Clinical trial NCT03802565
Conditions: Back Pain Acute Pain Back Spasm Upper Back Back Strain Muscle Cramp Muscle Spasm Low Back Pain
Sponsor: Neurana Pharmaceuticals, Inc.
Start date: 2019-02-01; Completion date: 2019-07-12
Enrollment: 415 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, randomized, placebo-controlled, parallel group study of the efficacy and safety of tolperisone (a non-opioid) or placebo administered as multiple doses three times a day (TID) in approximately 400 male and female subjects experiencing back pain due to or associated with muscle spasm.

Detailed description:

Arms: arm 1: TID (150 mg/day) arm 2: TID (300 mg/day) arm 3: TID (450 mg/day) arm 4: TID (600 mg/day) arm 5: TID
Interventions: intervention 1: Tolperisone intervention 2: Placebo
Intervention descriptions: intervention 1: TID intervention 2: Placebo

Protocol documents:
Prot_001.pdf: 
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CLINICAL TRIAL PROTOCOL: 201 
Title: 
Dose Ranging Study of Tolperisone in Acute Muscle Spasm of the 
Back, “STAR Study” 
Substance 
Identifier 
Tolperisone hydrochloride 
IND number 
069169 
Protocol Number 
201 
Sponsor 
Neurana Pharmaceuticals, Inc. 
4370 La Jolla Village Drive, Suite 860 
San Diego, CA 92122 
Date of Protocol 
Amendment # 
02 MAY 2019 version 
2.0 1 
Previous protocol 
15Nov2018, version 1.0 (initial protocol) 
Sponsor 
Representative 
Tom Wessel, M.D. 
Chief Medical Officer 
Neurana Pharmaceuticals, Inc. 
Conduct: In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Council for Harmonisation Guidelines on 
Good Clinical Practice (ICH E6 GCP) and regulatory requirements as applicable 
Confidentiality Statement 
The present protocol is the sole property of Neurana Pharmaceuticals, Inc. and it may not in full 
or in part be passed on, reproduced, published or otherwise disclosed without the express 
permission of Neurana Pharmaceuticals, Inc. 




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1.2. 
Principal Investigator (PI) – Amendment 1 
I have read and understand the contents of this clinical protocol 201, the STAR Study, and will 
adhere to the study requirements as presented, including all statements regarding confidentiality. 
In addition, I will conduct the study in accordance with current International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for 
Good Clinical Practice and applicable regulatory requirements: 
PI SIGNATURE 
 
 
DATE 
(DD/MMM/YYYY) 
 
 
 
 
 
 
 
 
PRINTED NAME 
 
 
____________________________________________ 


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2. 
PROTOCOL AMENDMENT 1: SUMMARY OF CHANGES 
The purpose of this amendment is to include additional subject exclusion criteria and/or further 
clarify existing exclusion criteria to ensure subjects with cardiovascular risk, any potential 
seizure risk, and subjects that share the same household, are related, or are a family or friend of 
any site staff are not enrolled in this study in order to ensure that this Phase 2, dose ranging study 
is conducted in a generally healthy, low-risk population. Additionally, this protocol was 
amended to clarify a procedural detail related to supine blood pressure collection and sitting 
heart rate collection. The locations of changes in this amendment and rationale are detailed in the 
table below. 
SECTION 
AMENDMENT 1 Rationale 
Cover page 
Updated Sponsor address due to office move. 
1. Signatures 
Updated to include Neurana Medical Operations and 
Medical Science approval signatures (removed Regulatory). 
2. Summary of Changes 
To summarize all changes in the amended protocol from 
previous (initial) version. 
3. Protocol Synopsis (Study 
Background), 7.3.2 
Tolperisone Dose Levels  
Clarified the typical approved dose range (generally up to 
450 mg/day) and that doses of up to 900 mg/day have been 
used in clinical trials. 
3. Protocol Synopsis (Subject 
Population), 9.2 Exclusion 
Criteria 
Addition of three exclusion criteria (#26, 27, 28) to exclude 
subjects with any cardiovascular risk, inclusive of 
cardiovascular disorders, QT prolongation, and defined 
blood pressure/heart rate criteria. 
Revised previous exclusion #19 (history of seizure disorder) 
to also include family history of seizure or head trauma with 
loss of consciousness. 
Revised previous exclusion #25 (site staff members and 
family) to also include friends of site staff as well as subjects 
living in the same household or who are related to each 
other. 
Additions are to ensure subject safety and that this Phase 2 
dose-ranging study is conducted in a generally healthy, low-
risk subject population. 
3. Protocol Synopsis (Safety 
Assessments), 11.2.1 Clinic 
Visit 1, 12.9 Vital Signs, 
29 Schedule of Procedures 
(footnote “p”) 
Corrected and clarified that all blood pressures collected are 
supine and standing; heart rate is while sitting after 
approximately 3 minutes at rest.  
5. Abbreviations and 
Definitions of Terms 
Updated table to include millisecond (msec). 


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SECTION 
AMENDMENT 1 Rationale 
12.12  Blood Collection for 
Tolperisone Plasma (PK) 
Concentrations (Optional) 
Increased expected number of PK samples collected during 
the course of the study from 80 to approximately 120 due to 
optional sites and subjects participating more in PK 
collection than originally anticipated. 
23. Informed Consent 
Added clarifying statement regarding need to reconsent or  
provide new consent when ICF is revised (after IRB 
approval).  
 
 
 
 


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3. 
SYNOPSIS 
Sponsor: 
Neurana Pharmaceuticals, Inc. 
Name of Finished Product: 
Tolperisone hydrochloride 
Name of Active Ingredient: 
Tolperisone hydrochloride 
Study Title: 
Dose Ranging Study of Tolperisone in Acute Muscle Spasm of the Back, “STAR Study” 
Study Number: 201 
Study Phase: 
Phase 2  
Study Background: 
Tolperisone hydrochloride (tolperisone) is a centrally active muscle relaxant that is an (non-
opioid) investigative drug in the US. It has been in therapeutic use elsewhere throughout the 
world since the 1960s. In many European countries, the highest approved dose is 450 mg/day 
(150 mg TID), while in some countries (e.g., Switzerland), doses of 600 mg/day are approved. 
Doses of up to 900 mg/day have been studied in clinical trials of adults with spasticity (see 
Investigator’s Brochure). 
The Phase 2 study with tolperisone is designed as a dose-ranging study to identify the 
recommended Phase 3 dose to aid in supporting the proposed claim of relief of back pain due 
to muscle spasm of acute onset. Doses for the Phase 2 study are based on years of historical 
use of tolperisone for treatment of painful muscle spasms where the therapeutic dose is 300 to 
450 mg per day.  
Study Design: 
This is a double-blind, randomized, placebo-controlled, parallel group study of the efficacy 
and safety of tolperisone or placebo administered as multiple doses three times a day (TID) in 
approximately 400 male and female subjects experiencing back pain due to or associated with 
muscle spasm. The tolperisone groups consist of dose levels of 150, 300, 450, and 600 mg 
administered TID in doses of 50, 100, 150, or 200 mg for 14 days, with a visit at 28 days as 
follow-up. Subjects randomized to the placebo group will receive matching placebo tablets 
TID for 14 days with a follow-up visit at Day 28. Subject participation will be approximately 
4 weeks.  
Subjects will be screened for eligibility for participation in the study at the Screening/Baseline 
Visit 1 (Day 1) after reviewing and signing the informed consent form. Subjects meeting all 
inclusion/exclusion criteria will then be randomized into the study (Day 1) and begin dosing 
this same day. If needed, screening assessments may be completed up to 3 days prior to Day 1 
(first dose) as described below.   
It is highly recommended to complete all screening and baseline assessments on the same day 
the subject presents at the site due to their acute pain relief needs.  However, to accommodate 
real world logistical issues and time constraints of either the subject or site, the site has the 
flexibility to allow completion of screening assessments within 3 days (-3 days) prior to Day 1 


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baseline assessments, deployment of study-provisioned smartphone/download of trial 
application on subject’s smartphone, randomization, and first dose (in that order).  
After completing all screening and baseline assessments by/on Day 1, subjects will receive all 
study drug and rescue medication (acetaminophen 500 mg) and will be instructed to begin 
taking their study drug that same day. Depending on the time of their clinic visit, they should 
be instructed to begin dosing with either the midday dose (12-2 pm) or the evening dose (6-8 
pm). Subjects will be instructed to continue taking study drug TID through Day 14 and 
complete dosing dairy and daily electronic Patient-Reported Outcomes (ePRO) assessments. 
Subjects will return to the clinic to complete the procedures listed in the Schedule of 
Procedures on Day 4 (±1 day; Visit 2) and Day 14 (+1 day, End of Treatment [EOT] visit, 
Visit 3). Subjects must also return to the clinic for a follow-up visit on Day 28 (+3 days, 
2-week follow-up visit, Visit 4). 
For all subjects, safety laboratory assessments will be performed on Day 1 
(Screening/Baseline visit, -3 to 0 days) and Day 14 (Visit 3). In addition, a sample for 
genotyping will be collected on Day 1 (Screening/Baseline visit). For select sites with 
additional consenting subjects, pharmacokinetic samples will be collected on Day 4 (Visit 2). 
 
 
Primary Objective: 
• To assess the efficacy of tolperisone daily doses 150, 300, 450, and 600 mg for relief 
of pain due to acute back muscle spasm. 
Randomization
Tolperisone 150 mg (50 mg/TID)
Tolperisone 300 mg (100 mg/TID)
Tolperisone 450 mg (150 mg/TID)
Tolperisone 600 mg (200 mg/TID)
Matching Placebo (TID)
Screening/
Enrollment
(-3 to 0 Days)
Follow-Up 
Safety Visit
(Day 28)
Day 1
Day 4
Day 14
Subject-Rated Pain Numerical Rating Scale (NRS)  
Daily ePRO Assessments & Dosing Diary thru 
Day 14
End of Treatment
Treatment   Start


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Secondary Objectives: 
• To assess the safety and tolerability of tolperisone in subjects with pain due to acute 
back spasm. 
• To determine the onset of action of tolperisone in treatment of pain due to acute back 
spasm. 
• To determine the duration of pain relief of tolperisone in treatment of pain due to acute 
back spasm. 
• To determine the need for rescue medication when treated with various doses of 
tolperisone for pain due to acute back spasm. 
Endpoints: 
Data for primary efficacy analysis will be assessed during the clinic visits by the subject on the 
study-provisioned tablet provided to each site for use at baseline, and at Days 4 and 14. 
Additional efficacy endpoints and dosing will be collected daily at specified times from the 
subjects via a smartphone/trial application for ePROs. At baseline, and at Days 4 and 14, 
efficacy endpoints will be assessed during the clinic visit on the study-provisioned tablet 
provided to each site. See the Schedule of Procedures for all assessments to be conducted 
during the study. For the endpoints below, baseline is defined as the last assessment prior to 
the first dose of study drug. 
Primary Endpoint:  
• Subject-rated pain due to acute back spasm using a Numerical Rating Scale (NRS; 0-10 
scale, from no pain to worst possible pain) on Day 14 “right now”.  
Secondary Endpoints: 
Efficacy Endpoints 
• Subject-rated pain due to acute back spasm using an NRS (0-10 scale, from no pain to 
worst possible pain) on Day 4 “right now”. 
• Subject rating of medication helpfulness (SRMH; 1-5 scale, from poor to excellent) on 
Days 4 and 14. 
• Subject-rated NRS (0-10 scale) of pain due to acute back spasm on Days 1 to 14; average 
over past 12 hours. 
• Subject-rated NRS (0-10 scale) of pain due to acute back spasm on Days 1 to 14, average 
over the past hour. 
• Subject-rated NRS (0-10 scale) of average pain due to acute back spasm on rest or 
movement, rated at the end of the day on Days 1 to 14. 
• Time to relief of pain due to acute back spasm using subject-rated NRS (0-10 scale) on 
Days 1 to 14. 
• Clinician’s Global Impression of Severity (CGI-S) (1–5 scale) at baseline (Day 1). 
• Clinician’s Global Impression of Change (CGI-C) (1-7 scale from worse to marked 
improvement) on Days 4 and 14. 
• Patient’s Global Impression of Severity (PGI-S) (1-5 scale) at baseline (Day 1). 
• Patient’s Global Impression of Change (PGI-C) based on subject’s global assessment 


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(1-7 scale, from worse to marked improvement) on Days 4 and 14. 
• Functionality assessment: fingers to floor distance (FFD) is an index of mobility of the 
spinal cord and is measured as distance in cm when standing with the spinal cord flexed 
with complete extension of knee joint, on Days 4 and 14 compared to baseline (Day 1) 
(assessments should be conducted at the same time of day for all three time points). 
• Disability assessment at baseline (Day 1), Day 4, and Day 14:  Oswestry Disability Index 
(ODI) questionnaire (10 questions with one answer each for pain intensity, personal care, 
lifting, walking, sitting, standing, sleeping, sex life [if applicable], social life, and 
traveling). 
• Use of rescue medications (measured daily, assessed as number of rescue tablets 
administered by the subject via smartphone/use of trial application). Patients are 
instructed not to take rescue medications on the day of clinic visits on Day 4 and 14. 
• Quality of sleep rated by subjects starting at baseline (Day 1) and on Days 2 to 14. 
• Visual Analogue Scale (VAS) score for subject-reported sleepiness measured in the 
clinic on Day 4. 
Safety Endpoints 
• Clinical evaluations 
§ Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
§ Orthostatic effects on blood pressure 
§ Physical examinations 
§ 12-lead electrocardiograms (ECGs) 
• Laboratory tests (blood chemistry, hematology, urinalysis, and urine pregnancy tests for 
women of childbearing potential) 
• Adverse events (AEs) 
Planned Number of Subjects and Sites:  
Approximately 400 male and female subjects between the ages of 18 and 65 years, with acute 
and painful muscle spasms of the back at the time of informed consent will be randomized into 
the study. 
The study will be conducted at approximately 45 clinical sites in the USA. 


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Subject Population: 
Inclusion Criteria: 
1. Ambulatory male or female, 18 to 65 years of age. 
2. Current acute back pain and/or stiffness due to acute and painful muscle spasm 
starting within 7 days prior to study entry and more than 8 weeks after the last 
episode of acute back pain. 
3. Subjects must have pain of 4 or more on the subject “right now” rating of pain 
intensity NRS scale of 0 – 10 points at baseline. 
4. Must be willing to discontinue all medication used for the treatment of pain or 
muscle spasm on study entry at Day 1 including but not restricted to:  
a. Ibuprofen (Motrin) 
  
b. Diclofenac (Voltaren) 
 
c. Celocoxib (Celebrex) 
 
d. Naproxen (Aleve) 
 
e. Tolmetin (Tolectin) 
 
f. Cyclobenzaprine (Flexeril) 
 
g. Cyclobenzaprine (Amrix) 
 
h. Metaxolone (Skelaxin) 
 
i. Methocarbamol (Robaxin) 
 
j. Other nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin)  
k. Carisoprodol (Soma) 
 
l. Tizanidine (Zanaflex, Sirdalud) 
 
5. Pain localized below the neck and above the inferior gluteal folds. 
6. Body mass index ranging between 18 and 35 kg/m². 
7. All subjects must be capable of understanding and complying with the protocol and 
have signed the informed consent document.  
8. Female subjects must have a negative urine 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 2 weeks 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, injectable, subdermal implant, vaginal or patch contraceptives, 
intrauterine device (IUD; copper or hormonal IUD), or double-barrier method (e.g., 
condom, diaphragm or cervical cap with spermicidal foam, cream, gel, or 
suppository). 
9. Subjects must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
Exclusion Criteria: 


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1. Unwillingness to stop taking pain or antispasmodic medication other than the study 
medication (specifically opioid use [e.g., Vicodin], barbiturates, and cannabis). 
2. Chronic back pain for the previous 3 months or longer, on more days than not. 
3. Radicular pain in the lower extremity (i.e. pain radiating below the knee), sciatica 
pain down the leg, or pain below the knee (indicating a lumber radiculopathy); 
radicular pain in the upper extremity, radiating into the forearm or hand (indicating a 
cervical radiculopathy). 
4. Concomitant severe pain in a region other than the back. 
5. Spinal surgery within 1 year of study entry. 
6. Back pain due to major trauma (e.g., motor vehicle accident, fracture of bone) unless 
resolved for more than 1 year. 
7. Treatment of back pain ongoing with non-pharmacological therapy (e.g. 
acupuncture, chiropractic adjustment, massage, Transcutaneous Electrical Nerve 
Stimulation [TENS], physiotherapy).  
8. Female subjects who are pregnant or lactating.  
9. Subjects who are taking Baclofen (Lioresal, Liofen, Gablofen, etc.) or Botox 
(onabotulinumtoxin A) for pain. 
10. Subjects who test positive for alcohol by breathalyzer test. 
11. Known history or symptoms suspicious of: 
a. Spinal fracture within previous 3 years 
b. Osteoporosis with fracture 
c. Cancer except cutaneous cancers (e.g.,melanoma, squamous cell carcinoma) 
d. Constitutional symptoms such as recent unexplained chills or weight loss 
e. Spinal infection  
f. Intravenous drug abuse  
g. Immunosuppression 
h. Cauda equina syndrome 
i. History of chronic severe scoliosis (childhood). 
12. Myasthenia gravis. 
13. Recent history of severe hepatic insufficiency, i.e., aspartate aminotransferase 
(AST)/alanine aminotransferase (ALT) above 3 times the upper limit of normal 
(ULN). 
14. Recent history of severe renal insufficiency, i.e., serum creatinine value above 
2.5 mg/dL. 
15. History or presence of a severe infection, major surgery or trauma, severe metabolic, 
endocrine or electrolyte disturbances. 
16. A major illness, requiring hospitalization during the 3 months before commencement 
of the screening period. 
17. Inflammatory arthritis or other diseases known to cause intermittent or chronic pain. 
18. 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. 


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19. History of seizure disorder other than Infantile Febrile Seizures, family history of 
seizure, or history of head trauma with loss of consciousness. 
20. Disability claim for back pain, or pending legal issue regarding back pain. 
21. Subjects who have received treatment with an investigational product/device within 
30 days prior to study entry. 
22. Subjects who have a history of allergic reaction to tolperisone, eperisone, or other 
skeletal muscle relaxants, lidocaine, acetaminophen or NSAIDs, or any components 
of these study medications. 
23. Any other condition that, in the opinion of the Investigator, would adversely affect 
the subject’s ability to complete the study or its measures. 
24. Subjects who are unwilling to stop taking moderate to potent inhibitors of 
cytochrome P450 (CYP) isozymes CYP2D6 and CYP2C19, which are likely to 
cause drug interactions with tolperisone HCl (e.g., medications such as paroxetine 
and fluvoxamine). 
25. Subjects who are a site staff member, relative, or friend of a site staff member or 
subjects in same household or subjects who are related to each other. 
26. Subjects with clinically significant cardiovascular disorders, such as ischemic heart 
disease, arrhythmias, poorly controlled hypertension, or history of acute myocardial 
infarction. 
27. Subjects with QT interval greater than 480 milliseconds (msec) or greater than 450 
msec if accompanied by a partial bundle branch block, or other clinically significant 
ECG abnormaility at Screening in the judgement of the Investigator. 
28. Subjects with diastolic blood pressure less than 50 mmHg or greater than 105 
mmHg; sitting heart rate less than 50 beats per minute (bpm) or greater than 110 
bpm (after approximately 3 minutes at rest); or heart rate by ECG less than 50 or 
greater than 110 bpm at Screening. 
Restrictions: 
Subjects are to abstain from using psychoactive prescription or non-prescription medications, 
psychoactive nutritional supplements or herbal preparations during their participation in the 
study.  
Subjects are to abstain from using any 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.  
Other medications that the subject routinely takes will be discussed and reviewed by the PI. 
All concomitant medication taken during the trial should be recorded with indication, daily 
dose, and start and stop dates of administration. 
Subjects are not allowed to consume alcoholic beverages prior to the study visit on Days 1, 4, 
and 14. At all other times, alcohol consumption is limited to no more than 2 alcoholic drinks 
or equivalent (beer [24 ounces or 710 mLs], wine [12 ounces or 355 mLs], or distilled spirits 
[3 ounces or 89 mLs] per day. 
Caffeinated beverages will be permitted to no more than 4 units per day amounts (1 unit = 120 


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mg caffeine, or about one eight-ounce cup of coffee). 
Subjects are to refrain from vigorous physical activity, heat and ice packs, and 
non-pharmacological therapies (e.g., acupuncture, chiropractic adjustment, massage therapy, 
TENS, physiotheraphy) during Days 1 to 14.  
Test Product, Dose, Mode of Administration, and Dose Regimen: 
Tolperisone 50, 100, 150, and 200 mg tablets and matching placebo will be provided for the 
study by the Sponsor. Dosing will be three times a day, with a single tablet administered at 
each dose for a daily dose of 150, 300, 450, and 600 mgs per day. Subjects should be 
instructed to dose at 6-8 am, 12-2 pm, and 6-8 pm daily for 14 days. Subjects will be prompted 
via reminders on their smartphone/trial application to take their study drug at least 1 hour 
before and within 2 hours of the morning and evening assessments. 
The subjects will be instructed to swallow the tablets whole, with approximately 4-6 ounces of 
water.  
• Subjects in Group A (n=80) will be randomized to receive (1) 50 mg tolperisone tablet, 
TID for 14 days, for a total daily dose of 150 mg. 
• Subjects in Group B (n=80) will be randomized to receive (1) 100 mg tolperisone 
tablet administered TID for 14 days, for a total daily dose of 300 mg. 
• Subjects in Group C (n=80) will be randomized to receive (1) 150 mg tolperisone 
tablet administered TID for 14 days, for a total daily dose of 450 mg. 
• Subjects in Group D (n=80) will be randomized to receive (1) 200 mg tolperisone 
tablet administered TID for 14 days, for a total daily dose of 600 mg. 
• Subjects in Group E (n=80) will be randomized to receive (1) placebo tablet 
administered TID for 14 days. 
Duration of Treatment: 
The total duration of study participation will be approximately 4 weeks, including Screening 
and Follow-up. Study drug treatment will be administered for 14 days. 
Safety Assessments: 
Adverse Events: 
Adverse events will be captured from the time of first dose (Day 1) until the final clinic visit 
(i.e., Day 28 follow-up visit [Visit 4] or, if applicable, Early Termination (ET) Visit). 
Pregnancy Test: 
A urine pregnancy test will be performed at Day 1 (Visit 1, Screening/Baseline visit, -3 to 0 
days) and at Days 14 (Visit 3) and 28 (Visit 4) for females of childbearing potential. A positive 
pregnancy test 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/Baseline visit, (Day 1, -3 to 0 days) and at the EOT/ET visit (Visit 
3, Day 14). A blood sample will be collected at baseline for DNA genotype testing for 
CYP450 2D6 polymorphism. Subjects will not be informed of the results of the genotype 


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testing since it is solely for research purposes to determine the phenotype of the enzymes 
responsible for metabolism of tolperisone.  No other DNA testing will be performed. 
Vital Signs: 
Vital signs, including supine and standing blood pressure, sitting heart rate (after 
approximately 3 minutes at rest), respiratory rate, and body temperature will be collected at 
Screening/Baseline (Day 1, -3 to 0 days), and at Days 4, 14, and 28 (All Visits). Weight and 
height will be measured at Screening/Baseline (Visit 1, Day 1, -3 to 0 days) only. 
Electrocardiogram: 
Twelve-lead ECG recording will be collected at Screening/Baseline (Day 1, -3 to 0 days) and 
EOT/ET (Visit 3, Day 14). 
Statistical Plan and Methods:  
Sample Size: 
The sample size for this study was determined from results of two previous studies. The first 
was a study in subjects with acute upper back, neck, or shoulder spasm and pain, which 
showed a difference of 0.4 in the average of Day 1 through Day 7 between the placebo and 
active groups, and standard deviations (SDs) between 1.76 and 1.93 (across placebo and active 
groups respectively; Collaku, 2017). A sample size of 400 subjects (80 per group) would 
provide at least 80% power to detect a difference of 0.9 between the placebo and treatment 
groups in the NRS scale, assuming a two-sample t-test at the 5% level of significance and a 
pooled SD of 2.0. This sample size assumes an effect size of 0.45 (0.9/2.0 = 0.45, using the 
formula Effect Size = Mean/SD), which is larger than that seen in the reference study but 
consistent with that seen in a second study. 
A second previous study in subjects with acute musculoskeletal spasm associated with low 
back pain showed effect sizes ranging from 0.57 to 0.62 for lumbar cinelgasia, based on a 
treatment difference of 9.6 at Day 3, with SDs of 15.5 (treated group) and 16.7 (placebo group) 
(Chandanwale, 2011). This study demonstrated effect sizes ranging from 1.1 to 1.6, based on a 
difference of 24.2 at Day 14 with SDs of 15.1 (treated group) and 23.0 (placebo group). The 
effect size of the current study is expected to be similar to that in Chandanwale, though sample 
size estimates have been made more conservative to provide sufficient power to detect smaller 
differences. Though the primary comparison of interest in this study is Day 14, the study is 
sufficiently powered to detect a treatment difference at Day 4 based on effect sizes ranging 
from 0.35 to 0.45. 


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Statistical Plan and Methods:  
Efficacy Analysis:  
The primary efficacy endpoint is subject-rated pain “right now” due to acute back spasm using 
an NRS (0-10) scale, from no pain to worst possible pain for the clinic visit on Day 14. This 
analysis will be performed using a linear test of trend across doses, using a mixed effect model 
for repeated measures. The model will include treatment and time as fixed effects, the 
treatment by time interaction, and the baseline NRS rating as a covariate. Differences in linear 
trend for each dose level versus placebo will be presented with 95% confidence intervals and 
associated p-values. The analysis performed for the primary endpoint will be repeated for the 
NRS at Day 4. Additional analyses for secondary efficacy endpoints will be conducted using 
repeated measures and analysis of covariance for continuous variables, a Wilcoxon Rank Sum 
test for categorical variables, and Kaplan-Meier analysis for time to pain relief. 
Safety Analysis: 
Safety measures will be summarized using descriptive statistics and listed for each subject. 
Safety analysis will be based on all subjects randomized who receive at least 1 dose of the 
study medication. The safety analysis will evaluate AEs 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. Serious adverse events (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 EOT 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. 


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4. 
TABLE OF CONTENTS 
1. 
SIGNATURES .............................................................................................................2 
1.1. 
Sponsor’s Representatives – Amendment 1 .................................................................2 
1.2. 
Principal Investigator (PI) – Amendment 1 ..................................................................3 
2. 
PROTOCOL AMENDMENT 1: SUMMARY OF CHANGES ..................................4 
3. 
SYNOPSIS ...................................................................................................................6 
4. 
TABLE OF CONTENTS ...........................................................................................16 
5. 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................20 
6. 
STUDY ADMINISTRATIVE STRUCTURE ...........................................................22 
6.1. 
Medical Monitor .........................................................................................................22 
6.2. 
Serious Adverse Event Reporting Contact Information - Sponsor .............................22 
6.3. 
Central Laboratory ......................................................................................................22 
7. 
BACKGROUND AND RATIONALE FOR THE STUDY .......................................22 
7.1. 
Introduction .................................................................................................................22 
7.2. 
Drug Profile ................................................................................................................24 
7.3. 
Rationale .....................................................................................................................24 
7.3.1. 
Study Design ...............................................................................................................24 
7.3.2. 
Tolperisone Dose Levels ............................................................................................25 
8. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................26 
8.1. 
Primary Objective .......................................................................................................26 
8.2. 
Secondary Objectives .................................................................................................26 
8.3. 
Primary Endpoint ........................................................................................................26 
8.4. 
Secondary Endpoints ..................................................................................................26 
9. 
SUBJECT DEFINITION ............................................................................................28 
9.1. 
Inclusion Criteria ........................................................................................................28 
9.2. 
Exclusion Criteria .......................................................................................................29 
9.3. 
Withdrawal Criteria ....................................................................................................30 
10. 
STUDY DESIGN .......................................................................................................31 
10.1. 
Summary of Study Design ..........................................................................................31 
10.2. 
Subject Assignment ....................................................................................................32 
10.2.1. 
Unblinding ..................................................................................................................32 
10.3. 
Treatment Compliance ................................................................................................32 
11. 
DAILY STUDY ACTIVITIES ...................................................................................32 


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11.1. 
Screening ....................................................................................................................32 
11.2. 
Study Periods ..............................................................................................................33 
11.2.1. 
Clinic Visit 1: Day 1 (Screening/Baseline) and up to Day -3 (Additional 
Screening Days, If Needed) ........................................................................................33 
11.2.2. 
Outpatient Assessments: Days 1-14 ...........................................................................34 
11.2.3. 
Clinic Visit 2: Day 4 (±1 Day) ...................................................................................35 
11.2.4. 
Clinic Visit 3: Day 14 (+ 1 Day, End of Treatment/Early Termination) ....................36 
11.2.5. 
Clinic Visit 4: Day 28 (+3 Days, Follow-Up Visit) ...................................................37 
12. 
STUDY PROCEDURES ............................................................................................37 
12.1. 
Numerical Rating Scale to Assess Subject’s Pain Level due to Muscle 
Spasm .........................................................................................................................37 
12.2. 
Subject Rated Medication Helpfulness (SRMH) ........................................................37 
12.3. 
Clinical Global Assessments (Clinician’s Global Impression of Severity, 
CGI-S and Clinician’s Global Impression of Change, CGI-C) ..................................38 
12.4. 
Subject-Rated Global Assessments (Patient’s Global Impression of 
Severity, PGI-S and Patient’s Global Impression of Change, PGI-C) .......................38 
12.5. 
Visual Analogue Scale (VAS) ....................................................................................38 
12.6. 
Functionality Assessment ...........................................................................................38 
12.7. 
Oswestry Disability Index (ODI) ................................................................................38 
12.8. 
Use of Rescue Medications ........................................................................................39 
12.9. 
Vital Signs ..................................................................................................................39 
12.10. 
12-Lead Electrocardiograms .......................................................................................39 
12.11. 
Clinical Laboratory Assessments ...............................................................................39 
12.12. 
Blood Collection for Tolperisone Plasma (PK) Concentrations (Optional) ...............40 
12.12.1. 
Sample Storage and Shipment ....................................................................................41 
12.13. 
DNA Genotype ...........................................................................................................41 
12.14. 
Blood Collection Volume for the Study .....................................................................41 
12.15. 
Medical History ..........................................................................................................41 
12.16. 
Physical and Neurological Examination .....................................................................41 
12.17. 
Pregnancy Test ............................................................................................................41 
13. 
STUDY DRUG ...........................................................................................................42 
13.1. 
Study Drug Administration .........................................................................................42 
13.2. 
Accountability .............................................................................................................42 
14. 
SUBJECT RESTRICTIONS ......................................................................................43 
14.1. 
Fluid, Food, and Lifestyle Restrictions .......................................................................43 


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15. 
DISCONTINUATION CRITERIA AND PROCEDURES .......................................43 
15.1. 
Premature Termination of Study/Closure of Study Sites ...........................................43 
16. 
EVALUATION AND REPORTING OF ADVERSE EVENTS ...............................44 
16.1. 
Adverse Event (AE) Definitions .................................................................................44 
16.1.1. 
Severity Assessment ...................................................................................................45 
16.1.2. 
Causality Assessment .................................................................................................45 
16.2. 
Routine Reporting .......................................................................................................45 
16.3. 
Serious Adverse Event Reporting ...............................................................................46 
17. 
STATISTICAL CONSIDERATIONS .......................................................................47 
17.1. 
General Considerations ...............................................................................................47 
17.2. 
Determination of Sample Size ....................................................................................47 
17.3. 
Analysis Populations ..................................................................................................48 
17.4. 
Statistical Analysis Methods .......................................................................................49 
17.4.1. 
Disposition and Demographics ...................................................................................49 
17.4.2. 
Efficacy Analysis ........................................................................................................49 
17.4.2.1. 
Primary Efficacy Analysis ..........................................................................................49 
17.4.2.2. 
Secondary Efficacy Analyses .....................................................................................49 
17.4.2.3. 
Handling of Dropouts or Missing Data ......................................................................50 
17.4.3. 
Safety Analysis ...........................................................................................................50 
17.4.3.1. 
Adverse Events ...........................................................................................................50 
17.4.3.2. 
Extent of Exposure to Study Drug ..............................................................................51 
17.4.3.3. 
Clinical Laboratory .....................................................................................................51 
17.4.3.4. 
Vital Signs ..................................................................................................................51 
17.4.3.5. 
Twelve-lead Electrocardiogram (ECG) ......................................................................51 
17.4.3.6. 
Physical and Neurological Examination .....................................................................51 
17.4.4. 
DNA Genotyping ........................................................................................................51 
17.4.5. 
Pharmacokinetic Analysis ..........................................................................................51 
18. 
BIOLOGICAL SPECIMENS .....................................................................................52 
19. 
CLINICAL AND LABORATORY DATA COLLECTION .....................................52 
19.1. 
Electronic Case Report Forms (eCRF) .......................................................................52 
19.2. 
Electronic Patient Reported Outcomes (ePRO) ..........................................................52 
19.3. 
Laboratory Results ......................................................................................................52 
20. 
STUDY DOCUMENTATION ...................................................................................53 


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20.1. 
Source Documents ......................................................................................................53 
20.2. 
Access to Records .......................................................................................................53 
20.3. 
Retention of Records ..................................................................................................53 
21. 
INSTITUTIONAL REVIEW BOARD (IRB) ............................................................53 
22. 
ETHICAL CONDUCT OF THE STUDY ..................................................................54 
23. 
INFORMED CONSENT ............................................................................................54 
24. 
CONFIDENTIALITY ................................................................................................54 
24.1. 
Confidentiality of Data ...............................................................................................54 
24.2. 
Confidentiality of Subject Records .............................................................................54 
25. 
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT ..................................55 
26. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55 
27. 
PUBLICATIONS .......................................................................................................56 
28. 
REFERENCES ...........................................................................................................57 
29. 
SCHEDULE OF PROCEDURES ..............................................................................58 
 
In-text Tables 
Table 1 
Sample Size Considerations .......................................................................................48 
Table 2 
Schedule of Procedures ...............................................................................................58 
 


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5. 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADME 
Absorption, distribution, metabolism and excretion 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
°C 
degrees Celsius 
CGI-C 
Clinician’s Global Impression of Change 
CGI-S 
Clinician’s Global Impression of Severity 
CI 
Confidence interval 
cm 
Centimeter 
CNS 
Central nervous system 
E 
number of events 
ECG 
Electrocardiogram 
eCRF 
Electronic report form 
ePRO 
Electronic patient reported outcomes 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FFD 
Fingers to floor distance 
g 
gram 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
HCl 
Hydrochloride 
IATA 
International Air Transport Association 
ICH 
International Council for Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 


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Abbreviation 
Definition 
LC/MS/MS 
Liquid chromatography with tandem mass spectrometric detection 
LOCF 
Last observation carried forward 
LOQ 
Limit of quantification 
LSMD 
Least squares mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter  
mm 
Millimeter 
msec 
Millisecond 
N 
Number 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
PGI-C 
Patient’s Global Impression of Change 
PGI-S 
Patient’s Global Impression of Severity 
pH 
Potential of hydrogen 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
PT 
Prothrombin time 
QA 
Quality assurance 
QC 
Quality control 
SAE 
Serious adverse event 
SD 
Standard deviation 
SE 
Standard error 
SOPs 
Standard operating procedures 
TEAE 
Treatment-emergent adverse event 
TENS 
Transcutaneous Electrical Nerve Stimulation 
TID 
Three times a day 
TSH 
Thyroid stimulating hormone 
VAS 
Visual Analogue Scale 


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6. 
STUDY ADMINISTRATIVE STRUCTURE 
6.1. 
Medical Monitor 
Helen Young M.D. 
Precision for Medicine (“Precision”) 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
Phone: 760.492.5698 
Email:  helen.young@precisionformedicine.com 
6.2. 
Serious Adverse Event Reporting Contact Information - Sponsor 
Serious adverse events (SAEs) should be reported to Precision within 24 hours via the EDC 
system after Investigator or Investigator’s representative becomes aware of their occurrence. 
6.3. 
Central Laboratory 
The central laboratory, ACM Global Central Laboratory ("ACM'), for serum chemistry, hematology 
and urinalysis will be used. 
 
The genotype laboratory, Machaon Diagnostics, (Machaon), testing for CYP450 2D6 
polymorphism will be used. 
7. 
BACKGROUND AND RATIONALE FOR THE STUDY 
7.1. 
Introduction 
Tolperisone, a centrally acting muscle relaxant, is widely used in Europe, Asia, and South 
America for the treatment of abnormally increased muscle tone. Tolperisone is an (non-opioid) 
oral formulation presented as film-coated tablets, and is being developed by Neurana 
Pharmaceuticals, Inc. for the treatment of symptoms associated with acute and painful back 
muscle spasms. 
The mechanism of action of tolperisone is not fully characterized. The most prominent effect of 
tolperisone 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 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 concentrations, channel blockade remains incomplete and reversible. Although it 
demonstrated significant binding to a variety of receptors in vitro, including the sigma σ1 
receptor, the functional effects of tolperisone at these targets is not known. In general, 
tolperisone causes a frequency-dependent decrease in action potential amplitude of axonal 
membranes. Excitability is then decreased, especially in cases of pathologically increased reflex 
activity. It has been proposed that tolperisone may exert a stronger inhibitory effect on sensory 
axons than motor axons, as indicated by inhibition of nociception-induced reflex muscle 
contraction and withdrawal in animal models. Vasodilatory properties of tolperisone have been 
repeatedly described in clinical studies. The mechanism of the blood flow-enhancing effect of 


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tolperisone has not been investigated systematically; however, Ca2+-channel antagonism, or the 
drug’s modest anti-alpha-adrenergic effects may be involved.  
Animal toxicity has been extensively profiled and in repeat dosing study in rats with daily doses 
of 100 mg/kg for 28 days being well-tolerated, and the no observed adverse effect level 
(NOAEL) considered to be 300 mg/kg/day. No target organs of toxicity were identified. In a 
three-part, 28-day toxicology study in dogs, the NOAEL was established as 20 mg/kg/day. 
Chronic oral toxicity studies in the rat (6-month) and dog (9-month) have been reported and have 
shown NOAELs of 50 and 5 mg/kg/day, respectively.  
Tolperisone was nonmutagenic in the Ames test and in two in vivo mouse bone marrow 
micronucleus tests. Tolperisone was, however, clastogenic in the in vitro chromosomal 
aberration assay in human lymphocytes and the in vitro mouse lymphoma TK assay. The in vitro 
genotoxic activity was attributed to 4-MMPPO, a degradation product of tolperisone. The ICH 
guidelines for genotoxic impurities require that levels remain below 10 ppm, equivalent to a 
daily maximum exposure of 1.5 ug. Based on daily dosing of 450 mg tolperisone, the calculated 
limit of 4-MMPPO is 3.3 ppm/tablet (corresponding to 1.5 µg per total daily dose). 
Carcinogenicity studies in rats and mice have shown no risk of carcinogenic potential. 
Tolperisone had no effect on fertility or in pre- and postnatal reproductive toxicity studies in rats 
and was non-teratogenic in rats and rabbits. 
Pharmacokinetic, toxicokinetic, and absorption, distribution, metabolism, and excretion (ADME) 
studies with tolperisone show the drug is highly absorbed (> 80%), widely distributed to major 
organs including the CNS, and excreted primarily by the kidneys. In vitro studies have 
demonstrated that tolperisone is rapidly converted into as many as 25 metabolites by liver 
microsomes from rat, dog, and human species. In vivo, both major human metabolites M4 and 
M5 are present at high levels in dogs. M4 is also present at high levels in the rat, but M5 is not. 
Tolperisone has been evaluated in five clinical studies conducted in healthy volunteers: two 
pharmacokinetic (PK) studies (Study 01-316-02 and Study 01-286-02); a safety and PK study 
(AV650-012), a drug-drug interaction study (AV650-019); and a study to assess sedative effects 
(Study 115). A total of 148 subjects were exposed to tolperisone in these studies. One double-
blind, placebo-controlled safety and efficacy study was conducted in patients, Study AV650-018 
(IND 74864) in patients with spasticity associated with multiple sclerosis (108 tolperisone during 
double-blind, 146 tolperisone during open-label). 
The pharmacokinetic studies conducted with tolperisone in male and female healthy volunteers 
have demonstrated a roughly linear relationship between dose and exposure that is more than 
dose-proportional across the investigated dose range (between 150 to 450 mg administered orally 
in single doses). Additionally, gender has no apparent influence on tolperisone’s 
pharmacokinetic behavior in human subjects. In contrast, the plasma exposure in rats was 
approximately twice as high in females as in males for a given dose. Food appears to increase the 
drug’s plasma exposure slightly in humans. 
Tolperisone is extensively metabolized in vivo, mainly by the liver enzymes CYP2D6 and 
CYP2C19. Moderate to potent inhibitors of CYP2D6 and CYP2C19 are thus likely to cause drug 
interactions with tolperisone. In a Phase 1 drug-drug interaction study, the tolperisone plasma 
exposure increased approximately 2 fold following concomitant administration with paroxetine 
(a CYP2D6 inhibitor) and increased by 3- to 4- fold following concomitant administration with 


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fluvoxamine (a CYP2C19 inhibitor). The CYP2D6 genotype (conferring ultra-fast, fast, 
intermediate and slow metabolizer phenotypes) influences tolperisone bioavailability. In one 
pharmacokinetic study, subjects who were classified as CYP2D6 intermediate metabolizers had 
approximately 50% higher exposure to tolperisone following oral dosing than fast metabolizers. 
Overall, the bioavailability increased with decreasing metabolic activity among the four 
genotypes. 
In a driving simulation, Study 115, assessed the sedation risk tolperisone. Study 115 was a 
randomized, placebo-controlled, multiple-dose 3-way cross-over study of safety and cognitive 
effects of multiple doses of 150 mg tolperisone administered three times daily (TID) in 35 male 
and female healthy volunteers. Treatment groups included 450 mg tolperisone (150 mg TID), 30 
mg cyclobenzaprine (i.e., 10 mg administered three times daily), and placebo. Subjects received 
3 days of each treatment. In this study, tolperisone was equivalent to placebo at Tmax, showed no 
drug accumulation or sedation effects following multiple doses, and showed no next day residual 
effects. 
The most common AE across all studies was headache, occurring in 14.2% of subjects in healthy 
volunteer studies and 15.3% of subjects in patient studies. No other AEs occurred in more than 
5% of subjects in either group of studies. 
This Phase 2 study will explore the efficacy and safety of tolperisone at doses up to 600 mg 
administered TID for 14 days in patients with acute and painful back muscle spasms.  
7.2. 
Drug Profile 
Full details of tolperisone pre-clinical and clinical safety and tolerability data are contained in the 
Investigator's Brochure. 
7.3. 
Rationale  
7.3.1. 
Study Design 
This is a double-blind, randomized, placebo-controlled, parallel group study of the efficacy and 
safety of tolperisone or placebo administered as multiple doses TID in approximately 400 male 
and female subjects experiencing back pain due to or associated with muscle spasm. The 
tolperisone groups consist of dose levels of 150, 300, 450, and 600 mg administered TID in 
doses of 50, 100, 150, or 200 mg for 14 days, with a visit at 28 days as follow-up. Subjects 
randomized to the placebo group will receive matching placebo tablets TID for 14 days with a 
follow-up visit at Day 28. Subject participation will be approximately 4 weeks.  


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The study design provides unbiased (through randomization) observations of the efficacy and 
safety of tolperisone over a range of doses (150 to 600 mg/day) administered for two weeks, as 
appropriate for acute back spasms and based on prior studies. 
 
See the Schedule of Procedures in Table 2. 
7.3.2. 
Tolperisone Dose Levels 
Tolperisone 50, 100, 150, and 200 mg tablets and matching placebo will be provided for the 
study by the Sponsor. Dosing will be three times a day/TID, with a single tablet administered at 
each dose for a total daily dose of 150, 300, 450, and 600 mg per day. Subjects should be 
instructed to dose at 6-8 am, 12-2 pm, and 6-8 pm daily for 14 days. Subjects who are 
experiencing significant pain following randomization will be allowed to take a single tablet of 
acetaminophen 500 mg up to three (3) times per day as a rescue medication. Rescue medication 
will be captured on the study-provisioned smartphone/trial application.  Subjects are not to take 
rescue medication on clinic visit days, Day 4 (Visit 2) and Day 14 (Visit 3). 
Doses for the Phase 2 study are based on many years of historical use of tolperisone for 
treatment of painful muscle spasms where the therapeutic dose is generally 300 to 450 mg per 
day. In addition, the total daily dose of 600 mg was selected to explore a higher dose range to 
optimize efficacy without impacting safety.  A previous clinical study (AV650-018) conducted 
in subjects with multiple scelerosis-associated spasticity using doses up to 900 mg/day for up to 
48 weeks did not show an increase in adverse events. 
See Investigator’s Brochure for further information. 
Randomization
Tolperisone 150 mg (50 mg/TID)
Tolperisone 300 mg (100 mg/TID)
Tolperisone 450 mg (150 mg/TID)
Tolperisone 600 mg (200 mg/TID)
Matching Placebo (TID)
Screening/
Enrollment
(-3 to 0 Days)
Follow-Up 
Safety Visit
(Day 28)
Day 1
Day 4
Day 14
Subject-Rated Pain Numerical Rating Scale (NRS)  
Daily ePRO Assessments & Dosing Diary thru 
Day 14
End of Treatment
Treatment   Start


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8. 
STUDY OBJECTIVES AND ENDPOINTS 
8.1. 
Primary Objective 
The primary objective of this study is to assess the efficacy of tolperisone daily doses 150, 300, 
450, and 600 mg for relief of pain due to acute back muscle spasm. 
8.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• To assess the safety and tolerability of tolperisone in subjects with pain due to acute 
back spasm. 
• To determine the onset of action of tolperisone in treatment of pain due to acute back 
spasm. 
• To determine the duration of pain relief of tolperisone in treatment of pain due to 
acute back spasm. 
• To determine the need for rescue medication when treated with various doses of 
tolperisone for pain due to acute back spasm. 
8.3. 
Primary Endpoint 
The primary endpoint for this study is subject-rated pain due to acute back spasm using a 
Numerical Rating Scale (NRS; 0-10 scale, from no pain to worst possible pain) on Day 14 
(“right now” time point). 
8.4. 
Secondary Endpoints 
The secondary endpoints for this study include the following. For these endpoints, baseline is 
defined as the last assessment prior to the first dose of study drug. 
Efficacy Endpoints: 
• Subject-rated pain due to acute back spasm using an NRS (0-10 scale, from no pain to 
worst possible pain) on Day 4 “right now”. 
• Subject rating of medication helpfulness (SRMH; 1-5 scale, from poor to excellent) 
on Days 4 and 14.  
• Subject-rated NRS (0-10 scale) of pain due to acute back spasm on Days 1 to 14; 
average over the past 12 hours.  
• Subject-rated NRS (0-10 scale) of pain due to acute back spasm on Days 1 to 14; 
average over the past hour. 
• Subject-rated NRS (0-10 scale) of average pain due to acute back spasm on rest or 
movement, rated at the end of the day on Days 1 to 14. 
• Time to relief of pain from baseline due to acute back spasm using subject-rated NRS 
(0-10 scale) on Days 1 to 14. 


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• Clinician’s Global Impression of Severity (CGI-S) (1–5 scale) at baseline (Day 1). 
• Clinician’s Global Impression of Change (CGI-C) 1-7 scale from worse to marked 
improvement) on Days 4 and 14. 
• Patient’s Global Impression of Severity (PGI-S) (1-5 scale) at baseline (Day 1). 
• Patient’s Global Impression of Change (PGI-C) based on subject’s global assessment 
(1-7 scale, from worse to marked improvement) on Days 4 and 14. 
• Functionality assessment: fingers to floor distance (FFD) is an index of mobility of 
the spinal cord and is measured as distance in cm when standing with the spinal cord 
flexed with complete extension of knee joint, on Days 4 and 14 compared to baseline 
(Day 1) (assessments should be conducted at the same time of day for all three time 
points). 
• Disability assessment at baseline (Day 1), Day 4, and Day 14: 
- Oswestry Pain and Disability (ODI) questionnaire (10 questions with one answer 
each for pain intensity, personal care, lifting, walking, sitting, standing, sleeping, 
sex life [if applicable], social life, and traveling). 
• Use of rescue medications (measured daily, assessed as number of rescue tablets 
administered by the subject via smartphone/use of trial application). Patients are 
instructed not to take rescue medications on the day of clinic visits on Day 4 and 14. 
• Quality of sleep rated by subjects starting at baseline (Day 1) and on Days 2 to 14. 
• Visual Analogue Scale (VAS) score for subject-reported sleepiness measured in the 
clinic on at Day 4. 
Safety Endpoints 
• Clinical evaluations include: 
- Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
- Orthostatic effects on blood pressure 
- Physical examinations 
- 12-lead electrocardiograms (ECGs) 
• Laboratory safety tests include blood chemistry, hematology, urinalysis, and urine 
pregnancy tests for women of childbearing potential 
• Adverse events (AEs) 


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9. 
SUBJECT DEFINITION 
A sufficient number of subjects will be screened to ensure the enrollment of approximately 
400 subjects. Individuals are eligible for this study if they meet all inclusion and no exclusion 
criteria. The criteria below will be assessed at the Screening/Baseline visit.  
9.1. 
Inclusion Criteria 
1. Ambulatory male or female, 18 to 65 years of age. 
2. Current acute back pain and/or stiffness due to acute and painful muscle spasm starting 
within 7 days prior to study entry and more than 8 weeks after the last episode of acute 
back pain. 
3. Subjects must have pain of 4 or more on the subject “right now” rating of pain intensity 
NRS scale of 0 – 10 points at baseline. 
4. Must be willing to discontinue all medication used for the treatment of pain or muscle 
spasm on study entry at Day 1 including but not restricted to:  
a. Ibuprofen (Motrin) 
  
b. Diclofenac (Voltaren) 
 
c. Celocoxib (Celebrex) 
 
d. Naproxen (Aleve) 
 
e. Tolmetin (Tolectin) 
 
f. Cyclobenzaprine (Flexeril) 
 
g. Cyclobenzaprine (Amrix) 
 
h. Metaxolone (Skelaxin) 
 
i. Methocarbamol (Robaxin) 
 
j. Other nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., aspirin) 
k. Carisoprodol (Soma) 
 
l. Tizanidine (Zanaflex, Sirdalud) 
5. Pain localized below the neck and above the inferior gluteal folds. 
6. Body mass index ranging between 18 and 35 kg/m². 
7. All subjects must be capable of understanding and complying with the protocol and have 
signed the informed consent document.  
8. Female subjects must have a negative urine 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 for 2 weeks 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, 
injectable, subdermal implant, vaginal or patch contraceptives, intrauterine device (IUD; 
copper or hormonal IUD), or double-barrier method (e.g., condom, diaphragm or cervical 
cap with spermicidal foam, cream, gel, or suppository). 
9. Subjects must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 


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9.2. 
Exclusion Criteria 
1. Unwillingness to stop taking pain or antispasmodic medication other than the study 
medication (specifically opioid use [e.g., Vicodin], barbiturates, and cannabis). 
2. Chronic pain for the previous 3 months or longer, on more days than not. 
3. Radicular pain in the lower extremity (i.e. pain radiating below the knee), sciatica pain 
down the leg, or pain below the knee (indicating a lumber radiculopathy); radicular pain 
in the upper extremity, radiating into the forearm or hand (indicating a cervical 
radiculopathy). 
4. Concomitant severe pain in a region other than the back. 
5. Spinal surgery within 1 year of study entry. 
6. Back pain due to major trauma (e.g., motor vehicle accident, fracture of bone) unless 
resolved for more than 1 year. 
7. Treatment of back pain ongoing with non-pharmacological therapy (e.g., acupuncture, 
chiropractic adjustment, massage, Transcutaneous Electrical Nerve Stimulation [TENS], 
physiotherapy).  
8. Female subjects who are pregnant or lactating. 
9. Subjects who are taking Baclofen (Lioresal, Liofen, Gablofen, etc.) or Botox 
(onabotulinumtoxin A) for pain. 
10. Subjects who test positive for alcohol by breathalyzer test. 
11. Known history or symptoms suspicious of: 
a. Spinal fracture within previous 3 years 
b. Osteoporosis with fracture 
c. Cancer except cutaneous cancers (e.g., melanoma, squamous cell carcinoma) 
d. Constitutional symptoms such as recent unexplained chills or weight loss 
e. Spinal infection  
f. Intravenous drug abuse  
g. Immunosuppression 
h. Cauda equine syndrome 
i. History of chronic severe scoliosis (childhood) 
12. Myasthenia gravis. 
13. Recent history of severe hepatic insufficiency, i.e., aspartate aminotransferase 
(AST)/alanine aminotransferase (ALT) above 3 times the upper limit of normal (ULN). 
14. Recent history of severe renal insufficiency, i.e., serum creatinine value above 2.5 mg/dL. 
15. History or presence of a severe infection, major surgery or trauma, severe metabolic, 
endocrine or electrolyte disturbances. 
16. A major illness, requiring hospitalization during the 3 months before commencement of 
the screening period. 
17. Inflammatory arthritis, or other diseases known to cause intermittent or chronic pain. 


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18. 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. 
19. History of seizure disorder other than Infantile Febrile Seizures, family history of seizure, 
or history of head trauma with loss of consciousness. 
20. Disability claim for back pain, or pending legal issue regarding back pain. 
21. Subjects who have received treatment with an investigational product/device within 
30 days prior to study entry. 
22. Subjects who have a history of allergic reaction to tolperisone, eperisone, or other 
skeletal muscle relaxants, lidocaine, acetaminophen or NSAIDs or any components of 
these study medications. 
23. Any other condition that, in the opinion of the Investigator, would adversely affect the 
subject’s ability to complete the study or its measures. 
24. Subjects who are unwilling to stop taking moderate to potent inhibitors of cytochrome 
P450 (CYP) isozymes CYP2D6 and CYP2C19, which are likely to cause drug 
interactions with tolperisone HCl (e.g., medications such as paroxetine and fluvoxamine). 
25. Subjects who are a site staff member, relative, or friend of a site staff member or subjects 
in same household or who are related to each other. 
26. Subjects with clinically significant cardiovascular disorders, such as ischemic heart 
disease, arrhythmias, poorly controlled hypertension, or history of acute myocardial 
infarction. 
27. Subjects with QT interval greater than 480 milliseconds (msec) or greater than 450 msec 
if accompanied by a partial bundle branch block, or other clinically significant ECG 
abnormaility at Screening in the judgement of the Investigator. 
28. Subjects with diastolic blood pressure less than 50 mmHg or greater than 105 mmHg; 
sitting heart rate less than 50 beats per minute (bpm) or greater than 110 bpm (after 
approximately 3 minutes at rest); or heart rate by ECG less than 50 or greater than 110 
bpm at Screening. 
9.3. 
Withdrawal Criteria 
Subjects will be advised that they are free to withdraw from the study at any time. Reasons that 
subjects may discontinue or be withdrawn from the study may include, but are not limited to: 
• AEs 
• Subject request 
• Investigator decision 
• Protocol non-compliance 
• Study termination by the Sponsor or Institutional Review Board (IRB).  
If a subject is withdrawn from the study, all efforts will be made to complete the Visit 3 (EOT) 
procedures at an Early Termination visit (see Section 11.2.4). All information, including the 
reason for withdrawal, should be reported on the applicable pages of the electronic case report 
form (eCRF).  


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For subjects who are lost to follow-up, three documented attempts will be made to contact the 
subject for follow-up information, including reason for discontinuation and follow-up of AEs.  
Subjects who withdraw from the study will not be replaced. 
10. 
STUDY DESIGN 
10.1. 
Summary of Study Design 
This is a double-blind, randomized, placebo-controlled, parallel group study of the efficacy and 
safety of multiple doses of tolperisone administered TID in approximately 400 male and female 
subjects experiencing back pain due to or associated with muscle spasm. The tolperisone groups 
consist of dose levels of 150, 300, 450, and 600 mg administered TID in doses of 50, 100, 150, 
or 200 mg for 14 days, with a visit at 28 days as follow-up. Subjects randomized to the placebo 
group will receive matching placebo tablets TID for 14 days. Subject participation will be 
approximately 4 weeks.  
Subjects will be screened for eligibility for participation in the study at Screening/Baseline 
Visit 1 (Day 1) after reviewing and signing the informed consent form. Subjects meeting all 
inclusion/exclusion criteria will then be randomized into the study (Day 1) and begin dosing this 
same day. If needed, screening assessments may be completed up to 3 days prior to Day 1 (first 
dose) as described below.  
It is highly recommended to complete all screening and baseline assessments on the same day 
the subject presents at the site due to their acute pain relief needs.  However, to accommodate 
real world logistical issues and time constraints of either the subject or site, the site has the 
flexibility to allow completion of screening assessments within 3 days (-3 days) prior to Day 1 
baseline assessments, deployment of study-provisioned smartphone/download of trial application 
on subject’s smartphone, randomization, and first dose (in that order).  
After completing all screening and baseline assessments by/on Day 1, subjects will receive all 
study drug and rescue medication (acetaminophen 500 mg) and will be instructed to begin taking 
their study drug that same day. Depending on the time of their clinic visit, they should be 
instructed to begin dosing with either the midday dose (12-2 pm) or the evening dose (6-8 pm). 
Subjects will be instructed to continue taking study drug TID through Day 14 and complete 
dosing diary and daily ePRO assessments. 
Subjects will return to the clinic to complete the procedures listed in the Schedule of Procedures 
on Day 4 (±1 day; Visit 2) and Day 14 (+1 day, End of Treatment [EOT] visit, Visit 3). Subjects 
must also return to the clinic for a follow-up visit on Day 28 (+3 days, 2-week follow-up visit, 
Visit 4). 
For all subjects, safety laboratory assessments will be performed on Day 1 (Screening/Baseline 
visit, -3 to 0 days) and Day 14 (Visit 3). In addition, a sample for genotyping will be collected on 
Day 1 (Screening/Baseline visit). For select sites with additional consenting subjects, 
pharmacokinetic samples will be collected on Day 4 (Visit 2). 
Please refer to Schedule of Procedures, Table 2. 


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10.2. 
Subject Assignment 
Randomization will occur only after the subject has been determined to be eligible for study 
participation based on the inclusion and exclusion criteria. Subjects will be randomly assigned to 
one of the following five treatment groups in a 1:1:1:1:1 ratio: tolperisone 50 mg TID 
(150 mg/day), tolperisone 100 mg TID (300 mg/day), tolperisone 150 mg TID (450 mg/day), 
tolperisone 200 mg TID (600 mg/day), matching placebo TID. Prior to each eligible subject’s 
participation, the next unique, sequentially available randomization number will be assigned to 
the subject using an interactive web response system. 
10.2.1. 
Unblinding  
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat a medical emergency of the subject. The 
decision to break the blind in emergency situations remains the responsibility of the Investigator, 
which will not be delayed or refused by the Sponsor. However, the Investigator should contact 
the Medical Monitor and Sponsor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. If it is medically imperative to know what study drug the subject is 
receiving, study drug should be temporarily discontinued if, in the opinion of the Investigator, 
continuing study drug can negatively affect the outcome of the subject’s treatment. 
The Principal Investigator has the ability to unblind single subjects within EDC system for 
emergency unblinding purposes. The Investigator should promptly notify the Medical Monitor of 
the emergency unblinding and the reason for breaking the blind, which should be clearly 
documented by the Investigator in the patient’s source documentation.  
10.3. 
Treatment Compliance  
Each subject will be instructed on the importance of returning his or her study drug and rescue 
medication at each applicable study visit (i.e., Visits 2 and 3). The subject will also be asked to 
enter daily dosing information on the smartphone/trial application and study staff will review this 
information with the subject at each site visit to assess the subject’s compliance with the study 
drug and rescue medication. Any missed doses will be noted by the subject on the 
smartphone/trial application.  
11. 
DAILY STUDY ACTIVITIES 
A complete Schedule of Procedures can be found in Table 2. 
 
11.1. 
Screening 
The Screening/Baseline visit (Visit 1) will include procedures as listed in Table 2. 
The informed consent document 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. 


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11.2. 
Study Periods  
See Table 2 in Section 29 for the schedule of procedures and assessments across the time points 
for the study. 
11.2.1. 
Clinic Visit 1: Day 1 (Screening/Baseline) and up to Day -3 (Additional 
Screening Days, If Needed)  
Subjects will visit the clinic site for their Screening/Baseline visit (Visit 1, -3 to 0 days) and 
undergo screening processes for entry into the study. Subjects who meet the inclusion and no 
exclusion criteria will be entered into the study.  
The following screening assessments will be conducted by the Investigator or designee prior to 
subject enrollment. If needed, the following screening assessments may be completed within 3 
days prior to Day 1 (-3 to 0 days): 
• Informed consent to be signed 
• A urine pregnancy test for all females of childbearing potential  
• Medical history and demographic data, including sex, age, race, ethnicity, body 
weight (kg), height (cm), body mass index (BMI) (kg/m2), and smoking habits 
• Physical examination  
• Neurological examination 
• The alcohol breathalyzer and urine drug screen 
• Laboratory tests (serum chemistry, hematology, and urinalysis) 
o blood sample for DNA genotyping for CYP450 2D6 polymorphism would be 
collected at same time of other required blood draw 
• Vital signs (supine and standing blood pressure [including orthostatic pressure]), 
sitting heart rate (after approximately 3 minutes at rest), respiratory rate, and body 
temperature,) 
• A 12-lead ECG 
• Prior and/or concomitant medications during the study will be recorded, as well as 
those that qualify as rescue medications (see Section 12.8) 
• Inclusion/exclusion criteria to be reviewed for qualification of the subject’s 
enrollment into the study 
The following baseline assessments will be conducted by the Investigator or designee prior to 
dosing on Day 1. If any screening assessments were completed prior to Day 1, 
inclusion/exclusion criteria are to be re-reviewed for qualification of the subject’s enrollment 
into the study: 
• Baseline assessments for study efficacy endpoints: 
- Subject rating of pain “right now” (NRS), must be 4 or greater 


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• Global severity of pain assessment by the physician and the subject on a scale of 1-5, 
with 1=none, 2=mild, 3=moderate, 4=severe, 5=very severe 
• Functionality assessment:  
- Fingers to Floor Distance (FFD)  
• Disability assessment: 
- Oswestry Pain and Disability Index (ODI) via the site study-provisioned tablet   
• Deploy subject smartphone/use of trial application to subject 
• Quality of sleep via the subject smartphone/use of trial application 
• Randomization  
• Dispense study drug (for 14 days of dosing) and rescue medication; sufficient for use 
by subjects for the entire duration of the study 
• AEs occurring after the first dose of study medication will be reported. Any 
concurrent medication use will be recorded. 
Subjects will receive all study drug and rescue medication on Day 1. Subjects will begin taking 
their study drug that same day. Depending on the time of their clinic visit, they should be 
instructed to begin dosing with either the midday dose (12-2 pm) or the evening dose (6-8 pm).  
Subjects will be provided a smartphone/use of trial application on Day 1, just prior to 
randomization. Subjects will be instructed on how to perform the assessments to be conducted by 
the subject at home/away from clinic and how to record the results on the smartphone/trial 
application.  
Subjects will be instructed to return to the clinic on Day 4 (Visit 2) and on Day 14 (EOT visit, 
Visit 3) and to bring all study drug and rescue medication with them as well as smartphone 
device.  Subjects must also return to the clinic for a safety follow-up visit on Day 28 (2-week 
follow-up visit, Visit 4).  
Subjects will be asked and reminded not to consume alcoholic beverages prior to their study visit 
on Days 1, 4, and 14 and to restrict their consumption during the study duration. At all other 
times, alcohol consumption is limited to no more than 2 alcoholic drinks or equivalent (beer [24 
ounces or 710 mLs], wine [12 ounces or 355 mLs], or distilled spirits [3 ounces or 89 mLs]) per 
day. 
Subjects will be reminded to restrict their consumption of caffeinated beverages to no more than 
4 units per day amounts (1 unit =120 mg caffeine or about one eight-ounce cup of coffee). 
Subjects will be reminded to refrain from vigorous physical activity, heat and ice packs, and 
non-pharmacological therapies (e.g., acupuncture, chiropractic adjustment, massage therapy, 
TENS, physiotherapy) during Days 1 to 14. 
11.2.2. 
Outpatient Assessments: Days 1-14 
The following subject assessments and procedures will be conducted by the subjects at 
home/away from the clinic in the morning, at midday, and in the evening. For Days 1, 4 and 14, 
these assessments are in addition to the clinic visit assessments. Throughout the study, site staff 


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will be instructed to review the ePRO/eDiary administration portal to ensure subject compliance 
with completion of the following ePRO assessments, study drug dosing, and use of rescue 
medications. 
 
Morning: Subjects should take the first daily dose of study drug (am dose; 6-8 am) with 
approximately 4-6 ounces of water, and then perform the following assessments 
between 8-10 am: 
• Subject rating of pain (NRS) for the average level of pain over the last 12 hours 
• Subject rating of pain (NRS) for the average level of pain over the past 1 hour 
• Quality of sleep 
Midday: Subjects should take the second daily dose of study drug (midday dose; 12-2 pm) 
with approximately 4-6 ounces of water. 
Evening: Subjects should take the third daily dose of study drug (evening dose; 6-8 pm) with 
approximately 4-6 ounces of water, and perform the following assessments between 
8-10 pm:  
• Subject rating of pain (NRS) for the average level of pain over the last 12 hours 
• Subject rating of pain (NRS) average pain over the past 1 hour 
• Rating of pain using NRS, for average pain at rest or movement  
• Daily activities (sedentary, walking activities, etc.) to be recorded by the subject at 
the end of the day  
• Use of any rescue medications throughout the day 
11.2.3. 
Clinic Visit 2: Day 4 (±1 Day) 
On Day 4, subjects return to the clinic to undergo the following assessments: 
• Alcohol breathalyzer and urine drug screen. A positive test result for urine drug or 
alcohol breathalyzer at any time during the study will terminate the subject from 
further participation in the study. 
• Abbreviated physical examination   
• Neurological examination 
• Vital signs 
• Document AEs  
• Subject rating of pain (NRS) “right now” via the site study-provisioned tablet 
• Subject rating of medication helpfulness via the site study-provisioned tablet 
• Global clinical impression of improvement by the physician (CGI-C) via the site 
study provisioned tablet 


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• Global impression of improvement by the subject (PGI-C) via the site study-
provisioned tablet 
• Functionality assessment:  
- Fingers to Floor Distance (FFD)  
• VAS via the site study-provisioned tablet 
• Disability assessment at Day 4: 
- Oswestry Disability Index (ODI) via the site study provisioned tablet 
• For the select group of sites and subjects who will undergo PK assessments, a single 
blood sample will be drawn on Day 4 after all other assessments have been 
completed. 
• Any changes or additions to prior concurrent medication use will be recorded. 
Confirm that no rescue medications were taken on Day 4 (Visit 2). 
• Site staff to review returned study drug and rescue medication against the eDiary 
dosing information to evaluate compliance.  
11.2.4. 
Clinic Visit 3: Day 14 (+ 1 Day, End of Treatment/Early Termination) 
On Day 14, subjects return to the clinic to undergo the following assessments:  
• Abbreviated physical examination  
• Neurological examination 
• Vital signs 
• Document AEs  
• Subject rating of pain (NRS) “right now” via the site study-provisioned tablet 
• Subject rating of medication helpfulness via the site study-provisioned tablet 
• Global clinical impression of improvement by the physician (CGI-C) via the site 
study-provisioned tablet 
• Global impression of improvement by the subject (PGI-C) via the site study-
provisioned tablet 
• Functionality assessment:  
- Fingers to Floor Distance (FFD)  
• Alcohol breathalyzer and urine drug screen  
• Disability assessment: 
- Oswestry Disability Index (ODI) via the site study-provisioned tablet 
• Urine pregnancy test for all females of childbearing potential 
• Laboratory evaluations  


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• 12-Lead ECG  
• Any changes or additions to prior concurrent medication use will be recorded. 
Confirm that no rescue medications were taken on Day 14 (Visit 3). 
• Site staff to review returned study drug and rescue medication against the eDiary 
dosing information to evaluate compliance.  
• Site staff to collect smartphone, if provisioned  
In the event that a subject discontinues or is withdrawn from the study early, the Day 14/EOT 
assessments should be completed at an Early Termination visit. 
11.2.5. 
Clinic Visit 4: Day 28 (+3 Days, Follow-Up Visit) 
Prior to discharge from the clinical study, the following procedures should be performed:  
• AEs will be recorded.  
• Any changes or additions to prior concurrent medication use will be recorded.  
• Vital signs  
• Abbreviated physical examination 
• Urine pregnancy test for all females of childbearing potential 
12. 
STUDY PROCEDURES 
12.1. 
Numerical Rating Scale to Assess Subject’s Pain Level due to Muscle 
Spasm 
The NRS is a scale of 0 to 10 (0=no pain, 10=worst possible pain). Subjects will use the NRS to 
evaluate their pain (“right now”) on Day 1 (baseline assessment) and on Days 4 (Visit 2) and 14 
(Visit 3) during the clinic visit via the site study-provisioned tablet.  
In addition, the NRS scale will be used by subjects for pain assessment at rest and upon 
movement in the evening (8–10 pm) on Days 1 to 14 recorded via the subject smartphone/use of 
trial application. Subjects will also be asked to rate their average pain level (NRS scale) over the 
past hour and the past 12 hours in the morning (8-10 am) and evening (8-10 pm) via the subject 
smartphone/use of trial application. 
12.2. 
Subject Rated Medication Helpfulness (SRMH) 
The SRMH is a categorical scale for subjects to assess medication helpfulness, where 1=poor, 
2=fair, 3=good, 4=very good, and 5=excellent. Medication helpfulness will be administered via 
the site study-provisioned tablet ePRO during the clinic visit on Days 4 and 14. 


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12.3. 
Clinical Global Assessments (Clinician’s Global Impression of 
Severity, CGI-S and Clinician’s Global Impression of Change, 
CGI-C) 
On Day 1, the CGI-S will be conducted by the physician using a 1-5 scale (1=no pain, 2=mild 
pain, 3=moderate pain, 4=severe pain, and 5=worst possible pain). 
The CGI-C will be conducted by the physician on Days 4 (Visit 2) and 14 (Visit 3) to assess 
global improvement using a 7-point scale (1=Very Much Worse, 2=Much Worse, 3=Minimally 
Worse, 4=No Change, 5=Minimally Improved, 6=Much Improved, and 7=Very Much 
Improved). 
The Investigator/evaluator will be provided with training to ensure consistent CGI-S and CGI-C 
assessments across investigational centers. To the greatest extent possible, the assessments for a 
particular subject should be performed by the same rater/evaluator at all study visits.  
12.4. 
Subject-Rated Global Assessments (Patient’s Global Impression of 
Severity, PGI-S and Patient’s Global Impression of Change, PGI-C) 
On Day 1 (Screening/Baseline visit), the PGI-S will be administered to assess the subject’s 
impression of severity of pain using a 1-5 scale (1=no pain, 2=mild pain, 3= moderate pain, 
4=severe pain, and 5=worst possible pain). 
The PGI-C will be administered on Days 4 (Visit 2) and 14 (Visit 3) to assess the subject’s 
global impression of improvement using a 7-point scale (1=Very Much Worse, 2=Much Worse, 
3=Minimally Worse, 4=No Change, 5=Minimally Improved, 6=Much Improved, and 7=Very 
Much Improved). 
12.5. 
Visual Analogue Scale (VAS)  
The VAS for subject-reported sleepiness will be measured in the clinic on Day 4 (Visit 2) using a 
visual analog scale from 0 = alert, wide awake; to 10 = very sleepy, difficulty remaining awake. 
12.6. 
Functionality Assessment 
On Day 1 (Screening/Baseline visit) and on Days 4 (Visit 2) and 14 (Visit 3), the subject’s 
functionality based on the Fingers to Floor Distance (FFD) test will be assessed at the clinical 
site. FFD is measured as the distance in cm from the patients right long finger to the floor when 
standing with the spinal cord flexed with complete extension of knee joint. The FFD should be 
conducted at the same time of day for each test on Days 1, 4, and 14. The Investigator/evaluator 
will be provided with training to ensure consistent FFD assessments across investigational 
centers. To the greatest extent possible, the assessments for a particular subject should be 
performed by the same evaluator at all study visits.  
12.7. 
Oswestry Disability Index (ODI) 
Disability will be assessed by the subject using the Oswestry Disability Index, which is based on 
10 questions with one answer each for: pain intensity, personal care, lifting, walking, sitting, 
standing, sleeping, sex life [if applicable], social life, and traveling). This will be conducted on 


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Day 1 (Screening/Baseline visit) and on Days 4 (Visit 2) and 14 (Visit 3) via the site study-
provisioned tablet . 
12.8. 
Use of Rescue Medications 
Concomitant use of rescue analgesia used during the study will be recorded as concomitant 
medications on the eCRF (see Section 14 for allowed and disallowed medications during the 
study) and will be analyzed at the time of report following dosing of study drug through Visit 4 
(Day 28). Subjects will receive acetaminophen (500 mg tablets) (Tylenol) for use as rescue 
medication if needed for pain during the study. Use of rescue medication will be recorded daily 
via smartphone/use of trial application . Subjects are instructed to not take any rescue 
medications on the day of the clinic visits, Days 4 (Visit 2) and 14 (Visit 3). 
12.9. 
Vital Signs 
Vital signs will include the measurement of supine and standing blood pressure, orthostatic 
assessments, sitting heart rate (after approximately 3 minutes at rest), respiratory rate, and body 
temperature. Vital signs will be measured on Day 1 (Screening/Baseline visit) and on Days 4, 14, 
and 28 (All Visits). Weight and height will be measured at Screening/Baseline only.  
12.10. 
12-Lead Electrocardiograms 
Standard 12-lead ECGs will be administered at the clinic on Day 1 (Screening/Baseline visit) and 
on Day 14 (Visit 3).  Normal, abnormal (not clinically significant or clinically significant) are 
collected. 
12.11. 
Clinical Laboratory Assessments 
A certified laboratory will be used as a central laboratory to perform all routine hematology, 
clinical chemistry, and urinalysis assessments. Planned laboratory analyses include:  


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Category 
Test Name  
Hematology 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin Time (PT)a 
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)a 
Urinalysis 
Bilirubin 
Occult blood 
Glucose 
Ketones 
Leukocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Other 
Urine drug and alcohol breathalyzerb,c 
Urine pregnancyd 
Note: The complete panel of safety labs (other than where footnoted) will be completed on Day 1 
(Screening/Baseline visit) and Day 14. 
a  Screening only. 
b Day 1 (Screening/Baseline), Day 4, and Day 14 (End of Treatment ). 
c  Includes testing for amphetamines, methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates – 
ethanol will be determined by breathalyzer. 
d  Urine pregnancy test at Days 1, 14, and 28 for females of childbearing potential. 
12.12. 
Blood Collection for Tolperisone Plasma (PK) Concentrations 
(Optional) 
In a subset of subjects (approximately 120) at select sites, blood samples for the determination of 
plasma tolperisone concentrations will be drawn on Day 4 (Visit 2) after completion of all study 
assessments. The results from the analyses will be used for determination of population PK of 
tolperisone.  
Plasma samples will be analyzed for tolperisone using a validated liquid chromatography with 
tandem mass spectrometric detection (LC/MS/MS) method (limit of quantification [LOQ]: 
1 ng/mL).  
Results will not be included in the Clinical Study Report. 


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12.12.1. 
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 the central laboratory (ACM). 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 laboratory. Please refer to the ACM Laboratory Manual for 
detailed instructions. 
12.13. 
DNA Genotype  
A blood sample will be collected at baseline for DNA genotype screening for CYP450 2D6 
polymorphism. No other DNA testing will be performed.  Samples will be shipped to the 
genotyping laboratory (Machaon) and stored until ready for use by the Sponsor. Samples will be 
labeled with a unique sample identification label and will not include any protected subject 
health information. Any results from future testing will not be provided to the site or subjects. 
Samples will be stored in a secure, limited access facility indefinitely, or disposed. Samples will 
be inventoried and traceability will be maintained as to where samples are stored and how 
samples are used (assay validation, or research and development).  Please refer to the Machaon 
Laboratory Manual for detailed instructions. 
12.14. 
Blood Collection Volume for the Study 
Up to 48 mL of blood will be collected for screening and EOT/ET clinical laboratory 
evaluations. In addition, a blood sample (approximately 5 mL) will be collected at baseline for 
DNA genotype screening for CYP450 2D6 polymorphism. In a subset of subjects (N=80), 
approximately 5 mL (1 x 5 mL samples) will be collected for PK analysis.  
12.15. 
Medical History 
A medical history will be performed at Screening/Baseline (Day 1). Each subject’s history of 
alcohol and drug use will be evaluated. Continued eligibility and adherence to protocol 
restrictions will be confirmed throughout the study.  
12.16. 
Physical and Neurological Examination 
A physical and neurological examination will be performed at Screening/Baseline (Day 1), on 
Day 4, and on Day 14. Only a physical examination will be performed on Day 28 (Visit 4). A 
physical examination will be performed at Screening/Baseline (Day 1). All other physical 
examinations may be abbreviated (i.e. disease-specific and symptom directed).  
12.17. 
Pregnancy Test 
A urine pregnancy test will be performed at Screening/Baseline for all females of childbearing 
potential. A urine pregnancy test will also be collected at Days 14 (Visit 3) and 28 (Visit 4) 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.  


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13. 
STUDY DRUG 
The Sponsor will supply tolperisone 50, 100, 150, and 200 mg tablets and matching placebo in a 
blinded fashion. Each subject will be provided with one bottle of study drug containing 42 tablets 
for 14 days of TID dosing. The study drug will be self-administered (TID) by the subjects. Each 
subject will also be provided with one bottle of rescue medication (acetaminophen 500 mg) 
containing 50 caplets (as is standard commercial packaging). 
Study drug and rescue medication should be stored at controlled room temperature (15-30 °C 
[59-86 °F]) and locked in a secure cabinet or room.  
13.1. 
Study Drug Administration 
Tolperisone 50, 100, 150, and 200 mg, or matching placebo should be taken by the subjects TID, 
at 6-8 am, 12-2 pm, and 6-8 pm on Days 2 to 14; the first dose of study drug will be administered 
by the subject on Day 1.  
All study medications will be administered orally with approximately 4-6 ounces of water. The 
subjects will be instructed to swallow the study tablet whole, without chewing the tablet. The 
subjects may take the study drug with or without food.  
Subjects will be prompted via reminders on their smartphone/trial application to take their study 
drug at least 1 hour before and within 2 hours of the morning and evening assessments. 
• Subjects in Group A (n=80) will be randomized to receive (1) 50 mg tolperisone tablet, 
TID for 14 days, for a total daily dose of 150 mg. 
• Subjects in Group B (n=80) will be randomized to receive (1) 100 mg tolperisone tablet 
administered TID for 14 days, for a total daily dose of 300 mg. 
• Subjects in Group C (n=80) will be randomized to receive (1) 150 mg tolperisone tablet 
administered TID for 14 days, for a total daily dose of 450 mg. 
• Subjects in Group D (n=80) will be randomized to receive (1) 200 mg tolperisone tablet 
administered TID for 14 days, for a total daily dose of 600 mg. 
• Subjects in Group E (n=80) will be randomized to receive (1) placebo tablet administered 
TID for 14 days.  
13.2. 
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.  


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14. 
SUBJECT RESTRICTIONS 
Subjects are to abstain from using psychoactive prescription or non-prescription medications, 
psychoactive nutritional supplements or herbal preparations during their participation in the 
study.  
Subjects are to abstain from using any 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.  
Other medications that the subject routinely takes will be discussed and reviewed by the PI. All 
concomitant medication taken during the trial should be recorded with indication, daily dose, and 
start and stop dates of administration. 
Subjects will receive study-provided rescue medication of acetaminophen tablets (500 mg) that 
can be taken up to 3 times per day as rescue medications if their pain is severe. All rescue 
medication should be entered via the smartphone/use of trial application daily through Day 14 
(Visit 3). Rescue medication is not to be taken on Days 4 (Visit 2) or 14 (Visit 3).  
14.1. 
Fluid, Food, and Lifestyle Restrictions 
Subjects are not allowed to consume alcoholic beverages prior to their study visit on Days 1, 4, 
and 14. At all other times, alcohol consumption is limited to no more than 2 alcoholic drinks or 
equivalent (beer [24 ounces or 710 mLs], wine [12 ounces or 355 mLs], or distilled spirits [3 
ounces or 89 mLs]) per day. 
Caffeinated beverages will be permitted to no more than 4 units per day amounts (1 unit = 
120 mg caffeine or about one eight-ounce cup of coffee). 
Subjects are to refrain from vigorous physical activity, heat and ice packs and 
non-pharmacological therapies (e.g. acupuncture, chiropractic adjustment, massage, TENS, 
physiotherapy, etc.) during Days 1 to 14. 
15. 
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. 
15.1. 
Premature Termination of Study/Closure of Study Sites 
The study may be terminated prematurely if 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 IRB. 


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16. 
EVALUATION AND REPORTING OF ADVERSE EVENTS  
16.1. 
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 medically qualified designate considers to be 
clinically important. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
require 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 condition(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. 
An 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). 


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16.1.1. 
Severity Assessment  
All AEs will be graded as mild, moderate, or severe according to the following definitions: 
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. 
16.1.2. 
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. 
16.2. 
Routine Reporting  
For the purposes of this study, the period of observation of AEs extends from the time of first 
dose (Day 1) until the final clinic visit (i.e., Day 28 follow-up visit [Visit 4] or, if applicable, 
Early Termination). 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 eCRF. 
Any AE that remains unresolved as of the last visit, the Investigator will attempt to resolve the 
event or determine the status of the event.  
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 clinic site. Open-ended questions will be asked. 
Classification will be performed by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 21.0 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 eCRF. 
However, medically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the eCRF. 
Pregnancy in a female subject on the study shall be reported to the Sponsor’s designee within 24 
hours of the knowledge of its occurrence by the Principal Investigator or designee (for 
pregnancies occurring during the course 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’s designee. 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 pregnancy will 
be reported on a Pregnancy Report Form. 
16.3. 
Serious Adverse Event Reporting  
The sites will notify the sponsor and sponsor’s designee 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 information is available. 
The SAE notification should be reported by completing the SAE report form in the EDC. 
 An SAE will be considered “unexpected” if the AE is not listed in the Investigator’s Brochure or 
is not listed at the specificity or severity that has been observed; or, if an Investigator’s 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. 
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 or as required per IRB once the Investigator or 
staff becomes 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. 


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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.  
17. 
STATISTICAL CONSIDERATIONS 
17.1. 
General Considerations 
This section describes the general approaches planned to analyze the data from this study.  
All efficacy and safety data will be displayed in subject data listings. Unless otherwise specified, 
Baseline is defined as the last observed measurement, whether scheduled or unscheduled, prior 
to study drug administration. All safety and efficacy endpoints will be summarized by dose level. 
In general, categorical variables will be summarized by the frequency counts and percentages. 
Continuous variables will be summarized by the number of non-missing observations (n), mean, 
standard deviation (SD), median, minimum, and maximum values.  
Unless otherwise specified, all statistical hypothesis testing will be two-sided using α = 0.05. 
Additional details of the planned analyses outlined here will be further described in the Statistical 
Analysis Plan.  
17.2. 
Determination of Sample Size 
The sample size for this study was determined from results of two previous studies. The first was 
a study in subjects with acute upper back, neck, or shoulder spasm and pain, which showed a 
difference of 0.4 in the average of Day 1 through Day 7 between the placebo and active groups, 
and SDs between 1.76 and 1.93 (across placebo and active groups respectively) (Collaku, 2017). 
A sample size of 400 subjects (80 per group) would provide at least 80% power to detect a 
difference of 0.9 between the placebo and treatment groups in the NRS scale, assuming a 
two-sample t-test at the 5% level of significance and a pooled SD of 2.0. This sample size 
assumes an effect size of 0.45 (0.9/2.0 = 0.45), using the formula Effect Size = Mean/SD), which 
is larger than that seen in the reference study but consistent with that seen in a second study.  
A second previous study in subjects with acute musculoskeletal spasm associated with back pain 
showed effect sizes ranging from 0.57 to 0.62 for lumbar cinelgasia, based on a treatment 
difference of 9.6 at Day 3, with SDs of 15.5 (treated group) and 16.7 (placebo group) 
(Chandanwale, 2011). This study demonstrated effect sizes ranging from 1.1 to 1.6, based on a 
difference of 24.2 at Day 14 with SDs of 15.1 (treated group) and 23.0 (placebo group). The 
effect size of the current study is expected to be similar to that in Chandanwale, though sample 
size estimates have been made more conservative to provide sufficient power to detect smaller 
differences. Though the primary comparison of interest in this study is Day 14, the study is 
sufficiently powered to detect a treatment difference at Day 4 based on effect sizes ranging from 
0.35 to 0.45. 
The power for this range of effect sizes across six different scenarios for a test of linear trend, as 
well as a comparison between the high dose and placebo only, is provided below, assuming n=80 
in each group. Assuming an effect size of 0.4 (averaging the lowest and highest effects sizes) 


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yields power estimates that are greater than 80% for each scenario tested, except when all 
treatment groups have identical differences from placebo. 
Sample size considerations are provided in Table 1. 
Table 1 
Sample Size Considerations 
 
Hypothesized Difference from Placebo 
 
Effect Size 
(High Dose vs. 
Placebo) 
Dose  
Group 1 
Dose 
Group 2 
Dose 
Group 3 
Dose  
Group 4 
   Power: 
Linear 
Contrast 
Power: 
High Dose 
vs. Placebo 
0.35 
0 
0 
0.35 
.35 
84% 
60% 
0 
0 
0.25 
0.35 
76% 
60% 
0 
0.08 
0.25 
0.35 
76% 
60% 
0 
0.12 
0.24 
0.35 
76% 
60% 
0.08 
0.16 
0.24 
0.35 
68% 
60% 
0.35 
0.35 
0.35 
0.35 
51% 
60% 
 
 
0.4 
0 
0 
0.4 
0.4 
92% 
71% 
0 
0 
0.2 
0.4 
81% 
71% 
0 
0.1 
0.3 
0.4 
87% 
71% 
0 
0.13 
0.26 
0.4 
85% 
71% 
0.05 
0.1 
0.26 
0.4 
81% 
71% 
0.1 
0.2 
0.3 
0.4 
81% 
71% 
0.4 
0.4 
0.4 
0.4 
62% 
71% 
 
 
0.45 
0 
0 
0.45 
0.45 
97% 
81% 
0 
0 
0.23 
0.45 
89% 
81% 
0 
0.1 
0.3 
0.45 
92% 
81% 
0 
0.14 
0.28 
0.45 
91% 
81% 
0.05 
0.1 
0.28 
0.45 
89% 
81% 
0.11 
0.22 
0.33 
0.45 
88% 
81% 
0.45 
0.45 
0.45 
0.45 
72% 
81% 
 
17.3. 
Analysis Populations 
The analysis populations will be defined as follows: 
• Intent-to-Treat (ITT) Population: All randomized subjects who receive any amount of 
study drug. This population will be used as the primary analysis population for all 
efficacy endpoints. Subjects will be included in this population based on their 
randomized treatment assignment.  
• Safety Population: All subjects who receive any amount of study drug. This 
population will be used for all summaries of safety data. Subjects will be included in 
this population based on the actual treatment received.   
• Per-Protocol (PP) Population: All randomized subjects who complete the study with 
no significant protocol violations that would affect the efficacy analyses. The 


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PP Population will be determined prior to database lock and will be used for 
sensitivity analyses on the primary and select secondary endpoints. 
17.4. 
Statistical Analysis Methods 
17.4.1. 
Disposition and Demographics 
The number and percentage of subjects in each analysis population will be summarized. Subject 
disposition, including the number of subjects randomized, dosed, completing the Day 14 visit, 
and not completing the Day 14 visit by reason for withdrawal will be summarized for the 
ITT Population. Subject demographics and baseline characteristics will also be summarized for 
the ITT Population and will include age, sex, race, ethnicity, height, and weight. 
17.4.2. 
Efficacy Analysis 
17.4.2.1. Primary Efficacy Analysis  
The primary efficacy endpoint is subject-rated pain “right now” due to acute back spasm using 
an NRS (0-10 scale, from no pain to worst possible pain) for the clinic visit on Day 14. This 
analysis will be performed using a linear test of trend across doses, using a mixed effect model 
for repeated measures. The model will include treatment and time as fixed effects, the treatment 
by time interaction, and the baseline NRS rating as a covariate. Differences in linear trend for 
each dose level versus placebo will be presented with 95% confidence intervals and associated 
p-values. 
17.4.2.2. Secondary Efficacy Analyses 
The analysis performed for the primary endpoint will be repeated for the NRS at Day 4. 
In addition to the primary efficacy analysis, subjects will also use the NRS scale to record pain 
intensity due to back spasm each day on an outpatient basis. Ratings will be averaged for both 
morning and evening recordings on Days 1 through Day 14 and summarized by dose level and 
day using descriptive statistics. Mean NRS pain intensity scores will also be plotted in a line 
graph over time, with associated standard errors (SEs) for Days 1 through 14. The analysis will 
be repeated using the evening values only for NRS scores on rest and also on movement. The 
comparison of each group to placebo will be conducted using a mixed effects model as described 
for the primary analysis. 
The SRMH and the Functionality Assessment: FFD will be analyzed using the same methods 
described for the primary endpoint. 
Global symptom assessments (CGI and PGI) will be summarized by the percentage of subjects 
reporting each individual response. The proportion of subjects in each category will be recorded 
at each day. The comparison of each group to placebo will be conducted using a Wilcoxon Rank 
Sum test.  
Quality of sleep will be analyzed using the same methods described for the global symptom 
assessments. 
Median time (in hours) to relief of pain on Days 1 and 14 compared to baseline will be plotted 
using Kaplan-Meier (K-M) curves. Estimates of the median times will be presented along with 


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their associated 95% confidence interval (CI) in a corresponding table. Treatment group 
comparisons will be summarized with hazard ratios and their associated 95% CI from a Cox 
Proportional Hazards regression model with treatment as the main effect and p-values from the 
generalized Wilcoxon test. 
Use of rescue medications will be summarized using frequency counts and percentages by 
generic drug name. Average daily use and total use will be tabulated using descriptive statistics. 
The Shapiro-Wilk test will be used to examine the assumption of normality. If this test is 
statistically significant (i.e., p ≤ 0.05) then the assumption of normality is violated and the total 
rescue medication consumption will be analyzed using a Wilcoxon Rank Sum test. Results will 
be expressed as median (range) and p-values. However, if the assumption of normality holds 
(i.e., Shapiro-Wilk p-value > 0.05), then the total rescue medication consumption will be 
analyzed using an analysis of variance (ANOVA) model with randomized treatment as the main 
effect. Results will be expressed as means, SDs, and least squares mean difference (LSMD) and 
SEs with associated 95% CI, and p-values. 
All other secondary endpoints will be summarized by dose using descriptive statistics. In 
addition, the comparison of each group to placebo will be conducted using an ANCOVA model, 
adjusting for baseline.  
17.4.2.3. Handling of Dropouts or Missing Data 
Efficacy analyses on the ITT Population will use the last observation carried forward (LOCF) 
method for handling missing data. Only post-baseline values will be carried forward. Efficacy 
analyses on the ITT Population will also be performed using observed data only. All other 
analyses will be based on observed data only. 
17.4.3. 
Safety Analysis 
Safety analysis will be based on all subjects randomized who receive at least one dose of the 
study drug. The safety analysis will evaluate adverse events and additional safety parameters.  
Additional safety parameters will be assessed from summaries of physical examinations, 12-lead 
ECGs and vital signs.  
17.4.3.1. Adverse Events 
Adverse events will be summarized by dose level. All adverse events will be coded from the 
verbatim text to the lower level term and mapped to preferred term and primary system organ 
class using the latest version of MedDRA. The number and percentage of subjects experiencing 
at least one AE will be summarized by body system, preferred term, and dose level. If 
appropriate, AEs will also be summarized by severity and relationship to study drug. Serious 
AEs, if any, will be tabulated. Summaries that are displayed by system organ class and preferred 
terms will be ordered by descending incidence of system organ class and preferred term within 
each system organ class. Summaries displayed by preferred term only will be ordered by 
descending incidence of preferred term.  
Summaries of the following types will be presented:  
• Overall summary of number of unique TEAEs and treatment-emergent SAEs and 
subject incidence of TEAEs meeting various criteria;  


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• Subject incidence of TEAEs by MedDRA system organ class and preferred term;  
• Subject incidence of TEAEs by severity, MedDRA system organ class, and preferred 
term; 
• Subject incidence of TEAEs by relationship to study drug, MedDRA system organ 
class, and preferred term;  
• Subject incidence of SAEs by MedDRA system organ class and preferred term. 
Adverse events will also be presented in subject listings. The duration of AEs will be determined 
and included in listings, along with the action taken and outcome. 
17.4.3.2. Extent of Exposure to Study Drug 
The total amount of study drug used by each subject as well as the mean daily amount of study 
drug used by each subject will be calculated. Total amount and mean daily amount of study drug 
will be summarized by dose level using descriptive statistics. 
17.4.3.3. Clinical Laboratory 
Clinical laboratory results and changes from baseline will be summarized by dose using 
descriptive statistics for all regularly scheduled visits. For each laboratory test, individual subject 
values will be listed and values outside of the standard reference range will be flagged. A 
separate listing will be provided to include all clinical laboratory values outside normal range 
(including Screening/Baseline Visit 1 and Day 14/ EOT examination) and will also include 
relevant demographic information. 
17.4.3.4. Vital Signs 
Vital sign (blood pressure, heart rate, respiratory rate, and body temperature) measurements and 
changes from baseline will be summarized by dose using descriptive statistics for regularly 
scheduled visits. Measurements will also be presented in a subject data listing. 
17.4.3.5. Twelve-lead Electrocardiogram (ECG) 
Individual subject results will be summarized categorically as normal, clinically significant 
abnormal, and not clinically significant abnormal by dose and presented in the subject data 
listings. 
17.4.3.6. Physical and Neurological Examination 
Neurological examination results will summarized in frequency tables by dose. Physical and 
neurological examination results will be presented in subject data listings.    
17.4.4. 
DNA Genotyping 
Results will be examined and summarized for CYP450 2D6 polymorphism, dose-response, and 
AE profile.  
17.4.5. 
Pharmacokinetic Analysis 
Details of the PK and associated statistical analyses will be included in a separate population PK 
Statistical Analysis Plan. 


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18. 
BIOLOGICAL SPECIMENS 
Whole blood samples and urine samples will be collected as outlined in the Schedule of 
Procedures (Table 2) for clinical chemistry, hematology, urinalysis, and optional PK and DNA 
genotyping.   
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.  
19. 
CLINICAL AND LABORATORY DATA COLLECTION 
19.1. 
Electronic Case Report Forms (eCRF) 
An eCRF 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 an eCRF should be completed. If information is 
not available, it should be documented as such.  
The completed eCRFs 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. 
19.2. 
Electronic Patient Reported Outcomes (ePRO) 
The ePROs will be collected in an electronic capture device (tablet and smartphone/use of trial 
application) that will be used at the clinic and by the subject at home/away from clinic to record 
pain assessments and other secondary endpoint assessments. A study-provisioned tablet will be 
used to document results at the clinic visits and a study-provisioned smart phone or study 
application on the subject’s own smartphone will be used to document results at the subject’s 
home/away from clinic over 14 days of study drug treatment. 
19.3. 
Laboratory Results 
Laboratory tests (clinical chemistry, hematology and urinalysis) will be analyzed by a certified 
laboratory (ACM) and reported to the clinic 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 dated and kept in the study subject file at the 
site for the Sponsor and will represent the source data. 


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20. 
STUDY DOCUMENTATION  
20.1. 
Source Documents 
Source documents may include, but are not limited to, laboratory reports, ECG tracings, 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 eCRFs 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. 
20.2. 
Access to Records 
As required by the International Council for Harmonisation-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 eCRFs 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. 
20.3. 
Retention of Records 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the Investigational Product. However, 
these documents should be retained for a longer period if required by the applicable legal 
requirements. 
21. 
INSTITUTIONAL REVIEW BOARD (IRB) 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to the Sponsor before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit patients for the study. The protocol must be re-approved by the IRB upon receipt of 
amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. The Sponsor will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
according to local regulations and guidelines. 


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22. 
ETHICAL CONDUCT OF THE STUDY 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and the Neurana Pharmaceuticals, Inc. policy on bioethics. 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Neurana Pharmaceuticals, Inc., its 
authorized representative, and Investigator abide by GCP, as described in ICH Guideline E6 and 
in accordance with the general ethical principles outlined in the Declaration of Helsinki. 
23. 
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 study. 
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.  In the event of a revised informed consent, all ongoing subjects and 
newly enrolled subjects should be administered and sign the most current IRB-approved ICF. 
24. 
CONFIDENTIALITY 
24.1. 
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 Food and Drug Administration (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.  
24.2. 
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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25. 
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 study-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 eCRFs. 
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. 
26. 
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 GCP. 


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27. 
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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28. 
REFERENCES 
Chandanwale AS, Chopra A, Goregaonkar A, et al. Evaluation of eperisone hydrochloride in 
the treatment of acute musculoskeletal spasm associated with low back pain: A randomized, 
double-blind, placebo-controlled trial. Journal of Postgraduate Medicine, 2011; 
57 (4):278-285. 
Collaku A, Yue Y, Reed K. Efficacy and safety of guaifenesin for upper back, neck, and 
shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, 
parallel-group study. Journal of Pain Research, 2017; 10:669-678. 
Dulin J, Kovacs L, Ramm S, et al. Evaluation of sedative effects of single and repeated doses 
of 50 mg and 150 mg Tolperisone Hydrochloride. Results of a prospective, randomized, 
double-blind, placebo-controlled trial. Pharmacopsychiat, 1998; 31:137-142. 
Kohnen R, Krüger H P, Dulin J. The human-experimental investigation of sedative effects 
from drugs in combination with alcohol. Psycho, 1995; 21:768-775. 
 


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29. 
SCHEDULE OF PROCEDURES 
Table 2 
Schedule of Procedures 
 
Visit 1  
Screening  
/Baseline 
Clinic Visit 
 
Visit 2 
Clinic 
Visit 
 
 
Visit 3 
EOT/Early 
Termination 
Clinic Visit 
Visit 4 
2-Week  
Follow-up 
Clinic Visit  
Day 1 (and 
if needed 
up to Day   
-3 a)  
Outpatient  
Days 2, 3 
Day 4 
±1 day  
Outpatient 
Days 5 - 13 
Day 14  
+1 day  
Day 28  
+3 days  
Informed consent 
X a 
 
 
 
 
 
Medical history and 
demographics b 
X a 
 
 
 
 
 
Physical and neurological 
examination c 
X a 
 
X 
 
X 
X  
Urine pregnancy test 
X a 
 
 
 
X 
X 
Urine drug screening and alcohol 
breathalyzer  
Xa 
 
X 
 
X 
 
Laboratory evaluations (serum 
chemistry, hematology, 
urinalysis) d 
X a 
 
 
 
X 
 
DNA genotyping e 
X  
 
 
 
 
 
Pharmacokinetics (optional) f  
 
 
X 
 
 
 
Inclusion/exclusion review 
X a 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Study drug and rescue 
medication dispensing  
X 
 
 
 
 
 
Subject smartphone/application 
deployment 
X 
 
 
 
 
 
Study drug dosingg 
X 
X 
X 
X 
X 
 
Study drug and rescue 
medication collection 
 
 
 
 
X 
 
Subject smartphone returned, if 
applicable 
 
 
 
 
X 
 
NRS, subject rating of pain “right 
now” h 
X 
 
X 
 
X 
 
Subject-rating of medication 
[study drug] helpfulness 
(SRMH)i 
 
 
X 
 
X 
 
NRS, subject rating of average 
pain over time j 
X 
X 
X 
X 
X 
 
NRS, subject rating of average 
pain on rest or movement k 
X 
X 
X 
X 
X 
 
Clinician’s Global Impression of 
Severity of pain (CGI-S)  
X 
 
 
 
 
 
Clinician’s Global Impression of 
Change of pain (CGI-C)  
 
 
X 
 
X 
 
Patient’s Global Impression of 
Severity of pain (PGI-S)  
X 
 
 
 
 
 


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Visit 1  
Screening  
/Baseline 
Clinic Visit 
 
Visit 2 
Clinic 
Visit 
 
 
Visit 3 
EOT/Early 
Termination 
Clinic Visit 
Visit 4 
2-Week  
Follow-up 
Clinic Visit  
Day 1 (and 
if needed 
up to Day   
-3 a)  
Outpatient  
Days 2, 3 
Day 4 
±1 day  
Outpatient 
Days 5 - 13 
Day 14  
+1 day  
Day 28  
+3 days  
Patient’s Global Impression of 
Change of pain (PGI-C)  
 
 
X 
 
X 
 
Visual Analogue Scale (VAS) of 
sleepiness 
 
 
X 
 
 
 
Functionality assessment: 
• 
Fingers to floor distance 
(FFD) l 
X 
 
X 
 
X 
 
Disability assessment: l 
• 
Oswestry Disability 
Index (ODI)m 
X 
 
X 
 
X 
 
Use of rescue medication  n 
X 
X 
X 
X 
X 
 
Daily activities (sedentary, 
walking activities, etc.)  
X 
X 
X 
X 
X 
 
Quality of sleep o 
X 
X 
X 
X 
X 
 
Vital sign measurements  p 
X a 
 
X 
 
X 
X 
Standard 12-lead 
electrocardiogram 
X a 
 
 
 
X 
 
Adverse events 
X 
 
X 
 
X 
X 
Concomitant Medications 
X a 
 
X 
 
X 
X 
Drug Accountability 
 
 
X 
 
X 
 
Note:   All darker shaded rows are to be completed on the subject’s study-provisioned smartphone or on their own phone 
using the trial application.   
All lighter shaded rows are to be completed at the clinic site and on the study-provisioned tablet by the Investigator 
Rater/Evaluator or subject, as applicable for assessments.   
All non-shaded rows are not captured in a study-provisioned site tablet or a subject smartphone/trial application; 
applicable information should be entered into the eCRF. 
EOT = End of Treatment; ePRO = electronic Patient Reported Outcomes; PK = pharmacokinetic 
a 
Screening assessments may be completed within 3 days prior to Day 1 (-3 to 0 days). If screening assessments are 
completed prior to Day 1, inclusion/exclusion criteria to be re-reviewed for qualification of the subject’s enrollment into the 
study prior to dosing on Day 1.  
b 
Including sex, age, race, ethnicity, body weight (kg), height (cm), body mass index (BMI) (kg/m2), and smoking habits. 
c 
Physical and neurological examination will be performed at Screening/Baseline (Day 1), on Day 4, and on Day 14. A 
physical examination only will be performed on Day 28. A complete physical examination will be performed at 
Screening/Baseline (Day 1). All other physical examinations may be disease-specific and symptom directed. 
d 
Laboratory Evaluations include hematology, serum chemistry, and urinalysis on Days 1 and 14. (See ACM lab manual for further 
instructions.) 
e 
 DNA genotyping for CYP450 2D6 polymorphism will be collected at same time of other required blood draw on Day 1. 
(See Machaon lab manual for further instructions.) 
f 
For the select group of sites and subjects who will undergo PK assessments, blood samples will be drawn on Day 4. (See 
ACM lab manual for further instructions.) 


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g 
Dosing will be three times per day, with a single tablet administered at each dose. Subjects should be instructed to dose at 6-
8 am, 12-2 pm, and 6-8 pm for 14 days and will enter their dosing information in the eDiary on the subject’s 
smartphone/trial application. 
h 
Subject rating of pain using Numerical Rating Scale (NRS, a scale of 0 to 10 where 0 = no pain, and 10=worst possible pain) 
for the level of pain that the subject is feeling “right now” due to back spasm (primary efficacy endpoint) administered by 
study-provisioned tablet ePRO at baseline, and on Days 4 and 14 in the clinic. 
i 
Subject rating of medication helpfulness (SRMH): a five point scale from 1=poor to 5=excellent, administered by study-
provisioned tablet ePRO on Days 4 and 14 in the clinic. 
j 
Subject rating of pain using NRS due to back spasm, measured daily in the morning 8 to 10 am and in the evening between 
8 to 10 pm from Days 1 through 14, for intensity of average pain due to spasm over last 12 hours, and subject rating of 
average pain over the past 1 hour, all on the subject’s smartphone/trial application. 
k 
Subject rating of average pain using NRS at rest and upon movement at the end of the day (between 8 to 10 pm) on Days 1 
to 14 on the subject’s smartphone/trial application.  
l 
Functionality assessments to be administered in the clinic on Days 1, 4 and 14. FFD is measured as distance in cm from the 
tips of the fingers to the floor when standing with the spinal cord flexed with complete extension of knee joint. This is not 
captured in an electronic device.  Enter score in eCRF. 
m 
The Oswestry Disability Index (10 sections with one answer each for: pain intensity, personal care, lifting, walking, sitting, 
standing, sleeping, sex life [if applicable], social life, and traveling) will be captured by study-provisioned tablet ePRO on 
Days 1, 4, and 14 in the clinic.  
n 
The use of study-provided rescue medication (acetaminophen 500 mg) taken to control their pain throughout the day will be 
captured in the subject’s smartphone/trial application daily from Day 1 through 14, at the end of the day. Subjects are not to 
take rescue medications on clinic visits on Days 4 and 14. 
o 
The subject’s quality of sleep will be captured on their smartphone/trial application starting at baseline visit in clinic and on 
a daily basis at home/away from clinic between 8 to 10 am for Days 1 to 14. In response to the question of “how did you 
sleep last night”, subject responses will be captured on a 5-point scale (from 1=not at all to 5=slept all night). 
p 
Vital signs include supine and standing blood pressure; sitting heart rate (after approximately 3 minutes at rest); respiratory 
rate; and body temperature on Days 1, 4, 14, and 28 (All Visits). Weight and height will be assessed at Visit 1 only. 

SAP_000.pdf: 
Neurana Pharmaceuticals, Inc. 
Statistical Analysis Plan
Protocol: 201 
 
Version 1.0; 06 AUG 2019
 
Confidential 
 
Page 1 of 34 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Neurana Pharmaceuticals, Inc.  
Protocol: 201 
 
 
 
 
Protocol Title: 
Dose Ranging Study of Tolperisone in Acute Muscle 
Spasm of the Back, “STAR Study” 
Protocol Version and Date: 
Amendment 1, Version 2.0; 02 May 2019  
Sponsor: 
Neurana Pharmaceuticals, Inc.  
3525 Del Mar Heights Rd, #609 
San Diego, CA 92130 
Prepared By: 
Sowmya Chollate  
Precision for Medicine, Oncology and Rare Disease 
6005 Hidden Valley Road, Suite 170 
Carlsbad, CA 92011 
Document Version and Date: 
Version 1.0; 06 August 2019 


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Protocol: 201 
 
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1 STATISTICAL ANALYSIS PLAN APPROVAL 
Sponsor: 
Neurana Pharmaceuticals, Inc.  
Clinical Protocol Number: 201 
Protocol Title: 
Dose Ranging Study of Tolperisone in Acute Muscle 
Spasm of the Back, “STAR Study” 
Document File Name: 
Neurana_201_SAP_v1.0_06AUG2019.pdf 
Document Version and 
Effective Date: 
Version 1.0; 06AUG2019 
Approved By: 
 
 
  
Amy Halseth, PhD 
Vice President, Medical Sciences 
Neurana Pharmaceuticals, Inc. 
 
Date 
 
  
Helen Young, MD 
Medical Consultant, Medical Regulatory & Safety 
Precision for Medicine, Oncology and Rare Disease 
 Date 
 
  
Sowmya Chollate, MS 
Biostatistician II 
Precision for Medicine, Oncology and Rare Disease 
 
Date 
 
  
Ed Lombardi 
Senior Manager, Biostatistics 
Precision for Medicine, Oncology and Rare Disease 
 
Date 
Amy Halseth PhD
Ed
Ed
Ed
Ed
Ed
Ed
Ed
Ed
Ed
Ed Lombardi
He
He
He
Helel n Young MD
So
So
So
So
So
So
So
So
So
So
So
So
Sowm
w
ya Chollate, MS


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Protocol: 201 
 
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2 TABLE OF CONTENTS 
 
1 
Statistical Analysis Plan Approval ............................................................................2 
2 
Table of Contents ........................................................................................................3 
3 
List of Abbreviations ..................................................................................................6 
4 
Introduction.................................................................................................................8 
5 
Study Objectives .........................................................................................................8 
5.1 
Primary Study Objective .......................................................................................8 
5.2 
Secondary Study Objective ...................................................................................8 
6 
Investigational Plan ....................................................................................................8 
6.1 
Overall Study Design .............................................................................................8 
6.2 
Schedule of Assessments ......................................................................................10 
6.3 
Treatment .............................................................................................................12 
6.3.1 
Treatment Administered ...............................................................................12 
6.3.2 
Method of Assigning Subjects to Treatment Groups .................................12 
6.4 
Efficacy and Safety Variables .............................................................................13 
6.4.1 
Efficacy Variable ............................................................................................13 
6.4.2 
Description of Safety Variables ....................................................................14 
6.4.3 
Population Pharmacokinetics (PK) ..............................................................17 
6.5 
Data Quality Assurance .......................................................................................17 
7 
Statistical Methods ....................................................................................................18 
7.1 
General Methodology ..........................................................................................18 
7.1.1 
Reporting Conventions ..................................................................................18 
7.1.2 
Summarization by Visit .................................................................................19 
7.1.3 
Baseline Value ................................................................................................19 
7.1.4 
Data Handling Rules ......................................................................................19 
7.1.5 
Standard Calculations ...................................................................................19 
7.2 
Analysis Populations ............................................................................................20 
7.3 
Study Subjects ......................................................................................................21 
7.3.1 
Disposition of Subjects ...................................................................................21 
7.3.2 
Protocol Deviations ........................................................................................21 
7.3.3 
Enrollment ......................................................................................................21 
7.4 
Efficacy Evaluation ..............................................................................................21 
7.4.1 
Datasets Analyzed ..........................................................................................21 
7.4.2 
Demographic and Other Baseline Characteristics ......................................22 
7.4.3 
Measurements of Treatment Compliance ...................................................22 
7.4.4 
Primary Efficacy Endpoint Analysis Methods ............................................23 
7.4.5 
Secondary Endpoint Analysis Methods .......................................................24 
7.4.6 
Statistical/Analytical Issues ...........................................................................27 
7.4.7 
Plasma Concentrations ..................................................................................28 
7.4.8 
Pharmacokinetic Analysis .............................................................................28 
7.5 
Safety Evaluation .................................................................................................28 
7.5.1 
Extent of Exposure .........................................................................................28 
7.5.2 
Adverse Events ...............................................................................................29 


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7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...............................................................................................30 
7.5.4 
Clinical Laboratory Evaluation ....................................................................30 
7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety ...............................................................................................................31 
7.6 
Determination of Sample Size .............................................................................32 
7.7 
Changes in the Conduct of the Study or Planned Analyses .............................33 
7.7.1 
Changes in Planned Analyses .......................................................................33 
7.7.2 
Other Changes ................................................................................................33 
8 
Reference List ............................................................................................................34 
 
 
 


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TABLE OF TABLES 
Table 1 List of Abbreviations ...........................................................................................6 
Table 2 Schedule of Assessments ....................................................................................10 
Table 3 Clinical Laboratory Assessments .....................................................................16 
Table 4 Expected Number of Doses ................................................................................22 
 
TABLE OF FIGURES 
Figure 1 Study Design ........................................................................................................9 
 
 


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3 LIST OF ABBREVIATIONS  
Table 1 List of Abbreviations  
 
Abbreviation 
Definition  
AE 
adverse event 
ALT 
Alanine Aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BUN 
Blood Urea Nitrogen 
CGI-C 
Clinician’s Global Impression of Change of pain 
CGI-S 
Clinician’s Global Impression of Severity of pain 
CI 
confidence interval 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOT 
End of Treatment 
ET 
Early Termination 
FFD 
Fingers to floor distance 
GGT 
Gamma glutamyltransferase 
ICH 
International Council for Harmonisation 
ITT 
Intent-to-Treat 
IWRS 
interactive web response system 
LOCF 
last observation carried forward 
LSM 
least-square mean 
LSMD 
least-square mean difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
NRS 
Numeric Rating Scale 
ODI 
Oswestry Disability Index 
PGI-C 
Patient’s Global Impression of Change of pain 
PGI-S 
Patient’s Global Impression of Severity of pain 
PP 
Per-Protocol 
PT 
Prothrombin time 
Q1 
25th percentile 
Q3 
75th percentile 
SAE 
serious adverse event 


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Abbreviation 
Definition  
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SI 
Système International 
SRMH 
Subject Rating of Medication Helpfulness 
TEAE 
treatment-emergent adverse event 
TID 
three times a day 
TSH 
Thyroid stimulating hormone 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
VAS 
Visual Analogue Scale 
 


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4 INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and detailed 
descriptions of the methods and presentation of data analyses proposed for Neurana 
Pharmaceuticals, Inc. Protocol 201 (Dose Ranging Study of Tolperisone in Acute Muscle Spasm of 
the Back “STAR Study”). Descriptions of planned analyses are provided in order to avoid post hoc 
decisions that may affect the interpretation of the statistical analysis. The statistical methods 
applied in the design and planned analyses of this study are consistent with the International 
Council for Harmonisation (ICH) guideline Statistical Principles for Clinical Trials (E9) (1998).  
This SAP will be finalized prior to data analysis and before treatment unblinding and database lock 
to provide full details to be presented in the clinical study report (CSR). Any changes between the 
statistical methods provided in the clinical study protocol and this SAP will be explained herein; 
any changes or deviations from this SAP relative to the final analysis will be fully documented in 
the CSR.  
5 STUDY OBJECTIVES 
5.1 
Primary Study Objective 
The primary objective of this study is to assess the efficacy of tolperisone daily doses 150, 300, 
450, and 600 mg for relief of pain due to acute back muscle spasm.  
5.2 
Secondary Study Objective 
The secondary objectives of this study are to: 
x Assess the safety and tolerability of tolperisone in subjects with pain due to acute back 
spasm;  
x Determine the onset of action of tolperisone in treatment of pain due to acute back spasm;  
x Determine the duration of pain relief of tolperisone in treatment of pain due to acute back 
spasm; and 
x Determine the need for rescue medication when treated with various doses of tolperisone 
for pain due to acute back spasm. 
6 INVESTIGATIONAL PLAN 
6.1 
Overall Study Design 
This is a double-blind, randomized, placebo-controlled, parallel group study of the efficacy and 
safety of tolperisone or placebo administered as multiple doses three times a day (TID) in 
approximately 400 male and female subjects experiencing back pain due to or associated with 
muscle spasm. This study will be conducted at approximately 45 clinical sites in the USA.  
The tolperisone groups consist of dose levels of 150, 300, 450, and 600 mg administered TID in 
doses of 50, 100, 150, or 200 mg for 14 days, with a visit at 28 days as follow-up. Subjects 


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randomized to the placebo group will receive matching placebo tablets TID for 14 days with a 
follow-up visit at Day 28. Subject participation will be approximately 4 weeks.  
Subjects will be screened for eligibility for participation in the study at the Screening/Baseline 
Visit 1 (Day 1) after reviewing and signing the informed consent form. Subjects meeting all 
inclusion/exclusion criteria will then be randomized into the study (Day 1) and begin dosing this 
same day.  
After completing all screening and baseline assessments by Day 1, subjects will receive all study 
drug and rescue medication (acetaminophen 500 mg) and will be instructed to begin taking their 
study drug that same day. Depending on the time of their clinic visit, they should be instructed to 
begin dosing with either the midday dose (12-2 pm) or the evening dose (6-8 pm). Subjects will be 
instructed to continue taking study drug TID through Day 14 and complete dosing dairy and daily 
electronic Patient-Reported Outcomes (ePRO) assessments. Subjects will return to the clinic to 
complete the procedures listed in the Schedule of Procedures on Day 4 (±1 day; Visit 2) and Day 
14 (+1 day, End of Treatment [EOT] visit, Visit 3). Subjects must also return to the clinic for a 
follow-up visit on Day 28 (+3 days, 2-week follow-up visit, Visit 4).  
Figure 1 Study Design 
 
 
 
 


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6.2 
Schedule of Assessments 
Table 2 Schedule of Assessments 
 
 
Visit 1 
Screening 
/Baseline 
Clinic Visit 
Visit 2 
Clinic 
Visit 
Visit 3 
EOT/Early 
Termination 
Clinic Visit 
Visit 4 
2-Week 
Follow-up 
Clinic Visit 
Day 1 (and 
if needed 
up to Day 
-3 a) 
Outpatient 
Days 2, 3 
Day 4 
±1 day 
Outpatient 
Days 5 - 13 
Day 14 
+1 day 
Day 28 
+3 days 
Informed consent 
X a 
Medical history and 
demographics b 
X a 
Physical and neurological 
examination c 
X a 
X 
X 
X 
Urine pregnancy test 
X a 
X 
X 
Urine drug screening and alcohol 
breathalyzer 
Xa 
X 
X 
Laboratory evaluations (serum 
chemistry, hematology, 
urinalysis) d 
 
X a 
X 
DNA genotyping e 
X 
Pharmacokinetics (optional) f 
 
X 
Inclusion/exclusion review 
X a 
Randomization 
X 
Study drug and rescue 
medication dispensing 
X 
Subject smartphone/application 
deployment 
X 
Study drug dosingg 
X 
X 
X 
X 
X 
Study drug and rescue 
medication collection 
 
X 
Subject smartphone returned, if 
applicable 
 
X 
NRS, subject rating of pain “right 
now” h 
X 
X 
X 
Subject-rating of medication 
[study drug] helpfulness 
(SRMH)i 
 
X 
X 
NRS, subject rating of average 
pain over time j 
X 
X 
X 
X 
X 
NRS, subject rating of average 
pain on rest or movement k 
X 
X 
X 
X 
X 
Clinician’s Global Impression of 
Severity of pain (CGI-S) 
X 
Clinician’s Global Impression of 
Change of pain (CGI-C) 
 
X 
X 


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Visit 1 
Screening 
/Baseline 
Clinic Visit 
Visit 2 
Clinic 
Visit 
Visit 3 
EOT/Early 
Termination 
Clinic Visit 
Visit 4 
2-Week 
Follow-up 
Clinic Visit 
Day 1 (and 
if needed 
up to Day 
-3 a) 
Outpatient 
Days 2, 3 
Day 4 
±1 day 
Outpatient 
Days 5 - 13 
Day 14 
+1 day 
Day 28 
+3 days 
Patient’s Global Impression of 
Severity of pain (PGI-S) 
X 
Patient’s Global Impression of 
Change of pain (PGI-C) 
 
X 
X 
Visual Analogue Scale (VAS) of 
sleepiness 
 
X 
Functionality assessment: 
x 
Fingers to floor distance 
(FFD) l 
 
X 
X 
X 
Disability assessment: l 
x 
Oswestry Disability 
Index (ODI)m 
 
X 
X 
X 
Use of rescue medication n 
X 
X 
X 
X 
X 
Daily activities (sedentary, 
walking activities, etc.) 
X 
X 
X 
X 
X 
Quality of sleep o 
X 
X 
X 
X 
X 
Vital sign measurements p 
X a 
X 
X 
X 
Standard 12-lead 
electrocardiogram 
X a 
X 
Adverse events 
X 
X 
X 
X 
Concomitant Medications 
X a 
X 
X 
X 
Drug Accountability 
 
X 
X 
Note:    All darker shaded rows are to be completed on the subject’s study-provisioned smartphone or on their own phone 
using the trial application. 
All lighter shaded rows are to be completed at the clinic site and on the study-provisioned tablet by the Investigator 
Rater/Evaluator or subject, as applicable for assessments. 
All non-shaded rows are not captured in a study-provisioned site tablet or a subject smartphone/trial application; 
applicable information should be entered into the eCRF. 
EOT = End of Treatment; ePRO = electronic Patient Reported Outcomes; PK = pharmacokinetic 
a 
Screening assessments may be completed within 3 days prior to Day 1 (-3 to 0 days). If screening assessments are  
completed prior to Day 1, inclusion/exclusion criteria to be re-reviewed for qualification of the subject’s enrollment into the 
study prior to dosing on Day 1. 
b 
Including sex, age, race, ethnicity, body weight (kg), height (cm), body mass index (BMI) (kg/m2), and smoking habits. 
c 
Physical and neurological examination will be performed at Screening/Baseline (Day 1), on Day 4, and on Day 14. A 
physical examination only will be performed on Day 28. A complete physical examination will be performed at 
Screening/Baseline (Day 1). All other physical examinations may be disease-specific and symptom directed. 
d 
Laboratory Evaluations include hematology, serum chemistry, and urinalysis on Days 1 and 14. (See ACM lab manual for further 
instructions.) 
e 
 DNA genotyping for CYP450 2D6 polymorphism will be collected at same time of other required blood draw on Day 1. 
(See Machaon lab manual for further instructions.) 
f 
For the select group of sites and subjects who will undergo PK assessments, blood samples will be drawn on Day 4. (See 
ACM lab manual for further instructions.) 


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g 
Dosing will be three times per day, with a single tablet administered at each dose. Subjects should be instructed to dose at 6-8 
am, 12-2 pm, and 6-8 pm for 14 days and will enter their dosing information in the eDiary on the subject’s smartphone/trial 
application. 
h 
Subject rating of pain using Numerical Rating Scale (NRS, a scale of 0 to 10 where 0 = no pain, and 10=worst possible pain) 
for the level of pain that the subject is feeling “right now” due to back spasm (primary efficacy endpoint) administered by 
study-provisioned tablet ePRO at baseline, and on Days 4 and 14 in the clinic. 
i 
Subject rating of medication helpfulness (SRMH): a five point scale from 1=poor to 5=excellent, administered by study-
provisioned tablet ePRO on Days 4 and 14 in the clinic. 
j 
Subject rating of pain using NRS due to back spasm, measured daily in the morning 8 to 10 am and in the evening between 
8 to 10 pm from Days 1 through 14, for intensity of average pain due to spasm over last 12 hours, and subject rating of 
average pain over the past 1 hour, all on the subject’s smartphone/trial application. 
k 
Subject rating of average pain using NRS at rest and upon movement at the end of the day (between 8 to 10 pm) on Days 1 
to 14 on the subject’s smartphone/trial application. 
l 
Functionality assessments to be administered in the clinic on Days 1, 4 and 14. FFD is measured as distance in cm from the 
tips of the fingers to the floor when standing with the spinal cord flexed with complete extension of knee joint. This is not 
captured in an electronic device.  Enter score in eCRF. 
m 
The Oswestry Disability Index (10 sections with one answer each for: pain intensity, personal care, lifting, walking, sitting, 
standing, sleeping, sex life [if applicable], social life, and traveling) will be captured by study-provisioned tablet ePRO on 
Days 1, 4, and 14 in the clinic. 
n 
The use of study-provided rescue medication (acetaminophen 500 mg) taken to control their pain throughout the day will be 
captured in the subject’s smartphone/trial application daily from Day 1 through 14, at the end of the day. Subjects are not to 
take rescue medications on clinic visits on Days 4 and 14. 
o 
The subject’s quality of sleep will be captured on their smartphone/trial application starting at baseline visit in clinic and on 
a daily basis at home/away from clinic between 8 to 10 am for Days 1 to 14. In response to the question of “how did you 
sleep last night”, subject responses will be captured on a 5-point scale (from 1=not at all to 5=slept all night). 
p 
Vital signs include supine and standing blood pressure; heart rate; respiratory rate; and body temperature on Days 1, 4, 14, 
and 28 (All Visits). Weight and height will be assessed at Visit 1 only. 
6.3 
Treatment 
6.3.1 
Treatment Administered 
Tolperisone 50, 100, 150, and 200 mg tablets and matching placebo will be provided for the study 
by the Sponsor. Dosing will be three times a day (TID), with a single tablet administered at each 
dose for a total daily dose of 150, 300, 450, and 600 mg. Subjects will be instructed to dose at 6-8 
am, 12-2 pm, and 6-8 pm daily for 14 days. Subjects will be prompted via reminders on their 
smartphone/trial application to take their study drug at least 1 hour before and within 2 hours of 
the morning and evening assessments.  
6.3.2 
Method of Assigning Subjects to Treatment Groups 
The study will be double-blinded. No treatment assignment information will be disclosed to any 
staff member (site, sponsor, or contract research organization) working on the trial, with the 
exception of the unblinded statistician and the pharmacovigilance representative in the event of 
emergency unblinding (only to be done when knowledge of treatment assignment is considered 
critical for patient care).  
Subjects will be randomized to treatment group (150mg/day, 300 mg/day, 450 mg/day, 
600mg/day or Placebo) in a 1:1:1:1:1 ratio and stratified by site. Upon confirmation that all study 
eligibility criteria have been met at Baseline (Day 0), unique randomization numbers will be 
assigned to subjects using an interactive web response system (IWRS) and the Investigator will 


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dispense a single bottle of tolperisone/placebo to the eligible patient. The assigned bottle number 
will be captured on the electronic case report form (eCRF).   
6.4 
Efficacy and Safety Variables 
6.4.1 
Efficacy Variable 
6.4.1.1 
Primary Efficacy Variable 
The primary efficacy endpoint is subject-rated pain “right now” due to acute back spasm using a 
Numerical Rating Scale (NRS; a scale of 0-10 where 0 = no pain and 10 = worst possible pain) on 
Day 14.  
6.4.1.2 
Secondary Efficacy Variables 
Secondary efficacy endpoints include assessments administered on a  study-provisioned tablet  at 
the clinical site on Day 1 (baseline), Day 4, and Day 14 or captured by the subject with 
smartphone/trial application daily at home from Day 1 to Day 14 (See Table 2)    
x Subject-rated pain due to acute back spasm “right now” using NRS on Day 4 
x Subject-rated average pain due to acute back spasm over past 12 hours using NRS on Days 
1 to 14, measured in morning and evening.  
x Subject-rated average pain  due to acute back spasm over past 1 hour using NRS on Days 1 
to 14, measured in morning and evening 
x Subject-rated average pain at rest due to acute back spasm using NRS on Days 1 to 14, 
measured in evening  
x Subject-rated average pain on movement due to acute back spasm using NRS on Days 1 to 
14, measured in evening  
x Subject rating of medication helpfulness (SRMH) using a scale of 1-5 on Days 4 and 14, 
where 1=poor, 2=fair, 3=good, 4=very good, and 5=excellent.  
x Time to relief of pain due to acute back spasm (days) from baseline using subject-rated 
NRS of pain over past 12 hours. The first NRS score of 2 or lower will be used to define 
relief.  
x Clinician’s Global Impression of Severity (CGI-S) using 1–5 scale at baseline (Day 1), 
where 1=no pain, 2=mild pain, 3=moderate pain, 4=severe pain, and 5=worst possible 
pain 
x Clinician’s Global Impression of Change (CGI-C) using a scale of 1-7 on Days 4 and 14, 
where 1=Very Much Worse, 2=Much Worse, 3=Minimally Worse, 4=No Change, 
5=Minimally Improved, 6=Much Improved, and 7=Very Much Improved 


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x Patient’s Global Impression of Severity (PGI-S) using  a scale of 1–5 scale at baseline 
(Day 1), where 1=no pain, 2=mild pain, 3=moderate pain, 4=severe pain, and 5=worst 
possible pain 
x Patient’s Global Impression of Change (PGI-C) based on subject’s global assessment using 
a scale of 1-7 on Days 4 and 14, where 1=Very Much Worse, 2=Much Worse, 
3=Minimally Worse, 4=No Change, 5=Minimally Improved, 6=Much Improved, and 
7=Very Much Improved). 
x Fingers to floor distance (FFD) measured at Baseline (Day 1), Day 4, and Day 14 
FFD is an index of mobility of the spinal cord and is measured as distance in cm when 
standing with the spinal cord flexed with complete extension of knee joint, on Days 4 and 
14 compared to baseline (Day 1) (assessments should be conducted at the same time of day 
for all three time points). 
x Oswestry Pain and Disability (ODI) assessment at baseline (Day 1), Day 4, and Day 14 
The ODI questionnaire contains 10 questions with one answer each for pain intensity, 
personal care, lifting, walking, sitting, standing, sleeping, sex life [if applicable], social 
life, and traveling). Scores are assigned for each section from 0 to 5 (5 being the worst 
case).    
ODI scores are derived based on the methods described in Mehra et.al. (2008). The 
method is equivalent to an ODI score calculated as (total score × 2) / (number of sections 
answered / 10), rounded to the nearest integer. The total score is the sum of the individual 
section scores.   
x Use of study-provided rescue medication [acetaminophen tablets (500 mg)] measured daily 
and assessed as number of rescue tablets administered by the subject and recorded via 
smartphone/use of trial application.  
x Quality of sleep as rated by subjects daily from Day 1 to Day 14. The rating scale is 1-5, 
where 1 = not at all to 5 = slept all night. Assessments are collected via smartphone/use of 
trial application.  
x Visual Analogue Scale (VAS) for subject-reported sleepiness as measured in the clinic on 
at Day 4 via tablet ePRO. Scale is from 0 to 10, where 0 = alert, wide awake to 10 = very 
sleepy, difficulty remaining awake.  
6.4.2 
Description of Safety Variables 
Safety variables include:  
x Adverse events and serious adverse events  


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x Clinical evaluations including vital signs (blood pressure, heart rate, respiratory rate, body 
temperature), orthostatic effects on blood pressure, physical examinations, and 12-lead 
electrocardiogram (ECG) 
x Laboratory tests including blood chemistry, hematology, and urinalysis 
6.4.2.1 
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. 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 occurring after the initiation of the study 
drug treatment are referred to as treatment-emergent adverse events (TEAEs).  
See Section 15.1 of the study Protocol for further details regarding the definition of AEs.  
6.4.2.2 
Serious Adverse Events 
An SAE or reaction is any untoward medical occurrence that at any dose:  
x Results in death,  
x Is life-threatening, 
x Requires inpatient hospitalization or prolongation of existing hospitalization, 
x Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
x Is a congenital anomaly or birth defect, 
x 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). 
See Section 15.3 of the study Protocol for further details regarding SAEs and reporting.  
6.4.2.3 
Laboratory Parameters 
A central laboratory will perform all laboratory testing. Table 3 lists all planned clinical 
laboratory tests to be performed.  
 
 


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Table 3 Clinical Laboratory Assessments 
Category 
Test Name 
Hematology 
Hemoglobin 
Hematocrit 
Platelets 
Prothrombin Time (PT)a 
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)a 
Urinalysis 
Bilirubin 
Occult blood 
Glucose 
Ketones 
Leukocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Other 
Urine drug and alcohol breathalyzerb,c 
Urine pregnancyd 
Note: The complete panel of safety labs (other than where footnoted) will be completed on Day 1 
(Screening/Baseline visit) and Day 14. 
a    Screening only. 
b    Day 1 (Screening/Baseline), Day 4, and Day 14 (End of Treatment ). 
c     Includes testing for amphetamines, methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine,      
        opiates – ethanol will be determined by breathalyzer. 
d    Urine pregnancy test at Days 1, 14, and 28 for females of childbearing potential.                 
6.4.2.4 
Other Safety Variables 
6.4.2.4.1 
Vital Signs 
Vital signs will include the measurement of supine and standing blood pressure, orthostatic 
assessments, heart rate, respiratory rate, and body temperature. Vital signs will be measured on 
Day 1 (Screening/Baseline visit) and on Days 4, 14, and 28. Weight and height will be measured 
at Screening/Baseline only. 


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6.4.2.4.2 
12-Lead Electrocardiogram 
Standard 12-lead ECGs will be administered at the clinic on Day 1 (Screening/Baseline visit) and 
on Day 14 (Visit 3). Results are collected as normal or abnormal (not clinically significant or 
clinically significant) only. 
6.4.2.4.3 
Physical and Neurological Examination 
A complete physical examination will be performed at Screening/Baseline (Day 1). Physical 
examinations may be abbreviated (i.e. disease-specific and symptom directed) on Days 4, 14, 28.  
A neurological examination will be performed at Screening/Baseline (Day 1), Day 4 and 14. 
Overall status (improved, stable, or deteriorated) will be collected.  
6.4.2.4.4 
Prior and Concomitant Medications  
Concomitant use of medications, including rescue analgesia other than study-provided 
acetaminophen taken for acute back spasms, used during the study will be recorded as 
concomitant medications on the eCRF (see Section 13 of the study protocol for allowed and 
disallowed medications during the study) and will be analyzed at the time of report following 
dosing of study drug through Visit 4 (Day 28). 
6.4.3 
Population Pharmacokinetics (PK) 
Blood samples for the determination of plasma tolperisone concentrations will be drawn on Day 4 
(Visit 2) after completion of all study assessments for a subset of subjects.  
6.5 
Data Quality Assurance 
Report summaries will be generated using validated Base SAS£ software, version 9.4 or higher, 
on a PC or server-based platform. Additional validated software may be used to generate 
analyses, as needed.  
All SAS programs that create outputs or supporting analysis datasets will be validated by a second 
statistical programmer or biostatistician. At a minimum, validation of programs will consist of a 
review of the program log, review of output or dataset format and structure, and independent 
confirmatory programming to verify output results or dataset content. Additionally, all outputs 
will undergo a review by a senior level team member before finalization. 
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, and 
extreme outliers through defensive programming applications, analysis-based edit checks, and 
other programmatic testing procedures. All findings will be forwarded to the project data manager 
for appropriate action and resolution.  


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7 STATISTICAL METHODS 
7.1 
General Methodology 
Data will be analyzed by Precision for Medicine biostatistics personnel. Statistical analyses will 
be reported with tables, figures, and listings, presented in rich text format, and using 
recommended ICH numbering. Output specifications for all tables, figures, and listings will be in 
conformance with guidelines specified by the ICH in Appendix 7 of the Electronic Common 
Technical Document Specification (Apr 2003).  
7.1.1 
Reporting Conventions 
Tables and figures will be summarized by tolperisone dose group/placebo. Tables summarizing 
demographics, baseline characteristics and all safety endpoints will also include a column for all 
tolperisone treated subjects combined. In general, all data collected and any derived data will be 
presented in subject data listings, for all enrolled subjects. Listings will be ordered by treatment 
group, site, subject number, and assessment or event date. The treatment group presented in 
listings will be based on the planned assignment, unless otherwise noted. 
In general, continuous variables will be summarized to indicate the study population sample size 
(N), number of subjects with available data (n), mean, SD, median, 25th (Q1) and 75th (Q3) 
quartiles, minimum, and maximum values. Categorical variables will be summarized by the 
population size (N), number of subjects with available data (n), number of subjects in each 
category, and the percentage of subjects in each category. Unless otherwise noted, the 
denominator to determine the percentage of subjects in each category will be based on the number 
of subjects with available data. Select ordinal data may be summarized using both descriptive 
statistics and counts and percentages of subjects in each category, as appropriate. 
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of summarization, 
as it is collected in its rawest form (i.e., on the electronic case report form [eCRF] or as provided 
within an external file) and are outlined as follows: 
x The mean and median will be rounded to one more decimal place than the precision of the 
variable of summarization; 
x Measures of variability (e.g., SD, SE) will be rounded to two more decimal places than the 
precision of the variable of summarization; and 
x Minimum and maximum values will be presented using the same precision as the variable 
of summarization. 
Other statistics (e.g., CIs) will be presented using the same general rules outlined above, or 
assessed for the most appropriate presentation based on the underlying data. 
Unless otherwise specified, 95% confidence intervals will be calculated for point estimates and 
statistical significance testing will be two-sided and performed using α=0.05. P-values will be 
reported for all statistical tests, rounded to four decimal places. P-values less than 0.0001 will be 


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displayed as “<0.0001”; p-values greater than 0.9999 will be displayed as “>0.9999”. Tests of 
interaction terms, if applicable, will be two-sided and performed using α=0.10. 
7.1.2 
Summarization by Visit 
Data summarized by study visit will be based on the nominal, scheduled visit from the eCRF or 
tablet. Analysis visits will be labelled as Baseline or Day 1, Day 4, Day 14, and Day 28 in all 
table summaries.  
Data collected for the last subject treatment visit completed will be summarized separately for:  
x The scheduled Day 14 (End of Treatment) visit for those subjects who complete the 
scheduled end of study visit, per protocol. This summary will be labeled as “Day 14” in 
the analysis.  
x The last visit completed on-study, combining data collected for subjects who complete 
the Day 14 (End of Treatment) visit as well as the early termination (ET) visit for those 
subjects who discontinue the study early. This summary will be labeled as “Day 14/ET” 
in the analysis. 
For assessments collected daily on the smartphone/trial application, visits will be summarized 
based on the study day relative to the date of treatment start for all data. However, statistical 
analyses will be conducted using Day 1 through 14 observations only.   
Data collected at unscheduled visits will not be included in by-visit summaries, but will be 
considered when endpoint derivations potentially include multiple visits (e.g., determination of 
baseline value, determination of worst post-baseline value, etc.). All data will be included in 
subject listings.  
7.1.3 
Baseline Value 
 
For analyses listed in this SAP, the baseline value is defined as the last measurement reported 
prior to the first dose of study drug, unless otherwise noted. 
7.1.4 
Data Handling Rules 
Unless otherwise noted, values reported as greater than or less than some quantifiable limit (e.g., 
“< 1.0”) will be summarized with the sign suppressed in summary tables and figures, using the 
numeric value reported. Data will display on subject listings to include the sign.  
If duplicate post-baseline subject reported outcomes are present for a study day and/or time point, 
the earlier of the duplicates recorded will be used for analysis. Duplicate data that is not used in 
table summaries for efficacy endpoints will be flagged with an asterisk in their respective listings. 
7.1.5 
Standard Calculations 
Where appropriate, the calculated study day of each assessment or event will be presented with 
the assessment or event date on subject data listings, where study day will be determined as: 


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x The assessment/event date minus the date of first dose of study drug, if the 
assessment/event date is prior to the date of first dose; and 
x The assessment/event date minus the date of first dose of study drug, plus one, if the 
assessment/event date is on or after the date of first dose. 
Other variables requiring calculations will be derived using the following formulas: 
x Days: A duration between two dates expressed in days will be calculated using the 
following conventions: 
o Later date – earlier date + 1, if the earlier date is on or after the date of first dose of 
study drug; or 
o Later date – earlier date, if the earlier date is prior to the date of first dose of study 
drug. 
o Change from Baseline: Change from baseline will be calculated as the post-baseline 
value minus the baseline value. 
7.2 
Analysis Populations 
The analysis populations are defined as follows:  
x Intent-to-Treat (ITT) Population: All randomized subjects who receive any amount of 
study drug. This population will be used as the primary analysis population for all efficacy 
endpoints. Subjects will be included in this population based on their randomized 
treatment assignment. 
x Safety Population: All subjects who receive any amount of study drug. This population 
will be used for all summaries of safety data. Subjects will be included in this population 
based on the highest dose level received. 
x Per-Protocol (PP) Population: All randomized subjects who complete the study treatment 
period with a minimum of 12 days of treatment and have no significant protocol violations 
that would affect the efficacy analyses. The PP Population will be determined prior to 
database lock and will be used for sensitivity analyses on the primary and select secondary 
endpoints. Subjects with major protocol deviations will be excluded from the efficacy 
analyses. See section 7.3.2 for further details on protocol deviations.  
Data summaries to be presented on both the Safety Population and the ITT Population will only 
be produced on both analysis sets if there is a difference in the population groups.   


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7.3 
Study Subjects 
7.3.1 
Disposition of Subjects 
Subject disposition will be summarized for all randomized subjects by tolperisone dose 
group/placebo and total tolperisone treated subjects combined. Summaries will include the 
number and percentage of subjects in each analysis population, subjects completing a minimum 
of 12 days of treatment, subjects completing the study, and those discontinuing the study early by 
the primary reason for discontinuation. Subject disposition will also be summarized separately for 
each study site. 
A data listing of study disposition will be presented by treatment group, site, and subject. 
7.3.2 
Protocol Deviations 
Major protocol deviations will be summarized by tolperisone dose group/placebo and for total 
tolperisone treated subjects combined for the ITT Population. Major protocol deviations are 
protocol deviations captured on-study that are deemed by the Sponsor to potentially impact the 
efficacy or safety conclusions of the study. Subjects with major protocol deviations will be 
excluded from the PP Population for analysis.  
All major protocol deviations will be determined and appropriately categorized prior to database 
lock and prior to breaking the blind of the treatment group assignments. The number and 
percentage of subjects with any major protocol violations as well as the number and percentage of 
subjects with violations within each category will presented. Anticipated protocol deviation 
categories include inclusion/exclusion criteria, investigation product, prohibited concomitant 
medications, visit schedule, procedures/tests, SAEs not reported/reported late, and other.  
A data listing of patients with all protocol deviations will be presented by treatment group, site, 
subject, and date of deviation. In addition to protocol violations, a data listing of informed consent 
and eligibility criteria will be presented. 
7.3.3 
Enrollment 
 
A data listing of the randomization scheme and treatment codes will be presented.  
 
7.4 
Efficacy Evaluation 
7.4.1 
Datasets Analyzed 
All efficacy summaries will be based on the ITT Population; select efficacy summaries will also 
be produced on the PP Population. A data listing of subjects excluded from the ITT or PP 
Population, to include the reason for exclusion, will be presented. 


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7.4.2 
Demographic and Other Baseline Characteristics 
Demographic variables including age, sex, ethnicity and race will be summarized by tolperisone 
dose group/placebo and for total tolperisone treated subjects combined for the Safety, ITT, and PP 
Populations. Age will be summarized using descriptive statistics. Frequency counts and 
percentages of subjects by age category, sex, ethnicity, and race categories will be summarized.  
Baseline characteristics including CYP450 2D6 polymorphism, smoking history, height, weight, 
and body mass index (BMI) will be summarized by tolperisone dose group/placebo and for total 
tolperisone treated subjects combined for the Safety, ITT, and PP Populations.  
Height, weight, and BMI at baseline will be summarized using descriptive statistics. Genotype 
and smoking history will be summarized with frequency counts and percentages.  
Genotype results will also be presented in a by-subject data listing.  
7.4.3 
Measurements of Treatment Compliance 
Compliance to the study treatment regimen will be determined as the total number of doses 
received divided by the expected number of doses received, multiplied by 100.  
The total number of doses received will be determined based on the number of protocol-required 
doses (i.e. 42 doses) minus the number of tablets returned as reported in the eCRF.  
Subjects are not expected to receive all three doses on the first (Day 1) and last (EOT/ET) day of 
dosing. The expected number of doses will be derived as outlined in Table 4. 
Table 4 Expected Number of Doses  
Row 
First Dose 
Time 
Doses expected 
Day 1 
Last Dose 
Time 
Doses expected 
EOS/ET 
Doses expected 
Day 1 & EOS/ET  
Doses not expected 
Day 1 & EOS/ET 
1 
12am-12pm 
3 
12am-12pm 
1 
4 
2 
2 
12am-12pm 
3 
12pm-6pm 
2 
5 
1 
3 
12am-12pm 
3 
6pm-12am 
3 
6 
0 
4 
12pm-6pm 
2 
12am-12pm 
1 
3 
3 
5 
12pm-6pm 
2 
12pm-6pm 
2 
4 
2 
6 
12pm-6pm 
2 
6pm-12am 
3 
5 
1 
7 
6pm-12am 
1 
12am-12pm 
1 
2 
4 
8 
6pm-12am 
1 
12pm-6pm 
2 
3 
3 
9 
6pm-12am 
1 
6pm-12am 
3 
4 
2 
Complete 14 day TID dosing 
If the first dose of study drug occurs in the morning (between 12am and 12pm) and the last dose 
occurs in the evening (between 6pm and 12am) then the expected number of doses should be 
calculated as 3 × (date of last dose – the date of first dose + 1) (Table 4: Row 3). 
 
 


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Partial dosing on First and Last Day of Dosing 
If the first dose occurs in the afternoon (between 12pm and 6pm) and last dose occurs in the 
morning (between 12am and 12pm), the expected number of doses should be calculated as 3 × 
(date of last dose – the date of first dose + 1) – (3 [doses not expected on first & last days]) to 
account for the fewer number of expected doses on the first and last days of treatment (Table 4: 
Row 4).  
For subjects with non-missing date of last dose, but missing time of last dose on the CRF, if the 
date of last dose on the CRF is equivalent to the last date of entry on the subject eDiary, the 
corresponding eDiary time point (AM, MID, PM) will be used for compliance calculations. 
Otherwise, if the last dose date on the CRF and date of latest entry on the eDiary are not 
equivalent, subjects will be imputed to have received 1 dose on the given CRF date of last dose.  
Dosing compliance will be summarized using descriptive statistics, by treatment group, based on 
the Safety Population. The number and percentages of subjects who are < 80% compliant and 
≥ 80% compliant within each treatment group will be summarized. A data listing of subject 
compliance will also be presented.  
7.4.4 
Primary Efficacy Endpoint Analysis Methods 
The primary efficacy endpoint is NRS subject-rated pain “right now” due to acute back spasm on 
Day 14 for all subjects in the ITT population. This analysis will be performed using a linear test 
of trend across all tolperisone doses.  
The null and alternate hypotheses to be tested are: 
 
H0:  There is no significant trend in NRS rating of pain “right now” across dose groups  
 
H1:  There is significant trend in NRS rating of pain “right now” across dose groups  
The linear test of trend will be performed using a mixed effect model for repeated measures 
(MMRM) using an unstructured covariance matrix to model within-patient errors. However, if the 
computational algorithm fails to converge, other covariance structures will be evaluated (e.g., 
compound symmetry). The covariance structure converging to the best fit, as determined by 
Akaike’s information criterion, will be used. The Kenward and Roger method will be used to 
calculate the denominator degrees of freedom for the test of fixed effects. Based on this model, 
the hypothesis test described above will be tested using a two-sided test at the alpha=0.05 level of 
significance.  
The response variable will be the observed NRS rating of pain “right now”. The observed value 
on Day 14 is the primary time point of interest. The model will include factors for treatment 
group (5 levels: placebo, 150 mg/day, 300 mg/day, 450 mg/day and 600 mg/day) and visit (three 
levels: Day 1/Baseline, Day 4, and Day 14) as fixed effects, the treatment by visit interaction, and 
the baseline NRS rating as a covariate. The primary analysis will be based on all available data 
without imputation. Day 14 will reflect subjects that have the completed the scheduled Day 14 
(Visit 3). Subjects discontinuing the study may be analyzed as part of the sensitivity analysis 
using data imputation methods (LOCF and Multiple Imputation) to address missing data.  


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The observed NRS rating and change from baseline values will be presented using descriptive 
statistics for each treatment group by visit. The p-value for the overall test of trend on Day 14 will 
be presented. The pairwise least-square mean (LSM) estimates and least-square mean differences 
(LSMD) for each tolperisone dose level versus placebo will also be presented with 95% 
confidence intervals of the LSMD and associated p-values for the Day 14 visit observed values.  
A plot of NRS subject rating of pain right now across study days will be presented.  
7.4.5 
Secondary Endpoint Analysis Methods  
7.4.5.1 
NRS Rating of pain “right now” on Day 4 
Analysis performed for the primary endpoint will be repeated for the NRS at Day 4 using the 
same MMRM model. Contrast and estimate statements will be used in the primary model to 
analyze the Day 4 values.     
7.4.5.2 
NRS Rating of pain over past 1 hour and 12 hours on Days 1 through 14 
NRS subject rating of pain over past 1 hour and 12 hours is collected daily as AM and PM 
assessments. The AM, PM and average of AM/PM values will be summarized descriptively by 
study day for each treatment group. Summaries for the 1 hour assessment and 12 hours 
assessment will be presented separately.  
An MMRM model using a linear test of trend will be performed similar to the primary endpoint. 
The model will include response as the average of the AM and PM NRS rating over past 1 hour or 
12 hours and factors for treatment group (5 levels: placebo, 150 mg/day, 300 mg/day, 450 mg/day 
and 600 mg/day) and visit (14 levels: Day 1 to Day 14) as fixed effects and the treatment by visit 
interaction.  
The pairwise least square mean (LSM) estimates and least-square mean differences (LSMD) for 
each tolperisone dose level versus placebo will be presented with 95% confidence intervals of the 
LSMD and associated p-values for the Day 14 visit. The p-value for the overall test of trend on 
Day 14 will also be presented.  
Plots of NRS subject rating of pain due to back spasm over past 12 hours and past 1 hour will be 
plotted with the average of the AM and PM assessments on the y-axis and study day on x-axis.  
7.4.5.3 
NRS Rating of pain at rest and on movement on Days 1 through 14 
NRS subject rating of pain at rest and with movement collected once daily in the evening for the 
14 day treatment period. The observed values will be summarized descriptively by study day for 
each treatment group. Summaries for the at rest assessment and with movement assessment will 
be presented separately. 
An MMRM model using a linear test of trend will be performed similar to the primary endpoint. 
Plots of NRS subject rating of pain at rest and with movement across study days will be 
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7.4.5.4 
Subject Rating of Medication Helpfulness 
 
SRMH values will be summarized categorically by treatment group for Days 4 and 14 for the ITT 
Population. The frequency and percentage of subjects in each response category will be presented. 
The comparison of each group to placebo will be conducted using a Wilcoxon Rank Sum test for 
the Day 14 values and p-values presented. 
7.4.5.5 
Fingers to Floor Distance  
 
Fingers to floor distance will be assessed at Baseline, Day 4, and Day 14 and will be analyzed 
using a linear test of trend similar to the primary endpoint on Day 14. Pairwise estimates of the 
observed value will be presented.  
7.4.5.6 
Global Symptom assessments (CGI and PGI) 
Global symptom assessments will be summarized by treatment group for the ITT population. 
CGI-S and PGI-S will be assessed at the baseline visit only. CGI-C and PGI-C will be assessed at 
Day 4 and Day 14. The frequency and percentage of subjects in each response category at 
Baseline, Day 4 and Day 14 will be presented. The comparison of each group to placebo will be 
conducted using a Wilcoxon Rank Sum test for the Day 14 values and p-values presented. 
7.4.5.7 
Quality of Sleep 
Quality of sleep will be analyzed using the same methods described for the global symptom 
assessments in section 7.4.5.6. The comparison of each group to placebo will be conducted using 
a Wilcoxon Rank Sum test for the Day 14 observed values.  
7.4.5.8 
Time to Pain Relief 
Time to pain relief (days) will assessed using the NRS assessment of subject rating of pain over 
the past 12 hours. NRS assessments on or after Day 2 will be considered for time to relief. The 
first post-baseline occurrence of an AM or PM 12-hour NRS score equal to 2 or lower (0 = no 
pain, 10 = worst possible pain) will be used as the criterion for relief.  
Subjects who withdraw from the study prior to the end of treatment visit or who complete the 
treatment period without having met the criteria for relief will be censored at the time of their last 
NRS assessment. Time to relief will be presented in days as (date of relief/censoring – date of 
first dose + 1).  
The number of subjects with relief and those censored will be summarized by treatment group for 
the ITT population. Estimates of the median times will be presented along with their associated 
95% confidence intervals. Treatment group comparisons will be summarized with hazard ratios 
and their associated 95% CI from a Cox Proportional Hazards regression model with treatment as 
the main effect and p-values from a generalized Wilcoxon test. 
The Kaplan Meier plots of time to pain relief by treatment group will be presented and display the 
subjects with relief and those censored at each study day.  


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A by subject listing of derived time to relief estimates will also be presented.  
7.4.5.9 
Rescue Medication Use 
The use of study provisioned medication will be summarized using frequency counts and 
percentages for the number of tablets consumed by treatment group for the ITT population. 
Descriptive statistics will also be presented by treatment group. The number of days of 
medication use, average daily use (caplets/day of medication use) and total use will be tabulated 
using descriptive statistics. The frequency and percentage of subjects with rescue medication 
entry will be presented.  
The Shapiro-Wilk test will be used to examine the assumption of normality for total rescue 
medication use across all dose groups. If this test is statistically significant (i.e., p ≤ 0.05) then the 
assumption of normality is violated and the total rescue medication consumption will be analyzed 
using a Wilcoxon Rank Sum test.  
However, if the assumption of normality holds (i.e., Shapiro-Wilk p-value > 0.05), then the total 
rescue medication consumption will be analyzed using an analysis of variance (ANOVA) model 
with randomized treatment as the main effect. The LSM and LSMD will be presented with 
associated 95% CI and p-values comparing each treatment group to placebo.  
A data listing of rescue medication use will be presented and include the average number of 
tablets consumed and total number of tablets rescue medication consumed for each subject.  
7.4.5.10 
Oswestry Disability Index 
ODI score (%) will be calculated as (total score × 2) / (number of sections answered / 10), 
rounded to the nearest integer, where the total score is the sum of the individual section scores.  
Observed ODI score and change from baseline will be summarized descriptively for each 
treatment group for the ITT population.  Each dose group will be compared to placebo using an 
ANCOVA model with observed value as the response, main effects for treatment group and a 
covariate adjusted for the baseline ODI score. The LSM, LSMD, 95% CI and p-values will be 
presented at Day 14.  
Individual section scores will be summarized separately for the ITT population by treatment 
group. The frequency and percentage of subjects in each response category at Baseline, Day 4 and 
Day 14 will be presented. The comparison of each group to placebo will be conducted using a 
Wilcoxon Rank Sum test for the Day 14 values and p-values presented. 
7.4.5.11 
Visual Analogue Scale of Sleepiness 
The Day 4 VAS ratings of sleepiness will be summarized descriptively by treatment group for the 
ITT population. Each dose group will be compared to placebo using an ANOVA model with the 
observed values as the response and main effects for treatment group. The LSM, LSMD, 95% CI 
and p-values will be presented.   


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7.4.5.12 
Daily Activities 
Daily activity scores will be summarized categorically for Days 1 to 14 by treatment group for the 
ITT population. The frequency and percentage of subjects in each response category will be 
presented. The comparison of each group to placebo will be conducted using a Wilcoxon Rank 
Sum test for the Day 14 values and p-values presented. 
7.4.6 
Statistical/Analytical Issues 
7.4.6.1 
Adjustments for Covariates 
The MMRM model to test for linear trend for the primary endpoint will include a covariate 
adjustment for the baseline value. Secondary endpoints utilizing an MMRM will be analyzed 
similarly when a baseline value is captured.  
7.4.6.2 
Handling of Dropouts or Missing Data 
Primary and secondary endpoints including all NRS assessments (right now, past 12 hours, past 1 
hour, at rest, on movement), Fingers to floor Distance, Clinician’s Global Impression, and 
Oswestry Disability Index assessments will be analyzed using both observed data and data 
imputed using last observation carried forward (LOCF), if the dropout rate is ≥ 5% (20/400 
subjects). In the LOCF method, the most recent non-missing value for the endpoint is carried 
forward to replace a missing value at a post-baseline visit within a subject. Baseline values will 
not be carried forward.   
Methods for multiple imputation (MI) for missing data may be explored for endpoints if the 
dropout rate is ≥ 15% (60/400 subjects).  
7.4.6.3 
Interim Analyses and Data Monitoring 
There are no interim analyses planned, nor is there a plan to establish a data monitoring 
committee for this study. 
7.4.6.4 
Multicenter Studies 
This is a multicenter study, with approximately 45 sites expected to participate. Efficacy data 
collected from all study sites will be pooled for data analysis. The effect of study site on the 
efficacy analysis results may be explored post-hoc, as needed. 
7.4.6.5 
Multiple Comparisons/Multiplicity 
There will be no adjustments for multiple comparisons in the efficacy analysis for this study. All 
of the above analyses will be conducted using two-sided tests at the alpha = 0.05 level of 
significance.  


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7.4.6.6 
Use of an “Efficacy Subset” of Subjects 
The primary efficacy analysis will be performed on the ITT population; the PP population will be 
utilized as a sensitivity analysis for the primary endpoint and secondary endpoints, including NRS 
(right now, past 12 hours, past 1 hour, at rest, on movement), Subject Rating of Medication 
Helpfulness, Fingers to Floor Distance, Clinician’s Global Impression assessments, and Oswestry 
Disability Index. The PP population will exclude subjects with major protocol violations. 
7.4.6.7 
Active-Control Studies Intended to Show Equivalence 
This study does not include an active-control product and is not intended to demonstrate 
equivalence between any two drug products. 
7.4.6.8 
Examination of Subgroups 
There are no planned analyses to assess efficacy results by subgroups.  
7.4.7 
Plasma Concentrations 
Plasma concentration measurements will be summarized in a separate report and is outside the 
scope of this SAP. 
7.4.8 
Pharmacokinetic Analysis 
Pharmacokinetic analysis will be summarized in a separate report and is outside the scope of this 
SAP. 
7.5 
Safety Evaluation 
Safety analysis will be carried out for the Safety Population, which will include all subjects who 
receive at least one dose of study drug. Subjects who do not complete the study, for whatever 
reason, will have all available data up until the time of termination included in the analysis. For 
safety analysis presented by study visit, the baseline value will be defined as the last value 
reported prior to first study drug administration. All analyses will be presented by treatment 
group.  
7.5.1 
Extent of Exposure 
Extent of exposure to study treatment will be summarized for the Safety Population by treatment 
group. The date of first and last dose is collected on the eCRF. If missing, subjects’ dosing eDiary 
data will be used to determine dates of first and last doses. The duration of exposure will be 
presented in days and calculated as the date of last dose of study drug minus the date of first dose 
of study drug, plus one. Duration of exposure, average dose received, and total dose received 
(mg) will be summarized using descriptive statistics.  
Total dose received will be derived based on the number of tablets returned at the end of 
treatment visit and the actual dose (mg) received. Average dose will be calculated as the total 


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dose divided by the duration of exposure. The planned number of doses for each subject is 42 (14 
days of TID dosing).  
7.5.2 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those adverse events (AEs) with 
onset on or after the first dose of study drug through 24 hours after the last dose of study drug. 
Existing events that worsened during this period will also be considered treatment emergent. If 
start time is not available, AEs with onset between the date of the first dose through the day after 
the date of last dose (+1 day) will be considered treatment-emergent.   
Adverse events with onset greater than 24 hours (or >1 day) after the date of the last dose of study 
drug through the date of the follow-up visit (Visit 4/Day 28) will be considered after-treatment 
events.  
Treatment-emergent and after-treatment AEs will be summarized by treatment group. Events 
reported with a partial onset date (e.g., month and year are reported but the day is missing) will be 
considered to be treatment-emergent if it cannot be confirmed that the event onset was prior to the 
first dose of study drug based on the available date entries. 
Verbatim terms on case report forms will be mapped to preferred terms and system organ classes 
using the Medical Dictionary for Regulatory Activities (MedDRA, version 21.1).   
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending incidence of system organ class and preferred term within each system organ class. 
Summaries displayed by preferred term only will be ordered by descending incidence of preferred 
term. Summaries of the following types will be presented: 
x Overall summary of number of unique TEAEs and treatment-emergent serious adverse 
events (SAEs) and subject incidence of TEAEs meeting various criteria; 
x Subject incidence of TEAEs by MedDRA system organ class and preferred term; 
x Subject incidence of TEAEs by MedDRA preferred term; 
x Subject incidence of TEAEs by severity grade, MedDRA system organ class, and 
preferred term; 
x Subject incidence of TEAEs by relationship to study drug, MedDRA system organ class, 
and preferred term;  
x Subject incidence of SAEs by MedDRA system organ class and preferred term; 
x Subject incidence of TEAEs Leading to Study Drug Discontinuation by MedDRA system 
organ class and preferred term; and 
x Subject incidence of TEAEs by CYP450 2D6 Genotype, MedDRA system organ class and 
preferred term.   


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x Subject incidence of After-treatment Adverse Events by MedDRA preferred term. 
At each level of summarization (e.g., any AE, system organ class, and preferred term), subjects 
experiencing more than one AE will be counted only once. In the summary of TEAEs by severity 
grade, subjects will be counted once at the highest severity reported at each level of 
summarization; in the summary of TEAEs by relationship, subjects will be counted once at the 
closest relationship to study drug. Related events include those reported as “Possibly Related” or 
“Definitely Related” to study drug; events considered not related are those reported as 
“Unrelated” to study drug.  
Adverse event data will be presented in data listings by patient, treatment group, and event. The 
study phase (e.g., treatment-emergent, after-treatment) will also be presented in the listing. 
Serious AEs and AEs leading to discontinuation, interruption or dose reduction, interruption of 
the study drug will be presented in separate data listings.  
7.5.3 
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
All deaths during the study, including the post treatment follow-up period, will be listed by 
subject, to include the primary cause of death. Serious AEs and other significant AEs, including 
those that led to discontinuation, interruption or dose reduction of the study drug, will be provided 
in separate subject data listings. 
7.5.4 
Clinical Laboratory Evaluation 
7.5.4.1 
Hematology and Chemistry 
All descriptive summaries of laboratory results will be based on data analyzed by the central 
laboratory and presented in Système International (SI) units, as suggested by the Center for 
Biologics Evaluation and Research and the Center for Drug Evaluation and Research Position on 
Use of SI Units for Lab Tests (Oct 2013). All data will be included in by-subject data listings. 
Laboratory measurements identified as abnormal (i.e., outside the normal range) will also be 
listed separately by subject, laboratory test, and unit.  
Serum chemistry and hematology clinical laboratory measurements will be summarized by 
treatment group and for total tolperisone treated subjects at Baseline, Day 14,and at Day 14/ET. 
Descriptive statistics will be presented for observed values and changes from baseline at each 
visit.  
7.5.4.2 
Urinalysis  
Urinalysis and microscopic urinalysis results will be summarized in by-subject data listings.  
7.5.4.3 
Pregnancy Test 
Pregnancy test results will be presented in a by-subject data listing 


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7.5.4.4 
Alcohol Breathalyzer Test 
Alcohol breathalyzer test results will be presented in a by-subject data listing 
7.5.4.5 
Urine Drug Screen 
Urine drug screen results will be presented in a by-subject data listing 
7.5.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
7.5.5.1 
Vital Signs 
Vital sign parameters including blood pressure (standing, supine, orthostatic), heart rate, 
respiratory rate and body temperature will be summarized by treatment group and for total 
tolperisone treated subjects. Descriptive statistics will be presented for results and change from 
baseline at each visit where parameters were scheduled to be collected.  
Orthostatic blood pressure will be calculated as the standing minus supine measurement for both 
systolic and diastolic blood pressure.  
Weight will be converted from lbs to kg using a conversion factor of 0.4536.  
7.5.5.2 
12-Lead Electrocardiogram 
Twelve-Lead ECG interval parameters will be summarized categorically as normal, clinically 
significant abnormal, and not clinically significant abnormal by treatment group and for total 
tolperisone treated subjects at each scheduled visit.  
7.5.5.3 
Neurological Examination 
Results of the neurological examination will be summarized categorically as improved, stable, 
and deteriorated by treatment group and for total tolperisone treated subjects at each scheduled 
visit.   
7.5.5.4 
Physical Examination 
Results of the physical examination will be presented in subject data listings by subject and study 
visit. 
7.5.5.5 
Concomitant and After-Treatment Medications 
Medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHODDE), version B3 March 1, 2018. Medications entered on the eCRF will be mapped to 
Anatomic Therapeutic Chemical (ATC) drug class (level 4) and drug name.  
Concomitant and after-treatment medications will be summarized separately for the Safety 
Population. The study phase of each medication will be determined programmatically based on 
medication start and end dates. A prior medication is defined as any medication administered 
prior to the date of the first dose of study drug. A concomitant medications is defined as any 


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medication administered on or after the date of the first dose of study drug through 24 hours after 
the date of last dose of study drug. If medication time is not available, any medication 
administered on or after the date of first dose through the day after the date of last dose (+1 day) 
will be considered concomitant. An after-treatment medication is defined as any medication 
administered greater than 24 hours (or >1 day) after the date of the last dose of study drug through 
the date of the follow-up visit (Visit 4/Day 28).  
A medication may be defined as both prior and concomitant. If it cannot be determined whether a 
medication was received prior to the start of study drug dosing due to partial or missing 
medication start and/or end dates, it will be considered a prior medication. Likewise, if it cannot 
be determined whether a medication was received after the start of study drug dosing, it will be 
considered concomitant. 
For both concomitant, and after-treatment medications summaries, the number and percentage of 
subjects receiving any medication will be summarized by treatment group and for total 
tolperisone treated subjects, as will the number and percentage receiving any medication by ATC 
drug class and generic drug name.  
Subjects reporting use of more than one medication at each level of summarization (any 
medication received, ATC class, and generic drug name) will be counted only once. ATC class 
terms will be displayed by descending order of incidence, as will generic drug names within each 
ATC class. The study phase during which each medication was received (e.g., prior, concomitant, 
or both) will be presented on the listing of prior and concomitant medications. 
A summary of concomitant analgesic medications received, outside of the study-provided 
medication, will also be presented. These medications will be identified from list of generic drug 
names and indications as determined by the sponsor prior to data base closure. Analgesic 
medications taken on Day 1 will not be considered as concomitant as use was allowed per 
protocol on Day 1 of treatment.  
All medications will be presented in a data listing by subject and medication name. The study 
phase during which each medication was received (e.g., prior, concomitant, or after-treatment) 
and whether the medication is a rescue medication will be presented on the listing.  
7.6 
Determination of Sample Size 
The sample size for this study was determined from results of two previous studies. The first was 
a study in subjects with acute upper back, neck, or shoulder spasm and pain, which showed a 
difference of 0.4 in the average of Day 1 through Day 7 between the placebo and active groups, 
and standard deviations (SDs) between 1.76 and 1.93 (across placebo and active groups 
respectively; Collaku, 2017). A sample size of 400 subjects (80 per group) would provide at least 
80% power to detect a difference of 0.9 between the placebo and treatment groups in the NRS 
scale, assuming a two-sample t-test at the 5% level of significance and a pooled SD of 2.0. This 
sample size assumes an effect size of 0.45 (0.9/2.0 = 0.45, using the formula Effect Size = 
Mean/SD), which is larger than that seen in the reference study but consistent with that seen in a 
second study. 


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A second previous study in subjects with acute musculoskeletal spasm associated with low back 
pain showed effect sizes ranging from 0.57 to 0.62 for lumbar cinesalgia, based on a treatment 
difference of 9.6 at Day 3, with SDs of 15.5 (treated group) and 16.7 (placebo group) 
(Chandanwale, 2011). This study demonstrated effect sizes ranging from 1.1 to 1.6, based on a 
difference of 24.2 at Day 14 with SDs of 15.1 (treated group) and 23.0 (placebo group). The 
effect size of the current study is expected to be similar to that in Chandanwale, though sample 
size estimates have been made more conservative to provide sufficient power to detect smaller 
differences. Though the primary comparison of interest in this study is Day 14, the study is 
sufficiently powered to detect a treatment difference at Day 4 based on effect sizes ranging from 
0.35 to 0.45. 
7.7 
Changes in the Conduct of the Study or Planned Analyses 
7.7.1 
Changes in Planned Analyses  
VAS ratings of sleepiness will be analyzed using an ANOVA in place of an ANCOVA model 
since no baseline values are collected to be used as a covariate. Daily activity scores and Subject 
Rating of Medication Helpfulness will be summarized categorically and the comparison of each 
group to placebo will be conducted using a Wilcoxon Rank Sum test for the Day 14 values 
instead of an MMRM or ANCOVA model.  
7.7.2 
Other Changes 
An independent audit of Site 21 (Mariano), conducted May 12 and May 15, 2019, described 
substantial evidence of clinical trial misconduct during the execution of the trial. Based on the 
inspection findings report (signed May 17, 2019), Site 21 subject data will be excluded from all 
analyses described in this SAP.  
 
 
 


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8 REFERENCE LIST 
[1] Chandanwale AS, Chopra A, Goregaonkar A, et al. Evaluation of eperisone hydrochloride in 
the treatment of acute musculoskeletal spasm associated with low back pain: A randomized, 
double-blind, placebo-controlled trial. Journal of Postgraduate Medicine, 2011; 57 (4):278-285. 
[2] Collaku A, Yue Y, Reed K. Efficacy and safety of guaifenesin for upper back, neck, and 
shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-
group study. Journal of Pain Research, 2017; 10:669-678. 
[3] Data Standards: Position on Use of SI Units for Lab Tests. U.S Food and Drug 
Administration; 25 October 2013. Available from: 
http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm372553.htm 
[4] International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Statistical principles for clinical trials (E9). International 
Conference on Harmonization; 1998. 
[5] M2 eCTD: Electronic Common Technical Document Specification Appendix 7, provided by 
the International Conference on Harmonization. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/uc
m073240.pdf 
[6] Mehra, A., Baker, D., Disney, S., & Pynsent, P. B. (2008). Oswestry Disability Index scoring 
made easy. Annals of the Royal College of Surgeons of England, 90(6), 497-9. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647244/pdf/rcse9006-497.pdf 
 
 


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