and evening 
snack) will be provided to the subjects while confined to the CRU.  
9.3 
Subject Assignment 
Prior to dosing, subjects will be randomly assigned to one of 6 treatment sequences (one for each 
permutation of treatment groups) and dosed with study medication (tolperisone, cyclobenzaprine 
or placebo) based upon a randomization scheme provided by Cognitive Research Corporation. 
Only the qualified person(nel) assigned to prepare and administer the study treatment will have 
access to the randomization schedule and dispensing records during the study period. 


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10 
DAILY STUDY ACTIVITIES 
A complete Schedule of Events can be found in Section 26. 
10.1 
Screening 
Screening (Visit 1) will include procedures as described in the Schedule of Activities and further 
in the protocol. Prior to randomization, subjects will be screened for simulator sickness and will 
receive standardized training on the driving simulator and CogScreen Symbol Digit Coding 
subtest. Screening procedures and screening assessments may be performed on different days but 
must be completed within 28 days before Period 1 (Visit 2). The Familiarization and Practice 
drives on the driving simulator must be completed no more than 21 days prior to Period 1. 
In addition, each potential study participant will have the following assessments done by the 
Investigator or designee within 28 days prior to study start: medical and social history and 
demographic data, including sex, age, race, ethnicity, body weight (kg), height (cm), 
BMI (kg/m2), and smoking habits. Each potential participant will receive a physical examination, 
vital signs (including supine and standing blood pressure and heart rate, respiration rate, and 
body temperature), ECG, ESS, and laboratory tests including hematology, serum chemistry, and 
urinalysis. Urine drug and alcohol breathalyzer tests will be conducted on all potential subjects. 
Serum pregnancy tests will be conducted on all females of childbearing potential. AEs will be 
assessed, and prior and concomitant medication use will be recorded. 
Only medically healthy subjects with clinically acceptable laboratory profiles and ECGs will be 
enrolled in the study. The informed consent documents will be discussed with each potential 
participant, and each individual will sign an informed consent document for the study prior to 
any study-specific procedures being performed. 
A positive test result for pregnancy, urine drug or alcohol breathalyzer will end the screening 
process. 
10.2 
Study Periods  
10.2.1 CRU Admission Days (Visits 2, 6, and 10: Days -1, 7, and 14) 
Within 28 days after the Screening visit, eligible subjects will return for Period 1 (Visit 2).  
Subjects who meet the inclusion and no exclusion criteria will be instructed to return to the clinic 
on Day -1 at approximately 4:00 PM. The following will be done on Days -1, 7, and 14: 
• A urine pregnancy test will be performed for all females of childbearing potential upon 
admission to the unit.  
• The alcohol breathalyzer and drug screen will be repeated. 
• Continued subject eligibility will be verified. 
• Dinner will be served at 5:00 PM. 


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• Subjects will be administered a practice trial of the CogScreen SDC test beginning at 
approximately 7:40 PM. 
• A practice drive (approximately 20 minutes) will be performed on the driving simulator 
beginning at approximately 8:00 PM.  
• Vital signs will be measured. 
• Any concurrent medication use will be recorded. 
• AEs will be assessed 
Subjects will spend the night at the CRU and will go to bed at 10:00 PM.   
10.2.2 CRU Inpatient Day 1 (Visits 3, 7, and 11: Days 1, 8, and 15) 
On Days 1, 8, and 15, subjects will be awakened and fed a standard breakfast at approximately 
6:00 AM. A pre-dose pharmacokinetic (PK) blood sample will be taken within 30 minutes before 
the first dose. Vital signs will be taken at 7:55 AM (±5 minutes). Subjects will be randomized to 
a treatment sequence on Day 1 and will be dosed with study medication (tolperisone 150 mg, 
cyclobenzaprine 10 mg, or placebo) according to the randomization schedule at 8:00 AM (±5 
minutes) on Days 1, 8, and 15. 
Subjects will be fed a standard lunch at approximately 11:30 AM. Prior to receiving the 2nd dose, 
vital signs will be taken at 1:55 PM (±5 minutes). Subjects will then be dosed with study 
medication (tolperisone 150 mg, cyclobenzaprine 10 mg, or placebo) at approximately 2:00 PM. 
At approximately 2:40 PM, subjects will perform the CogScreen SDC Test and KSS, and 
indicate their self-perceived safety to drive. Subjects will then be tested (approximately 1 hour 
after the 2nd dose) with the Country Vigilance-Divided Attention (CVDA) driving scenario on 
the CRCDS-MiniSim. Upon completion of the driving scenario, subjects will be administered 
visual analog scales to assess their motivation and self-appraisal of their driving performance. A 
PK blood sample will be taken post-driving test (15-30 minutes after the drive). A standard 
dinner will be provided at approximately 5:00 PM. 
During the period between the time of awakening and completion of all assessments on dosing 
days during each treatment period, subjects must stay out of bed. They are permitted to engage in 
non-strenuous activities. For example, they may read, play games, socialize, work on the 
computer, or walk around the room.   
Subjects are prohibited from having their cellphone turned on during any of the cognitive 
procedures (eg, driving, CogScreen, forms) throughout the trial (eg, including screening), and 
from the time of dosing until completion of cognitive testing during each of the treatment 
periods. 
Subjects will receive their 3rd dose of study drug at 10:00 PM (±5 minutes). They will spend the 
night at the CRU and will go to bed immediately following the 3rd dose. AEs and concurrent 
medication use will be recorded each day. 
10.2.3 CRU Inpatient Day 2 (Visits 4, 8, and 12: Days 2, 9, and 16)  
On Days 2, 9, and 16, subjects will be awakened and fed a standard breakfast at approximately 
6:00 AM. Beginning at approximately 6:30 AM, subjects will be administered the CogScreen 
SDC Test and KSS, and indicate their self-perceived safety to drive. Subjects will then be tested 


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with the CVDA driving scenario on the CRCDS-MiniSim. Upon completion of the driving 
scenario, subjects will be administered visual analog scales to assess their motivation and 
self-appraisal of their driving performance. Following completion of the VAS, a pre-dose PK 
blood sample will be drawn. Vital signs will be taken at 7:55 AM (±5 minutes). Subjects will 
then be dosed with study medication (tolperisone, cyclobenzaprine, or placebo) at 8:00 AM 
(±5 minutes). 
Subjects will be fed a standard lunch at approximately 11:30 AM. Prior to receiving the 2nd dose, 
vital signs will be taken at 1:55 PM (±5 minutes). Subjects will then be dosed with study 
medication (tolperisone, cyclobenzaprine, or placebo) at approximately 2:00 PM. A standard 
dinner will be provided at approximately 5:00 PM. 
Subjects will receive their 3rd dose of study drug at 10:00 PM (±5 minutes). They will spend the 
night at the CRU and will go to bed immediately following the 3rd dose. AEs and concurrent 
medication use will be recorded each day. 
10.2.4 Clinic Discharge Days (Visits 5, 9, and 13: Days 3, 10, and 17) 
On Days 3, 10, and 17, subjects will be awakened and fed a standard breakfast at approximately 
6:00 AM. A pre-dose PK blood sample will be taken within 30 minutes before the first dose. 
Prior to dosing, vital signs will also be taken at 7:55 AM (±5 minutes). Subjects will then be 
dosed with study medication (tolperisone, cyclobenzaprine, or placebo) at 8:00 AM 
(±5 minutes). 
At approximately 8:40 AM, subjects will be administered the CogScreen SDC Test and KSS, 
and indicate their self-perceived safety to drive. Subjects will then be tested (approximately 
1 hour after the 1st dose) on the CVDA driving scenario on the CRCDS-MiniSim. Upon 
completion of the driving scenario, subjects will be administered visual analog scales to assess 
their motivation and self-appraisal of their driving performance. A PK blood sample will be 
taken between 1.5 and 2 hours after the start of the drive (approximately 10:30 AM to 11:00 
AM). Subjects will be fed a standard lunch at approximately 11:30 AM. 
Prior to discharge from the CRU, the following will be performed: 
• AEs will be recorded.  
• Any concurrent medication use will be recorded.  
• Vital signs will be measured at 1:55 PM (±5 minutes). 
Subjects will leave the clinical site at approximately 2:00 PM. However, they will be advised to stay 
at the clinical site, if judged necessary by the physician in charge, for safety reasons. 
On Day 17, the following will also be done prior to discharge from the CRU: 


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• Physical Exam. 
• Twelve-lead ECG recording will be collected. 
• Blood samples for chemistry and hematology will be drawn. 
• Urine samples will be collected for urinalysis. 
10.3 
Day 24 ±3 Days (Visit 14: Follow-up Phone Call) 
Approximately 1 week after discharge from the CRU at Visit 13, site staff will conduct a follow 
up safety phone call. The site staff will ask the subject about their health and any medications 
they have taken since completing Visit 13. 
11 
STUDY PROCEDURES 
11.1 
CVDA Driving Scenario on the CRCDS-MiniSim 
The present study employs the CVDA driving scenario, a 62.1 mile (100 km), monotonous, 
two-lane highway driving task that includes a secondary visual vigilance task (DA). The 
monotonous Country Vigilance scenario has been demonstrated to be sensitive to detect the 
effects of fatigue or sleepiness on driving performance [1]. This scenario has been useful in 
measuring the effects of sleep deprivation, Obstructive Sleep Apnea, chronic primary insomnia, 
and is sensitive to central nervous system (CNS) depressants (e.g., alcohol and sedating 
antihistamines). Results obtained using this methodology are comparable to those obtained using 
over-the-road driving tests [2]. 
Subjects will perform the driving simulator test at the times specified in Section 10.  Data will be 
captured in electronic format. Details are provided in the Cognitive Research Corporation 
CRCDS Testing Operations Manual. 
11.2 
Karolinska Sleepiness Scale 
The KSS [3] will be used to assess subjective level of sleepiness. This is a subject self-report 
measure of situational sleepiness and provides an assessment of alertness/sleepiness at a 
particular point in time. The KSS has been found to correlate with electroencephalogram and 
behavioral variables [4].  Subjects indicate their level of alertness versus sleepiness according to 
the following scale: 
Karolinska Sleepiness Scale 
 
1=extremely alert 
2 
3=alert 
4 
5=neither alert nor sleepy 
6 
7=sleepy - but no difficulty remaining awake 
8 


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9=extremely sleepy – fighting sleep 
   
Subjects will self-report their KSS assessments at the times specified in Section 10.  The 
subject’s self-reported scores will be recorded in the case report form (CRF). 
11.3 
Self-perceived Safety to Drive Question 
Prior to driving, the subject will be asked a simple question as to whether they feel safe to drive 
(“Right now do you feel safe to drive?”). The subject will answer “yes” or “no”. The answer will 
be recorded in the CRF. 
11.4 
Digit Symbol Substitution Test (CogScreen Symbol Digit Coding; SDC) 
The CogScreen SDC subtest will be used in this study to measure attention, visual scanning, 
working memory, and speed of information processing. SDC is a computer analogue of the 
conventional symbol-substitution task found in the WAIS-R Digit Symbol subtest and the 
Symbol Digit Modalities Test [5].  
SDC will be administered by trained study site personnel. Subjects will perform the test prior to 
the driving simulation test at the times specified in Section 10. The subject will perform the test 
by interacting with a touchscreen monitor. Data will be captured in electronic format. Details are 
provided in the CogScreen® Examiner Manual, CogScreen LLC, 2016.   
11.5 
Visual Analog Scales (VAS) to Assess Subject’s Motivation and Self-Appraisal 
After completing the driving simulation, subjects will assess their own performance and their 
level of motivation to perform at their best during the driving simulation. 
Subjects will respond to 2 questions: 
1. How well you think you drove for the last 60 minutes? 
2. How motivated did you feel to drive at your best during the last 60 minutes of driving? 
Subjects will record their response to each question by drawing a vertical line on a 100 mm 
horizontal, linear visual analog scale.  For the self-assessment of driving performance, one end of 
the line is marked “Not Satisfactory”  and the other end of the line is marked “Satisfactory”.  For 
the motivation item, one end of the line is marked “Not Motivated” and the other end is marked 
“Motivated”. Scores on the 100 mm linear scale will be measured to the nearest millimeter from 
the left. The subject’s scores will be recorded in the CRF.   
11.6 
Vital Signs 
Vital signs will include the measurement of supine and standing blood pressure and heart rate, 
respiration rate, and body temperature. Weight and height will be measured at Screening only.  
11.7 
Clinical Laboratory Assessments 


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A certified laboratory will be used to perform all routine hematology, clinical chemistry, and 
urinalysis. Planned laboratory analyses include:  
Category 
Test Name  
Hematology 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin Time (PT)c 
Red blood cells 
White blood cells with differential (absolute) 
Chemistry 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase 
Blood urea nitrogen (BUN) 
Creatinine 
Gamma glutamyltransferase (GGT) 
Glucose 
Potassium 
Sodium 
Total and direct bilirubin 
Thyroid stimulating hormone (TSH)c 
Urinalysis 
Bilirubin 
Erythrocytes 
Glucose 
Ketones 
Leukocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Other 
Urine drug and alcohol breathalyzera,b 
Serum/urine Pregnancyd 
a Screening and end of study (EOS) (Day 17). 
b  Includes testing for amphetamines, methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
ethanol and opiates – ethanol will be determined by breathalyzer. 
c  Screening only. 
d  Serum pregnancy at Screening and urine pregnancy test at check-in for each period (Days -1, 7, and 14) for 
females of childbearing potential. 
Note: The complete panel of safety labs (other than where footnoted) will be completed at Screening and EOS 
(Day 17).   
11.8 
Blood Collection for Tolperisone Plasma Concentrations  
Blood samples for the determination of plasma tolperisone concentrations will be drawn prior to 
each AM dosing on Days 1-3 and post-driving test (15-30 minutes after the drive) on Days 1 and 
3.  
Blood samples will be collected into heparinized polypropylene tubes (~5.0 mL). The tubes 
should be mixed immediately after filling by gently inverting the tubes at least 8 to 10 times.  
Thereafter, the tubes will be centrifuged as soon as possible (within 30 minutes of collection) at a 
minimum of 1500 g for 15 minutes until cells and plasma are well separated. The resulting 


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plasma samples will be transferred into two (duplicate) 2 ml cryovial tubes and labeled 
appropriately. 
Plasma samples will be analyzed for tolperisone at Pharm-analyt Labor GmB, Ferdinand-Pichler-
Gasse 2, 2500 Baden, Austria, using a validated liquid chromatography with tandem mass 
spectrometric detection (LC/MS/MS) method (limit of quantification (LOQ): 1 ng/mL). A 
detailed method description, including validation, calibration and quality assurance procedures 
will be included in the bioanalytical report which will be part of the Final Study Report. 
11.8.1 Sample Storage and Shipment 
The samples will be frozen as soon as possible (within 4 hours) of collection and stored frozen at 
–20°C until time of shipment to Pharm-Analyt Labor, GmB, Ferdinand-Pichler-Gasse 2, 2500 
Baden, Austria for analysis. All samples will be shipped frozen with sufficient dry ice to 
maintain frozen conditions for at least 72 hours at times arranged between the study site and the 
analytical laboratory. Detailed shipping instructions will be provided separately. 
11.9 
Blood Collection Volume for the Study 
For Periods 1-3, a total of approximately 25 mL (5 x 5 mL samples) will be collected from each 
subject for PK analysis. In addition, up to 48 mL of blood will be collected for screening and 
EOS clinical laboratory evaluations.  
11.10 Medical and Social History 
A medical and social history will be performed at Screening. Each subject’s history of alcohol 
and drug use will be evaluated. Subject’s caffeine consumption and tobacco use will be 
evaluated to ensure that the protocol will be followed during the course of the study. Continued 
eligibility will be evaluated on Day -1 and adherence to protocol restrictions will be confirmed 
throughout the study.  
11.11 Physical Examination 
A physical examination will be performed at Screening and EOS.  
 
11.12 Epworth Sleepiness Scale 
The ESS will be used to exclude subjects who demonstrate excessive sleepiness prior to 
randomization.   
The ESS is an 8-item self-administered questionnaire which measures general level of daytime 
sleepiness. Individual items on the scale refer to daytime events likely to lead to sleepiness. For 
each item, the subject rates how likely they are to fall asleep. Subjects are asked to rate how 
likely they would be to doze off or fall asleep in each situation in contrast to feeling just tired 
based on their usual way of life in recent times. Each item (or situation such as sitting and 
reading) is rated on a 4-point scale that ranges from “0 = Would never doze” to “3 = High chance 


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of dozing.” The total score on the ESS is the sum of the responses to each of the 8 items. The 
range of possible scores for each responder is 0 to 24. A total score of <10 indicates that the 
individual is not likely suffering from excessive daytime sleepiness. Individual items are not 
analyzed and have no independent, valid interpretations. 
Subjects will complete the ESS at Screening. 
11.13 Pregnancy Test 
A serum pregnancy test will be performed at Screening for all females of childbearing potential.  
A urine pregnancy test will also be collected at each CRU check-in visit (Days -1, 7, and 14) for 
females of childbearing potential. A positive pregnancy test at any time during the study will 
immediately terminate the subject from further participation in the study.  
11.14 Study Drug Preparation and Dispensing 
The Sponsor will supply Tolperisone 150 mg tablets and matching placebo in an unblinded 
fashion. The sites or CRO on behalf of the sites will procure the cyclobenzaprine 10 mg tablets. 
To maintain the double-blind status of the study, the following dispensing and dosing procedures 
will be followed. The site will identify a qualified unblinded dispenser and alternate(s) who will 
be responsible for dispensing and administering the study treatment. Aside from dispensing and 
administering the study treatment, the qualified unblinded dispenser will not be otherwise 
involved in the study. Cognitive Research Corporation will provide randomization codes directly 
to the individual identified by the study site. The randomization codes will be kept in a secured 
area with access limited to only the assigned unblinded dispenser.  
The qualified unblinded dispenser will prepare study treatment for each subject in a designated 
dispensing room. Prior to administering the first dose, the qualified unblinded dispenser will 
assign the next available randomization number. For each dose administered, the unblinded 
dispenser will dispense the appropriate tablet into a dispensing cup and complete the study 
treatment dispensing record. The study treatment dispensing record will remain in a secure 
locked area with access limited to the qualified unblinded dispenser and the alternate(s). No 
other study personnel will be present in the designated dispensing room at the time of study 
treatment dispensing.  
11.15 Study Drug Administration 
To maintain the study blind for tolperisone 150 mg, cyclobenzaprine 10 mg, and placebo, 
subjects will be blindfolded during dosing in each Period. Subjects will be given one tablet at 
approximately 8:00 AM, 2:00 PM, and 10:00 PM daily on Days 1, 2, 8, 9, 15, and 16 and at 
8:00 AM on Days 3, 10, and 17. Dosing will be observed by a study staff member (qualified 
unblinded dispenser); no other study personnel will be present at the time of dosing. 
The qualified unblinded dispenser will place the tablet into a dispensing cup. The blindfolded 
subject will transfer the study treatment directly from the cup into their mouth. All study 
medications will be administered orally with 4-6 ounces of room temperature water. The subjects 


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will be instructed to swallow the study tablet whole, without chewing the tablet. Mouth and hand 
checks will be performed by CRU personnel for each dose of study drug administered. 
11.16 Concurrent Medication 
• Subjects are to abstain from using psychoactive prescription or non-prescription 
medications, psychoactive nutritional supplements or herbal preparations within 2 weeks 
or 5 half-lives (whichever is longer) of Day 1.  
• Subjects are to abstain from using any other medication or dietary supplement to promote 
sleep, including over the counter sleep medications, during their participation in the study. 
• Subject will abstain from using antihistamine or any other drugs that can cause 
drowsiness, and will discuss any new prescription with the investigator.  
• No other medications (with the exception of birth control) are to be taken by the subjects 
without prior approval from the Principal Investigator and the Sponsor unless it is a 
medical emergency. All concomitant medication taken during the trial should be recorded 
with indication, daily dose, and start and stop dates of administration. 
11.17 Fluid, Food, and Lifestyle Restrictions 
• Subjects are not allowed to consume alcoholic beverages from 48 hours prior to admission 
to the CRU on Days -1, 7, and 14 until discharged from the CRU following completion of 
all procedures of each Period on Days 3, 10, and 17. At all other times, alcohol 
consumption is limited to no more than 3 alcoholic beverages or equivalent (beer 
[284 mL], wine [125 mL], or distilled spirits [25 mL]) per day.  
• The subject will be cautioned regarding the operation of automobiles or other dangerous 
machinery, and activities made hazardous by decreased alertness. Subjects should also be 
cautioned that the CNS effects of tolperisone and or cyclobenzaprine may be additive to 
those of alcohol and other CNS depressants.  
• Subjects are not allowed to consume caffeine containing products from approximately 
1 pm on the days of admission to the CRU (Days -1, 7, and 14) until discharged from the 
CRU following completion of all procedures on Days 3, 10, and 17. At all other times, 
caffeinated beverages will be permitted to no more than 4 units per day amounts (1 unit = 
120 mg caffeine). 
• Subjects are to refrain from vigorous physical activity from 24 hours prior to admission to 
the CRU on Days -1, 7, and 14 until discharged from the CRU following completion of all 
procedures on Days 3, 10, and 17. 
11.18 Discontinuation Criteria and Procedures 
According to the Declaration of Helsinki, all subjects have the right to withdraw from a study at 
any time, regardless of their reasons. In addition, it is the right of the Investigator to remove 
subjects from the study as a result of AEs, protocol violation, or any other reason. 


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11.18.1Premature Termination of Study/Closure of Study Sites 
The study may be terminated prematurely if new toxicological findings or results affecting the 
safety of the subjects become available. A site may be closed prematurely if recruitment is too 
slow, poor quality data is produced, or there is evidence of attempted or proven fraud. 
In the event the Sponsor prematurely terminates the study, the Investigator will promptly notify 
the Institutional Review Board (IRB). 


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12 
EVALUATION AND REPORTING OF ADVERSE EVENTS  
12.1 
Adverse Event (AE) Definitions 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
AEs occurring after the initiation of the treatment are referred to as treatment emergent adverse 
events (TEAEs). An AE can therefore be any unfavorable and unintended sign (for example, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to this medicinal product. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug. 
An AE may be: 
• A new illness, 
• Worsening of a concomitant illness, 
• An effect of the study medication including comparator; it could be an abnormal 
laboratory value as well as a significant shift from baseline within normal range which 
the Principal Investigator or medical qualified designate considers to be clinically 
important. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
• Is a congenital anomaly or birth defect, 
• Is an important medical event (including development of drug dependence or drug abuse) 
that may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above (according to medical judgment of the Principal Investigator). 
12.1.1 Severity Assessment  
All AEs will be graded as mild, moderate, or severe according to the following definitions: 


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Mild: 
Causing no limitation of usual activities; the subject may experience slight 
discomfort. 
Moderate: 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
Severe: 
Causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
Every effort will be made to obtain an adequate evaluation of the severity. 
12.1.2 Causality Assessment  
Investigators are required to assess the causal relationship (i.e., whether there is reasonable 
possibility that the study drug caused the event) using the following definitions: 
• Unrelated: another cause of the adverse event is more plausible; a temporal sequence 
cannot be established with the onset of the adverse event and administration of the study 
agent; or a causal relationship is considered biologically implausible. 
 
• Possibly Related: There is a clinically plausible time sequence between onset of the 
adverse event and administration of the study agent, but the adverse event could also be 
attributed to concurrent or underlying disease, or the use of other drugs or procedures. 
Possible related should be used when the study agent is one or several biologically 
plausible adverse event causes. 
 
• Definitely Related: The adverse event is clearly related to use of the study agent. 
12.2 
Routine Reporting  
For the purposes of this study, the period of observation of AEs extends from the signing of the 
consent at the screening visit until the follow-up call. During this period, all AEs spontaneously 
reported by the subject, observed by the clinical staff, or elicited by general questioning will be 
recorded and reported in the CRF. 
Any AE which remains unresolved as of the last visit will require an evaluation and follow-up 
until the AE has been resolved or a reasonable explanation for its persistence found, or is deemed 
mild and safely resolving. 
In the case of AEs deemed related to the Investigational Product, every effort will be made to 
determine the final outcome. 
It is the Investigator’s responsibility to ensure subjects experiencing AEs receive appropriate 
follow-up, treatment where required, and that every action is well documented. 
Subjects will be questioned on their health status at the beginning of the study period and before 
the departure from the clinical site. Open-ended questions will be asked. 
Classification will be performed by System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA), version 19.0 or higher. 


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In general, AEs occurring secondary to other events (e.g., clinical sequelae or a cascade of 
events) should be identified by their primary cause. For example, if severe vomiting is known to 
result in dehydration, it is sufficient to record only vomiting as SAE or AE in the CRF. However, 
medically significant AEs occurring secondary to an initiating event that are separated in time 
should be recorded as independent events on the CRF. 
Pregnancy in a female subject on the study shall be reported to the sponsor within 24 hours of the 
knowledge of its occurrence by the Principal Investigator or designee (for pregnancies occurring 
during the course of the study or immediately following the end of the study). Because of the 
possibility that the fetus/embryo could have been exposed to the study drug through the parent 
and for the subject’s safety, the pregnancy will be followed up to determine its outcome, 
including spontaneous or voluntary termination, details of birth, presence or absence of any birth 
defects, congenital anomalies, or maternal and/or newborn complications. 
The pregnancy will be recorded and reported by the Principal Investigator or designee to the 
sponsor. Pregnancy follow-up will also be properly recorded to ensure quality and completeness 
of the data belonging to the study drug and will include an assessment of the possible causal 
relation between the study drug and any pregnancy outcome. Any SAE experienced during 
pregnancy will be reported on a SAE Report Form. 
12.3 
Serious Adverse Event Reporting  
The sites will notify the sponsor of any SAE, without regard to causality, within 24 hours after 
becoming aware of its occurrence.  
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (e.g., an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be documented. 
All follow-up information must be reported as soon as the relevant info is available. 
The notification should be directed to the following sponsor representatives: 
Gerald M. Penn, M.D. 
Medical Director, Mary Rutan Hospital Department of Pathology 
205 Palmer Rd. 
Bellefontaine, OH 43311 
gerald.penn@maryrutan.org 
Office:  (937) 651-6632 
Mobile:  (614) 563-7543  
An SAE will be considered “unexpected” if the AE is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if an investigator brochure is 
not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. "Unexpected," as used in this 
definition, also refers to AEs that are mentioned in the Investigator’s Brochure as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. 


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The sites will determine whether any serious unexpected related AE must be reported to the IRB. 
If so, the event will be reported via fax or email within 15 calendar days of the investigator or 
staff becoming aware of the event. 
The sponsor will determine whether the SAE must be reported in an expedited manner to the 
appropriate regulatory agencies. If so, the sponsor will report the event to the appropriate 
regulatory agencies, and all participating investigators. 
If reports of any new and unexpected AEs become available to the sponsor during the clinical 
portion of this study (related or not to the present study), the sponsor must advise the sites of 
those events.  
13 
STATISTICAL METHODS 
13.1 
Determination of Sample Size 
This study is designed to test non-inferiority of tolperisone doses relative to placebo, with a 
cyclobenzaprine test versus placebo to confirm the sensitivity of the simulator to detect treatment 
effects. The following assumptions were made in the sample size computation: (a) within-subject 
standard deviation for SDLP is approximately 6 cm; (b) the true difference between tolperisone 
doses and placebo is 0; and, (c) the non-inferiority (NI) margin is proposed to be 4.4 cm, which 
is the effect seen with 0.05% of BAC with this driving simulator scenario. Under these 
assumptions, a sample of 30 subjects would provide in excess of 90% power to establish non-
inferiority of tolperisone compared to placebo on any given dosing day in terms of the primary 
end point, SDLP. This sample size is considered more than adequate to detect cyclobenzaprine 
differences from placebo, which are anticipated to exceed the NI margin. 
13.2 
Analysis Populations 
• PK Population – All subjects with evaluable plasma concentration data will be included 
in the pharmacokinetic population.  
• Intent-to-Treat (ITT) Population – The ITT Population includes all randomized subjects 
who receive at least 1 dose of study drug in a given treatment period. This is the analysis 
population for efficacy analysis. Subjects will (in general) be included in all analyses for 
which data are non-missing. 
• Safety Population – The Safety Population includes all subjects who received at least 1 
dose of study drug. 
13.3 
Statistical Analysis – General Considerations 
This section describes the general approaches planned to analyze the data from this study.  
Additional details of the planned analyses outlined here, will be further described in the SAP.   
Doses of tolperisone will be considered non-inferior to placebo if the upper 95% confidence limit 
on the difference in SDLP between that dose and placebo is less than 4.4 cm (the NI margin).  
Cyclobenzaprine comparisons to placebo are to assess assay sensitivity and no adjustment to 


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alpha levels will be made for either the comparison of cyclobenzaprine to placebo or tolperisone, 
or for secondary endpoints or analyses.  Formal statistical tests (where performed) will be two-
sided and testing at the alpha=0.05 level of significance.   
The sequence of testing to control for multiplicity associated with comparisons of tolperisone to 
placebo (to assess NI) on multiple days is  Day 1 (single-dose) , followed by Day 3 (steady-
state), followed by Day 2 (residual effect).  Tolperisone will be considered NI to placebo if prior 
comparisons ( at time points in the sequence provided, above) also indicate non-inferiorty.    
In general, categorical variables will be summarized by the count (N) and percentage of subjects 
(%). Continuous variables will be summarized by the number of non-missing observations (N), 
mean, standard deviation (SD), median, minimum, and maximum values. 
All study data are to be displayed in the data listings. 
13.4 
Safety Analysis 
Safety measures will be summarized using descriptive statistics and listed for each subject. 
Safety analysis will be based on all subjects enrolled who receive at least 1 dose of the study 
medication. The safety analysis will evaluate adverse events and additional safety parameters.  
The number and percentage of subjects experiencing at least one AE will be summarized by 
body system, preferred term, and treatment. If appropriate, AEs will also be summarized by 
intensity and relationship to study drug. SAEs, if any, will be tabulated. 
Additional safety parameters will be assessed from summaries of physical examinations, 12-lead 
ECGs and vital signs. The 12-lead ECG results will be categorized as normal, clinically 
significant abnormal, and not clinically significant abnormal. Hematology, chemistry and 
urinalysis laboratory test results will be categorized relative to the normal ranges. The changes 
from baseline for each of these parameters from Screening to EOS will be presented.  Complete 
listings and summary tables for all safety information including AEs, laboratory safety data, 
ECG, vital signs and physical examination will be included in the study report. 
13.4.1 Adverse Events 
Adverse events will be summarized by treatment, MedDRA terminology (latest version), 
severity and relation to study drug. The descriptive statistics presented for each system-organ 
class and preferred term will be the number of subjects with event (N), the percent of subjects 
exposed with event (%), and the number of events (E). All AEs will be listed by subject, 
including demographic information, dose, MedDRA latest version, system organ class, and 
preferred term. 
13.4.2 Clinical Laboratory 
Clinical laboratory values will be summarized by descriptive statistics by dose. Changes from 
baseline in clinical laboratory values will be summarized by descriptive statistics. All clinical 
laboratory values outside normal range (including Screening/Visit 1 and EOS/Day 17 


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examination) will be listed by treatment and subject number, including demographic information 
and flagging of values. 
13.4.3 Vital Signs 
Vital signs (BP, HR and body temperature) will be summarized by dose using descriptive 
statistics. Changes from baseline in vital signs will be summarized by descriptive statistics for 
each dose. 
13.4.4 Twelve-lead ECG 
All ECG endpoints will be listed by dose, subject and time of assessment and summarized by 
descriptive statistics. Changes from baseline in ECG parameters will be summarized by 
descriptive statistics by dose. 
13.4.5 Physical Examination 
Subjects with any changes in the physical examination evaluation from Screening/Visit 1 to 
EOS/Day 17 will be listed. A description of the study population in terms of baseline measures 
and demographics will be presented. 
13.5 
Pharmacokinetic Analysis 
The correlations between plasma drug concentrations and key secondary end points will be 
evaluated. Details of the PK and associated statistical analyses will be included in the Statistical 
Analysis Plan. 
13.6 
Pharmacodynamic Analyses 
The primary endpoint, SDLP, will be analyzed using a normal theory mixed effects model with 
fixed effects for sequence, period, and treatment, and a random effect for subject within 
sequence. An unstructured covariance structure and Kenward-Roger degrees of freedom will be 
used.   
Pair-wise comparisons (hypothesis tests) of differences in least squares means, and 95% 
confidence intervals on differences will be provided for: 
 
 
 
 
 
Initial dose effect 
1. cyclobenzaprine versus placebo following Day 1 PM dose 
2. tolperisone versus placebo following Day 1 PM dose 
3. tolperisone versus cyclobenzaprine following Day 1 PM dose 
 
Next day residual dose effect 
 
4.  cyclobenzaprine versus placebo following Day 2 AM dose 
5. tolperisone versus placebo following Day 2 AM dose 


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6. tolperisone versus cyclobenzaprine following Day 2 AM dose 
 
Steady-state dose effect 
 
7. cyclobenzaprine versus placebo following Day 3 AM dose 
8. tolperisone versus placebo following Day 3 AM dose 
9. tolperisone versus cyclobenzaprine following Day 3 AM dose 
 
In addition, pair-wise within-subject differences in SDLP greater than 4.4 cm in absolute value 
(equal to the previously found difference between placebo and 0.05% Blood Alcohol Content 
(BAC) for the CRCDS) will be compared using McNemar’s test. These pair-wise, within subject 
differences in SDLP will also be tested for symmetry about zero [6] using the maximally 
selected McNemar test. 
Summary statistics will be provided (mean, SD, median, minimum, maximum) for SDLP for 
each time point and treatment group. 
Additional details of analysis for secondary endpoints of VAS, SDC, KSS, and driving 
performance endpoints will be specified in the SAP.  
The relationship between tolperisone plasma drug levels and driving performance (i.e., the 
primary endpoint of SDLP) will be assessed by correlational analyses.   
All pharmacodynamic results will be summarized in tabular format, with summary statistics 
(number [n], mean, SD, median, minimum, and maximum) and change from baseline, as 
appropriate by time point. 
14 
CLINICAL SUPPLIES 
14.1 
Product Description 
Tolperisone: 
Tolperisone 150 mg tablets will be provided by the Sponsor. Matching placebo tablets will also 
be provided. 
Cyclobenzaprine: 
The positive control product, cyclobenzaprine 10 mg tablets, will be procured for the study by 
the individual sites or CRO on behalf of the sites. 


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14.2 
Storage Requirements 
Study drug supplies should be stored at room temperature and locked in a secure cabinet or 
room. Only the Investigator or designated third party study personnel will have access to study 
drug. Only the qualified unblinded dispenser(s) will have access to randomization codes and 
study treatment assignments.  
14.3 
Accountability 
The Investigator or designated study personnel is responsible for keeping accurate records of the 
clinical supplies received from the Sponsor and the study drug administered to each subject. The 
study monitor(s) will review study drug records periodically during the conduct of the study. At 
the end of the study, all partial and empty containers must be returned to the Sponsor or they 
must be destroyed at the clinical study site according to site standard operating procedures 
(SOPs). Records of destruction of study drug at the study site must include bottle identifying 
information and number of tablets in each bottle.  
In accordance with Good Pharmacy Practices, gloves should always be worn by study personnel 
when directly handling investigational products.   


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15 
BIOLOGICAL SPECIMENS 
Whole blood samples and urine samples will be collected as outlined in the study flow chart for 
clinical chemistry, hematology, pharmacokinetics, and urinalysis. 
It is the responsibility of the Investigator to ensure that all personnel who will be handling, 
packaging, and/or shipping clinical specimens act in conformance with International Air 
Transport Association (IATA) regulations relating to the handling and shipping of hazardous 
goods.  
16 
CLINICAL AND LABORATORY DATA COLLECTION 
16.1 
Case Report Forms 
A CRF will be completed for each subject. All appropriate subject data gathered during the study 
will be recorded in English on these forms. 
Whenever possible, all information requested on a CRF should be completed. If information is 
not available, it should be documented as such.  
The completed CRFs for this study are the property of Neurana Pharmaceuticals, Inc. and should 
not be made available to third parties, except for authorized representatives of appropriate 
health/regulatory authorities, without written permission from Neurana Pharmaceuticals, Inc. 
16.2 
Laboratory Results 
Laboratory tests (clinical chemistry, hematology and urinalysis) will be analyzed by a certified 
laboratory and reported to the clinical site as results are generated. The Investigator will review 
and comment on any laboratory value reported outside the normal range provided by the 
laboratory. The laboratory data must be signed and kept in the study subject file at the site for the 
Sponsor and will represent the source data. 


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17 
STUDY DOCUMENTATION  
17.1 
Source Documents 
Source documents may include, but are not limited to, laboratory reports, ECG tracings, x-rays, 
radiologist reports, biopsy reports, ultrasound photographs, clinic notes or pharmacy records and 
any other similar reports or records of any procedure performed in accordance with the protocol. 
Source documents may also include CRFs or electronic devices when information is recorded 
directly onto such forms or devices. 
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
17.2 
Access to Records 
As required by the International Conference on Harmonization-Good Clinical Practice 
(ICH-GCP) guidelines and regulatory authorities the Investigator will allow Sponsor’s 
representative(s) direct access to all pertinent medical records in order to allow for the 
verification of data gathered in the CRFs and for the review of the data collection process. The 
records, including source documentation, must also be available for inspection by relevant 
regulatory health authorities. 
17.3 
Retention of Records 
All essential documents and records will be maintained at the study site for a period of 5 years.  
These documents may be retained for a longer period if required by the applicable regulatory 
requirement(s) or if needed by the Sponsor. 
18 
INSTITUTIONAL REVIEW BOARD (IRB) 
The Investigator is responsible for obtaining an approval for conduct of the study from the IRB, 
as well as approval of all subsequent major changes to the study, in compliance with local law. 
These approvals must be forwarded to the Sponsor. The IRB will comply with all federal, state, 
and local laws. Particular attention is drawn to the Food and Drug Administration (FDA) 
Regulation for IRB (21 CFR, Part 56 and ICH GCP guidelines). 
The Investigator shall also obtain from the IRB and submit to the Sponsor, a signed statement 
indicating that it complies with Good Clinical Practices. 


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19 
ETHICAL CONDUCT OF THE STUDY 
The study will be performed according to the Declaration of Helsinki, latest edition (Edinburgh, 
Scotland, October 2000) with approval from the IRB. 
20 
INFORMED CONSENT 
It is the responsibility of the Investigator to give each potential study subject, prior to inclusion 
into the study, full and adequate verbal and written information regarding the objectives and 
procedures of the study. The study subjects must be informed about their right to withdraw from 
the study at any time. It is the responsibility of the Investigator (who may delegate this task to 
other members of the study team) to obtain signed informed consent from all study subjects 
before any study related assessments are performed. Consent must be documented by the 
subject’s dated signature on an informed consent form along with the dated signature of the 
person conducting the consent discussion. A copy of the signed and dated consent form should 
be given to the subject before participation in the trial. 
The initial informed consent form and any subsequent revised written informed consent form, 
and any written information provided to the subject must receive the IRB approval/favorable 
opinion in advance of use. 
21 
CONFIDENTIALITY 
21.1 
Confidentiality of Data 
By signing this protocol, the Investigator affirms to the Sponsor that information furnished to the 
Investigator by the Sponsor will be maintained in confidence and such information will be 
divulged to the IRB and FDA, or similar or expert committee; affiliated institution; and 
employees only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be considered 
confidential by the Investigator, except to the extent that it is included in a publication with prior 
approval of the Sponsor.  
21.2 
Confidentiality of Subject Records 
By signing this protocol, the Investigator agrees that the Sponsor (or Sponsor representative), 
IRB or regulatory agency representatives may consult and/or copy study documents in order to 
verify case report form data. By signing the consent form, the subject agrees to this process. If 
study documents will be photocopied during the process of verifying case report form 
information, the subject will be identified by subject number only, full names/initials will be 
masked prior to transmission to the Sponsor, IRB or regulatory agency. 


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22 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT 
By signing this protocol, the Investigator agrees to conduct the study in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of GCP; and all 
applicable local laws, rules and regulations relating to the conduct of the clinical study. 
The Investigator also agrees to allow monitoring, audits, IRB review and regulatory agency 
inspection of trial-related documents and procedures and provide for direct access to all 
study-related source data and documents including access to the electronic data base for the 
study. 
The Investigator shall prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable local laws, rules and regulations; and, for each 
subject participating in the study, provide all data, and upon completion or termination of the 
clinical study submit any other reports to the Sponsor as required by this protocol or as otherwise 
required pursuant to any agreement with the Sponsor. 
Study documentation will be promptly and fully disclosed to the Sponsor by the Investigator 
upon request and also shall be made available at the Investigator’s site upon request for 
inspection, copying, review and audit at reasonable times by representatives of the Sponsor or 
any regulatory agencies. The Investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the study documentation 
and CRFs. 
ICH-GCP guidelines recommend that the Investigator inform the subject’s primary physician 
about the subject’s participation in the study if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
The Investigator will promptly inform the Sponsor of any regulatory agency inspection 
conducted for this study and provide the final results (i.e. final observations and responses) to the 
Sponsor. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this study. The Investigator will immediately 
disclose in writing to the Sponsor if any person who is involved in conducting the study is 
debarred or if any proceeding for debarment is pending or, to the best of the Investigator’s 
knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify the IRB. 


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23 
QUALITY CONTROL AND QUALITY ASSURANCE 
Designated personnel from the study site and the Sponsor or designee will be responsible for 
maintaining quality assurance (QA) and quality control (QC) systems to ensure that the trial is 
conducted and data are generated, documented and reported in compliance with the protocol, 
ICH Guideline E6 for Good Clinical Practices. 
24 
PUBLICATIONS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between Sponsor and the Investigator and/or the 
Investigator’s institution. The Sponsor must have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation. Any information identified by the Sponsor as confidential must be 
deleted prior to submission. 


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25 
REFERENCES 
1. CRCDS Operations Manual.  Cognitive Research Corporation. Data on file. 
2. Siemen A, Gargano C, Cha J, Drexel M, Bautmans A, Heirman I, Laethem T, Hochadel 
T, Gheyle L, Bleys K, Beals C, Stoch A, Kay G, & Struyk A. (2015). A randomized, 
crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-
Sim to the next-day residual effects of zopiclone. Therapeutic Advances in Drug Safety, 
6 (3), 86-97. 
3. Akerstedt T, Gillberg M.  (1990).  Subjective and objective sleepiness in the active 
individual.  International Journal of Neuroscience, 52, 29–37. 
4. Kaida M, Takahashi T, Åkerstedt A, Nakata Y, Otsuka T,  Haratani K, et al. (2006).  
Validation of the Karolinska sleepiness scale against performance and EEG variables.  
Clinical Neurophysiology, 117, 1574–81. 
5. Wechsler, D. (1981). Wechsler Adult Intelligence Scale-Revised. San Antonio: 
Psychological Corporation.  
6. Laska E, Meisner M, Wanderling J. A maximally selected test of symmetry about zero.  
Stat Med 2012;31:3178-91. 
 


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26 
SCHEDULE OF ACTIVITIES 
 
 
Screening
Period 1 
Period 2 
Period 3 
Follow-up 
Phone Call 
Procedures 
Day -28 
to -2 
(V1) 
Day -1 
(V2) 
Day 1
(V3) 
Day 2
(V4) 
Day 3
(V5) 
Day 7
(V6) 
Day 8
(V7) 
Day 9
(V8) 
Day 10
(V9) 
 
Day 14
(V10) 
Day 15
(V11) 
Day 16
(V12) 
Day 17
(V13) 
Day 24   
(±3 days) 
(V14) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Medical/Social History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Epworth Sleepiness Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Simulator Sickness 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Driving Simulation & 
Cognitive Testing practice 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Driving Simulation & 
Cognitive Testing 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
KSS 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Self-Perceived Questionnaire 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
VAS 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Vital Sign Measurementsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Standard 12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Evaluationsb 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum/Urine Pregnancy Testc
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Urine Drug Screening / 
Breathalyzer 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pharmacokinetic Samplingd
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Discharge from Clinic  
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 


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a 
Vital signs include supine and standing blood pressure and heart rate; respiration rate; and body temperature. Weight and height collected at Visit 1 only. 
b 
Laboratory Evaluations include hematology, serum chemistry, and urinalysis.   
c 
A serum pregnancy test will be performed at Screening and a urine pregnancy test will be performed upon each admission to the unit. 
d 
Blood samples for the determination of plasma tolperisone concentrations will be drawn prior to each AM dosing on Days 1-3 and post-driving test (15-30 
minutes after the drive) on Days 1 and 3.


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Appendix 1 
Prescribing Information for Cyclobenzaprine 
 
 


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Tolperisone hydrochloride 
Clinical Study Report - Protocol 115 
Neurana Pharmaceuticals, Inc. 
CONFIDENTIAL 
100 
Version 1.0 (9 May 2018) 
16.1.3 
List of Independent Ethics Committees (IECs) or Institutional 
Review Boards (IRBs) and Sample Consent Form 
Chesapeake IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
IRB Chairperson: Joy Cavagnaro, Ph.D., DABT, RAC 
The IRB membership roster dated 04/06/2017 and sample informed consent forms are provided. 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 1 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 11 May 2017 
Revised «PIApprovalDate» 
 
CONSENT TO TAKE PART IN A RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Name of Research Study:   
Driving Simulation Cross-Over Study of 
Sedative Effects of Tolperisone Compared to 
Cyclobenzaprine and Placebo 
 
Protocol Number:   
115 
 
Name of Company Sponsoring 
the Research Study:   
 
 
Neurana Pharmaceuticals, Inc. 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Additional Contact(s): 
(Study Staff) 
 
«AdditionalStaffMemberContacts» 
 
Address: 
«PiLocations» 
 
 
You have been asked to take part in a research study.  First, we want you to know that 
taking part in a research study is entirely voluntary.  Second, you need to know that 
there are important differences between being cared for in a research study and being 
cared for by your doctor outside of a research study.  Participating in a research study is 
not the same as getting regular medical care.  The purpose of regular medical care is to 
improve your health.  The purpose of a research study is to gather information.  Being in 
this study does not replace your regular medical care.  Therefore, it is important that you 
understand the difference between the regular care you get from your doctor and what 
is involved in this research study. 
 
This consent document gives you important information about the research study.    
Please read this information carefully before deciding to take part.  No one can make 
you take part and you can stop at any time.  If you choose to take part in this research 
study, you will need to sign and date this consent document and you will receive a copy 
of this signed and dated document for your records. 
 
This research study is being conducted for Neurana Pharmaceuticals, Inc.  Neurana 
Pharmaceuticals, Inc. is sponsoring the study and will be paying the study doctor and 
the study site to conduct the study. 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 2 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 11 May 2017 
Revised «PIApprovalDate» 
 
The following sections describe the research study.  Before you decide to take 
part, please take as much time as you need to ask questions with the study team, 
with family and friends, or with your personal physician or other healthcare 
professionals.  The study team will fully answer any questions you have before 
you make a decision.   
 
1. 
WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of this research study is to compare how certain drugs affect how you feel, 
how you perform on a simulated driving task, and your cognitive functioning after taking 
the drug. This research study will compare the effects of the following study drugs:  
tolperisone, cyclobenzaprine, and placebo. 
 
During the study, subjects will receive oral doses of 450 mg tolperisone (150 mg 
administered three times daily), 30 mg cyclobenzaprine (10 mg administered three times 
daily), and placebo. Subjects will receive each study treatment for the 3 days, with only 1 
dose being administered on the 3rd day. 
 
Tolperisone is marketed in multiple countries in Europe, and Asia, for muscle spasticity 
(tightness or stiffness) and muscle spasms. It will be studied in the United States to 
determine its safety and efficacy (how well it works). 
 
Cyclobenzaprine has been approved by the Food and Drug Administration in the USA 
as Flexiril®.  It is available by prescription to relax muscles.  The 10 mg dose three times 
per day represents the highest dose typically administered for adults with muscle 
spasms. 
 
Researchers use a placebo (sugar pill) to see if the study drug works better or is safer 
than not taking any drug. 
 
Because this is a research study, the study drugs will be given to you only during this 
study and not after the study is over.   
 
2. 
HOW MANY OTHER PEOPLE WILL BE IN THE STUDY? 
There will be about 30 male and female participants between the ages of 21-55 years 
enrolled in this study.  The study is being conducted at 1 or 2 different research sites in 
the USA.  About 15-30 people will be enrolled at this site. 
 
3. 
HOW LONG WILL PARTICIPATION IN THE STUDY LAST? 
If you decide to participate, you will be in this study for at least 3 weeks but no longer 
than 7 weeks. You will need to visit the research site 5 times during the study, including 
3 visits with 3 overnight stays.   
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 3 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 11 May 2017 
Revised «PIApprovalDate» 
 
4. 
 WHAT WILL HAPPEN BEFORE THE RESEARCH STUDY BEGINS? 
If you decide to take part in this study, we will ask you to sign this consent document 
before we conduct any study-related activities. 
 
5. 
WHAT WILL HAPPEN DURING THE RESEARCH STUDY? 
Screening Visit (Visit 1) 
After signing and dating this consent document, you will begin in the study with a 
screening visit.  The purpose of the screening visit is to find out if you meet all of the 
requirements to take part in this research study.   
 
During the screening visit, you will be asked to have the following tests and activities or 
assessments:  
  
♦ Provide a social and medical history; 
♦ An electrocardiogram (ECG, a recording of the heart’s rhythm) will be performed; 
♦ You will also be asked about any medications and treatments you are currently 
taking.  It is important to tell the study site staff if you are taking any “over the 
counter” medications, herbal or natural remedies or dietary supplements; 
♦ Physical examination and vital signs (includes an examination of major body 
systems, height, weight, blood pressure while lying down and standing, pulse 
[heartrate], oral temperature, and respiratory [breathing] rate); 
♦ You will provide a urine sample and be given a breathalyzer test. The urine 
sample will be used for safety laboratory assessments (urinalysis) and to detect 
drugs and alcohol that are not allowed in this study, including illegal drugs (such 
as: amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, 
cannabinoids, and opiates).  Your urine sample must test negative for all of these 
drugs, and your breathalyzer must test negative for alcohol to participate in the 
study; 
♦ You will be required to complete a questionnaire regarding your sleep habits;  
♦ Collection of about 2 teaspoons of blood. This blood sample will be used to 
determine if you have HIV (Human Immunodeficiency Virus) or hepatitis (liver 
problem), and will also measure blood counts (hematology) and organ function 
(blood chemistry).  For females who could become pregnant, the sample will also 
be used to help confirm if you are pregnant. If the HIV or hepatitis result is 
positive, the physician in charge of the study or designee will personally inform 
you and at that moment he or she will indicate the procedure to follow. Note that 
a positive result for HIV, hepatitis B, or hepatitis C must be reported to the public 
health department as required by law.  If you have any questions about what 
information is required to be reported, please ask the Study Doctor or study staff. 
All blood collections for this study will be taken by individual needle sticks into 
one of the veins in your arm. 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 4 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 11 May 2017 
Revised «PIApprovalDate» 
 
The following assessments may also be done while you are at the site for your 
screening visit or the study staff may ask that you come back to the site within the next 
4 weeks to complete them. If you return within 4 weeks to complete the following 
assessments, this will be an extra study visit (so you will have 6 visits in total).  
 
♦ You will learn more about driving simulators and practice for about 20 minutes. A 
driving simulator is an open booth with a steering wheel and computer screens. 
You will then complete a questionnaire that asks you how you feel after driving 
the simulator. Once you have completed the questionnaire you will complete 
another drive in the simulator for about 20 minutes. 
♦ You will complete a practice test that measures how your brain performs with 
regard to memory, attention, perception, action, problem solving and mental 
imagery capacity. The practice test will be completed on a computer. 
 
By the end of the screening period, the study doctor will determine if you are eligible to 
continue into the study.  If you will not be able to continue in the study, the study doctor 
will explain why.  
 
Study Treatment Period 1 
 
Visit 2 (Day -1 to Day 3) 
 
Day -1 
 
You will return to the site for your next visit (visit 2) in the evening (4:00 PM) before the 
first drug administration.  
 
When you arrive, the following tests, activities or assessments will be performed: 
 
♦ Review of any changes to your health; 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the last visit. It is important to tell your study doctor if you 
are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements, including multi-vitamins; 
♦ You will provide a urine sample. The urine sample will be used to determine if 
you are pregnant (if you are a female who can become pregnant) and to test for 
certain drugs that are not allowed in this study, including illegal drugs.  Your urine 
sample must test negative for all of these drugs to participate in the study;  
♦ You will take a breathalyzer test; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff; 
♦ You will complete a practice test that measures how your brain performs with 
regard to memory, attention, perception, action, problem solving and mental 
imagery capacity. The practice test will be completed on a computer; 
♦ You will be required to complete a 20-minute practice drive in the driving 
simulator; 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 5 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 11 May 2017 
Revised «PIApprovalDate» 
 
♦ You will be served dinner. 
 
After completing the assessments, the Study Doctor will determine if you are eligible to 
continue in the study. If you are not eligible, the Study Doctor will explain why. If you are 
eligible for the study, you will stay at the clinical site overnight and continue with the visit 
2 procedures (Day 1). If you enroll in the study, you will receive each of the study drugs 
(tolperisone, cyclobenzaprine, and placebo) for 3 days, but at different study visits. 
 
Day 1 
The next day, upon awakening, the following tests, activities or assessments will be 
performed: 
 
♦ You will be served breakfast; 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since yesterday. It is important to tell your study doctor if you 
are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
morning dose; 
♦ About one teaspoon of blood will be collected prior to study drug administration 
to compare how much study drug is in your system later; 
♦ You will be randomly assigned (by chance) and administered a study drug. This 
is a double-blind study, which means neither you nor the study team will know to 
which study drug you are assigned at each study visit. This is done to make sure 
the results of the study cannot be unfairly influenced by anyone. In case of urgent 
need, the study team can get this information quickly. At each visit, you will be 
blindfolded while you take your study drug and will not know what study drug you 
took. 
♦ You will be fed lunch; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
afternoon dose; 
♦ You will receive your afternoon dose of study drug; 
♦ You will be asked whether you feel safe to drive; 
♦ You will complete some pen and paper questions about how sleepy you are; 
♦ You will complete a test that measures how your brain performs with regard to 
memory, attention, perception, action, problem solving and mental imagery 
capacity. The test will be completed on a computer; 
♦ You will take a 60-minute drive on the driving simulator. You will be videotaped 
during this drive.  
♦ You will then complete a pen and paper test as to your own performance on the 
driving simulator and how ready and motivated you felt to drive at your best on 
the driving simulator. 
♦ About one teaspoon of blood will be drawn to use to compare how much study 
drug is in your system; 


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♦ You will be fed dinner; 
♦ You will receive your evening dose of study drug at about 10:00 PM; 
♦ You will spend the night at the clinical site and will go to bed immediately after 
taking your evening dose of study drug. 
 
Day 2 
The next day, upon awakening, the following tests, activities or assessments will be 
performed: 
 
♦ You will be served breakfast; 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the previous day. It is important to tell your study doctor if 
you are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
morning dose; 
♦ You will be asked whether you feel safe to drive; 
♦ You will complete some pen and paper questions about how sleepy you are; 
♦ You will complete a test that measures how your brain performs with regard to 
memory, attention, perception, action, problem solving and mental imagery 
capacity. The test will be completed on a computer; 
♦ You will take a 60-minute drive on the driving simulator. You will be videotaped 
during this drive.  
♦ You will then complete a pen and paper test as to your own performance on the 
driving simulator and how ready and motivated you felt to drive at your best on 
the driving simulator. 
♦ About one teaspoon of blood will be drawn to use to compare how much drug is 
in your system; 
♦ You will receive your morning dose of study drug at about 8:00 AM; 
♦ You will be fed lunch at about 11:30 AM; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
afternoon dose; 
♦ You will receive your afternoon dose of study drug; 
♦ You will be fed dinner at about 5:00 PM; 
♦ You will receive your evening dose of study drug at about 10:00 PM; 
♦ You will spend the night at the clinical site and will go to bed immediately after 
taking your evening dose of study drug. 
 
Day 3 
The next day, upon awakening, the following tests, activities or assessments will be 
performed: 
 
♦ You will be served breakfast; 


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♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the previous day. It is important to tell your study doctor if 
you are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
morning dose; 
♦ About one teaspoon of blood will be drawn to use to compare how much study 
drug is in your system; 
♦ You will receive your morning dose of study drug at about 8:00 AM; 
♦ About 30 minutes after your morning dose, you will be asked whether you feel 
safe to drive; 
♦ You will complete some pen and paper questions about how sleepy you are; 
♦ You will complete a test that measures how your brain performs with regard to 
memory, attention, perception, action, problem solving and mental imagery 
capacity. The test will be completed on a computer; 
♦ You will take a 60-minute drive on the driving simulator. You will be videotaped 
during this drive.  
♦ You will then complete a pen and paper test as to your own performance on the 
driving simulator and how ready and motivated you felt to drive at your best on 
the driving simulator. 
♦ About one teaspoon of blood will be drawn to use to compare how much study 
drug is in your system; 
♦ You will be fed lunch at about 11:30 AM; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff at about 1:55 
PM; 
 
When all assessments in Study Treatment 1 have been completed, a study staff 
member will schedule your next visit, which will occur in about 4 days. You will leave the 
clinical site at approximately 2:00 PM and can go home. However, you will be advised 
to stay at the clinical site, if the study doctor in charge feels it is necessary, for safety 
reasons. You will not be allowed to drive yourself home. You must arrange for someone 
to take you home.  
 
Study Treatment Periods 2 and 3 
 
Study Treatment Periods 2 and 3 will be exactly the same as Study Treatment Period 1.  
In between each visit (Study Treatment Period), you will not take any study drug while 
you are at home. 
 
At the end of the Study Treatment Period 3, after you have completed all study 
procedures and prior to discharge, the following tests, activities or assessments will be 
performed:  
 
♦ An ECG will be performed; 


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♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the last visit. It is important to tell your study doctor if you 
have taken any “over the counter” medication, herbal or natural remedies or 
dietary supplements, including multi-vitamins; 
♦ Physical examination and vital signs (includes an examination of major body 
systems, weight, blood pressure while lying down and standing, pulse [heart 
rate], oral temperature, and respiratory [breathing] rate); 
♦ About 2 teaspoons of blood will be collected. This blood sample will be used to 
measure blood counts (hematology) and organ function (blood chemistry).   
♦ You will provide a urine sample. The urine sample will be used for safety 
laboratory assessments (urinalysis).   
 
Follow-Up 
 
Approximately 1 week after discharge from the clinical site after Study Treatment Period 
3, site staff will conduct a follow-up safety phone call. The site staff will ask you subject 
about your health and any medications you have taken since being discharged from the 
clinical site.  Following this phone call, your participation in the study will be complete. 
 
6. 
HOW WILL I RECEIVE THE STUDY DRUG? 
This study involves 3 different study treatments (tolperisone, cyclobenzaprine, and 
placebo). You will receive a different study treatment during each of the 3 Study 
Treatment Periods. You will receive study drug 3 times on Day 1, 3 times on Day 2, and 
1 time on Day 3 of each Study Treatment Period. Prior to receiving study drug, you will 
be blindfolded so that you will not see which study drug you are taking.  Each dose of 
study drug will consist of 1 tablet.  You will take each dose of study drug with water. 
 
7. 
WHAT HAPPENS WHEN I FINISH TAKING THE STUDY DRUG? 
About 1 week after you have taken the last dose of study drug and completed the Study 
Treatment Period 3 assessments, you will receive a follow-up safety phone call from the 
clinical site staff.  Following this phone call, your participation in the study will be 
complete.  
 
8. 
WHAT ARE THE RISKS AND POSSIBLE DISCOMFORTS OF BEING IN THIS 
RESEARCH STUDY? 
Any clinical research may have some risks, which may include things that could make 
you sick, make you feel uncomfortable, or harm you.  You might experience negative 
effects related to the study drug while participating in the study.  All research 
participants taking part in the study will be watched carefully for any negative effects; 
however, the study team does not know all the effects that the study drug may have on 
you.  The study team may give you medicines to help reduce negative effects.  These 
effects may be mild or serious.  In some cases, these effects might be long lasting, or 
permanent, and may even be life threatening.  
 


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The negative events that are the most likely to happen to you if you take part in this 
study are listed below.   
 
For tolperisone: 
 
Common Side Effects: 
• Muscle weakness 
• Headache 
• Dizziness 
• Somnolence (drowsiness) 
• Vertigo (loss of balance) 
• Low blood pressure 
• Nausea 
• Vomiting 
• Abdominal (stomach) discomfort 
• Indigestion 
• Dry mouth 
 
For cyclobenzaprine: 
 
Common Side Effects: 
• Drowsiness 
• Somnolence ("sleepiness" or "drowsiness" – a state of strong desire for sleep, or 
sleeping for unusually long periods) 
• Dry mouth 
• Fatigue (tiredness) 
• Headache 
• Dizziness 
• Abdominal pain 
• Acid reflux 
• Constipation 
• Diarrhea 
• Nausea  
• Vomiting 
• Irritability 
• Decreased mental sharpness 
• Nervousness 
• Upper respiratory infection 
• Pharyngitis (sore throat) 
• Asthenia (weakness or lack of energy) 
• Indigestion 
• Unpleasant taste 
• Blurred vision 
 


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Placebo Risk:   
Taking a placebo may be similar to not taking any medication.   
 
Risks and possible discomforts you might experience from the study procedures 
include: 
 
Other Risks 
 
Since the use of the study drug is investigational when taken alone or in combination 
with other medications, there may be other risks that are unknown.  All drugs have a 
potential risk of an allergic reaction, which if not treated promptly, could become life 
threatening.  You should get medical help and contact the Study Doctor right away if 
you think you have any of the following symptoms of a serious allergic reaction:  trouble 
breathing, or swelling of the face, mouth, lips, gums, tongue or neck.  Other allergic 
reactions may include rash, hives, or blisters. 
 
If you experience the symptoms of an allergic reaction while outside the clinic, please 
go to the nearest hospital emergency department.  If you experience these symptoms 
while inside the clinic, please tell the study staff. 
 
It is important that you report all symptoms and side effects that you experience as soon 
as they occur, whether or not you think they are caused by the study drug.  The phone 
numbers for the study team are on the first page of this document. 
 
Blood draws: A blood draw may cause faintness, swelling of the vein, pain, redness, 
bruising, or bleeding at the site of puncture.  There is also a slight chance of infection. 
 
Simulator Sickness: You may feel sick after driving the simulator. This is a feeling similar 
to motion sickness. 
 
HIV/Hepatitis Testing:  Some of your blood will be tested for HIV, hepatitis B, and 
hepatitis C.  The study doctor may be required by law to report the result of these tests 
to the local health authority.  
 
Pregnancy Related Risks / Use of Birth Control 
 
Women who are pregnant or nursing a child may not participate in this study.  To 
participate in the study, you must confirm that, to the best of your knowledge, you are 
not now pregnant, and that you do not intend to become pregnant during the study or 
for at least one month after you complete the study.  If there is any possibility that you 
may become pregnant during the study, you will not be able to participate in the study. If 
you suspect that you have become pregnant during the study, you must notify the study 
doctor immediately.  You will not be able to participate in the study if you become 
pregnant.  
 


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Acceptable methods of birth control must be used for 14 days before taking the study 
drug and for 30 days after the end of the study. Acceptable methods of birth control 
include oral, injected, vaginal or patch contraceptives, IUD (copper intrauterine device), 
or double-barrier method (for example, condom, diaphragm or cervical cap with 
spermicidal foam, cream, gel or suppository). 
 
Pregnancy Follow Up 
 
If you become pregnant during the study or within 1 month after your last dose of study 
drug, please tell the Study Doctor immediately.  Please also tell the doctor who will be 
taking care of you during the pregnancy that you took part in this study.  The Study 
Doctor will ask if your pregnancy doctor is willing to provide updates on the progress of 
the pregnancy and its outcome.  If you agree, this information will be provided to the 
study sponsor for safety monitoring follow-up. 
  
9. 
ARE THERE ANY SPECIAL INSTRUCTIONS TO FOLLOW WHILE 
PARTICIPATING IN THIS STUDY? 
During this study, it is important that you: 
• Do not travel across time zones or work on a rotating shift during the study; 
• Do not work a night shift for one week before each study visit; 
• Do not consume alcohol for 48 hours prior to any study visit; 
• Do not consume caffeine or caffeinated products (medicines, supplements, 
foods, beverages or confections) from 1:00 PM on the day of each study visit 
until you return home after the visit; 
• Nicotine-containing products may not be used while at the research site;   
• Do not practice vigorous physical activity for 24 hours prior to any study visit; 
• The study doctor will tell you what medications are not allowed during the study.  
They include: 
o Do not use any sleep aids [for example, diphenhydramine hydrochloride 
(Benadryl, Unisom SleepGels, Tylenol PM, Nyquil ZZZ, Advil PM, others), 
doxylamine succinate (Unisom SleepTabs, Kirkland, others), melatonin, 
and valerian]; 
o Do not use any cold or allergy products containing an antihistamine (for 
example, Dimetapp® Cold and Allergy Elixir, Chlor-Trimeton®, 
Dramamine®, Benadryl® Allergy, Nytol®, Sominex®, Vicks NyQuil®, Alka-
Seltzer® Plus Night-Time Cold Medicine); 
• Go to bed between 9:00 pm and 12:00 am on the night before every study visit. 
 
 
 


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10. WHAT OPTIONS ARE AVAILABLE OTHER THAN BEING IN THIS STUDY? 
This research study is for research purposes only.  The only alternative is to not take 
part in this study. 
 
11. WHAT ARE POSSIBLE BENEFITS OF BEING IN THIS STUDY? 
This study is for research purposes only.  There is no direct benefit to you from your 
participation in the study.  Information learned from the study may help other people in 
the future. 
 
12. WHAT HAPPENS IF I AM INJURED AS A RESULT OF TAKING PART IN THIS 
RESEARCH STUDY? 
If you become ill or are hurt while you are in the study, get the medical care that you 
need right away. You must notify the study doctor immediately of any injury. If you have 
any questions concerning the availability of medical care or if you think you have 
experienced a research-related illness, injury or emergency, contact the study doctor 
using the contact information on the first page of this form.  
 
If you experience a research injury, the study doctor or study site will provide or arrange 
for medical treatment at no cost to you. Neurana Pharmaceuticals, Inc. will cover the 
costs of this treatment.  A research injury is any physical injury or illness caused by your 
taking part in this study. If you are injured by a medical treatment or procedure that you 
would have received even if you were not in this study, that is not a research injury. To 
help avoid injury, it is very important to follow all study directions. The sponsor has no 
plans for other financial compensation.   
 
To pay these medical expenses, the sponsor will need to know some information about 
you like your name, date of birth, and social security number or Medicare Health 
Insurance Claim Number. This is because the sponsor has to check to see if you 
receive Medicare and if you do, report the payment it makes to Medicare. 
 
You still have the right to make a claim through the legal system even if you sign this 
form, accept medical care, or accept payment for medical expenses. 
 
13. IS BEING IN THE STUDY VOLUNTARY? 
Yes.  Taking part in this research study is up to you.  You may choose not to take part, 
or you can change your mind and withdraw (drop out) later.  There will be no penalty, 
and you won’t lose any benefits you receive now or have a right to receive.    
 
We will tell you if we learn new information that could change your mind about taking 
part or continuing in this research study.  If you want to drop out, you should tell us.  We 
will make sure you can end the study in the safest way.  We will also talk to you about 
follow-up care, if needed. 
 


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The study doctor or the study sponsor may decide to take you out of the study without 
your agreement if:  
• You do not follow the directions of the study team; 
• The study doctor decides that the study is not in your best interest; 
• The study is stopped by the study sponsor, the institutional review board (IRB) (a 
group of people who review the research to protect your rights), or by a 
regulatory agency;   
• You become pregnant, intend to become pregnant or are nursing a child during 
this study. 
 
If you withdraw or are removed from the study, biological samples (for example, blood 
or urine samples) that have been collected from you (but not yet fully analyzed) can be 
destroyed by making a request to the study doctor in person or at the telephone number 
listed on the first page of this form.  However, any data already generated from your 
samples will be kept to preserve the value of the study.   
 
14. WHAT WILL I HAVE TO PAY FOR IF I TAKE PART IN THIS RESEARCH 
STUDY? 
There will be no charge to you for your participation in this study.  The study drug, 
study-related procedures, and study visits will be provided at no charge to you or your 
insurance company.   
 
The study drugs (tolperisone, cyclobenzaprine, and placebo) and all other study 
procedures will be provided at no charge while you are participating in this study. 
 
Will I Be Paid For Taking Part In This Study? 
 
You will be paid [total amount] to cover your out-of-pocket expenses.  You will get 
$_________ for each study visit you complete.  You will be paid at the end of each 
study visit / monthly for completed study visits / quarterly (every 3 months) for 
completed study visits. If you leave the study early for any reason, you will be paid for 
each study visit you have already completed.  You will not be compensated for any 
delay or cancellation occurring before the first visit of this study. 
 
Neurana Pharmaceuticals, Inc. may use information from your sample(s) to develop 
products or processes from which they may make a profit.  There are no plans to pay 
you or provide you with any products developed from this research. Neurana 
Pharmaceuticals, Inc. will own all products or processes that are developed using 
information from your sample(s). 
 
 
 
 


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15. CONFIDENTIALITY 
To ensure that your information collected for this study will be kept private, your name 
will not be used whenever possible.  A code will be used instead of your name.  All of 
your study data will be kept in a secure location. Please understand that representatives 
of the Food and Drug Administration (FDA), the sponsor of this study, and any other 
entities included in the section below, may review your study data for the purposes of 
verifying research data, and will see personal identifiers.   
 
16. IF I TAKE PART IN THIS RESEARCH STUDY, HOW WILL MY PRIVACY BE 
PROTECTED? 
A federal regulation, known as the Privacy Rule, gives you certain rights concerning the 
privacy of your health information.  The Privacy Rule was issued under a law called the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Researchers 
covered by this regulation are required to get your authorization (permission) to use and 
disclose (share with others) any health information that could identify you.  
 
If you sign this informed consent form, you are giving permission for the use and 
disclosure of your health information for purposes of this research study.  You do not 
have to give this permission.  However, if you do not, you will not be able to take part in 
the study. 
 
Who Will Use and Disclose My Health Information? 
 
The study team may use your health information to conduct, review, and determine the 
results of the study.  The study team may also use your information to prepare reports 
or publications about the study.  However, your name will not appear in any report or 
publication.  
  
What Health Information will be Used and Disclosed? 
 
During the study, the study team will use, collect, and record health information about 
you (your “records”).  Your records will include any information about you that the study 
team needs to do the study, including information from the procedures described above. 
Your records may include other health information about you and will include identifying 
information such as your name and address. The study team will record some of this 
information on “study forms” provided by the study sponsor.  Your name or address will 
not appear on the study forms.  Instead, you will be assigned a participant identification 
number.   
 
The study team will send the completed study forms to the study sponsor and may 
share this information with others, as described below.    
 
  
 


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Representatives from the groups identified below may also need to look at your records 
(which identify you) to make sure that the information on the study forms is correct or 
that the study was conducted properly.  Reviews like that will take place at the research 
site or where the records are stored and can take place after the study is over.   
 
Who Will Receive My Health Information? 
 
Your study information may be shared with the following people or groups: 
 
• The study sponsor (Neurana Pharmaceuticals, Inc.) or its representatives, 
including companies it hires to provide study-related services  
• Researchers who are conducting this study at other research sites  
• The Institutional Review Board (ethics committee) that approved this study and 
any other committees responsible for overseeing the research 
• Government health agencies (such as the Food and Drug Administration) in the 
US or other countries 
• Your study doctor may inform your primary physician about your participation in 
the study if you have a primary physician and you agree to the primary physician 
being informed.   
  
Will My Information Be Protected by the Privacy Rule After it is Disclosed to 
Others? 
 
The study site is required by the Privacy Rule to protect your health information.  After 
your information is shared with others, such as the study sponsor, it may no longer be 
protected by the Privacy Rule.  The people who receive this information could use it in 
ways not discussed in this form and could disclose it to others.  However, the study 
sponsor will use and disclose your information only for research or regulatory purposes 
or to prepare research publications.  In addition to using it for this study, the study 
sponsor may reanalyze the study data at a later date or combine your information with 
information from other studies for research purposes not directly related to this study.  
The goal of any such research would be to learn more about drugs or diseases or to 
help design better studies in the future.  When using your information in these ways, the 
study sponsor may share it with regulatory authorities, other researchers, its business 
partners, or companies it hires to provide research-related services.  This could result in 
transfer of your information outside the United States.  However, your name will never 
appear in any study sponsor reports or publications, or in any future disclosures 
by the study sponsor. 
 
What Happens if I Leave the Study Early? 
 
If you stop participating in the study early for any reason, the study team will tell the 
study sponsor why.  If the study team asks you to come to any more study visits and if 
you agree, the study team will send the study sponsor information from those visits as 
well.  All information collected about you may continue to be used and disclosed.   
 


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Will My Authorization Ever Expire? 
 
This Authorization does not have an expiration date.  The study team may need to 
correct or provide missing information about you even after your study participation is 
over.  The review of your medical records (described above) may also take place after 
the study is over. 
 
May I Take Back My Authorization? 
 
You have the right to take back (revoke) your Authorization at any time by writing to the 
study doctor at the address listed on the first page of this form. 
 
If you revoke your Authorization, the study team will not collect any new health 
information about you.  However, they can continue to use and disclose any already 
collected information if that is necessary for the reliability (the scientific value) of the 
study.  The study sponsor can also still keep and use any information that it has already 
received.  If you revoke your Authorization, you can no longer continue to participate in 
the study. 
 
May I Look At My Study Information? 
 
You have a right to see and make copies of your medical records.  However, to ensure 
the reliability of the study, you will need to wait to see your study records until the study 
is completed.   
 
17. WHERE CAN I FIND ADDITIONAL INFORMATION ABOUT THIS RESEARCH 
STUDY OR THE RESEARCH RESULTS? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time.  It may be many years; however, before research results are posted. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18. GETTING ANSWERS TO YOUR QUESTIONS OR CONCERNS ABOUT THE 
STUDY 
You can ask questions about this consent form or the study (before you decide to start 
the study, at any time during the study, or after completion of the study).  Questions 
may include: 
 
• Who to contact in the case of a research-related injury or illness; 
• Payment or compensation for being in the study, if any; 
• Your responsibilities as a study subject; 
• Eligibility to participate in the research; 
• The study doctor’s or study site’s decision to exclude you from participation; 
• Results of tests and/or procedures; 
• Other questions, concerns, or complaints. 
 
Contact the study doctor or study staff listed on the first page of this form with 
any questions, concerns or complaints.   
 
 
19. GETTING ANSWERS TO YOUR QUESTIONS ABOUT YOUR RIGHTS AS A 
RESEARCH SUBJECT 
This study has been reviewed by an Institutional Review Board (IRB). This Committee 
reviewed this study to help ensure that your rights and welfare are protected and that 
this study is carried out in an ethical manner. 
 
For questions about your rights as a research subject, contact:  
 
• By mail: 
Study Subject Adviser 
Chesapeake IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:        877-992-4724 
• or by email:              adviser@chesapeakeirb.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00021652. 
 
An IRB is a group of people who review research studies to protect the rights and 
welfare of research participants.   


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20. SIGNATURES: 
I have read the information in this informed consent document.  I have had an 
opportunity to ask questions and all of my questions have been answered to my 
satisfaction. I voluntarily agree to take part in this study.  I voluntarily agree to allow 
study staff to collect, use and share my health data as specified in this form. I do not 
give up any of my legal rights by signing this consent document.   
 
I have been told that I will receive a signed and dated copy of this document. 
 
_________________________________________ 
Printed name of Study Participant 
 
______________________________________     ______________ _____________ 
Signature of Study Participant 
 Date of signature Time 
 
 
PERSON OBTAINING CONSENT 
 
____________________________________  
 
 
Printed Name of the Person Conducting the 
Consent Discussion  
 
 
_____________________________________ 
______________ 
_____________ 
Signature of the Person Conducting the  
Date of signature 
Time 
Consent Discussion †  
 
 
 
 
 
 
†The Investigator, or a suitably qualified and trained person designated by the 
Investigator to conduct the informed consent process, must sign and date the consent 
document during the same interview when the subject signs the consent document. 
 
 
 


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21. WOMEN OF CHILDBEARING POTENTIAL ADDENDUM 
If you are a female of childbearing potential, by signing this form you agree to use 
adequate contraception during and for 1 month following completion of the study.  
 
You must have a negative serum pregnancy test at screening, must be postmenopausal 
(amenorrhea for at least 2 years), surgically sterile, or practicing or agree to practice an 
effective method of birth control if they are sexually active before study entry, during the 
study and one month after the end of the study by using an acceptable method of 
contraception. Acceptable methods of birth control must be used for at least 14 days 
prior to the use of study drug. Acceptable methods of birth control include oral, injected, 
vaginal or patch contraceptives, IUD (copper intrauterine device), or double-barrier 
method (for example, condom, diaphragm or cervical cap with spermicidal foam, cream, 
gel or suppository). 
 
 
 
_________________________________________ 
Printed name of Study participant 
 
______________________________________     ______________ _____________ 
Signature of Study participant 
Date of signature Time 
 
 
PERSON OBTAINING CONSENT 
 
____________________________________  
 
 
Printed Name of the Person Conducting the 
Consent Discussion  
 
 
_____________________________________ 
______________ 
_____________ 
Signature of the Person Conducting the  
Date of signature 
Time 
Consent Discussion †  
 
 
 
 
 
 
†The investigator, or a suitably qualified and trained person designated by the 
investigator to conduct the informed consent addendum process, must sign and date 
the consent document during the same interview when the subject signs the consent 
document. 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
CONSENT TO TAKE PART IN A RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Name of Research Study:   
Driving Simulation Cross-Over Study of 
Sedative Effects of Tolperisone Compared to 
Cyclobenzaprine and Placebo 
 
Protocol Number:   
115 
 
Name of Company Sponsoring 
the Research Study:   
 
 
Neurana Pharmaceuticals, Inc. 
 
 
Principal Investigator: 
(Study Doctor) 
 
David P. Walling, Ph.D. 
 
Telephone: 
 
(866) 787-4257 
(714) 910-9247 (24 Hours) 
 
 
Address: 
Collaborative Neuroscience Network 
2600 Redondo Avenue, Suite 500 
Long Beach, CA    90806 
 
 
 
You have been asked to take part in a research study.  First, we want you to know that 
taking part in a research study is entirely voluntary.  Second, you need to know that 
there are important differences between being cared for in a research study and being 
cared for by your doctor outside of a research study.  Participating in a research study is 
not the same as getting regular medical care.  The purpose of regular medical care is to 
improve your health.  The purpose of a research study is to gather information.  Being in 
this study does not replace your regular medical care.  Therefore, it is important that you 
understand the difference between the regular care you get from your doctor and what 
is involved in this research study. 
 
This consent document gives you important information about the research study.    
Please read this information carefully before deciding to take part.  No one can make 
you take part and you can stop at any time.  If you choose to take part in this research 
study, you will need to sign and date this consent document and you will receive a copy 
of this signed and dated document for your records. 
 
This research study is being conducted for Neurana Pharmaceuticals, Inc.  Neurana 
Pharmaceuticals, Inc. is sponsoring the study and will be paying the study doctor and 
the study site to conduct the study. 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
The following sections describe the research study.  Before you decide to take 
part, please take as much time as you need to ask questions with the study team, 
with family and friends, or with your personal physician or other healthcare 
professionals.  The study team will fully answer any questions you have before 
you make a decision.   
 
1. 
WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of this research study is to compare how certain drugs affect how you feel, 
how you perform on a simulated driving task, and your cognitive functioning after taking 
the drug. This research study will compare the effects of the following study drugs:  
tolperisone, cyclobenzaprine, and placebo. 
 
During the study, subjects will receive oral doses of 450 mg tolperisone (150 mg 
administered three times daily), 30 mg cyclobenzaprine (10 mg administered three times 
daily), and placebo. Subjects will receive each study treatment for the 3 days, with only 1 
dose being administered on the 3rd day. 
 
Tolperisone is marketed in multiple countries in Europe, and Asia, for muscle spasticity 
(tightness or stiffness) and muscle spasms. It will be studied in the United States to 
determine its safety and efficacy (how well it works). 
 
Cyclobenzaprine has been approved by the Food and Drug Administration in the USA 
as Flexiril®.  It is available by prescription to relax muscles.  The 10 mg dose three times 
per day represents the highest dose typically administered for adults with muscle 
spasms. 
 
Researchers use a placebo (sugar pill) to see if the study drug works better or is safer 
than not taking any drug. 
 
Because this is a research study, the study drugs will be given to you only during this 
study and not after the study is over.   
 
2. 
HOW MANY OTHER PEOPLE WILL BE IN THE STUDY? 
There will be about 30 male and female participants between the ages of 21-55 years 
enrolled in this study.  The study is being conducted at 1 or 2 different research sites in 
the USA.  About 15-30 people will be enrolled at this site. 
 
3. 
HOW LONG WILL PARTICIPATION IN THE STUDY LAST? 
If you decide to participate, you will be in this study for at least 3 weeks but no longer 
than 7 weeks. You will need to visit the research site 5 times during the study, including 
3 visits with 3 overnight stays.   
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
4. 
 WHAT WILL HAPPEN BEFORE THE RESEARCH STUDY BEGINS? 
If you decide to take part in this study, we will ask you to sign this consent document 
before we conduct any study-related activities. 
 
5. 
WHAT WILL HAPPEN DURING THE RESEARCH STUDY? 
Screening Visit (Visit 1) 
After signing and dating this consent document, you will begin in the study with a 
screening visit.  The purpose of the screening visit is to find out if you meet all of the 
requirements to take part in this research study.   
 
During the screening visit, you will be asked to have the following tests and activities or 
assessments:  
  
♦ Provide a social and medical history; 
♦ An electrocardiogram (ECG, a recording of the heart’s rhythm) will be performed; 
♦ You will also be asked about any medications and treatments you are currently 
taking.  It is important to tell the study site staff if you are taking any “over the 
counter” medications, herbal or natural remedies or dietary supplements; 
♦ Physical examination and vital signs (includes an examination of major body 
systems, height, weight, blood pressure while lying down and standing, pulse 
[heartrate], oral temperature, and respiratory [breathing] rate); 
♦ You will provide a urine sample and be given a breathalyzer test. The urine 
sample will be used for safety laboratory assessments (urinalysis) and to detect 
drugs and alcohol that are not allowed in this study, including illegal drugs (such 
as: amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, 
cannabinoids, and opiates).  Your urine sample must test negative for all of these 
drugs, and your breathalyzer must test negative for alcohol to participate in the 
study; 
♦ You will be required to complete a questionnaire regarding your sleep habits;  
♦ Collection of about 2 teaspoons of blood. This blood sample will be used to 
determine if you have HIV (Human Immunodeficiency Virus) or hepatitis (liver 
problem), and will also measure blood counts (hematology) and organ function 
(blood chemistry).  For females who could become pregnant, the sample will also 
be used to help confirm if you are pregnant. If the HIV or hepatitis result is 
positive, the physician in charge of the study or designee will personally inform 
you and at that moment he or she will indicate the procedure to follow. Note that 
a positive result for HIV, hepatitis B, or hepatitis C must be reported to the public 
health department as required by law.  If you have any questions about what 
information is required to be reported, please ask the Study Doctor or study staff. 
All blood collections for this study will be taken by individual needle sticks into 
one of the veins in your arm. 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
The following assessments may also be done while you are at the site for your 
screening visit or the study staff may ask that you come back to the site within the next 
4 weeks to complete them. If you return within 4 weeks to complete the following 
assessments, this will be an extra study visit (so you will have 6 visits in total).  
 
♦ You will learn more about driving simulators and practice for about 20 minutes. A 
driving simulator is an open booth with a steering wheel and computer screens. 
You will then complete a questionnaire that asks you how you feel after driving 
the simulator. Once you have completed the questionnaire you will complete 
another drive in the simulator for about 20 minutes. 
♦ You will complete a practice test that measures how your brain performs with 
regard to memory, attention, perception, action, problem solving and mental 
imagery capacity. The practice test will be completed on a computer. 
 
By the end of the screening period, the study doctor will determine if you are eligible to 
continue into the study.  If you will not be able to continue in the study, the study doctor 
will explain why.  
 
Study Treatment Period 1 
 
Visit 2 (Day -1 to Day 3) 
 
Day -1 
 
You will return to the site for your next visit (visit 2) in the evening (4:00 PM) before the 
first drug administration.  
 
When you arrive, the following tests, activities or assessments will be performed: 
 
♦ Review of any changes to your health; 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the last visit. It is important to tell your study doctor if you 
are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements, including multi-vitamins; 
♦ You will provide a urine sample. The urine sample will be used to determine if 
you are pregnant (if you are a female who can become pregnant) and to test for 
certain drugs that are not allowed in this study, including illegal drugs.  Your urine 
sample must test negative for all of these drugs to participate in the study;  
♦ You will take a breathalyzer test; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff; 
♦ You will complete a practice test that measures how your brain performs with 
regard to memory, attention, perception, action, problem solving and mental 
imagery capacity. The practice test will be completed on a computer; 
♦ You will be required to complete a 20-minute practice drive in the driving 
simulator; 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
♦ You will be served dinner. 
 
After completing the assessments, the Study Doctor will determine if you are eligible to 
continue in the study. If you are not eligible, the Study Doctor will explain why. If you are 
eligible for the study, you will stay at the clinical site overnight and continue with the visit 
2 procedures (Day 1). If you enroll in the study, you will receive each of the study drugs 
(tolperisone, cyclobenzaprine, and placebo) for 3 days, but at different study visits. 
 
Day 1 
The next day, upon awakening, the following tests, activities or assessments will be 
performed: 
 
♦ You will be served breakfast at 6:00 AM; 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since yesterday. It is important to tell your study doctor if you 
are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
morning dose; 
♦ About one teaspoon of blood will be collected prior to study drug administration 
to compare how much study drug is in your system later; 
♦ You will be randomly assigned (by chance) and administered a study drug. This 
is a double-blind study, which means neither you nor the study team will know to 
which study drug you are assigned at each study visit. This is done to make sure 
the results of the study cannot be unfairly influenced by anyone. In case of urgent 
need, the study team can get this information quickly. At each visit, you will be 
blindfolded while you take your study drug and will not know what study drug you 
took. 
♦ You will be fed lunch; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
afternoon dose; 
♦ You will receive your afternoon dose of study drug; 
♦ You will be asked whether you feel safe to drive; 
♦ You will complete some pen and paper questions about how sleepy you are; 
♦ You will complete a test that measures how your brain performs with regard to 
memory, attention, perception, action, problem solving and mental imagery 
capacity. The test will be completed on a computer; 
♦ You will take a 60-minute drive on the driving simulator. You will be videotaped 
during this drive.  
♦ You will then complete a pen and paper test as to your own performance on the 
driving simulator and how ready and motivated you felt to drive at your best on 
the driving simulator. 
♦ About one teaspoon of blood will be drawn to use to compare how much study 
drug is in your system; 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
♦ You will be fed dinner; 
♦ You will receive your evening dose of study drug at about 10:00 PM; 
♦ You will spend the night at the clinical site and will go to bed immediately after 
taking your evening dose of study drug. 
 
Day 2 
The next day, upon awakening, the following tests, activities or assessments will be 
performed: 
 
♦ You will be served breakfast at 6:00 AM; 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the previous day. It is important to tell your study doctor if 
you are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
morning dose; 
♦ You will be asked whether you feel safe to drive; 
♦ You will complete some pen and paper questions about how sleepy you are; 
♦ You will complete a test that measures how your brain performs with regard to 
memory, attention, perception, action, problem solving and mental imagery 
capacity. The test will be completed on a computer; 
♦ You will take a 60-minute drive on the driving simulator. You will be videotaped 
during this drive.  
♦ You will then complete a pen and paper test as to your own performance on the 
driving simulator and how ready and motivated you felt to drive at your best on 
the driving simulator. 
♦ About one teaspoon of blood will be drawn to use to compare how much drug is 
in your system; 
♦ You will receive your morning dose of study drug at about 8:00 AM; 
♦ You will be fed lunch at about 11:30 AM; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
afternoon dose; 
♦ You will receive your afternoon dose of study drug; 
♦ You will be fed dinner at about 5:00 PM; 
♦ You will receive your evening dose of study drug at about 10:00 PM; 
♦ You will spend the night at the clinical site and will go to bed immediately after 
taking your evening dose of study drug. 
 
Day 3 
The next day, upon awakening, the following tests, activities or assessments will be 
performed: 
 
♦ You will be served breakfast at 6:00 AM; 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the previous day. It is important to tell your study doctor if 
you are taking any “over the counter” medication, herbal or natural remedies or 
dietary supplements; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff prior to your 
morning dose; 
♦ About one teaspoon of blood will be drawn to use to compare how much study 
drug is in your system; 
♦ You will receive your morning dose of study drug at about 8:00 AM; 
♦ About 30 minutes after your morning dose, you will be asked whether you feel 
safe to drive; 
♦ You will complete some pen and paper questions about how sleepy you are; 
♦ You will complete a test that measures how your brain performs with regard to 
memory, attention, perception, action, problem solving and mental imagery 
capacity. The test will be completed on a computer; 
♦ You will take a 60-minute drive on the driving simulator. You will be videotaped 
during this drive.  
♦ You will then complete a pen and paper test as to your own performance on the 
driving simulator and how ready and motivated you felt to drive at your best on 
the driving simulator. 
♦ About one teaspoon of blood will be drawn to use to compare how much study 
drug is in your system; 
♦ You will be fed lunch at about 11:30 AM; 
♦ Blood pressure while lying down and standing, pulse, oral temperature, and 
respiratory rate (breathing rate) will be obtained by the study staff at about 1:55 
PM; 
 
When all assessments in Study Treatment 1 have been completed, a study staff 
member will schedule your next visit, which will occur in about 4 days. You will leave the 
clinical site at approximately 2:00 PM and can go home. However, you will be advised 
to stay at the clinical site, if the study doctor in charge feels it is necessary, for safety 
reasons. You will not be allowed to drive yourself home. You must arrange for someone 
to take you home.  
 
Study Treatment Periods 2 and 3 
 
Study Treatment Periods 2 and 3 will be exactly the same as Study Treatment Period 1.  
In between each visit (Study Treatment Period), you will not take any study drug while 
you are at home. 
 
At the end of the Study Treatment Period 3, after you have completed all study 
procedures and prior to discharge, the following tests, activities or assessments will be 
performed:  
 
♦ An ECG will be performed; 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
♦ You will be asked how you are feeling and if there have been any changes in 
your medications since the last visit. It is important to tell your study doctor if you 
have taken any “over the counter” medication, herbal or natural remedies or 
dietary supplements, including multi-vitamins; 
♦ Physical examination and vital signs (includes an examination of major body 
systems, weight, blood pressure while lying down and standing, pulse [heart 
rate], oral temperature, and respiratory [breathing] rate); 
♦ About 2 teaspoons of blood will be collected. This blood sample will be used to 
measure blood counts (hematology) and organ function (blood chemistry).   
♦ You will provide a urine sample. The urine sample will be used for safety 
laboratory assessments (urinalysis).   
 
Follow-Up 
 
Approximately 1 week after discharge from the clinical site after Study Treatment Period 
3, site staff will conduct a follow-up safety phone call. The site staff will ask you subject 
about your health and any medications you have taken since being discharged from the 
clinical site.  Following this phone call, your participation in the study will be complete. 
 
6. 
HOW WILL I RECEIVE THE STUDY DRUG? 
This study involves 3 different study treatments (tolperisone, cyclobenzaprine, and 
placebo). You will receive a different study treatment during each of the 3 Study 
Treatment Periods. You will receive study drug 3 times on Day 1, 3 times on Day 2, and 
1 time on Day 3 of each Study Treatment Period. Prior to receiving study drug, you will 
be blindfolded so that you will not see which study drug you are taking.  Each dose of 
study drug will consist of 1 tablet.  You will take each dose of study drug with water. You 
must swallow the study tablet whole, without chewing the tablet. 
 
7. 
WHAT HAPPENS WHEN I FINISH TAKING THE STUDY DRUG? 
About 1 week after you have taken the last dose of study drug and completed the Study 
Treatment Period 3 assessments, you will receive a follow-up safety phone call from the 
clinical site staff.  Following this phone call, your participation in the study will be 
complete.  
 
8. 
WHAT ARE THE RISKS AND POSSIBLE DISCOMFORTS OF BEING IN THIS 
RESEARCH STUDY? 
Any clinical research may have some risks, which may include things that could make 
you sick, make you feel uncomfortable, or harm you.  You might experience negative 
effects related to the study drug while participating in the study.  All research 
participants taking part in the study will be watched carefully for any negative effects; 
however, the study team does not know all the effects that the study drug may have on 
you.  The study team may give you medicines to help reduce negative effects.  These 
effects may be mild or serious.  In some cases, these effects might be long lasting, or 
permanent, and may even be life threatening.  


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 9 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
 
The negative events that are the most likely to happen to you if you take part in this 
study are listed below.   
 
For tolperisone: 
 
Common Side Effects: 
• Muscle weakness 
• Headache 
• Dizziness 
• Somnolence (drowsiness) 
• Vertigo (loss of balance) 
• Low blood pressure 
• Nausea 
• Vomiting 
• Abdominal (stomach) discomfort 
• Indigestion 
• Dry mouth 
 
For cyclobenzaprine: 
 
Common Side Effects: 
• Drowsiness 
• Somnolence ("sleepiness" or "drowsiness" – a state of strong desire for sleep, or 
sleeping for unusually long periods) 
• Dry mouth 
• Fatigue (tiredness) 
• Headache 
• Dizziness 
• Abdominal pain 
• Acid reflux 
• Constipation 
• Diarrhea 
• Nausea  
• Vomiting 
• Irritability 
• Decreased mental sharpness 
• Nervousness 
• Upper respiratory infection 
• Pharyngitis (sore throat) 
• Asthenia (weakness or lack of energy) 
• Indigestion 
• Unpleasant taste 
• Blurred vision 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
Placebo Risk:   
Taking a placebo may be similar to not taking any medication.   
 
Risks and possible discomforts you might experience from the study procedures 
include: 
 
Other Risks 
 
Since the use of the study drug is investigational when taken alone or in combination 
with other medications, there may be other risks that are unknown.  All drugs have a 
potential risk of an allergic reaction, which if not treated promptly, could become life 
threatening.  You should get medical help and contact the Study Doctor right away if 
you think you have any of the following symptoms of a serious allergic reaction:  trouble 
breathing, or swelling of the face, mouth, lips, gums, tongue or neck.  Other allergic 
reactions may include rash, hives, or blisters. 
 
If you experience the symptoms of an allergic reaction while outside the clinic, please 
go to the nearest hospital emergency department.  If you experience these symptoms 
while inside the clinic, please tell the study staff. 
 
It is important that you report all symptoms and side effects that you experience as soon 
as they occur, whether or not you think they are caused by the study drug.  The phone 
numbers for the study team are on the first page of this document. 
 
Blood draws: A blood draw may cause faintness, swelling of the vein, pain, redness, 
bruising, or bleeding at the site of puncture.  There is also a slight chance of infection. 
 
Simulator Sickness: You may feel sick after driving the simulator. This is a feeling similar 
to motion sickness. 
 
HIV/Hepatitis Testing:  Some of your blood will be tested for HIV, hepatitis B, and 
hepatitis C.  The study doctor may be required by law to report the result of these tests 
to the local health authority.  
 
Pregnancy Related Risks / Use of Birth Control 
 
Women who are pregnant or nursing a child may not participate in this study.  To 
participate in the study, you must confirm that, to the best of your knowledge, you are 
not now pregnant, and that you do not intend to become pregnant during the study or 
for at least one month after you complete the study.  If there is any possibility that you 
may become pregnant during the study, you will not be able to participate in the study. If 
you suspect that you have become pregnant during the study, you must notify the study 
doctor immediately.  You will not be able to participate in the study if you become 
pregnant.  
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
Acceptable methods of birth control must be used for 14 days before taking the study 
drug and for 30 days after the end of the study. Acceptable methods of birth control 
include oral, injected, vaginal or patch contraceptives, IUD (copper intrauterine device), 
or double-barrier method (for example, condom, diaphragm or cervical cap with 
spermicidal foam, cream, gel or suppository). 
 
Pregnancy Follow Up 
 
If you become pregnant during the study or within 1 month after your last dose of study 
drug, please tell the Study Doctor immediately.  Please also tell the doctor who will be 
taking care of you during the pregnancy that you took part in this study.  The Study 
Doctor will ask if your pregnancy doctor is willing to provide updates on the progress of 
the pregnancy and its outcome.  If you agree, this information will be provided to the 
study sponsor for safety monitoring follow-up. 
  
9. 
ARE THERE ANY SPECIAL INSTRUCTIONS TO FOLLOW WHILE 
PARTICIPATING IN THIS STUDY? 
During this study, it is important that you: 
• Do not travel across time zones or work on a rotating shift during the study; 
• Do not work a night shift for one week before each study visit; 
• Do not consume alcohol for 48 hours prior to any study visit; 
• Do not consume caffeine or caffeinated products (medicines, supplements, 
foods, beverages or confections) from 1:00 PM on the day of each study visit 
until you return home after the visit; 
• Nicotine-containing products may not be used while at the research site;   
• Do not practice vigorous physical activity for 24 hours prior to any study visit; 
• The study doctor will tell you what medications are not allowed during the study.  
They include: 
o Do not use any sleep aids [for example, diphenhydramine hydrochloride 
(Benadryl, Unisom SleepGels, Tylenol PM, Nyquil ZZZ, Advil PM, others), 
doxylamine succinate (Unisom SleepTabs, Kirkland, others), melatonin, 
and valerian]; 
o Do not use any cold or allergy products containing an antihistamine (for 
example, Dimetapp® Cold and Allergy Elixir, Chlor-Trimeton®, 
Dramamine®, Benadryl® Allergy, Nytol®, Sominex®, Vicks NyQuil®, Alka-
Seltzer® Plus Night-Time Cold Medicine); 
• Go to bed between 9:00 pm and 12:00 am on the night before every study visit. 
• Do not have your cellphone turned on during any of the cognitive procedures (for 
example, driving, CogScreen, forms) and from the time you receive the study 
drug until you complete the cognitive tests during each treatment period. 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
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David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
 
 
 
10. WHAT OPTIONS ARE AVAILABLE OTHER THAN BEING IN THIS STUDY? 
This research study is for research purposes only.  The only alternative is to not take 
part in this study. 
 
11. WHAT ARE POSSIBLE BENEFITS OF BEING IN THIS STUDY? 
This study is for research purposes only.  There is no direct benefit to you from your 
participation in the study.  Information learned from the study may help other people in 
the future. 
 
12. WHAT HAPPENS IF I AM INJURED AS A RESULT OF TAKING PART IN THIS 
RESEARCH STUDY? 
If you become ill or are hurt while you are in the study, get the medical care that you 
need right away. You must notify the study doctor immediately of any injury. If you have 
any questions concerning the availability of medical care or if you think you have 
experienced a research-related illness, injury or emergency, contact the study doctor 
using the contact information on the first page of this form.  
 
If you experience a research injury, the study doctor or study site will provide or arrange 
for medical treatment at no cost to you. Neurana Pharmaceuticals, Inc. will cover the 
costs of this treatment.  A research injury is any physical injury or illness caused by your 
taking part in this study. If you are injured by a medical treatment or procedure that you 
would have received even if you were not in this study, that is not a research injury. To 
help avoid injury, it is very important to follow all study directions. The sponsor has no 
plans for other financial compensation.   
 
To pay these medical expenses, the sponsor will need to know some information about 
you like your name, date of birth, and social security number or Medicare Health 
Insurance Claim Number. This is because the sponsor has to check to see if you 
receive Medicare and if you do, report the payment it makes to Medicare. 
 
You still have the right to make a claim through the legal system even if you sign this 
form, accept medical care, or accept payment for medical expenses. 
 
13. IS BEING IN THE STUDY VOLUNTARY? 
Yes.  Taking part in this research study is up to you.  You may choose not to take part, 
or you can change your mind and withdraw (drop out) later.  There will be no penalty, 
and you won’t lose any benefits you receive now or have a right to receive.    
 
We will tell you if we learn new information that could change your mind about taking 
part or continuing in this research study.  If you want to drop out, you should tell us.   


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 13 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
We will make sure you can end the study in the safest way.  We will also talk to you 
about follow-up care, if needed. 
 
The study doctor or the study sponsor may decide to take you out of the study without 
your agreement if:  
• You do not follow the directions of the study team; 
• The study doctor decides that the study is not in your best interest; 
• The study is stopped by the study sponsor, the institutional review board (IRB) (a 
group of people who review the research to protect your rights), or by a 
regulatory agency;   
• You become pregnant, intend to become pregnant or are nursing a child during 
this study. 
 
If you withdraw or are removed from the study, biological samples (for example, blood 
or urine samples) that have been collected from you (but not yet fully analyzed) can be 
destroyed by making a request to the study doctor in person or at the telephone number 
listed on the first page of this form.  However, any data already generated from your 
samples will be kept to preserve the value of the study.   
 
14. WHAT WILL I HAVE TO PAY FOR IF I TAKE PART IN THIS RESEARCH 
STUDY? 
There will be no charge to you for your participation in this study.  The study drug, 
study-related procedures, and study visits will be provided at no charge to you or your 
insurance company.   
 
The study drugs (tolperisone, cyclobenzaprine, and placebo) and all other study 
procedures will be provided at no charge while you are participating in this study. 
 
Will I Be Paid For Taking Part In This Study? 
 
You will be compensated according to the following payment schedule. 
Screening, Day 3, Day 10, and Day 17:  $75.00 
Day -1, Day 1, Day 2, Day 7, Day 8, Day 9, Day 14, Day 15, and Day 16: $200.00 
Day 24 Phone Call: $38.00 
If you do not complete the study, you will only be compensated for the visits that you 
have completed. You will be compensated for completed visits at least quarterly with 
final payment within 30 days of the end of your participation the study.  
If you test positive for illicit drugs during the screening process, you will not be paid for 
that visit.  If you are participating in this or any other study at more than one site, you 
will not be paid for any visits.  


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 14 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
If you enroll in this study in more than one site please be aware that you will be 
terminated from the study as this is prohibited. 
 
Neurana Pharmaceuticals, Inc. may use information from your sample(s) to develop 
products or processes from which they may make a profit.  There are no plans to pay 
you or provide you with any products developed from this research. Neurana 
Pharmaceuticals, Inc. will own all products or processes that are developed using 
information from your sample(s). 
 
15. CONFIDENTIALITY 
To ensure that your information collected for this study will be kept private, your name 
will not be used whenever possible.  A code will be used instead of your name.  All of 
your study data will be kept in a secure location. Please understand that representatives 
of the Food and Drug Administration (FDA), the sponsor of this study, and any other 
entities included in the section below, may review your study data for the purposes of 
verifying research data, and will see personal identifiers.   
 
16. IF I TAKE PART IN THIS RESEARCH STUDY, HOW WILL MY 
PRIVACY BE PROTECTED? 
A federal regulation, known as the Privacy Rule, gives you certain rights 
concerning the privacy of your health information.  The Privacy Rule was 
issued under a law called the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Researchers covered by this 
regulation are required to get your authorization (permission) to use and 
disclose (share with others) any health information that could identify you.  
 
If you sign this informed consent form, you are giving permission for the 
use and disclosure of your health information for purposes of this research 
study.  You do not have to give this permission.  However, if you do not, 
you will not be able to take part in the study. 
 
Who Will Use and Disclose My Health Information? 
 
The study team may use your health information to conduct, review, and 
determine the results of the study.  The study team may also use your 
information to prepare reports or publications about the study.  However, 
your name will not appear in any report or publication.  
 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 15 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
What Health Information will be Used and Disclosed? 
 
During the study, the study team will use, collect, and record health 
information about you (your “records”).  Your records will include any 
information about you that the study team needs to do the study, including 
information from the procedures described above. Your records may 
include other health information about you and will include identifying 
information such as your name and address. The study team will record 
some of this information on “study forms” provided by the study sponsor.  
Your name or address will not appear on the study forms.  Instead, you will 
be assigned a participant identification number.   
 
The study team will send the completed study forms to the study sponsor 
and may share this information with others, as described below.    
 
Representatives from the groups identified below may also need to look at 
your records (which identify you) to make sure that the information on the 
study forms is correct or that the study was conducted properly.  Reviews 
like that will take place at the research site or where the records are stored 
and can take place after the study is over.   
 
Who Will Receive My Health Information? 
 
Your study information may be shared with the following people or groups: 
 
• The study sponsor (Neurana Pharmaceuticals, Inc.) or its 
representatives, including companies it hires to provide study-related 
services  
• Researchers who are conducting this study at other research sites  
• The Institutional Review Board (ethics committee) that approved this 
study and any other committees responsible for overseeing the 
research 
• Government health agencies (such as the Food and Drug 
Administration) in the US or other countries 
• Your study doctor may inform your primary physician about your 
participation in the study if you have a primary physician and you 
agree to the primary physician being informed.   
  


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 16 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
Will My Information Be Protected by the Privacy Rule After it is 
Disclosed to Others? 
 
The study site is required by the Privacy Rule to protect your health 
information.  After your information is shared with others, such as the study 
sponsor, it may no longer be protected by the Privacy Rule.  The people 
who receive this information could use it in ways not discussed in this form 
and could disclose it to others.  However, the study sponsor will use and 
disclose your information only for research or regulatory purposes or to 
prepare research publications.  In addition to using it for this study, the 
study sponsor may reanalyze the study data at a later date or combine your 
information with information from other studies for research purposes not 
directly related to this study.  The goal of any such research would be to 
learn more about drugs or diseases or to help design better studies in the 
future.  When using your information in these ways, the study sponsor may 
share it with regulatory authorities, other researchers, its business partners, 
or companies it hires to provide research-related services.  This could 
result in transfer of your information outside the United States.  However, 
your name will never appear in any study sponsor reports or 
publications, or in any future disclosures by the study sponsor. 
 
 
What Happens if I Leave the Study Early? 
 
If you stop participating in the study early for any reason, the study team 
will tell the study sponsor why.  If the study team asks you to come to any 
more study visits and if you agree, the study team will send the study 
sponsor information from those visits as well.  All information collected 
about you may continue to be used and disclosed.   
 
Will My Authorization Ever Expire? 
 
This Authorization does not have an expiration date.  The study team may 
need to correct or provide missing information about you even after your 
study participation is over.  The review of your medical records (described 
above) may also take place after the study is over. 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 17 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
May I Take Back My Authorization? 
 
You have the right to take back (revoke) your Authorization at any time by 
writing to the study doctor at the address listed on the first page of this 
form. 
 
If you revoke your Authorization, the study team will not collect any new 
health information about you.  However, they can continue to use and 
disclose any already collected information if that is necessary for the 
reliability (the scientific value) of the study.  The study sponsor can also still 
keep and use any information that it has already received.  If you revoke 
your Authorization, you can no longer continue to participate in the study. 
 
In California and any other state that requires an expiration date, the 
Authorization will expire 50 years after you sign this authorization document. 
 
 
                                                                                  ____/____/____ 
Signature of Research Subject                                      Date 
 
___________________________________                                       
Printed Name of Research Subject           
 
 
May I Look At My Study Information? 
 
You have a right to see and make copies of your medical records.  However, to ensure 
the reliability of the study, you will need to wait to see your study records until the study 
is completed.   
 
17. WHERE CAN I FIND ADDITIONAL INFORMATION ABOUT THIS RESEARCH 
STUDY OR THE RESEARCH RESULTS? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time.  It may be many years; however, before research results are posted. 
 
 
 
 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 18 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
18. GETTING ANSWERS TO YOUR QUESTIONS OR CONCERNS ABOUT THE 
STUDY 
You can ask questions about this consent form or the study (before you decide to start 
the study, at any time during the study, or after completion of the study).  Questions 
may include: 
 
• Who to contact in the case of a research-related injury or illness; 
• Payment or compensation for being in the study, if any; 
• Your responsibilities as a study subject; 
• Eligibility to participate in the research; 
• The study doctor’s or study site’s decision to exclude you from participation; 
• Results of tests and/or procedures; 
• Other questions, concerns, or complaints. 
 
Contact the study doctor or study staff listed on the first page of this form with 
any questions, concerns or complaints.   
 
 
19. GETTING ANSWERS TO YOUR QUESTIONS ABOUT YOUR RIGHTS AS A 
RESEARCH SUBJECT 
This study has been reviewed by an Institutional Review Board (IRB). This Committee 
reviewed this study to help ensure that your rights and welfare are protected and that 
this study is carried out in an ethical manner. 
 
For questions about your rights as a research subject, contact:  
 
• By mail: 
Study Subject Adviser 
Chesapeake IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:        877-992-4724 
• or by email:              adviser@chesapeakeirb.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00021652. 
 
An IRB is a group of people who review research studies to protect the rights and 
welfare of research participants.   


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 19 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
20. SIGNATURES: 
I have read the information in this informed consent document.  I have had an 
opportunity to ask questions and all of my questions have been answered to my 
satisfaction. I voluntarily agree to take part in this study.  I voluntarily agree to allow 
study staff to collect, use and share my health data as specified in this form. I do not 
give up any of my legal rights by signing this consent document.   
 
I have been told that I will receive a signed and dated copy of this document. 
 
_________________________________________ 
Printed name of Study Participant 
 
______________________________________     ______________ _____________ 
Signature of Study Participant 
 Date of signature Time 
 
 
PERSON OBTAINING CONSENT 
 
____________________________________  
 
 
Printed Name of the Person Conducting the 
Consent Discussion  
 
 
_____________________________________ 
______________ 
_____________ 
Signature of the Person Conducting the  
Date of signature 
Time 
Consent Discussion †  
 
 
 
 
 
 
†The Investigator, or a suitably qualified and trained person designated by the 
Investigator to conduct the informed consent process, must sign and date the consent 
document during the same interview when the subject signs the consent document. 
 
 
 


Neurana Pharmaceuticals, Inc. / Protocol Number 115 
Page 20 of 20 
 
David P. Walling, Ph.D. 
Chesapeake IRB Approved Version 11 May 2017 
Revised 19 Jul 2017 
 
21. WOMEN OF CHILDBEARING POTENTIAL ADDENDUM 
If you are a female of childbearing potential, by signing this form you agree to use 
adequate contraception during and for 1 month following completion of the study.  
 
You must have a negative serum pregnancy test at screening, must be postmenopausal 
(amenorrhea for at least 2 years), surgically sterile, or practicing or agree to practice an 
effective method of birth control if they are sexually active before study entry, during the 
study and one month after the end of the study by using an acceptable method of 
contraception. Acceptable methods of birth control must be used for at least 14 days 
prior to the use of study drug. Acceptable methods of birth control include oral, injected, 
vaginal or patch contraceptives, IUD (copper intrauterine device), or double-barrier 
method (for example, condom, diaphragm or cervical cap with spermicidal foam, cream, 
gel or suppository). 
 
 
 
_________________________________________ 
Printed name of Study participant 
 
______________________________________     ______________ _____________ 
Signature of Study participant 
Date of signature Time 
 
 
PERSON OBTAINING CONSENT 
 
____________________________________  
 
 
Printed Name of the Person Conducting the 
Consent Discussion  
 
 
_____________________________________ 
______________ 
_____________ 
Signature of the Person Conducting the  
Date of signature 
Time 
Consent Discussion †  
 
 
 
 
 
 
†The investigator, or a suitably qualified and trained person designated by the 
investigator to conduct the informed consent addendum process, must sign and date 
the consent document during the same interview when the subject signs the consent 
document. 
 


Chesapeake IRB Membership Roster
OHRP/FDA IRB Registration Number: IRB#00000790
Member’s Name
Profession
Status
GP*Mo-5
GP*Tu-1
GP*W-2
GP*Th-4
GP*F-3
Willard Abe Andes, M.D.
Oncologist - Hematology/Oncology
Physician Scientist
Alternate
Alternate
Alternate
Member
Alternate
N
Sarah Altier, Ed.D.
Educator
Non-Scientist
Member
Alternate
Alternate
Alternate
Alternate
N
Joy Cavagnaro, Ph.D., DABT, RAC
Toxicologist/Regulatory Affairs Consultant
Other Scientist
Alternate
Member**
Alternate
Alternate
Alternate
N
George Cianciolo, Ph.D.
Immunologist
Other Scientist
Alternate
Alternate
Alternate
Member
Member
N
Laura Clark, M.D.
Physician –Anesthesiologist
Physician Scientist
Alternate
Alternate
Alternate
Member
Alternate
N
Thomas H. Closson, B.S., RPh, CIP
Pharmacist  
Other Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
Y
Walter Durkin, M.D.
Physician – Oncologist
Physician Scientist
Member
Alternate
Alternate
Alternate
Alternate
N
Daniel Fernicola, M.D., FACC
Physician-Cardiologist
Physician Scientist
Alternate
Member
Alternate
Alternate
Alternate
N
Janelle Flowers, M.Ed.
Guidance Counselor
Non-Scientist
Member
Alternate
Alternate
Alternate
Member
N
Robert Frenck, Jr. M.D.
Physician - Pediatrics, Infectious Disease
Physician Scientist
Alternate
Alternate
Alternate
Member
Alternate
Paul Goebel Jr., B.S., CIP
Human Subject Protection Consultant
Non Scientist
Alternate
Member
Alternate
Member
Alternate
N
C. Vernon Gray, Ph.D.
County Government Administrator
Non Scientist
Alternate
Alternate
Member
Alternate
Alternate
N
Melinda Group, B.S., R.Ph. 
Hospital and Research Pharmacist
Other Scientist
Member
Alternate
Alternate
Alternate
Member
N
G. Levering Keely, B.S.N., M.P.A.
Nurse, Device specialist
Other Scientist
Alternate
Alternate
Alternate
Member
Alternate
N
Janet Keyser, B.S.
Clinical Development & Compliance Consultant
Other Scientist
Alternate
Alternate
Alternate
Alternate
Member
N
Peter LaCount, MHS, M.Ed.
Compliance Director
Non Scientist
Alternate
Member
Alternate
Alternate
Alternate
N
Kelley Letter, B.B.A.
Regulatory Affairs, IRB specialist 
Non Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
y
Joseph Markoff, M.D., Ph.D.
Ophthalmologist, Neuroscientist
Physician Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
N
Joseph McPhillips, Ph.D.
Clinical Research Consultant
Other Scientist
Alternate
Alternate
Member
Alternate
Alternate
N
David C. Miller, M.D., MBA, FAAFP
Physician-Family Practice
Physician Scientist
Alternate
Alternate
Alternate
Alternate
Member
N
Tiffani Moss, BA, MS, CIP
Regulatory Affairs, IRB specialist 
Non Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
Y
Karen Near, M.D., M.S.
Physician – Internal Med., Infectious Diseases
Physician Scientist
Alternate
Alternate
Member
Alternate
Alternate
N
Kyle Patrick, D.O. 
Physician - Medical Research
Physician Scientist
Alternate
Alternate
Alternate
Member
Alternate
N
Gail Povar, M.D., M.P.H., FACP
Physician-Internal Medicine
Physician Scientist
Alternate
Member
Alternate
Alternate
Alternate
N
Troy Priest, B.A., J.D.
Attorney
Non Scientist
Alternate
Alternate
Alternate
Member**
Member**
N
Albert Razzetti, M.D.
Physician – Internal Medicine / Pulmonologist
Physician Scientist
Member
Alternate
Alternate
Alternate
Alternate
N
Mitchell Reddish, Ph.D.
University Professor, Religious Studies, Ethicist
Non-Scientist
Member**
Alternate
Alternate
Alternate
Alternate
N
Aixa Rey, Pharm.D.
Clinical Pharmacist
Other Scientist
Alternate
Alternate
Member
Alternate
Alternate
N
Deborah Reynolds, R.N., OCN
Oncology Nurse
Other Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
N
Carol Sadorra, Ph.D.
Research Consultant
Non Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
N
Clifford Selsky, M.D. Ph.D.
Phsician – Pediatrics, Hematology Oncology
Physician Scientist
Member
Alternate
Alternate
Alternate
Alternate
N
John Sever, M.D., Ph.D.
Physician-Pediatrics, Infectious Diseases
Physician Scientist
Alternate
Member
Alternate
Alternate
Member
N
Cheri Smith, B.BA., LCSW-C
Social Work, Subject Advocate
Non Scientist
Alternate
Alternate
Member
Alternate
Alternate
N
Karen Gabel Speroni, Ph.D., R.N.
Nursing Research Director/Consultant
Other Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
N
Neil W. Steinhorn, J.D.
Attorney, Prisoner Representative
Non Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
N
Affiliated
Y/N
Page 1 of 2
Version 04/06/2017


Chesapeake IRB Membership Roster
OHRP/FDA IRB Registration Number: IRB#00000790
Member’s Name
Profession
Status
GP*Mo-5
GP*Tu-1
GP*W-2
GP*Th-4
GP*F-3
Affiliated
Y/N
Amy Strahl, CIP
Regulatory Affairs, IRB specialist 
Non Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
Y
Anita Tarzian, Ph.D., R.N.
Ethics and Research Consultant / Ethicist
Other Scientist
Alternate
Alternate
Member**
Alternate
Alternate
N
Marc Teitelbaum, M.D., M.S.
Physician – OB/Gyn, Clinical Safety Director
Physician Scientist
Member
Member
Alternate
Alternate
Alternate
N
Katherine Tkaczuk, M.D.
Physician-Oncologist/Hematologist
Physician Scientist
Alternate
Alternate
Member
Alternate
Alternate
N
Susan Trimbo, Ph.D.
Scientific Affairs Consultant – Nutrition
Other Scientist
Alternate
Alternate
Alternate
Alternate
Alternate
N
*General Panel (GP), **Chair
Chesapeake IRB has been awarded Full Accreditation from the Association for the Accreditation of Human Research Protection Programs®, Inc. (AAHRPP).
Chesapeake IRB is organized and operates in compliance with FDA regulations as described in 21 CFR Parts 50 and 56, DHHS regulations as described in 45 CFR 46, guidelines resulting from the International Conference on
Harmonization (ICH), Good Clinical Practice (GCP), and potentially The Common Rule as appropriate. In addition, the IRB operates in compliance with the portions of the Health Insurance Portability and Accountability Act of
1996 (HIPAA Privacy Rule) that apply to research, as described in 45 CFR Parts 160 and 164.
Page 2 of 2
Version 04/06/2017

SAP_001.pdf: 
Tolperisone hydrochloride 
Clinical Study Report - Protocol 115 
Neurana Pharmaceuticals, Inc. 
 
 
 
CONFIDENTIAL 
106 
Version 1.0 (9 May 2018) 
 
16.1.9 
Documentation of Statistical Methods 
 
16.1.9.1 
Statistical Analysis Plan 
16.1.9.2 
MiniSim Drive Summary Measures 
 
 


Tolperisone hydrochloride 
Clinical Study Report - Protocol 115 
Neurana Pharmaceuticals, Inc. 
 
 
 
CONFIDENTIAL 
107 
Version 1.0 (9 May 2018) 
 
16.1.9.1 Statistical Analysis Plan 
 
The Statistical Analysis Plan dated 13 October 2017 is attached. 
 


  
STATISTICAL ANALYSIS PLAN  
 
PROTOCOL: 115 
 
Driving Simulation Cross-Over Study of Sedative Effects of 
Tolperisone Compared to Cyclobenzaprine and Placebo   
 
 
SPONSOR:  
Neurana Pharmaceuticals, Inc. 
3525 Del Mar Heights Rd, #609  
San Diego, CA 92130 
 
PRODUCT:  
Tolperisone hydrochloride, NR100 
 
AUTHOR: 
 
Jeffrey S Finman, PhD 
 
 
Jupiter Point Pharma Consulting, LLC 
 
 
796 Shennecossett Road 
Groton, CT 06340 
 
Julie M Jones, PhD 
Breckenridge Statistics, Inc. 
226 S Main St. Unit 20 
PO Box 1849 
Breckenridge, CO 80424 
 
 
 
DATE: 
 
October 13, 2017 
 
 
STATUS: 
 
Final Version 1.0 
 
 
 
 
 
 




TABLE OF CONTENTS 
 
 
1 
LIST OF ABBREVIATIONS ............................................................................................ 5 
2 
INTRODUCTION ............................................................................................................. 6 
3 
STUDY OBJECTIVE ....................................................................................................... 6 
3.1 
PRIMARY OBJECTIVE ......................................................................................................................... 6 
3.2 
SECONDARY OBJECTIVE ................................................................................................................... 6 
4 
STUDY DESIGN .............................................................................................................. 6 
4.1 
DURATION OF STUDY ......................................................................................................................... 6 
4.2 
NUMBER OF SUBJECTS (STUDY POPULATION).............................................................................. 6 
4.3 
DESIGN AND TREATMENTS ............................................................................................................... 6 
TABLE 1 SCHEMATIC OF DESIGN ..................................................................................... 8 
4.4 
TREATMENTS ...................................................................................................................................... 8 
4.4.1 
Tolperisone Dose Level ................................................................................................................ 8 
4.4.2 
Positive Control Dose Level .......................................................................................................... 8 
4.5 
RANDOMIZATION ................................................................................................................................ 9 
4.5.1 
SCHEDULE OF EVENTS AND ASSESSMENTS ........................................................................ 9 
TABLE 2 SCHEDULE OF ACTIVITIES ............................................................................... 10 
5 
OUTCOME VARIABLE DEFINITIONS ......................................................................... 12 
5.1 
SCREENING AND BASELINE ASSESSMENT .................................................................................. 12 
5.2 
PHARMACODYNAMIC ASSESSMENTS ........................................................................................... 12 
5.2.1 
CVDA DRIVING SCENARIO ON THE CRCDS-MiniSim .......................................................... 12 
5.2.2 
KAROLINSKA SLEEPINESS SCALE (KSS) ............................................................................ 12 
5.2.3 
SELF PERCEIVED SAFETY TO DRIVE QUESTION ................................................................ 13 
5.2.4 
COGSCREEN SYMBOL DIGIT CODING (SDC) ....................................................................... 13 
5.2.5 
VISUAL ANALOG SCALE (VAS) TO ASSESS MOTIVATION AND SELF-APPRAISAL ........ 13 
5.3 
PHARMACODYNAMIC ENDPOINTS ................................................................................................. 14 
5.3.1 
PRIMARY ENDPOINT ................................................................................................................ 14 
5.3.2 
SECONDARY ENDPOINTS ....................................................................................................... 14 
5.4 
SAFETY ASSESSMENTS .................................................................................................................. 14 
5.4.1 
SECONDARY SAFETY ENDPOINTS ........................................................................................ 14 
5.4.2 
ADVERSE EVENTS.................................................................................................................... 15 
5.4.3 
CLINICAL LABORATORY EVALUATIONS .............................................................................. 15 
5.4.4 
PHYSICAL EXAMINATION ........................................................................................................ 16 
5.4.5 
VITAL SIGNS .............................................................................................................................. 16 
5.4.6 
12-LEAD ELECTROCARDIOGRAM .......................................................................................... 16 
5.5 
CONCOMITANT MEDICATIONS........................................................................................................ 16 
5.6 
SCREENING ASSESSMENTS ........................................................................................................... 17 
5.6.1 
EPWORTH SLEEPINESS SCALE ............................................................................................. 17 
6 
STATISTICAL ANALYSES ........................................................................................... 17 
6.1 
STATISTICAL METHODOLOGY ........................................................................................................ 17 
6.1.1 
DETERMINATION OF SAMPLE SIZE ....................................................................................... 17 
6.1.2 
ANALYSIS POPULATIONS ....................................................................................................... 18 
6.1.3 
STATISTICAL ANALYSES – GENERAL CONSIDERATIONS ................................................. 18 
6.1.4 
MULTIPLE COMPARISONS ...................................................................................................... 18 
6.1.5 
PROCEDURES FOR HANDLING MISSING DATA ................................................................... 19 


6.2 
SCREENING AND BASELINE CHARACTERISTICS ......................................................................... 19 
6.3 
SUBJECT DISPOSITION .................................................................................................................... 19 
6.4 
STUDY MEDICATION ADMINISTRATION ......................................................................................... 20 
6.5 
PHARMACODYNAMIC ANALYSES ................................................................................................... 20 
6.5.1 
PRIMARY ANALYSIS ................................................................................................................ 20 
6.5.2 
SECONDARY ANALYSES ......................................................................................................... 21 
6.6 
SAFETY ANALYSES .......................................................................................................................... 22 
6.6.1 
ADVERSE EVENTS (AE) ........................................................................................................... 23 
6.6.2 
CLINICAL LABORATORY EVALUATIONS .............................................................................. 23 
6.6.3 
PHYSICAL EXAMINATION ........................................................................................................ 23 
6.6.4 
VITAL SIGNS .............................................................................................................................. 23 
6.6.5 
12-LEAD ELECTROCARDIOGRAM .......................................................................................... 24 
6.7 
CONCOMITANT MEDICATIONS........................................................................................................ 24 
6.8 
CONCENTRATION DATA .................................................................................................................. 24 
6.9 
ADDITIONAL COLLECTED DATA ...................................................................................................... 24 
7 
REFERENCES .............................................................................................................. 24 
8 
TABLES, LISTINGS, AND FIGURES ........................................................................... 25 
8.1 
TABLES ............................................................................................................................................... 25 
8.2 
LISTINGS ............................................................................................................................................ 29 
8.3 
FIGURES ............................................................................................................................................ 30 
 


1 LIST OF ABBREVIATIONS 
AE(s) 
Adverse event(s)                     
BAC 
Blood Alcohol Content 
BMI 
Body mass index 
CRCDS-MiniSim 
Cognitive Research Corporation Driving Simulator-MiniSim 
CRF 
Case report form 
CVDA 
Country Vigilance-Divided Attention 
DA 
Divided attention 
ECG 
Electrocardiogram 
EOS 
End of study 
ESS 
Epworth Sleepiness Scale 
HIV 
Human immunodeficiency virus 
ITT 
Intent-to-Treat 
KSS 
Karolinska Sleepiness Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm 
Millimeter 
N 
Number 
NI 
Non-inferiority 
PK 
Pharmacokinetic 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDC 
Symbol Digit Coding 
SDLP 
Standard deviation of lateral position 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three times a day 
VAS 
Visual analog scale 
 
 


2 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned statistical analyses for the study 
entitled “Driving Simulation Cross-Over Study of Sedative Effects of Tolperisone Compared 
to Cyclobenzaprine and Placebo” finalized 28 April 2017.  
3 
STUDY OBJECTIVE 
3.1 PRIMARY OBJECTIVE 
The primary objective of this study is:  
• 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. 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). 
3.2 SECONDARY OBJECTIVE 
The secondary objective of this study is:  
• to assess the safety of 150 mg TID tolperisone dosing for 3 days in healthy 
volunteers. 
4 
STUDY DESIGN 
4.1 DURATION OF STUDY 
The total duration of study participation will be approximately 4 weeks (range 4-8 weeks), 
including Screening and Follow-up.  Subject participation will be approximately 3 weeks as 
outpatients with 3 days each week as overnight clinic participants.   
4.2 NUMBER OF SUBJECTS (STUDY POPULATION) 
A sufficient number of subjects will be enrolled to ensure a total of 30 normal, healthy, male 
and female subjects between the ages of 21 and 55 years (at the time of informed consent) 
will complete all dosing periods, including the driving assessment.  
4.3 DESIGN AND TREATMENTS 
This will be a randomized, placebo-controlled, multiple-dose 3-way cross-over study of the 
safety and cognitive effects of multiple doses of 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 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.  
Subjects will be discharged on Day 3 with instructions to return to the clinic on Day 7 and 
Day 14 to repeat the above procedures with the second and third treatments.  
A follow-up phone call will be conducted 1 week (±3 days) following discharge from the clinic 
on Day 17 to assess for continued safety. 
A schematic of the study design is presented in Table 1. 


Table 1 Schematic of Design 
Hour 
Day -1 
Day 1 
Day 2 
Day 3 
Days 4-7 
6:00 (WASHOUT) 
Breakfast 
Breakfast 
Breakfast 
  
7:00   
Driving 
Simulation 
WASHOUT 
8:00   
AM Dosing 
AM Dosing 
AM Dosing 
  
9:00 
  
Driving 
Simulation 
  
10:00  
 
 
 
 
11:30   
Lunch 
Lunch 
Lunch 
  
12:00   
  
13:00   
  
14:00   
PM Dosing 
PM Dosing 
Discharge 
  
15:00 
  
Driving 
Simulation 
  
16:00 Check-in 
  
17:00  Dinner 
Dinner 
Dinner 
  
18:00   
  
19:00   
  
20:00 
Practice Cog 
& Driving 
Simulation 
  
21:00   
  
22:00 Bedtime 
HS 
Dosing/Bedtime 
HS 
Dosing/Bedtime 
  
  
4.4 TREATMENTS 
4.4.1 Tolperisone Dose Level 
For the tolperisone treatment arm, tolperisone will be administered three times per day, with 
1 tablet administered at 8:00 AM (AM dose), 2:00 PM (PM dose), and 10:00 PM (HS dose) 
daily for 2 days and 1 tablet at 8:00 AM on Day 3. Depending upon randomization sequence 
tolperisone dosing will take place at Visit 1, 2, or 3. Each dose will be a 150 mg tablet of 
tolperisone, for a total daily dose of 450 mg on Days 1 and 2, and a total dose of 150 mg on 
Day 3.  
4.4.2 Positive Control Dose Level 
Cyclobenzaprine will serve as the positive control to demonstrate assay sensitivity. For the 
cyclobenzaprine treatment arm, cyclobenzaprine will be administered three times per day, 
with 1 tablet administered at 8:00 AM (AM dose), 2:00 PM (PM dose), and 10:00 PM (HS 
dose) daily for 2 days and 1 tablet at 8:00 AM on Day 3. Depending upon randomization 
sequence, cyclobenzaprine dosing will take place at Visit 1, 2, or 3. Each dose will be a 10 


mg tablet of cyclobenzaprine, for a total daily dose of 30 mg on Days 1 and 2, and a total 
dose of 10 mg on Day 3. 
4.5 RANDOMIZATION 
Prior to dosing, subjects will be randomly assigned to one of 6 treatment sequences (one for 
each permutation of treatment groups) and dosed with study medication (tolperisone, 
cyclobenzaprine or placebo) based upon a randomization scheme provided by Cognitive 
Research Corporation. Only the qualified person(nel) assigned to prepare and administer 
the study treatment will have access to the randomization schedule and dispensing records 
during the study period. 
4.5.1 SCHEDULE OF EVENTS AND ASSESSMENTS 
The schedule of study events and assessments are presented in Table 2.


Table 2 Schedule of Activities 
 
 
Screenin
g 
Period 1 
Period 2 
Period 3 
Follow-up 
Phone 
Call 
Procedures 
Day -28 
to -2 
(V1) 
Day -1 
(V2) 
Day 1 
(V3) 
Day 2 
(V4) 
Day 3 
(V5) 
Day 7 
(V6) 
Day 8 
(V7) 
Day 9 
(V8) 
Day 10 
(V9) 
 
Day 14 
(V10) 
Day 15 
(V11) 
Day 16 
(V12) 
Day 17 
(V13) 
Day 24   
(±3 days) 
(V14) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Medical/Social History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Epworth Sleepiness Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Simulator Sickness 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Driving Simulation & 
Cognitive Testing practice 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Driving Simulation & 
Cognitive Testing 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
KSS 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Self-Perceived 
Questionnaire 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
VAS 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Vital Sign Measurementsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Standard 12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 


 
 
Screenin
g 
Period 1 
Period 2 
Period 3 
Follow-up 
Phone 
Call 
Procedures 
Day -28 
to -2 
(V1) 
Day -1 
(V2) 
Day 1 
(V3) 
Day 2 
(V4) 
Day 3 
(V5) 
Day 7 
(V6) 
Day 8 
(V7) 
Day 9 
(V8) 
Day 10 
(V9) 
 
Day 14 
(V10) 
Day 15 
(V11) 
Day 16 
(V12) 
Day 17 
(V13) 
Day 24   
(±3 days) 
(V14) 
Laboratory Evaluationsb 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum/Urine Pregnancy 
Testc 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Urine Drug Screening / 
Breathalyzer 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pharmacokinetic Samplingd 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Discharge from Clinic  
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
a 
Vital signs include supine and standing blood pressure and heart rate; respiration rate; and body temperature. Weight and height collected at 
Visit 1 only. 
b 
Laboratory Evaluations include hematology, serum chemistry, and urinalysis.   
c 
A serum pregnancy test will be performed at Screening and a urine pregnancy test will be performed upon each admission to the unit. 
d 
Blood samples for the determination of plasma tolperisone concentrations will be drawn prior to each AM dosing on Days 1-3 and post-driving 
test (15-30 minutes after the drive) on Days 1 and 3 
 
 


 
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5 
OUTCOME VARIABLE DEFINITIONS 
5.1 SCREENING AND BASELINE ASSESSMENT 
Screening: 
Demographic characteristics of age, sex, race, ethnicity, height, weight, and body 
mass index (BMI), informed consent, substance use (social history), inclusion 
criteria, exclusion criteria, medical history, physical examination, vital signs, 12-
lead electrocardiogram (ECG), laboratory results, urine drug screen, alcohol 
screen, pregnancy test, Epworth Sleepiness Scale (ESS), CogScreen Training 
and practice, driving simulator training and practice, simulator sickness 
questionnaire, prior medications, and concomitant medications will be collected 
at Screening. 
 
Baseline Assessment: 
Eligibility, vital signs, urine drug screen, alcohol screen, pregnancy test, 
pharmacokinetic sampling, CogScreen practice, driving simulator practice, 
adverse events, and concomitant medications will be collected at Baseline. 
5.2 PHARMACODYNAMIC ASSESSMENTS 
5.2.1 CVDA DRIVING SCENARIO ON THE CRCDS-MiniSim 
The present study employs the Cognitive Research Corporation Driving 
Simulator (CRCDS) Country Vigilance-Divided Attention (CVDA) driving 
scenario, a 62.1 mile (100 km), monotonous, two-lane highway driving task that 
includes a secondary visual vigilance task (Divided Attention DA). The 
monotonous Country Vigilance scenario has been demonstrated to be sensitive 
to detect the effects of fatigue or sleepiness on driving performance [CRCDS]. 
This scenario has been useful in measuring the effects of sleep deprivation, 
Obstructive Sleep Apnea, chronic primary insomnia, and is sensitive to central 
nervous system (CNS) depressants (e.g., alcohol and sedating antihistamines). 
Results obtained using this methodology are comparable to those obtained using 
over-the-road driving tests [Siemen, 2015]. 
Subjects will perform the driving simulator test at the times specified in Table 2.  
Data will be captured in electronic format. Details are provided in the Cognitive 
Research Corporation CRCDS Testing Operations Manual. 
5.2.2 KAROLINSKA SLEEPINESS SCALE (KSS) 
 
The Karolinska Sleepiness Scale (KSS) (Akerstedt 1990) will be used to assess 
subjective level of sleepiness.  This is a subject self-report measure of situational 
sleepiness and provides an assessment of alertness/sleepiness at a particular 
point in time.  The KSS has been found to correlate with electroencephalogram 
and behavioral variables (Kaida 2006).   It is a 9-point categorical Likert scale: 
 


 
 
 
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(1) extremely alert 
(2) 
(3) alert 
(4) 
(5) neither sleepy nor alert 
(6) 
(7) sleepy - but no difficulty remaining awake 
(8) 
(9) extremely sleepy-fighting sleep 
 
5.2.3 SELF PERCEIVED SAFETY TO DRIVE QUESTION 
Prior to driving the subject will be asked a simple question as to whether they feel 
safe to drive (“Right now do you feel safe to drive?”).  Subject will answer “yes” or 
“no”.   
5.2.4 COGSCREEN SYMBOL DIGIT CODING (SDC) 
The CogScreen Symbol Digit Coding (SDC) subtest will be used in this study to 
measure attention, visual scanning, working memory, and speed of information 
processing.  SDC is a computer analogue of the conventional digit symbol 
substitution task found in the WAIS-R Digit Symbol subtest and the Symbol Digit 
Modalities Test (Wechsler 1981).  
SDC will be administered by trained study site personnel.  The subject will 
perform the test by interacting with a touchscreen monitor.  Data will be captured 
in electronic format.  Details are provided in the CogScreen® Examiner Manual, 
CogScreen LLC, 2016.   
5.2.5 VISUAL ANALOG SCALE (VAS) TO ASSESS MOTIVATION AND 
SELF-APPRAISAL 
After completing the driving simulation, subjects will assess their own 
performance and their level of motivation to perform at their best during the 
driving simulation. 
 
Subjects will respond to 2 questions: 
1. How well you think you drove for the last 60 minutes? 
2. How motivated did you feel to drive at your best during the last 60 minutes 
of driving? 
 
Subjects will record their response to each question by drawing a vertical line on 
a 100 mm horizontal, linear visual analog scale (VAS). For the self-assessment 
of driving performance, one end of the line is marked “Not Satisfactory” and the 
other end of the line is marked “Satisfactory”.  For the motivation item, one end of 


 
 
 
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the line is marked “Not Motivated” and the other end is marked “Motivated”. 
Scores on the 100 mm linear scale will be measured to the nearest millimeter 
from the left.  The subject’s scores will be recorded in the case report form 
(CRF).   
 
5.3 PHARMACODYNAMIC ENDPOINTS 
5.3.1 PRIMARY ENDPOINT 
The primary endpoint for this study is simulated driving performance as 
measured by standard deviation of lateral position (SDLP) using the CRCDS-
MiniSim. 
5.3.2 SECONDARY ENDPOINTS 
The secondary endpoints for this study are: 
• SDLP 
• KSS 
• Self-reported readiness to drive (“Right now do you feel safe to drive?) 
• VAS for motivation 
• VAS for self-appraisal of driving performance 
• SDC: 
o Number of correct responses  
o Accuracy 
o Standard deviation of reaction time 
• Other Driving Performance Endpoints 
o Lane exceedance; including number, maximum, and duration 
o Average speed, speed deviation, excessive speeding count, 
speeding ratio 
o Excessive Ay (cornering speed threshold exceeded)  
o Total collisions 
o DA measures: Correct Responses, Omission Errors, Commission 
Errors, Reaction Time, Standard Deviation of Reaction Time 
• Plasma drug levels and driving performance  
5.4 SAFETY ASSESSMENTS 
5.4.1 SECONDARY SAFETY ENDPOINTS 
The secondary safety endpoints for this study are: 
• Adverse events (AEs) 
• Laboratory safety tests (blood chemistry, hematology,  urinalysis, serum 
and urine pregnancy tests for women of childbearing potential) 
• Physical examinations 
• Vital signs 


 
 
 
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• Orthostatic effects 
• 12-lead electrocardiograms (ECGs) 
5.4.2 ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a subject administered 
a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. AEs occurring after the initiation of the treatment 
are referred to as treatment emergent adverse events (TEAEs). An AE can 
therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to this medicinal product. 
AEs will be captured from the time of obtaining informed consent until discharge 
from the study. 
5.4.3 CLINICAL LABORATORY EVALUATIONS 
A certified laboratory will be used to perform all routine hematology, clinical 
chemistry, and urinalysis. Planned laboratory analyses include:  
 
Category 
Test Name  
Hematology 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin Timec 
Red blood cells 
White blood cells with differential (absolute) 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase  
Alkaline phosphatase 
Blood urea nitrogen 
Creatinine 
Gamma glutamyltransferase 
Glucose 
Potassium 
Sodium 
Total and direct bilirubin 
Thyroid stimulating hormonec 
Urinalysis 
Bilirubin 
Erythrocytes 
Glucose 
Ketones 
Leukocytes 
Nitrite 


 
 
 
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Category 
Test Name  
pH 
Protein 
Specific gravity 
Urobilinogen 
Other 
Urine drug and alcohol breathalyzera,b 
Serum/urine Pregnancyd 
a Screening and end of study (EOS) (Day 17). 
b  Includes testing for amphetamines, methamphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, ethanol and opiates – ethanol will be 
determined by breathalyzer. 
c  Screening only. 
d  Serum pregnancy at Screening and urine pregnancy test at check-in for each 
period (Days -1, 7, and 14) for females of childbearing potential. 
Note: The complete panel of safety labs (other than where footnoted) will be 
completed at Screening and EOS (Day 17).   
5.4.4 PHYSICAL EXAMINATION 
A physical examination will be performed at Screening and End of Study (Day 
17). 
5.4.5 VITAL SIGNS  
Vital signs will include the measurement of supine and standing blood pressure 
and heart rate, respiration rate, and body temperature. Weight and height will be 
measured at Screening only.  
Vital signs, including supine and standing blood pressure and heart rate, 
temperature and respiration rate will be collected at the following visits/time 
points: 
• Screening,  
• Day -1, 7, and 14 upon clinic check-in, 
• Day 1, 2, 3, 8, 9, 10, 15, 16, and 17 prior to and 4 hours post AM dosing. 
5.4.6 12-LEAD ELECTROCARDIOGRAM 
Twelve-lead ECG recording will be collected at Screening and End of Study (Day 
17). 
5.5 CONCOMITANT MEDICATIONS  
The use of any concomitant medication taken during the study, including any 
medication taken for the treatment of AEs, will be recorded in the case report 
form (CRF). Recording of a concomitant medication will include the medication 
name, indication, dose, route, frequency, date started and date stopped. 


 
 
 
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5.6 SCREENING ASSESSMENTS 
5.6.1 EPWORTH SLEEPINESS SCALE 
The Epworth Sleepiness Scale (ESS) will be used to exclude subjects who 
demonstrated excessive sleepiness prior to randomization.   
 
The ESS is an 8-item self-administered questionnaire to measure general level of 
daytime sleepiness.  The Scale is based on questions referring to situations that 
vary in their likelihood to induce a person to fall asleep.  Subjects are asked to 
rate how likely they would be to doze off or fall asleep in each situation in 
contrast to feeling just tired based on their usual way of life in recent times.  Each 
item (or situation such as sitting and reading) is rated on a 4-point Likert scale 
that ranges from “0 = Would never doze” to “3 = High chance of dozing.”  The 
total score on the Scale is the sum of the responses to each of the 8 items; 
therefore, the range of possible scores for each responder is 0 to 24.  A total 
score of <10 indicates that the patient is not suffering from excessive daytime 
sleepiness.  Individual items are not analyzed and have no independent, valid 
interpretations. 
 
Subjects will complete the ESS at Screening. 
 
6 
STATISTICAL ANALYSES 
All programming and analyses will be performed using SAS software v9.4. 
6.1 STATISTICAL METHODOLOGY  
6.1.1 DETERMINATION OF SAMPLE SIZE 
This study is designed to test non-inferiority (NI) of tolperisone doses relative to 
placebo, with a cyclobenzaprine test versus placebo to confirm the sensitivity of 
the simulator to detect treatment effects. The following assumptions were made 
in the sample size computation: (a) within-subject standard deviation for SDLP is 
approximately 6 cm; (b) the true difference between tolperisone doses and 
placebo is 0; and, (c) the NI margin is proposed to be 4.4 cm, which is the effect 
seen with 0.05% of blood alcohol content (BAC) with this driving simulator 
scenario. Under these assumptions, a sample of 30 subjects would provide in 
excess of 90% power to establish NI of tolperisone compared to placebo on any 
given dosing day in terms of the primary end point, SDLP. This sample size is 
considered more than adequate to detect cyclobenzaprine differences from 
placebo, which are anticipated to exceed the NI margin. 


 
 
 
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6.1.2 ANALYSIS POPULATIONS 
6.1.2.1 
SAFETY POPULATION 
The Safety Population includes all subjects who received at least 1 dose of study 
drug, according to the treatment received in any given treatment period. 
6.1.2.2 
INTENT-TO-TREAT (ITT) POPULATION 
The Intent-to-Treat (ITT) Population includes all randomized subjects who 
receive at least 1 dose of study drug, according to the planned treatment in a 
given treatment period. This is the analysis population for efficacy analysis. 
Subjects will (in general) be included in all analyses for which data are non-
missing.  
6.1.2.3 
PHARMACOKINETIC (PK) POPULATION 
The Pharmacokinetic (PK) Population includes all subjects with evaluable plasma 
concentration data.  
6.1.3 STATISTICAL ANALYSES – GENERAL CONSIDERATIONS 
In general, categorical variables will be summarized by the count (N) and 
percentage of subjects (%).  Continuous variables will be summarized by the 
number of non-missing observations (N), mean, standard deviation (SD), 
median, minimum, and maximum values. 
Formal statistical tests (where performed) will be two-sided and testing at the 
alpha=0.05 level of significance.   
All study data are to be displayed in the data listings. 
6.1.4 MULTIPLE COMPARISONS 
There are a number of comparisons of interest from which conclusions with 
respect to the NI of tolperisone vs. placebo will result.  Initially, the statistical 
significance of the cyclobenzaprine vs. placebo (p<0.05) comparison is 
necessary to validate the experiment as having the ability to detect effects (i.e., 
assay sensitivity). 
Subsequently, the NI of tolperisone to placebo (for initial dose, next day residual, 
and steady-state dose comparisons) will result in a conclusion of NI of 
tolperisone relative to placebo.  For NI conclusions, the alternative hypothesis (of 
NI) will be considered established if the upper 95% confidence limit for 
tolperisone vs placebo difference is less than the pre-specified NI margin of 4.4 
cm. 
Cyclobenzaprine comparisons to placebo are to assess assay sensitivity and no 
adjustment to alpha levels will be made for either the comparison of 


 
 
 
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cyclobenzaprine to placebo or tolperisone, or for secondary endpoints or 
analyses.   
The sequence of testing to control for multiplicity associated with comparisons of 
tolperisone to placebo (to assess NI) on multiple days is Day 1 (single-dose), 
followed by Day 3 (steady-state), followed by Day 2 (residual effect).  Tolperisone 
will be considered NI to placebo if prior comparisons (at time points in the 
sequence provided, above) also indicate NI.    
6.1.5 PROCEDURES FOR HANDLING MISSING DATA 
Subjects who discontinue, will only contribute to the pair-wise comparisons for 
which they have data. 
 
For subjects that have incomplete data within an assessment, data will be listed 
but not summarized and/or analyzed for that assessment. 
 
6.2 SCREENING AND BASELINE CHARACTERISTICS 
Summary tables will be constructed for the following screening or baseline data:  
demographic characteristics of age, sex, ethnic origin, height, weight and BMI for 
the safety population (Table 14.1.3), reason for screen failures (Table 14.1.4), 
medical history (Table 14.1.7), prior medications (Table 14.3.8.1), laboratory 
examinations (Tables 14.3.3.1-14.3.5.2), vital signs (Tables 14.3.6.1-14.3.6.5.3), 
and physical examination abnormalities (Table 14.3.8.1).  
 
Data listings will be provided for the following screening and baseline data:  
screen failures (Listing 16.2.2.3), inclusion/exclusion criteria (Listing 16.2.3.2.1), 
inclusion/exclusion criteria violations (Listing 16.2.3.2.2), characteristics of age, 
sex, race, ethnicity (Listing 16.2.4.1), substance use (Listing 16.2.4.2, medical 
history (Listing 16.2.4.3), simulator sickness questionnaire (Listing 16.2.4.4), ESS 
(Listing 16.2.4.5), pharmacokinetic sampling (Listing 16.2.5.2), driving simulator 
(Listings 16.2.6.1.1-16.2.6.1.X), AEs (Listing 16.2.7.1) laboratory collections 
(Listing 16.2.8.1-16.2.8.3, urine drug screen, alcohol screen, and pregnancy test 
(Listing 16.2.8.4), prior medication (Listing 16.2.8.6.1), physical examination 
(Listing 16.2.8.7), 12-lead ECG (Listings 16.2.8.8.1 and 16.2.8.8.2), and vital 
signs, height, weight, and BMI (Listing 16.2.8.9).  
 
6.3 SUBJECT DISPOSITION 
The number of subjects in each study population group will be presented by 
sequence (Table 14.1.1).  The number of subjects randomized, completing each 
visit, discontinuing at each visit, and completing the study will be presented by 


 
 
 
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sequence (Table 14.1.2).  A listing for study populations will be presented by 
subject (Listing 16.2.2.1). 
 
For subjects discontinuing, individual subject information will be listed (Listing 
16.2.1 respectively).  
 
An important protocol deviation listing will be provided by subject (Listing 
16.2.2.2).  Deviations will be summarized category of deviation (Table 14.1.6). 
 
Subjects excluded from the pharmacodynamics analyses will be listed (Listing 
16.2.3.1). 
6.4 STUDY MEDICATION ADMINISTRATION  
Study drug administration data will be listed by subject (Listing 16.2.5.1).  The 
number of days exposed for each of the three treatment populations will be 
summarized (Table 14.1.5). 
6.5 PHARMACODYNAMIC ANALYSES 
6.5.1 PRIMARY ANALYSIS 
The primary endpoint, SDLP, will be analyzed using a mixed model repeated 
measures with fixed effects for sequence, period, and treatment, with repeated 
observations for subjects.  An unstructured covariance structure and Kenward-
Roger degrees of freedom will be used.  In the event an unstructured covariance 
structure fails to converge, a variance components covariance structure will be 
assumed.  
 
In addition to assessments of treatment effect, p-values for significance testing of 
period and sequence effects will be provided.   
 
Pair-wise comparisons (hypothesis tests) of differences in least squares means, 
and 95% confidence intervals on differences will be provided (Table 14.2.1.1) for: 
 
Initial dose effect 
1. 
cyclobenzaprine versus placebo following Day 1 PM dose 
2. 
tolperisone versus placebo following Day 1 PM dose 
3. 
tolperisone versus cyclobenzaprine following Day 1 PM dose 
 
Next day residual dose effect 
 
4.  
cyclobenzaprine versus placebo following Day 2 AM dose 
5. 
tolperisone versus placebo following Day 2 AM dose 
6. 
tolperisone versus cyclobenzaprine following Day 2 AM dose 


 
 
 
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Steady-state dose effect 
 
7. 
cyclobenzaprine versus placebo following Day 3 AM dose 
8. 
tolperisone versus placebo following Day 3 AM dose 
9. 
tolperisone versus cyclobenzaprine following Day 3 AM dose 
 
 
In addition, pair-wise within-subject differences in SDLP greater than 4.4 cm in 
absolute value (equal to the previously found difference between placebo and 
0.05% Blood Alcohol Content (BAC) for the CRCDS) will be compared using 
McNemar’s test. Pair-wise, within subject differences in SDLP will also be tested 
for symmetry about zero (Laska 2012) using the maximally selected McNemar 
test (Table 14.2.1.2.1-14.2.1.2.9). 
 
Summary statistics for raw values and change from baseline will be provided 
(mean, SD, median, minimum, maximum) for SDLP for each time point and 
treatment group.  Figures will be provided for the within subject difference scores 
by treatment and day as both a histogram and scatter plot.   
 
Data listings for driving simulator data will be provided (Listing 16.2.6.1.1-
16.2.6.1.X). 
 
6.5.2 SECONDARY ANALYSES 
Secondary endpoints of VAS, SDC, and driving performance endpoints will be 
evaluated and presented similarly, however Lane Exceedance will be log 
transformed (more specifically ln(x+1)) prior to analyses.   
 
Tables will be presented in the same format as the primary output: 
• VAS for motivation (Table 14.2.2.1) 
• VAS for self-appraisal of driving performance (Table 14.2.2.2) 
• Symbol Digit Coding: 
o Number of correct responses (Table 14.2.3.1) 
o Accuracy (Table 14.2.3.2) 
o Standard deviation of reaction time (Table 14.2.3.3) 
• Other Driving Performance Endpoints 
o Lane exceedance; including number, maximum, and duration 
(Tables 14.2.4.1-14.2.4.3) 
o Average speed, speed deviation, excessive speeding count, 
speeding ratio (Tables 14.2.5.1-14.2.5.4) 
o Excessive Ay and Total Collisions(cornering speed threshold 
exceeded) (Table 14.2.6) 


 
 
 
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o Divided Attention (DA): Correct Responses, Omission Errors, 
Commission Errors, Reaction Time, Standard Deviation of Reaction 
Time (Tables 14.2.8.1-14.2.8.5) 
o KSS (Table 14.2.9) 
 
A data listing for KSS will be provided (Listing 16.2.6.2).  A data listing for SDC 
will be provided (Listing 16.2.6.3).  A data listing for the two VAS results will be 
provided (Listing 16.2.6.4). 
 
Additional Secondary Analyses: 
 
Total Collisions: 
Summary statistics will be provided (mean, SD, median, minimum, maximum) for 
total number of collisions for each time point and treatment group (Table 14.2.7).  
Additionally, differences in number of collisions for each pair-wise comparison 
will be provided with their corresponding Wilcoxon Signed Rank p-value.  A bar 
chart will be provided pooling total number of collisions by 0, 1, 2, or >=3 for all 3 
treatment groups.  
 
Self-reported readiness 
Pair-wise comparisons for readiness to drive will be analyzed using McNemar’s 
test (Table 14.2.10).  
 
Plasma drug levels 
Blood samples for the determination of plasma tolperisone concentrations will be 
drawn prior to each AM dosing on Days 1-3 and post-driving test (15-30 minutes 
after the drive) on Days 1 and 3. The relationship between initial dose effect, next 
day residual dose effect, and steady-state dose effect plasma drug levels and 
driving performance (i.e. the primary endpoint of SDLP) will be assessed by 
correlation.  Both the Spearman and Pearson correlations will be reported 
(Tables 14.2.11.2-14.2.11.22). 
6.6 SAFETY ANALYSES 
Safety analysis will be based on the safety population. Safety measures will be 
summarized using descriptive statistics and listed for each subject. 
MedDRA thesaurus will be used to map AEs verbatim to preferred terms and 
body systems.  WHOdrug thesaurus (Sep 1, 2016) will be used to map prior 
medication and concomitant medication verbatim to preferred terms and ATC 
Class. 
 


 
 
 
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6.6.1 ADVERSE EVENTS (AE) 
AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA 
version 20.0) coding system. Frequency tables will be presented by dose group 
summarizing: 
• all treatment emergent AEs (Table 14.3.1.1),  
• all treatment emergent treatment-related (defined as possibly or definitely 
related) AEs (Table 14.3.1.2),  
• all serious treatment emergent AEs (Table 14.3.2.1) 
• all AEs leading to discontinuation (Table 14.3.2.2). 
 
Listings will be presented to provide: 
• all AEs (Listing 16.2.7.1) 
• all treatment related AEs (terms including definitely and probably related) 
(Listing 16.2.7.2). 
6.6.2 CLINICAL LABORATORY EVALUATIONS 
Each laboratory examination observed value and change from baseline (when 
appropriate) will be summarized for hematology, blood chemistry, and urinalysis 
for each treatment at screening and end of study (Tables 14.3.2.1, 14.3.3.1, and 
14.3.4.1).  Shift tables will be constructed for hematology, blood chemistry, and 
urinalysis (Tables 14.3.2.2, 14.3.3.2, and 14.3.4.2).   
 
Subject laboratory examination data listings will be provided (Listings 16.2.8.1-
16.2.8.4).  All clinical laboratory values outside normal range (including 
Screening/Visit 1 and EOS/Day 17 examination) will be listed by treatment and 
subject number, including demographic information and flagging of values 
(Listing 16.2.8.5). 
6.6.3 PHYSICAL EXAMINATION 
A listing of physical examination data will be provided by subject (Listing 
16.2.8.7.1). Subjects with any changes in the physical examination evaluation 
from Screening/Visit 1 to EOS/Day 17 will be listed (Listing 16.2.8.7.2). 
6.6.4 VITAL SIGNS 
Summary statistics (n, mean, standard deviation, minimum, median, and 
maximum) will be presented for the raw values and change from baseline 
(defined as pre-dose Day 1 Period 1) values at each time point for all vital signs 
(including orthostatic vital signs) (Tables 14.3.6.1-14.3.6.5.3). 
 
A data listing of vital sign data will be provided by treatment and subject (Listing 
16.2.8.9). 
  


 
 
 
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6.6.5 12-LEAD ELECTROCARDIOGRAM 
Each ECG parameter observed value and change from screening will be 
summarized (Table 14.3.7.1).  The ECG results will be categorized as normal, 
clinically significant abnormal, and not clinically significant abnormal. A shift table 
for ECG abnormalities will be provided (Table 14.3.7.2). 
 
A data listing of ECG results for each parameter will be provided by subject 
(Listing 16.2.8.8.1).  A data listing of ECG normality will be provided by subject 
(Listing 16.2.8.8.2). 
6.7   CONCOMITANT MEDICATIONS 
Concomitant medications will be summarized (n and %) by ATC class and 
preferred term (Table 14.3.8.2).   
 
Concomitant medications will be listed by subject (Listing 16.2.8.6.2). 
6.8  CONCENTRATION DATA 
Concentration data will be summarized (n and %) by treatment (Table 14.2.11). 
 
Concentration data will be listed by treatment and subject (Listing 16.2.5.2). 
6.9  ADDITIONAL COLLECTED DATA 
General comments will be listed by subject (Listing 16.2.8.10). 
 
7 
  REFERENCES 
Akerstedt T, Gillberg M.  (1990).  Subjective and objective sleepiness in the 
active individual.  International Journal of Neuroscience, 52, 29–37. 
 
CRCDS Operations Manual.  Cognitive Research Corporation. Data on file.   
 
Kaida M, Takahashi T, Åkerstedt A, Nakata Y, Otsuka T,  Haratani K, et al.  
(2006).  Validation of the Karolinska sleepiness scale against performance and 
EEG variables.  Clinical Neurophysiology, 117, 1574–81. 
 
Laska E, Meisner M, Wanderling J. A maximally selected test of symmetry about 
zero.  Stat Med 2012;31:3178-91. 
 
Siemen A, Gargano C, Cha J, Drexel M, Bautmans A, Heirman I, Laethem T, 
Hochadel T, Gheyle L, Bleys K, Beals C, Stoch A, Kay G, & Struyk A. (2015). A 
randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of 
the CRCDS Mini-Sim to the next-day residual effects of zopiclone. Therapeutic 
Advances in Drug Safety, 6 (3), 86-97. 


 
 
 
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Wechsler, D. (1981). Wechsler Adult Intelligence Scale-Revised. San Antonio: 
Psychological Corporation. 
 
 
8 
  TABLES, LISTINGS, AND FIGURES 
Tables, listings, and figures numbering and titles will be finalized by the Sponsor 
at a later date.   
8.1 TABLES 
Table 14.1.1 
Study Populations 
Table 14.1.2 
Subject Disposition (Safety population) 
Table 14.1.3 
Subject Demographics (Safety population) 
Table 14.1.4 
Reason for Screening Failures 
Table 14.1.5 
Drug Exposure (Safety population) 
Table 14.1.6 
Protocol Deviations (Safety population) 
Table 14.1.7 
Medical History (Safety population) 
Table 14.2.1.1 
Standard Deviation of Lateral Position (SDLP) (ITT 
Population) 
Table 14.2.1.2.1 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Cyclobenzaprine 
versus Placebo Day 1 PM Dose) 
Table 14.2.1.2.2 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Tolperisone versus 
Placebo Day 1 PM Dose) 
Table 14.2.1.2.3 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Tolperisone versus 
Cyclobenzaprine Day 1 PM Dose) 
Table 14.2.1.2.4 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Cyclobenzaprine 
versus Placebo Day 2 AM Dose) 
Table 14.2.1.2.5 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Tolperisone versus 
Placebo Day 2 AM Dose) 
Table 14.2.1.2.6 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Tolperisone versus 
Cyclobenzaprine Day 2 AM Dose) 
Table 14.2.1.2.7 
Standard Deviation of Lateral Position (SDLP) Analysis of 


 
 
 
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Symmetry about Zero (ITT Population – Cyclobenzaprine 
versus Placebo Day 3 AM Dose) 
Table 14.2.1.2.8 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Tolperisone versus 
Placebo Day 3 AM Dose) 
Table 14.2.1.2.9 
Standard Deviation of Lateral Position (SDLP) Analysis of 
Symmetry about Zero (ITT Population – Tolperisone versus 
Cyclobenzaprine Day 3 AM Dose) 
Table 14.2.2.1 
Visual Analog Scale (VAS) Motivation (ITT Population) 
Table 14.2.2.2 
Visual Analog Scale (VAS) Self-appraisal (ITT Population) 
Table 14.2.3.1 
Symbol Digit coding (SDC) Number of Correct Responses 
(ITT Population) 
Table 14.2.3.2 
Symbol Digit coding (SDC) Accuracy (ITT Population) 
Table 14.2.3.3 
Symbol Digit coding (SDC) Standard Deviation of Reaction 
Time (ITT Population) 
Table 14.2.4.1 
Driving Performance Lane Exceedance: Number (ITT 
Population) 
Table 14.2.4.2 
Driving Performance Lane Exceedance: Maximum (ITT 
Population) 
Table 14.2.4.3 
Driving Performance Lane Exceedance: Duration (ITT 
Population) 
Table 14.2.5.1 
Driving Performance Average Speed (ITT Population) 
Table 14.2.5.2 
Driving Performance Speed Deviation (ITT Population) 
Table 14.2.5.3 
Driving Performance Excessive Speed Count (ITT 
Population) 
Table 14.2.5.4 
Driving Performance Speeding Ratio (ITT Population) 
Table 14.2.6 
Driving Performance Excessive Ay and Total Collisions 
(Cornering Speed Threshold Exceeded) (ITT Population) 
Table 14.2.7 
Driving Performance Total Collisions (ITT Population) 
Table 14.2.8.1 
Driving Performance Divided Attention – Correct Responses 
(ITT Population) 
Table 14.2.8.2 
Driving Performance Divided Attention – Omission Errors 
(ITT Population) 
Table 14.2.8.3 
Driving Performance Divided Attention – Commission Errors 
(ITT Population) 
Table 14.2.8.4 
Driving Performance Divided Attention – Reaction Time (ITT 
Population) 
Table 14.2.8.5 
Driving Performance Divided Attention – Standard Deviation 
of Reaction Time (ITT Population) 
Table 14.2.9 
Karolinska Sleepiness Scale (KSS) (ITT Population) 
Table 14.2.10 
Self-Reported Readiness (ITT Population) 


 
 
 
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Table 14.2.11.1 
Plasma Concentration by Time Point (Safety Population) 
Table 14.2.11.2 
Correlation of ln(Plasma Drug Levels) to SDLP 
Table 14.2.11.3 
Correlation of ln(Plasma Drug Levels) to Visual Analog Scale 
(VAS) Motivation 
Table 14.2.11.4 
Correlation of ln(Plasma Drug Levels) to Visual Analog Scale 
(VAS) Self-appraisal 
Table 14.2.11.5 
Correlation of ln(Plasma Drug Levels) to Symbol Digit Coding 
(SDC) Number of Correct Responses 
Table 14.2.11.6 
Correlation of ln(Plasma Drug Levels) to Symbol Digit Coding 
(SDC) Accuracy 
Table 14.2.11.7 
Correlation of ln(Plasma Drug Levels) to Symbol Digit Coding 
(SDC) Standard Deviation of Reaction Time 
Table 14.2.11.8 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Lane Exceedance Number 
Table 14.2.11.9 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Lane Exceedance Maximum 
Table 14.2.11.10 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Lane Exceedance Duration 
Table 14.2.11.11 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Average Speed 
Table 14.2.11.12 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Speed Deviation 
Table 14.2.11.13 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Speed Count 
Table 14.2.11.14 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Speeding Ratio 
Table 14.2.11.15 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Excessive Ay (Cornering Speed Threshold Exceeded) 
Table 14.2.11.16 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Total Collisions 
Table 14.2.11.17 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Divided Attention – Correct Responses 
Table 14.2.11.18 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Divided Attention – Omission Errors 
Table 14.2.11.19 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Divided Attention – Commission Errors 
Table 14.2.11.20 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Divided Attention – Reaction Time 
Table 14.2.11.21 
Correlation of ln(Plasma Drug Levels) to Driving Performance 
Divided Attention – Standard Deviation of Reaction Time 
Table 14.2.11.22 
Correlation of ln(Plasma Drug Levels) to Karolinska 


 
 
 
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Sleepiness Scale (KSS) Pre-Drive 
Table 14.3.1.1 
Treatment-Emergent Adverse Events by Maximum Severity 
(Safety Population)  
Table 14.3.1.2 
Treatment-related, treatment-emergent adverse events by 
maximum severity (Safety Population) 
Table 14.3.2.1 
Serious Adverse Events  (Safety Population) 
Table 14.3.2.2 
Adverse Events Leading to Discontinuation (Safety 
Population) 
Table 14.3.3.1 
Hematology Change From Screening  
 (Safety Population) 
Table 14.3.3.2 
Hematology Shift Table (Safety Population) 
Table 14.3.4.1 
Blood Chemistry Change From Screening  
 (Safety Population) 
Table 14.3.4.2 
Blood Chemistry Shift Table (Safety Population) 
Table 14.3.5.1 
Urinalysis Change From Screening (Safety Population) 
Table 14.3.5.2 
Urinalysis Shift Table  (Safety Population) 
Table 14.3.6.1 
Vital Sign Change from Baseline – Temperature (Safety 
population) 
Table 14.3.6.2 
Vital Sign Change from Baseline – Respiration Rate (Safety 
population) 
Table 14.3.6.3.1 
Vital Sign Change from Baseline – Supine Heart Rate (Safety 
population) 
Table 14.3.6.3.2 
Vital Sign Change from Baseline – Standing Heart Rate 
(Safety population) 
Table 14.3.6.3.3 
Vital Sign Change from Baseline – Orthostatic Heart Rate 
(Safety population) 
Table 14.3.6.4.1 
Vital Sign Change from Baseline – Supine Systolic Blood 
Pressure (Safety population) 
Table 14.3.6.4.2 
Vital Sign Change from Baseline – Standing Systolic Blood 
Pressure (Safety population) 
Table 14.3.6.4.3 
Vital Sign Change from Baseline – Orthostatic Systolic Blood 
Pressure (Safety population) 
Table 14.3.6.5.1 
Vital Sign Change from Baseline – Supine Diastolic Blood 
Pressure (Safety population) 
Table 14.3.6.5.2 
Vital Sign Change from Baseline – Standing Diastolic Blood 
Pressure (Safety population) 
Table 14.3.6.5.3 
Vital Sign Change from Baseline – Orthostatic Diastolic 
Blood Pressure (Safety population) 
Table 14.3.7.1 
ECG Change From Baseline (Safety population) 


 
 
 
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Table 14.3.7.2 
ECG Shift Table (Safety population) 
Table 14.3.8.1 
Prior Medication (Safety population) 
Table 14.3.8.2 
Concomitant Medications (Safety population) 
 
 
8.2 LISTINGS 
 
Listing 16.2.1 
Subject Disposition (Safety Population) 
Listing 16.2.2.1 
Study Population (Safety Population) 
Listing 16.2.2.2 
Important Protocol Deviations (Safety Population) 
Listing 16.2.2.3 
Screen Failures 
Listing 16.2.3.1 
Subjects Who Were Excluded From ITT Population (Safety 
Population) 
Listing 16.2.3.2.1 Inclusion, Exclusion, and Eligibility Criteria Legend 
Listing 16.2.3.2.2 Inclusion and Exclusion Criteria Violations (Safety Population) 
Listing 16.2.4.1 
Demographics and Baseline Characteristics (Safety Population) 
Listing 16.2.4.2 
Substance Use  (Safety Population)  
Listing 16.2.4.3 
Medical History (Safety Population) 
Listing 16.2.4.4 
Simulator Sickness Questionnaire (Safety Population) 
Listing 16.2.4.5 
Epworth Sleepiness Scale (ESS) (Safety Population) 
Listing 16.2.5.1 
Study Drug Administration (Safety Population)  
Listing 16.2.5.2 
Plasma Concentration (Safety Population)  
Listing 16.2.6.1.1 Driving Simulator Part 1 of X (Safety Population) 
Listing 16.2.6.1.X Driving Simulator Part X of X (Safety Population) 
Listing 16.2.6.2 
Karolinska Sleepiness Scale (KSS)  (Safety Population)  
Listing 16.2.6.3 
Cogscreen Symbol Digit Coding (SDC) (Safety Population)  
Listing 16.2.6.4 
Visual Analog Scale (VAS) (Safety Population) 
Listing 16.2.7.1 
Treatment-Emergent Adverse Events (Safety Population) 
Listing 16.2.7.2 
Treatment-Related Treatment-Emergent Adverse Events (Safety 
Population) 
Listing 16.2.8.1 
Hematology - Laboratory Collections (Safety Population) 
Listing 16.2.8.2 
Blood Chemistry - Laboratory Collections (Safety Population) 
Listing 16.2.8.3 
Urinalysis - Laboratory Collections (Safety Population) 
Listing 16.2.8.4 
Drug Screen, Alcohol Screen, Pregnancy, HCV-AB, HbsAg, HIV 
Test Results (Safety Population) 
Listing 16.2.8.5 
Laboratory Values Outside of Normal Range (Safety Population) 
Listing 16.2.8.6.1 Prior Medications (Safety Population)  
Listing 16.2.8.6.2 Concomitant Medications (Safety Population)  


 
 
 
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Listing 16.2.8.7.1 Physical Examination (Safety Population)  
Listing 16.2.8.7.2 Shift in Physical Examination (Safety Population)  
Listing 16.2.8.8.1 12-Lead Electrocardiogram Results (Safety Population) 
Listing 16.2.8.8.2 12-Lead Electrocardiogram Assessment (Safety Population) 
Listing 16.2.8.9 
Vital Signs (Safety Population) 
Listing 16.2.8.10 General Comments (Safety Population) 
8.3  FIGURES 
 
Figure 14.2.1.1.1 Within Subject Difference Scores in SDLP by Treatment  
Figure 14.2.1.2.1 Within Subject Difference Scores (Cyclobenzaprine - Placebo) 
(ITT Population - Day 1 PM Dose) 
Figure 14.2.1.2.2 Within Subject Difference Scores (Tolperisone - Placebo) (ITT 
Population – Day 1 PM Dose) 
Figure 14.2.1.2.3 Within Subject Difference Scores (Tolperisone - 
Cyclobenzaprine) (ITT Population – Day 1 PM Dose) 
Figure 14.2.1.2.4 Within Subject Difference Scores (Cyclobenzaprine - Placebo) 
(ITT Population - Day 2 AM Dose) 
Figure 14.2.1.2.5 Within Subject Difference Scores (Tolperisone - Placebo) (ITT 
Population – Day 2 AM Dose) 
Figure 14.2.1.2.6 Within Subject Difference Scores (Tolperisone - 
Cyclobenzaprine) (ITT Population – Day 2 AM Dose) 
Figure 14.2.1.2.7 Within Subject Difference Scores (Cyclobenzaprine - Placebo) 
(ITT Population - Day 3 AM Dose) 
Figure 14.2.1.2.8 Within Subject Difference Scores (Tolperisone - Placebo) (ITT 
Population – Day 3 AM Dose) 
Figure 14.2.1.2.9 Within Subject Difference Scores (Tolperisone - 
Cyclobenzaprine) (ITT Population – Day 3 AM Dose) 
Figure 14.2.11.2.1 Within Subject Difference Scores in SDLP by Plasma 
Concentration for Tolperisone Day 1 
Figure 14.2.11.2.2 Within Subject Difference Scores in SDLP by Plasma 
Concentration for Tolperisone Day 2 
Figure 14.2.11.2.3 Within Subject Difference Scores in SDLP by Plasma 
Concentration for Tolperisone Day 3 
Figure 14.2.7 
Total Collisions 
 


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Table 14.1.1  
Study Populations 
 
 
 
 
Placebo 
Tolperisone 450 mg 
Cyclobenzaprine 30 
mg  
Overall 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
Study Population 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
Screening Failures 
 
 
 
xx  
Safety Population* 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
ITT Population** 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
xx (xx.xx) 
PK Population *** 
 
 
 
 
 
 
 
* The Safety Population includes all subjects who received at least 1 dose of study drug 
** The Intent-to-Treat (ITT) Population includes all randomized subjects who receive at least 1 dose of study drug in a given treatment 
period. This is the analysis population for efficacy analysis. Subjects will (in general) be included in all analyses for which data are 
non-missing. 
*** The Pharmacokinetic (PK) Population includes all subjects with evaluable plasma concentration data. 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.2.1


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Table 14.1.2  
Subject Disposition 
(Safety Population) 
 
 
Placebo  
Tolperisone 
450 mg 
Cyclobenzaprine 
30 mg  
Overall 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
Study Population 
n (%) 
n (%) 
n (%) 
n (%) 
Completed Study 
xx    xx.x 
xx    xx.x 
xx    xx.x 
xx    xx.x 
Withdrew From Study 
xx    xx.x 
xx    xx.x 
xx    xx.x 
xx    xx.x 
          XXXXXXX 
xx    xx.x 
xx    xx.x 
xx    xx.x 
xx    xx.x 
          YYYYYYY  
xx    xx.x 
xx    xx.x 
xx    xx.x 
xx    xx.x 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.2.1


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Table 14.1.3  
Demographics and Baseline Characteristics 
(Safety Population) 
 
 
Placebo  
Tolperisone 450 
mg 
Cyclobenzaprine 
30 mg  
Overall 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
Age 
 
 
 
 
     N 
xx 
xx 
xx 
xx 
     Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum, Maximum 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
Sex                     
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
      Male         n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
      Female       n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
Race 
 
 
 
 
  Caucasian        n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
  Black            n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
  Hispanic         n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
  Asian            n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
  Native American  n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
  Other            n (%)      
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
Ethnicity 
 
 
 
 
  Hispanic or  
     Latino        n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
  Not Hispanic or  
     Latino        n (%) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
xx    (xx.x) 
Height (cm) 
 
 
 
 
     N 
xx 
xx 
xx 
xx 
     Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum, Maximum 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
Weight (kg) 
 
 
 
 


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     N 
xx 
xx 
xx 
xx 
     Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum, Maximum 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
BMI (kg/m^2) 
 
 
 
 
     N 
xx 
xx 
xx 
xx 
     Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum, Maximum 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
 
 
 
 
 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.4.1 and Listing 16.2.8.9


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Table 14.1.4  
Reason for Screening Failures 
 
 
 
Overall 
 
(N=xx) 
 
n (%) 
Reason #1 
xx    xx.x 
etc 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
xx    xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.2.3 


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Table 14.1.5 
Drug Exposure  
(Safety Population) 
 
 
 
Placebo  
Tolperisone 450 
mg 
Cyclobenzaprine 
30 mg  
Overall 
Characteristic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
Days 
 
 
 
 
     N 
xx 
xx 
xx 
xx 
     Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum, Maximum 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.5.1 


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Table 14.1.6 
Protocol Deviations 
(Safety Population) 
 
 
 
 
 
Overall 
 
(N=xx) 
Deviation Category 
n (%) 
 
 
xxxx 
xx (xx.xx) 
yyyy 
xx (xx.xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.2.2 


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Table 14.1.7 
Medical History 
 (Safety Population) 
 
 
Overall 
 
(N=xx) 
Category 
n % 
HEENT 
xx  (xx.x) 
etc 
xx  (xx.x) 
 
 
 
Subjects with more than one occurrence in a category are only counted once. 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.4.3


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Table 14.2.1.1 
Standard Deviation of Lateral Position (SDLP)  
(ITT Population) 
 
 
 
 
Placebo  
Tolperisone 450 mg 
Cyclobenzaprine 30 
mg  
 
Day 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Day X 
N 
xx 
xx 
xx 
 
 
Mean (SD) 
xx.xxxx (xx.xx) 
xx.xxxx (xx.xx) 
xx.xxxx (xx.xx) 
 
 
Median 
xx.x  
xx.x  
xx.x  
 
 
Min, Max 
xx.xxxx , xx.xxxx 
xx.xxxx , xx.xxxx 
xx.xxxx , xx.xxxx 
 
 
 
 
 
 
 
 
 
Model Fixed Effects 
of Interest 
Tolperisone 450 mg 
vs PBO 
Cyclobenzaprine vs 
PBO 
Tolperisone 450 mg 
vs Cyclobenzaprine 
 
Diff in LSMean 
 
xx.xxxx 
xx.xxxx 
xx.xxxx 
 
95%CI* 
 
(xx.xx , xx.xx) 
(xx.xx , xx.xx) 
(xx.xx , xx.xx) 
 
p-value Treatment* 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
p-value Sequence* 
0.xxxx 
 
 
 
 
p-value Period* 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat table for VAS, SDC, KSS, and other driving performance measures (see SAP for proposed table list). 
Mixed model repeated measures with fixed effects for sequence, period, and treatment, repeated assessments for subjects, unstructured 
covariance structure, and Kenward-Roger degrees of freedom.    
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.6.1.X 


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Table 14.2.1.2.1 
Standard Deviation of Lateral Position (SDLP) Analysis of Symmetry about Zero 
(ITT Population – Cyclobenzaprine 30 mg  versus Placebo) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Threshold 
Sign
Low
Neutral
High 
McNemar
Nominal P-value
 
 
x.xxxx 
-/+
xx
xx
xx 
x.xxxx
0.xxxxx
x.xxxx 
-/+
xx
xx
xx 
x.xxxx
0.xxxxx
 
 
 
 
 
 
 
 
Repeat for each comparison 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.6.1.X 


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Table 14.2.7 
Driving Performance Total Collisions  
(ITT Population) 
 
 
 
 
Placebo  
Tolperisone 450 
mg 
Cyclobenzaprine 
30 mg  
 
Day 
Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
 
Day 1 
 N 
xx 
xx 
xx 
 
 
 Mean 
x.x 
x.x 
x.x 
 
 
 SD 
x.xx 
x.xx 
x.xx 
 
 
 Median 
x.x 
x.x 
x.x 
 
 
 Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Diff in # of Collisions 
Tolperisone 450 
vs PBO  
Cyclobenzaprine 
30 mg 
Tolperisone vs 
Cyclobenzaprine  
 
 N 
xx 
xx 
xx 
 
 Mean 
x.x 
x.x 
x.x 
 
 SD 
x.xx 
x.xx 
x.xx 
 
 Median 
x.x 
x.x 
x.x 
 
 Min, Max 
xx, xx 
xx, xx 
xx, xx 
etc 
p-value* 
 
0.xxxx 
0.xxxx 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Wilcoxon Signed Ranks test. 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.6.1.X 


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Table 14.2.12 
Self-Reported Readiness 
(ITT Population) 
 
 
 
First Treatment 
Second Treatment 
N(%) 
 
Day 
Comparison 
 
 
p-value* 
Day 1 
 xxxxxxxxxxxxxx 
No 
No 
xx (xxx.x%) 
0.xxxx 
 
  
Yes 
No 
xx (xxx.x%) 
0.xxxx 
 
  
No 
Yes 
xx (xxx.x%) 
0.xxxx 
 
  
Yes 
Yes 
xx (xxx.x%) 
0.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*McNemar’s test. 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.6.X 


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Table 14.2.11.1 
Plasma Concentration 
 (PK Population) 
 
 
 
 
Tolperisone 450 mg 
Timepoint 
(N=xx) 
 
 
XXXX 
N 
xx 
 
Mean (SD) 
xx.xxxx (xx.xx) 
 
Median 
xx.x  
 
Geometric Mean 
xx.xxxx 
 
Min, Max 
xx.xxxx , xx.xxxx 
 
 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.5.2 


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Table 14.2.11.2 
Correlation of ln(Plasma Drug Levels) to SDLP  
(ITT Population) 
 
 
 
 
Tolperisone 450 mg 
 
Day 
(N=xx) 
 
 
 
 
Day X 
Pearson Correlation   
x.xxxx 
 
 
Spearman Correlation  
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listings 16.2.5.2 and 16.2.6.1.1 


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Table 14.3.1.1  
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity  
(Safety population) 
 
 
Placebo  
Tolperisone 450 mg 
Cyclobenzaprine 
30 mg  
Overall 
 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
Primary System Organ Class\ 
 Preferred Term\ 
   Severity 
n(%)    
n(%)         
n(%)       
n(%)        
 
 
 
 
 
Total Number of Adverse Events 
xxx 
xxx 
xxx 
xxx 
Any primary system organ class 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  Mild 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  Moderate 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  Severe 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
SOC 1  
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  Mild 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  Moderate 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
  Severe 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 Preferred  Term 1 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
   Mild 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
   Moderate 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
   Severe  
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
xx(xx.x) 
 
 
 
 
 
 Etc 
 
 
 
 
 
NOTE FOR PROGRAMMING: repeat table for treatment related (with footnote defining related) 14.3.1.2 
Primary system organ classes are presented alphabetically; preferred terms are sorted within primary system organ  class alphabetically.  
Subjects with more than one occurrence in a category are only counted once.  
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.7.1


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Table 14.3.2.1 
Serious Adverse Events  
(Safety Population) 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat for AE leading to discontinuation Table 14.3.2.2 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: screening, placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
Subject 
No./ 
Age/ 
Sex 
Subject 
No. 
Seq 
AE 
Number 
AE Term/ 
Preferred 
Term/ 
SOC Class 
Start 
Date/ 
Start 
Time 
End 
Date/ 
End Time Frequency 
Maximum 
Severity Serious? 
Relationship 
to Study  
Drug 
Action 
Taken 
Due to AE Outcome 
Sequelae 
xx-xxx/ 
xx 
/X 
 
xx-xxx XXX xx 
xxxxxxxxxxx 
xxxxxxxxxx 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
YYYYMMDD 
hh:mm 
Single Episode/ 
Intermittent/Continuous 
Mild/ 
Moderate/ 
Severe 
Yes 
Unrelated/  
Possibly  
Related/ 
Definitely 
Related  
No 
Action/ 
etc  
Resolved  
without  
Sequelae/ 
etc 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 14.3.3.1 
Hematology Change From Screening  
 (Safety population) 
 
 
 
 
Overall 
Labtest (Units) 
(N=xx) 
Screening  
 
Observed 
n 
xx 
 
Mean (SD) 
xx.xxx (xx.xxx) 
 
Median 
xx.xxx 
 
Min, Max 
xx.x , xx.x 
 
 
 
End of Study 
n 
xx 
Observed 
Mean (SD) 
xx.xxx (xx.xxx) 
 
Median 
xx.xxx 
 
Min, Max 
xx.x , xx.x 
 
 
 
End of Study 
n 
xx 
Change from 
Screening 
Mean (SD) 
xx.xxx (xx.xxx) 
 
Median 
xx.xxx 
 
Min, Max 
xx.x , xx.x 
 
 
 
 
 
[repeat for each lab/parameter] 
NOTE FOR PROGRAMMING: Repeat for blood chemistry (Table 14.3.4.1), urinalysis (Table 14.3.5.1), and ECG (Table 14.3.7.1) 
Change N reflects number of subjects with both screening and end of study evaluation. 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.8.1 


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Table 14.3.3.2 
Hematology Shift Table 
(Safety Population) 
 
 
 
Overall  
 
 
(N=xx) 
Laboratory  
Examination 
Shift Category 
n (%) 
xxxxxxxxxx          
LOW TO LOW 
xx (xx.x) 
 
LOW TO NORMAL 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
[repeat for each lab] 
NOTE FOR PROGRAMMING: Repeat for blood chemistry (Table 14.3.4.2), urinalysis (Table 14.3.5.2), and ECG (Table 14.3.7.2). 
 
 
 
 
 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.8.1


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Table 14.3.6.3.1  
Vital Signs Change From Baseline – Supine Heart Rate  
 (Safety population) 
 
 
 
Overall  
Placebo  
(N=xx) 
Tolperisone 
450 mg 
(N=xx) 
Cyclobenzaprine  
30 mg   
(N=xx) 
Heart Rate (bpm) 
(N=xx) 
 
 
 
Screening  
 
 
 
Observed 
n 
xx 
 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
 
 
 
 
Min, Max 
xx.x , xx.x 
 
 
 
 
 
 
 
 
 
Day 1 Pre-dose 
 
 
 
Observed 
n 
 
xx 
xx 
xx 
 
Mean (SD) 
 
xx.x (xx.xx) xx.x (xx.xx) 
xx.x (xx.xx) 
 
Min, Max 
 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
  
 
 
etc 
 
 
 
Observed 
n 
 
xx 
xx 
xx 
 
Mean (SD) 
 
xx.x (xx.xx) xx.x (xx.xx) 
xx.x (xx.xx) 
 
Min, Max 
 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
  
 
 
 
etc 
 
 
 
Change 
n 
 
xx 
xx 
xx 
 
Mean (SD) 
 
xx.x (xx.xx) xx.x (xx.xx) 
xx.x (xx.xx) 
 
Min, Max 
 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
  
 
 
 
[repeat for all post dose measurements] 
 
NOTE FOR PROGRAMMING: Repeat for all vitals tables 
Note for programming trt columns populated for visits after baseline visit.  Orthostatic tables need footnote defining standing-supine. 
Baseline defined as pre-dose Day 1. 
Note: Change N reflects number of subjects with both baseline and at least one post-dose assessment. 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing  16.2.8.9


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Table 14.3.8.1   
Prior Medications  
(Safety population) 
 
 
 
 
Overall 
 
 
(N=xx) 
ATC Class/Preferred Term 
 
n % 
Any ATC Class with medication 
 
xx  xx.x 
ATC Therapeutic Class 1 
 
 
     -Total 
 
xx  xx.x 
     Ingredient 1 
 
xx  xx.x 
     Ingredient 2 
 
xx  xx.x 
     Ingredient 3 
 
xx  xx.x 
ATC Therapeutic Class 2 
 
xx  xx.x 
     -Total 
 
xx  xx.x 
     Ingredient 1 
 
xx  xx.x 
     Ingredient 2 
 
xx  xx.x 
etc. 
 
 
[repeat for all ingredients and ATC 
classes/ingredients] 
 
 
 
 
 
ATC classes are presented alphabetically; preferred terms are sorted within ATC class alphabetically. 
Subjects with more than one occurrence in a category are only counted once. 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.8.6.1 


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Table 14.3.8.2 
Concomitant Medications 
(Safety population) 
 
 
 
 
Overall 
 
 
(N=xx) 
ATC Class/Preferred Term 
 
n % 
Any ATC Class with 
medication/surgery 
 
xx  xx.x 
ATC Therapeutic Class 1 
 
 
     -Total 
 
xx  xx.x 
     Ingredient 1 
 
xx  xx.x 
     Ingredient 2 
 
xx  xx.x 
     Ingredient 3 
 
xx  xx.x 
ATC Therapeutic Class 2 
 
xx  xx.x 
     -Total 
 
xx  xx.x 
     Ingredient 1 
 
xx  xx.x 
     Ingredient 2 
 
xx  xx.x 
etc. 
 
 
[repeat for all ingredients and ATC 
classes/ingredients] 
 
 
 
 
ATC classes are presented alphabetically; preferred terms are sorted within ATC class alphabetically. 
Subjects with more than one occurrence in a category are only counted once. 
SAS Program Name:    
 
Date: 
 
 
 
Source Data:  Listing 16.2.8.6.2 
 


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Listing 16.2.1 
Subject Disposition 
(Safety Population) 
 
 
 
Subject No. 
Sequence 
Visit 
Date 
Completed / 
Premature 
Withdrawal  
Date 
Reason for Withdrawal 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
Completed /  
Withdrew 
YYYYMMDD 
Adverse Event 
etc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    


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Page X of Y 
 
 
 
 
 
 
Listing 16.2.2.1 
Study Population 
 
Subject No. 
Sequence 
Safety* 
ITT** 
PK*** 
xx-xxx 
XXX 
Yes/no 
Yes/no 
Yes/no 
xx-xxx 
XXX 
Yes/no 
Yes/no 
Yes/no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
* The Safety Population includes all subjects who received at least 1 dose of study drug 
** The Intent-to-Treat (ITT) Population includes all randomized subjects who receive at least 1 dose of study drug in a given treatment 
period. This is the analysis population for efficacy analysis. Subjects will (in general) be included in all analyses for which data are 
non-missing. 
*** The Pharmacokinetic (PK) Population includes all subjects with evaluable plasma concentration data. 
   
SAS Program Name:       
 
Date:    
 
 


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Page X of Y 
Listing 16.2.2.2 
Important Protocol Deviations 
(Safety Population) 
 
 
Subject No. 
Sequence 
Deviation Category 
Description of Deviation 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:   


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Listing 16.2.2.3 
Screen Failures 
 
 
Investigator 
No. 
Screening 
Number 
Visit Date 
Date of Birth 
Date of 
Informed 
Consent 
Age 
Sex 
Race 
Race 
Other 
 
 
 
 
Ethnicity
Reason 
for 
Screen 
Failure 
 
 
 
 
 
 
 
 
 
 
 
xx 
xxx 
YYYYMMDD 
YYYYMMDD 
YYYYMMDD 
xxx Female xxxxxx 
xxxxxxxx xxxxxxxx xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAS Program Name:       
 
Date:    
 
 


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Page X of Y 
Listing 16.2.3.1 
Subjects Who Were Excluded From ITT Population 
(Safety Population) 
 
Subject No.    Sequence 
Reason for Exclusion 
xx-xxx 
XXX 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    


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Listing 16.2.3.2.1 
Inclusion, Exclusion, and Eligibility Criteria Legend  
 
 
To be populated 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.3.2.2 
Inclusion and Exclusion Criteria Violations  
(Safety Population) 
 
Subject 
No. 
    
Sequence 
    
Visit 
    
Category 
    
Question 
Number 
    Inclusion/Exclusion 
Question       
    
Result 
xx-xxx 
XXX 
XXXX 
XXXXXXXXX 
XXXXXXX 
XXXXXXXXXXXXXXXX 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 8  
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Page X of Y 
Listing 16.2.4.1 
Demographics and Baseline Characteristics  
(Safety Population) 
 
 
Subject No. 
Sequence 
Visit 
Date 
Date of 
Birth 
Date of 
Informed 
Consent  
Age 
Sex 
Race 
Race Other 
 Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
 
xx-x 
XXX 
YYYYMMDD YYYYMMDD 
YYYYMMDD 
xxx 
Female 
xxxxxx 
xxxxxx 
xxxxxxxxxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 9  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.4.2 
Substance Use 
(Safety Population) 
 
 
 
Subject No. 
Sequence 
Status 
Substance 
Quantity 
Frequency 
Start Date 
End Date 
xx-xxx 
XXX 
XXXXXXXXXXXXX  
xx 
xx 
xx 
YYYYMMDD 
YYYYMMDD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 10  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
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Page X of Y 
Listing 16.2.4.3 
Medical History  
(Safety Population) 
 
 
 
 
Subject No. Sequence 
Date of Visit 
System 
Condition 
Date of 
Diagnosis 
Status 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxx 
xxxxxxxxxxxxxxxxxxx YYYYMMDD Resolved, Stable, Unstable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 11  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.4.4 
Simulator Sickness Questionnaire  
(Safety Population) 
 
 
Subject No. Sequence 
Date of Visit 
Was the Simulator Sickness 
Questionnaire Completed? 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 12  
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Page X of Y 
Listing 16.2.4.5 
Epworth Sleepiness Scale (ESS) 
 (Safety Population) 
 
Subject No. 
Sequence 
Date of Visit 
Situation 
Result 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxxxxxxxxxxxxx 
0-3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 13  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
 Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.5.1 
Study Drug Administration 
(Safety Population) 
 
Treatment: 
Subject 
Number Sequence 
Visit  
Date 
Visit  
Date of 
Randomization 
Randomization 
Number 
Date of 
Administration 
Time of 
Administration 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
xxxxx 
YYYYMMDD 
xxx 
YYYYMMDD 
hh:mm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 14  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.5.2 
Plasma Concentration 
(Safety Population) 
 
 
Treatment: 
Subject 
No. 
Sequence 
Visit Date 
Visit  
Time Point 
Not Done 
Date of 
Draw 
Time of 
Draw 
Concentration 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxxxxx 
xxxxx 
xxxx 
YYYYMMDD 
hh:mm 
xxxxx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 
 
 
 
 
 
 
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 15  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.6.1.1 
Driving Simulator Part 1 of X 
(Safety Population) 
Treatment: 
Subject 
No. 
Sequence Visit 
Test 
Not 
Done 
Start 
Date 
Start 
Time 
Feel Safe to 
Drive? 
Columns 
TBD 
  
xx-xxx 
XXX 
xxxx xxxxxxxxxxxxxxxx xxx 
YYYYMMDD hh:mm 
Yes/No 
xx.xx   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 16  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.6.1.X 
Driving Simulator Part X of X 
(Safety Population) 
 
Treatment: 
 
Subject 
No. 
Sequence Visit 
Visit 
Date 
Feel Safe to 
Drive? 
Columns 
TBD 
  
xx-xxx 
XXX 
xxxx YYYYMMDD 
Yes/No 
xx.xx   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 17  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.6.2 
Karolinska Sleepiness Scale (KSS) 
(Safety Population) 
Treatment: 
 
Subject 
No. 
Sequence 
Visit  
Visit Date 
Test 
Not Done 
 
Start Date Start Time Score (1-9) 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxx 
YYYYMMDD 
Pre-Dose/ 
Post-Dose 
xxxx 
 
YYYYMMDD 
hh:mm 
x 
 
 
 
 
 
 
 
 
 
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date: 
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 18  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.6.3 
Cogscreen Symbol Digit Coding (SDC) 
(Safety Population) 
 
Treatment: 
 
Subject 
No. Sequence 
   
Visit 
Not  
Done 
 Start 
Date 
Start  
Time 
Test 
Total 
Number of 
Correct 
Responses 
Accuracy 
Speed  
Variability 
xx-xxx 
XXX 
xxxxx Yes/no YYYYMMDD 
xx.xx 
xxxxxxxxxx 
xx 
xxx.xx 
x.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date: 
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 19  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
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Page X of Y 
Listing 16.2.6.4 
Self-Rating of Driving Simulator Performance Visual Analog Scale (VAS) 
(Safety Population) 
 
Subject 
No. Sequence Visit 
Visit 
Date 
Not Done 
How Well do You 
Think You Drove For 
The Last 60 
Minutes? 
How Motivated Did You 
Feel To Drive At Your 
Best During Your Last 
60 Minutes of Driving? 
xx-xxx 
XXX 
xxxxxx YYYYMMDD 
Yes/blank 
xxx 
Yes/mm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
 
SAS Program Name:       
 
Date:


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 20  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.7.1 
Adverse Events  
(Safety Population) 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: screening, placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
Subject 
No./ 
Age/ 
Sex 
Subject 
No. 
Seq 
AE 
Number 
AE Term/ 
Preferred 
Term/ 
SOC Class 
Start 
Date/ 
Start 
Time 
End 
Date/ 
End Time Frequency 
Maximum 
Severity Serious? 
Relationship 
to Study  
Drug 
Action 
Taken 
Due to AE Outcome 
Sequelae 
xx-xxx/ 
xx 
/X 
 
xx-xxx XXX xx 
xxxxxxxxxxx 
xxxxxxxxxx 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
YYYYMMDD 
hh:mm 
Single Episode/ 
Intermittent/Continuous 
Mild/ 
Moderate/ 
Severe 
Yes/no Unrelated/  
Possibly  
Related/ 
Definitely 
Related  
No 
Action/ 
etc  
Resolved  
without  
Sequelae/ 
etc 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 21  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
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Page X of Y 
Listing 16.2.7.2 
Treatment-Related, Treatment-Emergent Adverse Events  
(Safety Population) 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
Subject 
No./ 
Age/ 
Sex 
 
Seq 
AE 
Number 
AE Term/ 
Preferred 
Term/ 
SOC Class 
Start 
Date/ 
Start 
Time 
End 
Date/ 
End Time Frequency 
Maximum 
Severity Serious? 
Relationship 
to Study  
Drug 
Action Taken 
with Study  
Medication 
Action 
Taken  
to Treat 
AE 
Outcome 
Sequelae 
xx-xxx/ 
xx 
/X 
 
XXX xx 
xxxxxxxxxxx 
xxxxxxxxxx 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
YYYYMMDD 
hh:mm 
Single Episode/ 
Intermittent/Continuous 
Mild/ 
Moderate/ 
Severe 
Yes/no Unrelated/  
Possibly  
Related/ 
Probably  
Related  
None/ 
Dosage  
Increased/ 
Dose  
Reduced/  
Dose  
Interrupted/ 
Dose  
Permanently  
Discontinued/ 
Not 
applicable  
No 
Action/ 
Subject  
Withdrawn 
from 
Study/ 
Treatment 
Given/ 
Other 
Resolved  
without  
Sequelae/ 
Resolved 
with 
Sequelae/ 
Resolved 
with  
Death: 
Event 
Contributed 
to Death/  
Resolved 
with  
Death: 
Event  
did not  
Contribute 
to Death/  
Ongoing/ 
Lost to  
Follow-Up 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 22  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
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Page X of Y 
Listing 16.2.8.1  
Hematology - Laboratory Collections 
(Safety Population) 
 
Treatment: 
 
Subject 
No. 
Sequence 
Visit 
Date Sample 
Collected 
Time Sample 
Collected 
Accession 
Number 
Test 
Result 
Units 
Normal 
Range Low 
Normal 
Range High 
Flag 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
xxxxxx 
xxxxxx 
Xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 23  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
 Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.2  
Blood Chemistry - Laboratory Collections 
(Safety Population) 
 
Treatment: 
 
 
 
 
Subject 
No. 
Sequence 
Visit 
Date Sample 
Collected 
Time Sample 
Collected 
Accession 
Number 
Test 
Result 
Units 
Normal 
Range Low 
Normal 
Range High 
Flag 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
xxxxxx 
xxxxxx 
Xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 24  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
 Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.3  
Urinalysis - Laboratory Collections 
(Safety Population) 
 
Treatment: 
 
 
Subject 
No. 
Sequence 
Visit 
Date Sample 
Collected 
Time Sample 
Collected 
Accession 
Number 
Test 
Result 
Units 
Normal 
Range Low 
Normal 
Range High 
Flag 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
xxxxxx 
xxxxxx 
Xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 25  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
 Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.4 
Drug Screen, Alcohol Screen, Pregnancy, Test Results 
(Safety Population) 
 
Treatment: 
 
Subject 
No. 
Sequence 
Visit Date 
Visit 
Test 
Results 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxxxxx 
xxxxxxxx 
xxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 26  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.5  
Laboratory Values Outside of Normal Range  
(Safety Population) 
 
Treatment: 
 
 
Subject 
No. 
Sequence 
Visit 
Date Sample 
Collected 
Time Sample 
Collected 
Category 
Test 
Result 
Units 
Normal 
Range Low 
Normal 
Range High 
Flag 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
xxxxxx 
xxxxxx 
Xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 27  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.6.1 
Prior Medications 
(Safety Population) 
 
 
Subject No. 
Sequence 
Visit  
Date 
Medication/ 
Preferred Term/ 
ATC Class 
Indication 
Dose 
Units 
Freq 
Route 
Date Started 
Date Stopped 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxxxxx/ 
xxxxxxxx/ 
xxxxxxxx 
xxxxx 
xxxx 
xxxx 
xxxxxxx 
xxxxxxx 
YYYYMMDD 
YYYYMMDD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
  
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 28  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.6.2 
Concomitant Medications 
(Safety Population) 
 
Subject 
No. 
Sequence 
Medication/ 
Preferred 
Term/ 
ATC Class 
Indication 
Dose 
Units Frequency 
Route  
Date Started Date Stopped 
Ongoing 
Med Taken 
Due to AE? 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxx/ 
xxxxxxxx/ 
xxxxxxxx 
xxx 
xxxx 
xxxx 
xxxx 
xxxxxxx 
YYYYMMDD 
YYYYMMDD 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 29  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.7.1 
Physical Examination 
(Safety Population) 
 
Subject 
No. 
Sequence 
Visit Date 
Visit 
Site 
Other 
specification 
Physical examination  
result 
Abnormal 
Finding 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxxxx 
xxxxxxxxxxx 
xxxxxx 
Normal/abnormal/not done 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 30  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.7.2 
Shift in Physical Examination  
(Safety Population) 
 
Subject 
No. 
Sequence 
Visit Date 
Visit 
Site 
Other 
specification 
Physical examination  
result 
Abnormal 
Finding 
xx-xxx 
XXX 
YYYYMMDD 
xxxxxxxx 
xxxxxxxxxxx 
xxxxxx 
Normal/abnormal/not done 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 31  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.8.1 
12-Lead Electrocardiogram Results  
 (Safety Population) 
 
 
Treatment: 
 
Subject 
No. 
Sequence 
Date of 
Assessment 
Time of 
Assessment 
Not  
Done 
Visit 
Ventricular 
Heart Rate 
(beats/min) 
PR 
Interval 
(msec) 
QRS 
Interval 
(msec) 
QT  
Interval 
(msec) 
 
QTcF 
Interval 
 (msec) 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
hh:mm 
xx 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 32  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.8.2 
12-Lead Electrocardiogram Assessment 
(Safety Population) 
 
 
Treatment: 
 
Subject  
No. 
Sequence 
Visit 
Date of ECG 
Time of 
ECG  
Clinical 
Evaluation 
Abnormality  Clinical Significance* 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
xxxxxxxxxx 
YYYYMMDD 
hh:mm 
Normal/ 
Abnormal 
NCS/ 
Abnormal CS 
xxxxxxxxxx 
NCS/CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
*NCS=not clinically significant, CS=clinically significant. 
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 33  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.9 
Vital Signs 
(Safety Population) 
 
 
Treatment: 
 
Subject 
No. 
Sequence 
Date of 
Assessment 
Time of 
Assessment 
Not  
Done 
Visit 
Time 
Point Position 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m^2) 
Temperature 
(C) 
 
Heart 
Rate (bpm) 
Blood 
Pressure 
(mm Hg) 
Respiration 
Rate 
(breaths/min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
XXX 
YYYYMMDD 
hh:mm 
xx 
xxxxxx 
xxxx 
xxxxxxx 
xx 
xx 
xx.x 
xx 
xxx 
xxx/xxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
SAS Program Name:       
 
Date:    
NOTE TO PROGRAMMER: placebo, 450 mg tolperisone, 30 mg cyclobenzaprine 
 


Neurana Pharmaceuticals Inc.                                                                Confidential                                                                                                Page 34  
                                                                                                     SAP Version Final 1.0                                                                                     Neurana 115 
Neurana 115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Listing 16.2.8.10 
General Comments 
(Safety Population) 
 
 
 
Subject No. 
Sequence 
CRF page 
SDTM Domain 
Comments 
 
 
 
 
 
xx-xxx 
XXX 
xx 
xx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A=placebo, B=450 mg tolperisone, C=30 mg cyclobenzaprine  
 
SAS Program Name:       
 
Date: