Conditions: Neck Pain Back Pain Spasm
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the effect of cyclobenzaprine hydrochloride (HCl) extended release (CER) 15 mg capsule once daily in participants with muscle spasms associated with acute painful musculoskeletal conditions.

Detailed description:
The drug being tested in this study was cyclobenzaprine hydrochloride (HCl) extended-release (CER). CER was being tested to treat participants who had muscle spasms associated with acute painful musculoskeletal conditions. This study looked at medication helpfulness, relief from muscle spasms and pain, and improvement in range of motion and daily living activities.

The study enrolled 180 participants. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups which remained undisclosed to the participant and study doctor during the study:

* CER 15 mg
* Placebo (dummy inactive pill) - this was a capsule that looks like the study drug but had no active ingredient

All participants were asked to take one capsule at the same time each day throughout the study.

This multi-center trial was conducted in the Russian Federation. The overall time to participate in this study was up to 45 days. Participants made multiple visits to the clinic, and were contacted by telephone after the last dose of study drug for a follow-up assessment.

Arms:
arm 1: Cyclobenzaprine Hydrochloride (HCl) extended-release, 15 mg capsules, orally, once daily for 14 days. arm 2: Cyclobenzaprine HCl extended release placebo-matching capsules, orally, once daily for 14 days.

Interventions: intervention 1: Cyclobenzaprine HCl intervention 2: Placebo
Intervention descriptions: intervention 1: Cyclobenzaprine HCl extended-release capsules intervention 2: Cyclobenzaprine HCl extended release placebo-matching capsules

Protocol document:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Trial to 
Study the Efficacy and Safety of Cyclobenzaprine HCl Extended Release (CER) 15 mg in 
Subjects with acute cervical and/or lower back pain due to Muscle Spasms of Local Origin
NCT Number: NCT02814565
Protocol Approve Date: 16 Aug 2016
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


1.0 TITLE P 
AGE 
PROTOCOL 
Title 
A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Trial to Study the 
Efficacy and Safety of Cyclobenzaprine HCl Extended Release (CER) 15 mg in Subjects with acute 
cervical and/or lower back pain due to Muscle Spasms of Local Origin  
Short title 
 Cyclobenzaprine HCl Extended Release 15mg versus Placebo in Treatment of acute cervical and/or 
lower back pain due to Muscle Spasms of Local Origin  
Sponsor: 
Takeda Pharmaceutical LLC.,  
2, bld.1, Usacheva ul.  
Moscow 119048, Russia 
Study Number: 
CYC-RR-001 
IND Number: 
EudraCT Number: 
N/A 
N/A 
Date: 
Compound: 
16 Aug 2016 
Cyclobenzaprine 
HCl Extended 
Release 
(Myorix®)
Amendment Number: 3 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
06 October 2014 
Initial Protocol 
Not applicable 
Russia 
01 July 2015 
1 
Substantial 
Russia 
19 July 2016 
2 
Substantial 
Russia 
16 Aug 2016 
3 
Non-Substantial 
Russia 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by the recipient that 
no information contained herein will be published or disclosed without written authorization from Takeda except to the extent necessary 
to obtain informed consent from those persons to whom the drug may be administered. Furthermore, the information is only meant for 
review and compliance by the recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable 
conduct of the study. 


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Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 4 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, and 
well-being of study subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 Appendix B – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance with 
the uses contemplated in Appendix D of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Russia 
Location of Facility (Country) 
 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 5 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ............................................................................. 2 
1.1 
Contacts ......................................................................................................................... 2 
1.2 
Approval........................................................................................................................ 3 
2.0 
STUDY SUMMARY .......................................................................................................... 9 
3.0 
STUDY REFERENCE INFORMATION ........................................................................ 12 
3.1 
Study-Related Responsibilities ................................................................................... 12 
3.2 
Coordinating Investigator ........................................................................................... 12 
3.3 
List of Abbreviations .................................................................................................. 13 
3.4 
Corporate Identification .............................................................................................. 14 
4.0 
INTRODUCTION ............................................................................................................ 15 
4.1 
Background ................................................................................................................. 15 
4.2 
Rationale for the Proposed Study ................................................................................ 15 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 17 
5.1 
Objectives.................................................................................................................... 17 
5.1.1 Primary Objective ................................................................................................. 17 
5.1.2 Secondary Objective ............................................................................................. 17 
5.1.3 Additional Objectives ........................................................................................... 17 
5.2 
Endpoints .................................................................................................................... 17 
5.2.1 Primary Endpoints................................................................................................. 17 
5.2.2 Secondary Endpoints............................................................................................. 17 
5.2.3 Additional Endpoints ............................................................................................ 17 
6.0 
STUDY DESIGN AND DESCRIPTION ......................................................................... 19 
6.1 
Study Design ............................................................................................................... 19 
6.2 
Justification for Study Design, Dose, and Endpoints.................................................. 20 
6.3 
Premature Termination or Suspension of Study or Investigational Site ..................... 21 
6.3.1 Criteria for Premature Termination or Suspension of the Study .......................... 21 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ......... 21 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) .................................................................. 21 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .............. 22 
7.1 
Inclusion Criteria......................................................................................................... 22 
7.2 
Exclusion Criteria ....................................................................................................... 22 
7.3 
Excluded Medications and Treatments ....................................................................... 24 
7.4 
Diet, Fluid, Activity Control  and Treatment Facilities .............................................. 25 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ............................................ 26 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject ...................................... 27 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ........................................................ 28 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 6 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
8.1 
Study Medication and Materials ................................................................................. 28 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling...................................... 28 
8.1.2 Storage .................................................................................................................. 29 
8.1.3 Dose and Regimen ................................................................................................ 29 
8.1.4 Overdose ............................................................................................................... 29 
8.2 
Investigational drug Assignment and Dispensing Procedures .................................... 31 
8.3 
Randomization Code Creation and Storage ................................................................ 31 
8.4 
Investigational Drug Blind Maintenance .................................................................... 31 
8.5 
Unblinding Procedure ................................................................................................. 31 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs ...................................... 31 
9.0 
STUDY PLAN .................................................................................................................. 33 
9.1 
Study Procedures......................................................................................................... 33 
9.1.1 Informed Consent Procedure ................................................................................ 33 
9.1.2 Demographics, Medical History, and Medication History Procedure .................. 33 
9.1.3 Physical Examination Procedure .......................................................................... 33 
9.1.4 Weight, Height ...................................................................................................... 33 
9.1.5 Vital Sign Procedure ............................................................................................. 33 
9.1.6 Primary Efficacy Measurement ............................................................................ 33 
9.1.7 Documentation of Concomitant Medications ....................................................... 37 
9.1.8 Documentation of Concurrent Medical Conditions .............................................. 37 
9.1.9 Procedures for Clinical Laboratory Samples ........................................................ 37 
9.1.10 Contraception and Pregnancy Avoidance Procedure ............................................ 38 
9.1.11 Pregnancy .............................................................................................................. 39 
9.1.12 ECG Procedure ..................................................................................................... 40 
9.1.13 Documentation of Screen Failure ......................................................................... 40 
9.1.14 Documentation of Randomization ........................................................................ 40 
9.2 
Monitoring Subject Treatment Compliance ................................................................ 40 
9.3 
Schedule of Observations and Procedures .................................................................. 41 
9.3.1 Screening ............................................................................................................... 41 
9.3.2 Randomization ...................................................................................................... 41 
9.3.3 Visit 2 (Day 3) and Visit 3 (Day 7) ....................................................................... 43 
9.3.4 Visit 4 (Day 15) or Early Termination .................................................................. 43 
9.3.5 Follow-up call ....................................................................................................... 43 
9.3.6 Post Study Care ..................................................................................................... 44 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................. 45 
10.1 
Definitions ................................................................................................................... 45 
10.1.1 PTEs ...................................................................................................................... 45 
10.1.2 AEs ........................................................................................................................ 45 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 7 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
10.1.3 Additional Points to Consider for PTEs and AEs ................................................. 45 
10.1.4 SAEs...................................................................................................................... 47 
10.1.5 Severity of PTEs and AEs ..................................................................................... 48 
10.1.6 Causality of AEs ................................................................................................... 48 
10.1.7 Relationship to Study Procedures ......................................................................... 48 
10.1.8 Start Date............................................................................................................... 48 
10.1.9 Stop Date ............................................................................................................... 48 
10.1.10 
Frequency ........................................................................................................ 49 
10.1.11 
Action Concerning Study Medication ............................................................. 49 
10.1.12 
Outcome .......................................................................................................... 49 
10.2 
Procedures ................................................................................................................... 49 
10.2.1 Collection and Reporting of AEs .......................................................................... 49 
10.2.2 Collection and Reporting of SAEs ........................................................................ 50 
10.2.3 Reporting of Abnormal Liver Function Tests ....................................................... 51 
10.3 
Follow-up of SAEs...................................................................................................... 51 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities ..... 51 
11.0 
STUDY-SPECIFIC COMMITTEES ................................................................................ 52 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................. 53 
12.1 
CRFs............................................................................................................................ 53 
12.2 
Record Retention......................................................................................................... 53 
13.0 
STATISTICAL METHODS ............................................................................................. 55 
13.1 
Statistical and Analytical Plans ................................................................................... 55 
13.1.1 Analysis Sets ......................................................................................................... 55 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................ 55 
13.1.3 Efficacy Analysis .................................................................................................. 55 
13.1.4 Safety Analysis ..................................................................................................... 57 
13.2 
Interim Analysis and Criteria for Early Termination .................................................. 58 
13.3 
Determination of Sample Size .................................................................................... 58 
14.0 
CONTROL AND QUALITY ASSURANCE................................................................... 59 
14.1 
Study-Site Monitoring Visits ...................................................................................... 59 
14.2 
Protocol Deviations ..................................................................................................... 59 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................. 59 
15.0 
ETHICAL ASPECTS OF THE STUDY .......................................................................... 60 
15.1 
IRB and/or IEC Approval ........................................................................................... 60 
15.2 
Subject Information, Informed Consent, and Subject Authorization .......................... 60 
15.3 
Subject Confidentiality ............................................................................................... 61 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 62 
15.4.1 Publication and Disclosure.................................................................................... 62 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 8 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
15.4.2 Clinical Trial Registration ..................................................................................... 62 
15.4.3 Clinical Trial Results Disclosure .......................................................................... 63 
15.5 
Insurance and Compensation for Injury ...................................................................... 63 
16.0 
REFERENCES.................................................................................................................. 64 
Appendix E Instruction for Medical Use – Myorix ................................................................ 73 
 
LIST OF IN-TEXT TABLES 
Table 8.a 
Dose and Regimen ................................................................................................ 29 
Table 9.a 
Clinical Laboratory Tests ...................................................................................... 38 
Table 10.a 
Takeda Medically Significant AE List .................................................................. 47 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................................... 20 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures............................................................................... 67 
Appendix B 
Responsibilities of the Investigator ....................................................................... 69 
Appendix C 
Elements of the Subject Informed Consent........................................................... 70 
Appendix D 
Investigator Consent to Use of Personal Information ........................................... 72 
Appendix E   Instruction for Medical Use - Myorix ..................................................................... 72 
 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 9 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Pharmaceutical LLC. 
Compound: 
Cyclobenzaprine HCl Extended Release 
Title of Protocol: A Randomized, Double-Blind, 
Parallel-Group, Placebo-Controlled, Multicenter Trial to 
Study the Efficacy and Safety of Cyclobenzaprine HCl 
Extended Release (CER) 15 mg in Subjects with acute  
cervical and/or lower back pain due to Muscle Spasms of 
Local Origin 
IND No.: N/A 
EudraCT No.: N/A 
Study Number: CYC-RR-001 
Phase: IIIb 
Study Design: 
This is a randomized, double-blind, placebo-controlled, parallel-group 2-arm study assessing the safety and efficacy of 
CER in subjects with muscle spasms. 
Primary Objectives: 
The primary objective of this study is to assess the effect of CER 15 mg once daily in subjects with muscle spasms 
associated with musculoskeletal conditions. 
Secondary Objectives: 
The secondary objective for this study is to assess effect on subject rating parameters of CER 15 mg once daily.  
Additional Objectives    
Safety objective 
The safety objective for this study is to assess the safety and tolerability of CER 15 mg once daily.  
Subject Population: Males and females aged 18 to 50 years inclusive, experiencing cervical or lower back pain (as 
assessed by the subject) due to muscle spasms (confirmed by the physician) for no more than 14 days. 
Number of Subjects: 
Total number of patients to be randomized is 180: 90 into 
Placebo group and 90 into CER 15 mg group 
Number of Sites:  
Approximately 10 sites in Russian Federation will be 
included  
Dose Level(s): 
 
Cyclobenzaprine HCl Extended Release, 15 mg, 
once daily  
 
Placebo of Cyclobenzaprine HCl Extended Release, 
once daily 
Route of Administration: 
Oral 
Duration of Treatment: 
14 days 
Period of Evaluation: 
Screening period - ≤5 days 
Treatment period – 14 days 
Follow up period – 21 days 
Total evaluation period is 35-40 days 
Main Criteria for Inclusion: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures.  
3. The Subject is experiencing for no more than 14 days cervical and/or lower back pain (as assessed by the subject) due 
to muscle spasms (confirmed by the physician) associated with musculoskeletal conditions (codes M54.2 Cervicalgia 
and/or M54.5 Low back pain according to ICD-10). 
4. The subject is male or female and aged 18 to 50 years, inclusive. 
5. Female subjects require to be either 2 years postmenopausal or surgically sterile by bilateral tubal ligation, 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 10 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
hysterectomy, or bilateral oophorectomy, or, if premenopausal, had to be using an approved contraceptive method. 
6. Female subjects of child-bearing potential must have a negative urine human chorionic gonadotropin (hCG) test 
result for pregnancy at study entry. 
7. After signing the informed consent form, the subject agrees not to make changes to dietary, exercise, or smoking 
habits and not to enter a weight loss program during his/her participation in the study. 
Main Criteria for Exclusion: 
1. The subject has muscular pain secondary to acute trauma or fractures (e.g., due to osteoporosis). Such conditions 
could have been ruled out based on medical history, x-ray, or physical examination; 
2. The subject suffers from muscle spasms/pain related to polymyalgia rheumatica or ankylosing spondylitis 
(Bekhterev's disease). Such conditions could have been ruled out based on medical history, x-ray, or physical 
examination; 
3. The subject has received any investigational compound within 30 days prior to Screening;  
4. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 1 month after 
participating in this study; or intending to donate ova during such time period; 
5. The subject has a history of drug abuse or recent (within the last 12 months) history of excessive alcohol consumption 
defined as >2 drinks/day (>3 oz of 80 proof alcohol or equivalent); 
6. Patients with mild, moderate, severe liver impairment; 
7. The subject is a study site employee, or is in a dependent relationship with a study site employee who is involved in 
conduct of this study or may consent under duress; 
8. The subject takes any concomitant medication including over-the-counter and herbal products for muscle spasms. If a 
subject is taking such medications, the medications has to be discontinued before starting the study; 
9. The subject takes or took within last 14 days medications, such as selective serotonin reuptake inhibitors (SSRIs), 
       serotonin norepinephrine reuptake inhibitors (SNRIs),  tricyclic antidepressants (TCAs), MAO inhibitors,                 
       tramadol, bupropion, meperidine, verapamil,  topical, anti-inflammatory medications; 
 
10. The subject takes or took within last 3 days medications, such as non-steroid anti-inflammatory drugs (NSAIDs), 
intramuscular vitamin injections containing anaesthetics (such as vitamin Milgamma); 
11. The subject has a history or clinical manifestations of significant medical condition, such as: hyperthyroidism, acute 
recovery phase of myocardial infarction, arrhythmias, heart block or conduction disturbances, congestive heart 
failure, angle-closure glaucoma, urinary retention, increased intraocular pressure. 
12. The subject has a known history of positive screen for hepatitis B surface antigen, hepatitis C antibody, or human 
immunodeficiency virus (HIV) antibody.  
13. The subject has a history of malignant disease  within 5 years prior to Screening.  
14. Drug abuse in anamnesis 
Main Criteria for Evaluation and Analyses: 
The primary endpoints for this study are: 
• 
The percentage of subjects with subject’s rating of medication helpfulness impression on Day 3 of treatment. 
Secondary endpoints for this study are: 
 
The percentage of subjects with physician’s clinical global assessment on Day 3 of treatment. 
 
The percentage of subjects with subject’s rating of medication helpfulness impression on Day 7 and 14 of 
treatment. 
 
The percentage of subjects with physician’s clinical global assessment on Day 7 and Day 15. 
 
The percentage of subjects with subject-rated global impression (relief from local pain, restriction in activities of 
daily living, restriction of movement, intensity of local pain) of  on Day 3, 7 and 14 of treatment. 
 
The percentage of subjects defined as responders on Day 3, 7 and 14 of treatment. 


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Company Confidential Information


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 12 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Coordinating Investigator  
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in the 
study. Selection criteria for this investigator will include significant knowledge of the study protocol, 
the study medication, their expertise in the therapeutic area and the conduct of clinical research as 
well as study participation. The Signatory Coordinating Investigator will be required to review and 
sign the clinical study report and by doing so agrees that it accurately describes the results of the 
study. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 13 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
3.3 
List of Abbreviations 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CER  
CNS 
Cyclobenzaprine HCl Extended Release  
central nervous system 
(e)CRF 
case report form (electronic or paper) 
CRO 
contract research organization 
CSR 
clinical study report 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCDT 
Global Clinical Development Team 
GCP 
Good Clinical Practice 
GGT 
-glutamyl transferase 
hCG 
HCl 
human chorionic gonadotropin 
hydrochloride 
HIV 
ICD-10 
human immunodeficiency virus 
International Classification of Diseases, 10th revision  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LFT 
MAO 
liver function tests 
monoamine oxidase 
MedDRA 
NSAIDs 
Medical Dictionary for Regulatory Activities 
nonsteroidal anti-inflammatory drugs  
PTE 
pretreatment event 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
SNRIs 
statistical analysis plan 
serotonin norepinephrine reuptake inhibitors 
SOP 
SSRIs 
TCAs 
standard operating procedure 
selective serotonin reuptake inhibitors 
tricyclic antidepressants 
ULN 
USP 
upper limit of normal 
United States Pharmacopeia 
WBC 
white blood cell 
WHO 
World Health Organization 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 14 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
3.4 
Corporate Identification  
TDC Japan 
Takeda Development Center Japan 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Centre Europe Ltd. 
TDC Americas 
Takeda Development Center Americas, Inc. 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 15 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
4.0 
INTRODUCTION 
4.1 
Background 
Neck or back pain due to muscle spasms may occur at almost any time during the life cycle.  
Chronic persistent low back and neck pain is seen in 25% to 60% of patients, one-year or longer after 
the initial episode. Spinal pain is associated with significant economic, societal, and health impact. 
Chronic pain syndrome has been defined as a complex condition with physical, psychological, 
emotional, and social components. The prevalence of chronic pain in the adult population ranges from 
2% to 40%, with a median point prevalence of 15%. [Manchikanti, L; Singh, V; Datta, S; Cohen, SP; 
Hirsch, JA; American Society of Interventional Pain, Physicians (Jul–Aug 2009). "Comprehensive 
review of epidemiology, scope, and impact of spinal pain.". Pain physician 12 (4): E35–70. PMID 
19668291]. 
Cyclobenzaprine hydrochloride (HCl) is a centrally acting skeletal muscle relaxant closely related to 
the tricyclic antidepressants that acts mainly on the brainstem to decrease tonic somatic motor 
activity. Some activity at spinal cord sites may also contribute to its therapeutic effects. It is used as an 
adjunct treatment for relief of muscle spasm associated with musculoskeletal conditions. 
Cyclobenzaprine may also provide relief in a small percentage of patients with fibromyalgia. 
Following oral administration, its effects begin within one hour and the effects of a single dose last as 
long as 12 to 24 hours. 
 
4.2 
Rationale for the Proposed Study 
Muscular tonic syndromes mostly occur in overstrained muscles. Patients with muscular tonic 
syndrome usually complain of pain either in spine or in shoulder and pelvic girdle muscles (in the 
lower back, neck, and shoulder). Pain usually decreases after rest, kneading and stretching the 
muscles. Muscular tonic syndrome can perform sanogenetic function, protecting the affected area 
from further damage. However, long-term persistent muscle spasm leads to negative consequences 
such as increased load on bony and ligamentous structures that accelerates the development of 
degenerative changes in the skeletal system. It can also lead to a transformation from muscular tonic 
syndrome to myofascial pain syndrome. 
The main feature of myofascial pain syndrome is the presence of trigger point (s) - the site of local 
muscle gelosis. Its stimulation causes local tenderness and irradiation of the pain. Trigger points can 
resolve spontaneously in the absence of supporting factors. On the contrary, preserving the original 
exposure pathogenic factor contributes to the formation of secondary triggers, and an increase in area 
of pain. 
In the treatment of muscular tonic pain the main role belongs to local interventions aimed at muscle 
relaxation or at the "destruction" of trigger points in case of myofascial pain syndrome. An effective 
pain control can significantly reduce the therapy terms and the use of NSAIDs, among others, is a 
common method of myofascial pain relieve. However their usage can be insufficient as they don’t 
affect the spasm itself.   


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 16 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
Muscle relaxants can be a substantial aid for muscular tonic and myofascial pain syndromes treatment 
as they reduce the intensity of pain, decrease painful muscle tension and improve physical activity. 
Pain caused by involvement of the intervertebral discs, the facet joints of the spine, muscles and other 
reasons increases the activity of the cord motor neurons. That results in muscle spasm, which plays a 
significant role in the maintenance of the pain syndrome. Pathologically increased muscle tone has 
various mechanisms to enhance pain: direct stimulation of pain receptors in the muscles or 
deterioration of muscles blood supply. These result in a vicious circle, leading to the muscle spasm 
and associated pain aggravation. Muscle relaxants break the "pain - muscle spasm - pain" circle and 
therefore are able to accelerate the convalescence process. [Danilov, A.; Russian Medical Journal, 
2010, #1].  Myorix is one of the muscle relaxants that can be used for treatment of pain associated 
with muscle spasms.  
Russian Federal Law #61-FZ (dated 12-Apr-2010) “About circulation of medicinal agents” requires 
that all new for Russian market pharmaceutical products for medical use should undergo clinical trials 
on Russian Federation territory before their registration. The Law allows not to conduct clinical trial 
for registration purposes if the Russian Federation was included previously in international 
multicentre clinical trials which have been conducted for the product. 
The main purpose of this study is to explore the efficacy and safety of Cyclobenzaprine 15 mg once 
daily in the treatment of acute cervical and/or lower back pain due to muscle spasms of local origin in 
Russian patients and to provide clinical trial data for Cyclobenzaprine market registration in Russian 
Federation. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 17 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
The primary objective of this study is to assess the effect of CER 15 mg once daily in subjects with 
muscle spasms associated with musculoskeletal conditions. 
5.1.2 Secondary Objective 
The secondary objective of this study is to assess the effect on subject rating parameters of CER 15 
mg once daily. 
5.1.3 Additional Objectives  
Safety objective 
The safety objective for this study is to assess the safety and tolerability of CER 15 mg once daily.  
 
5.2 
Endpoints 
5.2.1 Primary Endpoints 
• The percentage of subjects with subject’s rating of medication helpfulness impression on Day 
3 of treatment. 
5.2.2 Secondary Endpoints                                     
• The percentage of subjects with physician’s clinical global assessment on Day 3 of treatment. 
• The percentage of subjects with subject’s rating of medication helpfulness impression on Day 
7 and 14 of treatment. 
• The percentage of subjects with physician’s clinical global assessment on Day 7 and 15 of 
treatment. 
• The percentage of subjects with subject-rated global impression (relief from local pain, 
restriction in activities of daily living, restriction of movement, intensity of local pain) of  on 
Day 3, 7 and 14 of treatment. 
• The percentage of subjects defined as responders on Day 3, 7 and 14 of treatment. 
• The percentage of subjects with physician rated assessment of presence of muscle sparm, 
presence of local pain, limitation of range of motion, limitation of activities of daily living on 
Day 3, 7 and 15. 
5.2.3 Additional Endpoints  
Safety Endpoints 
 AEs. 
 Clinical laboratory tests (hematology, serum chemistry and urinalysis). 
 Vital sign measurements (weight, blood pressure, and heart rate). 
 12-lead electrocardiogram (ECG). 


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Company Confidential Information


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 20 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
Figure 6.a 
Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
 Study design including primary and secondary criteria for evaluation  and methods of 
measurement will be similar to previous pivotal Cyclobenzaprine studies in order to determine 
positive efficacy trend of Cyclobenzaprine 15 mg versus Placebo;   
 The randomized, double-blind, parallel, placebo-controlled design will reduce bias in different 
treatment regimens with respect to efficacy and safety.  Randomization will provide maximum 
assurance that subject characteristics are similar across the treatment groups. Blinding subjects 
and all study personnel who will be involved in their assessment to the study treatment will 
maintain the objectivity of the assessment;  
 A placebo arm has been added, since the primary endpoint is a subjective score and the placebo 
control allows to better evaluate the treatment effect of Cyclobenzaprine;  
 A placebo arm is acceptable because the study is of short duration and the cervical and/or lower 
back pain due to muscle spasms is not considered a life-threatening condition if untreated. 
Moreover, rescue therapy will be implemented in lack of efficacy cases before subject is 
discontinued from the study;   
 The dose level of Cyclobenzaprine 15 mg once daily is chosen for this study as the approved dose 
for the treatment of the pain due to muscle spasms of local origin. The Cyclobenzaprine 15 mg 
once daily has shown its efficacious and safe in adult patients with the pain due to muscle spasms, 
so it is expected that the same dose will be effective and safe in Russian patients. 
The endpoint assessment for this study will take place on Day 3 instead of Day 4 (as utilized in 1105 
and 1106 studies) which is based on cyclobenzaprine MR 30 mg pharmacokinetic parameters Tmax 
Randomization - 
Day 1 
Day 3 
+/-1 day 
Day 7 
+/-1 day 
Day 15 – Study 
Completion  
+ 1 day 
Visit 1 - 1st Dose 
Visit 2 
Visit 3 
Visit 4 
Screening (≤5 Days Prior 
to Randomization) 
Cyclobenzaprine HCl 
Extended Release 15 mg 
Placebo 
AE Follow up call  
(3 weeks after last 
IMP dose) +/-1 day 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 21 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
= 10.5±3.32 hours and t1/2 = 27.7±8.56 hours and implies capturing probable earlier clinical 
effects of the drug than it was shown in previous studies. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study. 
 New information or other evaluation regarding the safety or efficacy of the study medication that 
indicates a change in the known risk/benefit profile for Cyclobenzaprin HCl, such that the risk is 
no longer acceptable for subjects participating in the study. 
 Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve the 
primary study objectives or compromises subject safety. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure adequate 
performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee (IEC) 
or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be provided by 
the sponsor; the procedure will be followed by applicable investigational sites during the course of 
termination or study suspension. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 22 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures.  
3. The Subject is experiencing for no more than 14 days cervical and/or lower back pain (as assessed 
by the subject) due to muscle spasms (confirmed by the physician) associated with 
musculoskeletal conditions (defined by codes M54.2 Cervicalgia and/or M54.5 Low back pain 
according to ICD-10). 
4. The subject is male or female and aged 18 to 50 years, inclusive. 
5. Female subjects require to be either 2 years postmenopausal or surgically sterile by bilateral tubal 
ligation, hysterectomy, or bilateral oophorectomy, or, if premenopausal, had to be using an 
approved contraceptive method*. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.109.1.10 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.119.1.11 Pregnancy. 
 
6. Female subjects of child-bearing potential must have a negative urine human chorionic 
gonadotropin (hCG) test result for pregnancy at study entry. 
7. After signing the informed consent form, the subject agrees not to make changes to dietary, 
exercise, or smoking habits and not to enter a weight loss program during his/her participation in 
the study. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject has muscular pain secondary to acute trauma or fractures (e.g., due to osteoporosis). 
Such conditions could have been ruled out based on medical history, x-ray, or physical 
examination. 
2. The subject suffers from muscle spasms/pain related to polymyalgia rheumatica or ankylosing 
spondylitis (Bekhterev's disease). Such conditions could have been ruled out based on medical 
history, x-ray, or physical examination; 
3. The subject has received any investigational compound within 30 days prior to Screening.  
4. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or 
within 1 month after participating in this study; or intending to donate ova during such time 
period.  


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 23 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
5. The subject has a history of drug abuse or recent (within the last 12 months) history of excessive 
alcohol consumption defined as >2 drinks/day (>3 oz of 80 proof alcohol or equivalent). 
6. Patients with mild, moderate, severe liver impairment. 
7. The subject is an immediate family member,  study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.  
8. The subject takes any concomitant medication including over-the-counter and herbal products for 
muscle spasms. If a subject is taking such medications, the medications has to be discontinued 
before starting the study. 
9. The subject takes or took within last 14 days medications, such as: 
a. selective serotonin reuptake inhibitors (SSRIs); 
b. serotonin norepinephrine reuptake inhibitors (SNRIs); 
c.  tricyclic antidepressants (TCAs); 
d. MAO inhibitors; 
e. tramadol; 
f. bupropion;  
g. meperidine;  
h. verapamil;topical anti-inflammatory medications, including patches  
i. paracetamol 
j. opioid analgesics  
10. The subject takes or took within last 3 days medications, such as: 
a. non-steroid anti-inflammatory drugs (NSAIDs); 
b. Intramuscular vitamin injections containing anaesthetics (such as vitamin Milgamma). 
11. The subject has a history or clinical manifestations of significant medical condition, such as:  
a. hyperthyroidism;  
b. acute recovery phase of myocardial infarction; 
c. arrhythmias, heart block or conduction disturbances; 
d. congestive heart failure; 
e. angle-closure glaucoma; 
f. urinary retention; 
g. increased intraocular pressure. 
12. The subject has abnormal physical findings or a medical condition that might have placed the 
subject at risk or interfered with the subject’s ability to participate in the study. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 24 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
13. The subject has any known condition or disorder that might have affected absorption of the study 
drug. 
14. The subject has a history of hypersensitivity or allergies to cyclobenzaprine and/or tricyclic 
antidepressants or any of their components. 
15. The subject has a history of hypersensitivity to any NSAIDs including salicylate sensitivity.  
16. The subject has a history of thrombocytopenia. 
17. The subject has a history of gastro-intestinal bleeding, cerebrovascular bleeding or other bleeding 
disorders. 
18. The subject had active or history of recurrent peptic ulcer/haemorrhage (two or more distinct 
episodes of proven ulceration or bleeding) 
19. The subject has a history of severe renal impairment  
20. The subject had a major surgery during the 6 months preceding study entry. 
21. The subject has a language barrier or any other problems precluding good communication or 
cooperation. 
22. The subject has any reason to believe that he/she would not be able to complete the evaluations 
needed in this study. 
23. The subject has a known history of positive screen for hepatitis B surface antigen, hepatitis C 
antibody, or human immunodeficiency virus (HIV) antibody. 
24. The subject has a history of malignant disease  within 5 years prior to Screening.  
25. Drug abuse in anamnesis 
 
7.3 
Excluded Medications and Treatments 
 
Drug Class 
Disallowed Prior 
to Screening 
Disallowed During the Study for 
Chronic 
Use 
Episodic 
Use 
Comments or 
Exceptions 
Analgesics 
 tramadol 
 meperidine 
 paracetamol 
 opioid analgesics 
 
 
14 days 
14 days 
14 days 
14 days 
 
+ 
+ 
+ 
+ 
 
+* 
+* 
+* 
+* 
Concomitant use of 
Cyclobenzaprine with 
listed medications can 
lead to a potentially 
life-threatening 
serotonin syndrome 
and /or affect the study 
results. 
Antiarrhythmics 
 verapamil 
 
14 days 
 
+ 
 
+ 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 25 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
 
Antidepressants 
 selective serotonin 
reuptake inhibitors 
 serotonin 
norepinephrine 
reuptake inhibitors 
 tricyclic 
antidepressants 
 MAO inhibitors 
 
Bupropion 
 
 
14 days 
 
 
+ 
 
 
+ 
 
14 days 
+ 
+ 
 
14 days 
 
+ 
 
+ 
14 days 
+ 
+ 
14 days 
+ 
+ 
 Topical 
anti-inflammatory 
medications 
(including patches) 
14 days 
 
 
+ 
 
 
+* 
 
 
 
 NSAIDs 
 intramuscular 
vitamin injections 
containing 
anaesthetics (such 
as Milgamma)  
3 days 
3 days 
+ 
+ 
+* 
       + 
 
 
*Analgesics will be allowed only as add-on rescue therapy, to be used before the subject is 
discontinued due to lack of efficacy.  
Subjects will be instructed not to take any medications, including over-the-counter products, without 
first consulting with the investigator. 
Medications necessary for the well-being of the subject will be allowed during the study. 
7.4 
Diet, Fluid, Activity Control  and Treatment Facilities 
The subject will be asked not to make changes to dietary, exercise, or smoking habits and not to enter 
a weight loss program during his/her participation in the study. Subjects will be warned that 
cyclobenzaprine, especially when used with alcohol or other CNS depressants, may impair mental 
and/or physical abilities required for performance of hazardous tasks, such as operating machinery or 
driving a motor vehicle. 


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7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the case report form ([e]CRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.12. 
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
 Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.9), if the following circumstances occur at any time 
during study medication treatment: 
– alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented.  
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
(e)CRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE or 
lack of efficacy). 
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
6. Pregnancy. The subject is found to be pregnant.  
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.11. 
7. Lack of efficacy. The necessity to use rescue medication (any analgesics) AND/OR the 
investigator has determined that the subject is not benefiting from investigational treatment and, 
continued participation would pose an unacceptable risk to the subject.  
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF. 


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7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study when the 
subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by the 
investigator. In addition, efforts should be made to perform all procedures scheduled for the Early 
Termination Visit. Discontinued or withdrawn subjects will not be replaced. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including important 
sections describing the management of clinical trial material. 
8.1 
Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 Investigational drug 
Cyclobenzaprine HCl is a skeletal muscle relaxant which relieves muscle spasm of local origin 
without interfering with muscle function. The active ingredient in Cyclobenzaprine HCl 
extended-release capsules is cyclobenzaprine hydrochloride, USP. Cyclobenzaprine hydrochloride 
(HCl) is a white, crystalline tricyclic amine salt with the empirical formula C20H21N·HCl and a 
molecular weight of 311.9. It has a melting point of 217°C, and a pKa of 8.47 at 25°C. It is freely 
soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. 
If aqueous solutions are made alkaline, the free base separates. Cyclobenzaprine HCl is designated 
chemically as 3-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine 
hydrochloride, and has the following structural formula: 
 
Cyclobenzaprine HCl capsules contain the following inactive ingredients: diethyl phthalate NF, 
ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, Opadry® Clear YS-1-7006, sugar spheres 
NF (20-25 mesh), and titanium dioxide. Cyclobenzaprine HCl 15 mg capsules also contain D&C 
yellow #10, FD&C green #3, and FD&C red #40. 
The detailed information about the Drug, including list of AE is presented in the Protocol Appendix E. 
8.1.1.2 Rescue Medication 
NSAIDs, topical over-the-counter medications and other analgesics will be allowed as rescue therapy 
only and to be used before the subject is discontinued due to lack of efficacy. 
8.1.1.3 Sponsor-Supplied Drug 
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
Cyclobenzaprine ER (CER) 15 mg and Placebo will be supplied to the study sites as identical, similar 
size, opaque, white capsules packed into 40 cubic centimeters High Density Polyethylene bottles, 
containing 60 capsules. To avoid any overdose each study subjects will receive one 40 cubic 
centimeters High Density Polyethylene bottles, containing 20 capsules with CER 15 mg or Placebo, 


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CONFIDENTIAL 
according to their randomized treatment assignment according to the procedure outlined in Section 
9.3.2. 
8.1.2 Storage 
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 
8.1.3 Dose and Regimen 
Table 8.a 
Dose and Regimen 
Treatment 
Group 
Dose 
Treatment Description 
 
 
Active 
Placebo 
A 
Placebo QD 
N/A 
1 capsule of placebo, orally 
 
B 
Cyclobenzaprine 
15 mg QD 
1 capsule containing 15 mg of 
Cyclobenzaprine HCl 
Modified-Release, orally 
N/A 
 
 
 
 
 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational drug, to 
or by a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page of 
the (e)CRF, in order to capture this important safety information consistently in the database. Cases of 
overdose without manifested signs or symptoms are not considered AEs. AEs associated with an 
overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment Events and 
Adverse Events. 
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated in accordance with the  
compound-specific instructions.  
All of the cases of cyclobenzaprine HCl overdose which were reported to five regional poison centers 
were reviewed for the years 1989 to 1993. A total of 750 charts were identified with cyclobenzaprine 
HCl exposure; and of these, 523 charts had sufficient data for evaluation. There were 121 cases in 
which multiple drugs were involved, and 402 cases involving only the ingestion of cyclobenzaprine 
HCl. The ages of the patients ranged from 7 months to 77 years with a mean of 20 years; and children 


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6-years-old or younger comprised 26% of the overdose cases. Overall, 63% of the patients were 
females. 
None of the overdosed patients died. The most common adverse effects were lethargy, sinus 
tachycardia, and agitation. Both hypertension and hypotension were observed. Other than sinus 
tachycardia, dysrhythmias occurred infrequently; and none were life-threatening. No seizures 
occurred In situations where the times of ingestion were known, any symptoms of overdose were 
manifested within 4 hours. The ingested doses of cyclobenzaprine HCl ranged from 5 mg to 1000 mg 
with a mean of 133 mg. The mean dose of cyclobenzaprine HCl ingested by asymptomatic patients 
was 45 mg, and the mean dose of cyclobenzaprine HCl ingested by symptomatic patients was 183 mg 
[Spiller HA, Winter ML, Mann KV, Borys DJ, Muir S, Krenzelok EP. Five-year multicenter 
retrospective review of cyclobenzaprine toxicity. J Emerg Med. 1995 Nov-Dec;13(6):781-5.]. 
Treatment  
Treatment for overdose primarily involved symptomatic and supportive care. Rapid decontamination 
of the gastrointestinal tract was required. The other types of therapies used included mechanical 
ventilation, treatment with dopamine, the administration of a fluid bolus, sedation, and Foley 
catheterization. Overdoses with less than 100 mg of cyclobenzaprine HCl did not require treatment 
beyond gastrointestinal decontamination. Therefore, the recommended treatment for cyclobenzaprine 
HCl overdose begins with emptying the stomach as quickly as possible by emesis followed by gastric 
lavage. After gastric lavage, activated charcoal may be administered. Twenty grams to 30 g of 
activated charcoal may be given every 4 to 6 hours during the first 24 to 48 hours after ingestion. An 
electrocardiogram should be taken, and close monitoring of cardiac function must be instituted if 
there is any evidence of dysrhythmia. Maintenance of an open airway, adequate fluid intake, and 
regulation of body temperature are necessary. 
The intravenous administration of 1 mg to 3 mg of physostigmine salicylate is reported to reverse 
symptoms of poisoning by atropine and other drugs with anticholinergic activity; therefore, 
physostigmine may be helpful in the treatment of cyclobenzaprine HCl overdose. Because 
physostigmine is rapidly metabolized, the dosage should be repeated as required, particularly if 
life-threatening signs, such as arrhythmias, convulsions, and deep coma recur or persist after the 
initial dose of physostigmine. 
Because physostigmine itself may be toxic, it is not recommended for routine use.6 Standard medical 
measures should be used to manage circulatory shock and metabolic acidosis. Cardiac arrhythmias 
may be treated with neostigmine, pyridostigmine, or propranolol. When signs of cardiac failure occur, 
the use of a short-acting digitalis preparation should be considered. Close monitoring of cardiac 
function for not less than five days is advisable. 
Anticonvulsants may be given to control seizures. Dialysis is probably of no value because of the low 
plasma concentrations of cyclobenzaprine HCl.Since overdosage is often deliberate, patients may 
attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental 
overdosage have occurred with this class of drugs. 
In conclusion, cyclobenzaprine HCl does not appear to produce the life-threatening cardiovascular or 
neurologic effects of the cyclic antidepressants in doses less than 1 g. Lethargy and anticholinergic 
effects are prominent, though serious toxicity is infrequent. 


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8.2 
Investigational drug Assignment and Dispensing Procedures 
Subjects will be assigned to receive their treatment according to the schedule allocated to each study 
site. 
After ICF signing the investigator or investigator’s designee will access the IVRS/IWRS to obtain the 
subject study number. 
The investigator or the investigator’s designee will utilize the IVRS/IWRS to randomize the subject 
into the study. The medication identification (ID) number of the investigational drug will then be 
provided by the IVRS/IWRS. The investigational drug will be dispensed on the Baseline visit.  
8.3 
Randomization Code Creation and Storage  
The randomization code will be assigned via IVRS/IWRS.  
8.4 
Investigational Drug Blind Maintenance  
The investigational drug blind will be maintained using the IVRS/IWRS. 
8.5 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information concerning 
the investigational drug is necessary for the medical treatment of the subject. In the event of a medical 
emergency, if possible, the medical monitor should be contacted before the investigational drug blind 
is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IVRS/IWRS. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The date, 
time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the (e)CRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the subject 
must be withdrawn from the study.  
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use of 
sponsor-supplied drug (Cyclobenzaprin or placebo), the investigator or designee must maintain 
records of all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each 
subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by signing bottom half of the packing list and sending 
by e-mail per instructions provided at site initiation visit. If there are any discrepancies between the 


Cyclobenzaprine HCl Extended Release 
 
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Page 32 of 79 
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CONFIDENTIAL 
packing list versus the actual product received, Takeda and/or its designee must be contacted to 
resolve the issue. The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs, 
received and dispensed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to: 
 Continuously monitoring expiration dates  
 Frequently verifying that actual inventory matches documented inventory. 
 Verifying that the log is completed for each Medication ID number received / dispensed at the 
site. 
 Verifying that all containers used are documented accurately on the log. 
 Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately. 
The IVRS/IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a minimum: 
protocol number and title, name of investigator, site identifier and number, description of 
sponsor-supplied drugs, expiry date and amount dispensed including initials, seal, or signature of the 
person dispensing the drug, and the date and amount returned to the site by the subject, including the 
initials, seal, or signature of the person receiving the sponsor-supplied drug. The log should include 
all required information as a separate entry for each subject to whom sponsor-supplied drug is 
dispensed.  
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee will 
perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied drugs are 
returned to the sponsor or its designee for destruction. The investigator or designee will retain a copy 
of the documentation regarding sponsor-supplied drug accountability, return, and/or destruction, and 
originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied drug 
during the study conduct. On expiry date notification from the sponsor or designee, the site must 
complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, Takeda 
or its designee will prepare additional labels, certificates of analyses, and all necessary documentation 
for completion of the procedure at the sites. 


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CONFIDENTIAL 
9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix AAppendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the time 
that informed consent is obtained; this subject number will be used throughout the study. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, and smoking status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.8). 
Medication history information to be obtained includes any medication relevant to eligibility criteria 
and efficacy/safety evaluation stopped at or within 14 days prior to signing of informed consent. 
9.1.3 Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of investigational drug) 
will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other (if applicable). All 
subsequent physical examinations should assess clinically significant changes from the assessment 
prior to first dose examination. 
9.1.4 Weight, Height 
A subject should have weight and height  measured while wearing indoor clothing and with shoes off.   
9.1.5 Vital Sign Procedure 
Vital signs will include sitting blood pressure (resting more than 5 minutes), and pulse (bpm). 
9.1.6 Primary Efficacy Measurement  
The measures of effectiveness in this study will include: 
 Subject’s rating of medication helpfulness:  
 


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Page 34 of 79 
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CONFIDENTIAL 
Subjects will be asked to assess it on a daily basis (in the daily diary), using the following 
5-point rating scale: “How would you rate this study medication in improving your 
condition?" 
“0 = poor” 
“1 = fair” 
“2 = good” 
“3 = very good” 
“4 = excellent” 
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 Physician’s clinical global assessment : 
 
The investigator will be asked to assess their clinical global impression of change compared to 
Baseline, based on physical examination, degree of muscle spasm (presence of muscle spasm 
assessment), reaction to palpation (presence of local pain assessment), limitation of range of 
motion, and evaluation of the patient's reported functional assessment (limitation of activities 
of daily living assessment). The following 5-point rating scale will be used: 
“1 = worse” 
"2 = no change" 
"3 = slight improvement" 
"4 = moderate improvement" 
“5 = marked improvement” 
Assessment will be made for the Day 3, 7 and 15. 
 
 The subject-rated relief from local pain: 
Subjects will be asked to assess on a daily basis (in the daily diary) their level of relief from 
local pain due to the muscle spasm (in either the lower back or cervical spine) compared to 
Baseline (Visit 1) using the following 5-point rating scale: 
"1 = no relief” 
“2 = a little relief” 
“3 = some relief” 
“4 = a lot of relief” 
“5 = complete relief”  
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 The subject-rated restriction in activities of daily living: 
Subjects will be asked to assess on a daily basis (in the daily diary) the change in the severity 
of restriction in the activities of daily living compared to Baseline (Visit 1) using the following 
5-point rating scale: 
“1 = worsening” 
“2 = no change” 
“3 = mild improvement:” 
“4 = moderate improvement” 
”5 = marked improvement”  
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 


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Cyclobenzaprine HCl Extended Release 
 
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CONFIDENTIAL 
 
 Limitation of range of motion 
The physician was asked to assess at each visit, the subject’s limitation of range of motion 
using the following 5-point rating scale: 
“1 = none” (no limitation in range of motion) 
“2 = mild” (restriction of the normal motion by 10-15%) 
“3 = moderate” (restriction of the motion by no more than 50%) 
“4 = moderately severe” (restriction of the expected motion by no more than 80%) 
“5 = severe” (the subject has great difficulty in attempting to perform one or more of the major 
motions) 
 
 Limitation of activities of daily living 
The physician was asked to assess by both direct observation and historical questioning, the 
limitation of activities of daily living using the following 5-point rating scale at each visit: 
“1 = none” (no limitation of activities of daily living) 
“2 = mild” (the subject is able to perform his customary tasks, but with discomfort) 
“3 = moderate” (the subject is able to perform partially with discomfort some essential tasks 
and activities) 
“4 = moderately severe” (the subject performs partially with great difficulty some essential 
tasks and activities) 
“5 = severe” (the subject is unable to perform most of the essential tasks or activities) 
 
9.1.7 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is not 
provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the end of 
the study), and all medication including vitamin supplements, over-the-counter medications, and oral 
herbal preparations, must be recorded in the (e)CRF. 
 
9.1.8 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present at 
signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at screening examination. The condition (ie, 
diagnosis) should be described. 
9.1.9 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 10 mL, and the approximate total volume of 
blood for the study is 20 mL.  


Cyclobenzaprine HCl Extended Release 
 
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CONFIDENTIAL 
Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Red blood cells (RBC) 
White blood cells (WBC) 
Hemoglobin 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
pH 
Protein 
 
Other: 
Urine 
hCG for pregnancy (only for female subjects of childbearing 
potential) 
 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and urinalysis. 
The results of laboratory tests will be returned to the investigator, who is responsible for reviewing 
and filing these results. 
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT) should be performed within a maximum of 7 
days and preferably within 48-72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.) 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator must 
contact the Medical Monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study medication, discussion of the relevant subject details and possible alternative 
etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3 Reporting of 
Abnormal Liver Function Tests for reporting requirements). 
The investigator or designee is responsible for transcribing or attaching laboratory results to the 
(e)CRF. The investigator will maintain a copy of the laboratory accreditation and the reference ranges 
for the laboratory used. 
9.1.10 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 3 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female partner 
of childbearing potential* must use barrier contraception (eg, condom with spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. 
From signing of informed consent (for oral contraceptives – for at  least 90 days prior to Screening), 
throughout the duration of the study, and for 3 weeks after last dose of study medication, female 
subjects of childbearing potential* who are sexually active with a nonsterilized male partner** must 
use adequate contraception. In addition they must be advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined as at 
least 1 year since last regular menses with an FSH >40 IU/L or at least 2 years since last regular 


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CONFIDENTIAL 
menses, confirmed before any study medication is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. In 
this study the acceptable methods of contraception are:  
Barrier methods (each time the 
subject has intercourse): 
Intrauterine devices 
(IUDs): 
Hormonal 
contraceptives***: 
 Male condom PLUS spermicide. 
 Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide. 
 Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide. 
 Copper T PLUS condom 
or spermicide. 
 #Progesterone T PLUS 
condom or spermicide. 
 Implants. 
 Hormone shot/injection. 
 Combined pill. 
 Minipill. 
 Patch. 
 Vaginal ring PLUS male 
condom and spermicide. 
***In case oral contraceptives are used for less than 90 days before screening barrier methods should 
be used in addition to oral contraceptives.  
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they understand 
the requirements for avoidance of pregnancy, donation of ova during the course of the study. 
During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy tests 
will be performed only for women of childbearing potential and subjects will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures (Appendix 
AAppendix A). 
9.1.11 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 12 weeks after the last dose, should also be recorded 
following authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study medication, eg, after Visit 1 or within 21 
days of the last dose of active study medication, the pregnancy should be reported immediately, using 
a pregnancy notification form, to the contact listed in Section 1.0. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. Subjects 
randomized to placebo need not be followed. 
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time she 


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Study No. CYC-RR-001 
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CONFIDENTIAL 
became pregnant and provide details of treatment the subject received (blinded or unblinded, as 
applicable). 
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The outcome, 
including any premature termination, must be reported to the sponsor. An evaluation after the birth of 
the child will also be conducted. 
9.1.12 ECG Procedure 
A standard 12-lead ECG will be recorded at Screening and Study termination. The investigator (or a 
qualified observer at the investigational site) will interpret the ECG using 1 of the following 
categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically 
significant. 
9.1.13 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is found to be not eligible at this visit, the investigator should complete the (e)CRF. 
The data to be collected in CRF for Screen Failures as a minimum: Subject Number and Initials, Date 
of Informed consent, Demographics data, Inclusion/Exclusion criteria, PTEs/SAEs, Date of Screen 
failure. 
The primary reason for screen failure is recorded in the (e)CRF using the following categories: 
 PTE/AE. 
 Did not meet inclusion criteria or did meet exclusion criteria.  
 Significant protocol deviation. 
 Lost to follow-up. 
 Voluntary withdrawal (specify reason). 
 Study termination. 
 Other (specify reason). 
Subject numbers assigned to subjects who fail screening should not be reused. 
9.1.14 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible for 
randomization into the treatment phase. 
If the subject is found to be not eligible for randomization, the investigator should record the primary 
reason for failure on the applicable (e)CRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be required to bring the dispensed study medication bottle to each site visit.  
Treatment compliance will be checked by Investigator at Visits 2, and 3. In case of compliance 
deviation all subjects should be reinstructed about the dosing requirement during study contacts. The 


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Study No. CYC-RR-001 
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CONFIDENTIAL 
authorized study personnel conducting the re-education must document the process in the subject 
source records. 
Treatment compliance for entire treatment period will be calculated at V4 using the formula: 
Compliance in % = (# tablets taken during treatment period / # tablets to be taken during treatment 
period)*100 
Any noncompliance from the administered dose must be documented as protocol deviation. 
If treatment compliance is outside of 70% - 130% ranges for the entire treatment period, it should be 
reported as significant protocol deviation. 
 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix AAppendix A. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 Screening  
Subjects will be screened within ≤5 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See Section 
9.1.12 for procedures for documenting screening failures. 
Procedures to be completed at Screening include: 
 Informed consent. 
 Demographics, medical history and medication history. 
 Physical examination. 
 Vital signs. 
 Weight. 
 Height 
 ECG procedure. 
 Concomitant medications.  
 Concurrent medical conditions. 
 Collection of blood and urine samples for hematology, serum chemistry, urine pregnancy testing 
(if applicable), and urinalysis. 
 Assessment of Inclusion/Exclusion Criteria   
 Pre-Treatment Events   
9.3.2 Randomization 
Randomization will take place on Day1 (could be the same day at which Screening visit took place). 
The following procedures will be performed and documented during Randomization: 


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Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 43 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
9.3.3 Visit 2 (Day 3) and Visit 3 (Day 7)  
Subjects will visit the clinic on Day 3  and on Day 7. The following assessments will be performed at 
the both visits: 
 Vital Signs.   
 concomitant medications.  
 Adverse Events.  
 The investigator will assess: presence of muscle spasm, presence of local pain, limitation of 
activities of daily living, and limitation of range of motion. 
 Physician’s clinical global assessment based on presence of muscle spasm, presence of local pain, 
limitation of range of motion, and limitation of activities of daily living will be recorded.  
 Subject diaries will be reviewed. Completed pages will be collected by Investigator, then the diary 
will be despensed to subject again. 
 Study drug returned and medication compliance checked, then study drug will be dispensed again. 
9.3.4 Visit 4 (Day 15) or Early Termination 
The Visit 4 will be performed on Day 15 or at the Early Termination Visit. The following procedures 
will be performed and documented: 
 Physical examination. 
 Vital signs. 
 Weight 
 Collection of blood and urine samples for hematology, serum chemistry, urine pregnancy testing 
(if applicable), and urinalysis. 
 Inquiry regarding any concomitant medications. 
 Inquiry for Adverse Events.  
 ECG procedure. 
 The investigator will assess: presence of muscle spasm, presence of local pain, limitation of 
activities of daily living, and limitation of range of motion. 
 Physician’s clinical global assessment based on presence of muscle spasm, presence of local pain, 
limitation of range of motion, and limitation of activities of daily living was recorded. 
 Subject diary collection and review.  
 Unused study drug return and compliance calculation. 
 For all subjects receiving study medication, the investigator must complete the End of Study 
(e)CRF page. 
9.3.5 Follow-up call 
Follow-up telephone calls will be used to monitor AEs for 3 weeks after the last dose of study drug. 


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9.3.6 Post Study Care 
The study medication will not be available upon completion of the subject’s participation in the study. 
The subject should be returned to the care of a physician and standard therapies as required. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study medication; 
it does not necessarily have to have a causal relationship with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject administered 
a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or not it 
is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent events 
for pre existing conditions underlying disease should not be considered PTEs or AEs.) 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in dose of study medication or a concomitant medication. 
 Be considered unfavorable by the investigator for any reason. 
 PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE. 
Diagnoses vs signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as a 
PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
 Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention. 


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 If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported 
appropriately as a PTE or as an AE. 
Pre-existing conditions: 
 Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline evaluations 
(eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a concurrent 
condition, the worsening or complication should be recorded appropriately as a PTE (worsening 
or complication occurs before start of study medication) or an AE (worsening or complication 
occurs after start of study medication). Investigators should ensure that the event term recorded 
captures the change in the condition (eg, “worsening of…”). 
 If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the change 
in the condition from Baseline (eg “worsening of…”). 
 If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”). 
Worsening of PTEs or AEs: 
 If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
 If the subject experiences changes in severity of an AE/serious PTE, the event should be captured 
once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of informed 
consent are not considered PTEs or AEs. However, if a preplanned procedure is performed early 
(eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of the 
condition should be captured appropriately as a PTE or an AE. Complications resulting from any 
planned surgery should be reported as AEs. 


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Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition should 
not be recorded as PTEs or AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
 Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as an 
AE. The investigator must make the distinction between exacerbation of pre-existing illness and 
lack of therapeutic efficacy. 
Overdose: 
 Cases of overdose with any medication without manifested side effects are NOT considered PTEs 
or AEs, but instead will be documented on an Overdose page of the (e)CRF. Any manifested side 
effects will be considered PTEs or AEs and will be recorded on the AE page of the (e)CRF. 
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
 The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life threatening or 
fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Takeda Medically Significant AE List  
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylaxis 


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Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis  
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Confirmed or suspected transmission of infectious agent by a 
medicinal product 
 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be ruled 
out, although factors other than the drug, such as underlying diseases, complications, concomitant 
drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed as 
Not Related.  
10.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject and/or 
physician. 
10.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 


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10.1.10 Frequency  
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication  
 Drug withdrawn – a study medication is stopped due to the particular AE. 
 Dose not changed – the particular AE did not require stopping a study medication. 
 Unknown – only to be used if it has not been possible to determine what action has been taken. 
 Not Applicable – a study medication was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study medication was already stopped 
before the onset of the AE. 
10.1.12 Outcome 
 Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 
 Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the particular 
AE/PTE with the condition remaining “recovering/resolving”. 
 Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the intensity 
of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed study period 
has got worse than when it started; is an irreversible congenital anomaly; the subject died from 
another cause with the particular AE/PTE state remaining “Not recovered/not resolved”. 
 Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with some 
persisting paresis. 
 Fatal – the AEs/PTEs which are considered as the cause of death.  
 Unknown – the course of the AE/PTE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to participate 
in the study and continue until the subject is first administered study medication (Visit 1) or until 
screen failure. For subjects who discontinue prior to study medication administration, PTEs are 
collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study medication 
(Visit 1). Routine collection of AEs will continue 3 weeks after the last dose of study drug.  


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10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?” may be asked. Subjects may 
report AEs occurring at any other time during the study. Subjects experiencing a serious PTE must be 
monitored until the symptoms subside and any clinically relevant changes in laboratory values have 
returned to baseline or there is a satisfactory explanation for the change. Non-serious PTEs, related or 
unrelated to the study procedure, need not to be followed-up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study medication or 
not, must be monitored until the symptoms subside and any clinically relevant changes in laboratory 
values have returned to baseline or until there is a satisfactory explanation for the changes observed. 
All PTEs and AEs will be documented in the PTE/AE page of the (e)CRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information will 
be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Severity. 
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs). 
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of the 
suspected procedure. 
6. Action concerning study medication (not applicable for PTEs). 
7. Outcome of event. 
8. Seriousness. 
Patient diaries will not be used as a primary means to collect AEs. However, should the investigator 
become aware of a potential AE through the information collected with this instrument, proper 
follow-up with the patient for medical evaluation should be undertaken. Through this follow-up if it is 
determined that an AE not previously reported has been identified, normal reporting requirements 
should be applied. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the study medication(s) 


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 Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in Section 
1.1.  
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.2.3 Reporting of Abnormal Liver Function Tests  
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. If a subject is noted to have ALT or AST >3 ×ULN and 
total bilirubin >2 ×ULN for which an alternative etiology has not been identified, the event should be 
recorded as an SAE and reported as per Section 10.2.210.2.2. The investigator must contact the 
Medical Monitor for discussion of the relevant subject details and possible alternative etiologies, such 
as acute viral hepatitis A or B or other acute liver disease or medical history/concurrent medical 
conditions. Follow-up laboratory tests as described in Section 9.1.9 must also be performed.  
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and fax it 
immediately, within 24 hours of receipt. Copies of any relevant data from the hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or IECs, 
as applicable, in accordance with national regulations in the countries where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited report within 7 days 
for fatal and life-threatening events and 15 days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues where 
these might materially alter the current benefit-risk assessment of an investigational medicinal 
product or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a copy of 
all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be used 
in this study.  


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary. 
12.1 
CRFs  
Completed (e)CRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. (e)CRFs must be completed in English.  
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda personnel 
(or designees) and will be answered by the site.  
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included.  
The principal investigator must review the (e)CRFs for completeness and accuracy and must sign and 
date the appropriate (e)CRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the (e)CRFs. 
 
(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic visits by 
study monitors. The sponsor or its designee will be permitted to review the subject’s medical and 
hospital records pertinent to the study to ensure accuracy of the (e)CRFs. The completed (e)CRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, except 
for authorized representatives of appropriate governmental health or regulatory authorities, without 
written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all participating 
subjects, medical records, temporary media such as thermal sensitive paper, source worksheets, all 
original signed and dated informed consent forms, subject authorization forms regarding the use of 
personal health information (if separate from the informed consent forms), {copies of all paper CRFs 
and query responses/ electronic copy of eCRFs, including the audit trail}, and detailed records of drug 
disposition to enable evaluations or audits from regulatory authorities, the sponsor or its designees. 
Any source documentation printed on degradable thermal sensitive paper should be photocopied by 
the site and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application is not 


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approved, until at least 2 years after the investigation is discontinued and regulatory authorities are 
notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until an 
amount of time specified by applicable regulatory requirements or for a time specified in the Clinical 
Study Site Agreement between the investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. Unblinding of subject’s treatment assignment will only occur after database 
lock. This document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
The Full Analysis Set (FAS) will consist of subjects who received at least one dose of investigation 
product.  Subjects in the FAS population will be analysed according to their original treatment 
assignment regardless of the treatment received.  
The safety analysis set will consist of subjects who received at least one dose of investigational 
product.  Subjects in the safety population will be analysed according to their treatment received, 
regardless of treatment assigned; subjects who received ≥ 1 dose of CER 15 mg will be analyzed in 
the CER 15 mg treatment group.  
The per-protocol (PP) analysis set will consist of subjects no major protocol violations, and who 
received at least 1 dose of investigational product. 
13.1.2  Analysis of Demographics and Other Baseline Characteristics 
All data collected in this study will, where applicable, be summarised by treatment regimen using 
descriptive statistics.  For continuous variables mean values, standard deviations, median and lower 
and upper percentiles, minimum and maximum will be calculated.  For categorical variables 
frequencies and percent will be calculated. 
13.1.3  Efficacy Analysis 
All efficacy analyses will be based on an FAS subject population.  The primary efficacy endpoint will 
also be analysed using the PP subject population.  Unless otherwise specified, all statistical tests will 
be conducted against a 2-sided alternative hypothesis at the 0.05 level of significance.   
For all efficacy evaluations, if the subject discontinued the double-blind treatment phase prior to Day 
15, the last available post treatment (final) evaluation was used to estimate the remaining missing 
evaluations (ie, last observation carried forward [LOCF]). For reference, the observed values were 
summarized and analyzed using the same methods as the LOCF values.  
Primary Efficacy Endpoints 
For the primary efficacy analysis, the subject's rating of medication helpfulness at Day 3 will be 
analyzed for the difference between the Placebo and the 15mg CER treatment group using a 2-sample 
Wilcoxon rank sum test. The primary end point is a 5-point ordinal rating scale from 0=Poor to 
4=Excellent. This study will evaluate differences between Placebo and CER treatment on the 
percentages for each of the 5-grade scale categories. Therefore, the 2-sample Wilcoxon sum rank test 


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will compare the shift of ordinal distributions of responses in both treatment groups. Only differences 
between the treatment groups at the significance level of 0.05 will be considered statistically 
significant. Frequency counts and percentages showing the distribution of the subject's rating of 
medication helpfulness at Day 3 will be provided to summarize these parameters.  
A supportive analysis on responders will be done to confirm the results of the primary analysis. A 
responder will be defined as a subject who had a rating of either "very good" or "excellent" for the 
subject's rating of medication helpfulness at Day 3 . A continuity-adjusted Chi-square test will be used 
to compare the number of "responders" between the Placebo and the CER treatment group. The 
number and percent of subjects who met the definition of responder at Day 3 will be presented. 
The primary analysis and supportive analysis will be repeated for day 7 and day 14. 
Trends in the distribution of ratings by treatment group will be compared across the 3 visits to 
determine if there were any qualitative differences in the pattern of treatment response. Differences 
between treatments in the distribution of ratings at the 3 visits will analysed using a weighted least 
squares model for marginal homogeneity including a parameter for treatment and treatment-by-visit 
interaction. Trends over time in the proportion of responders among the treatment groups will be 
assess assessed qualitatively by comparing the patterns of change in proportion of responders from 
Day 3 through Day 14. Repeated-measures analysis of proportions using Generalized Estimating 
Equations (GEE) will be used for comparisons among treatments of the trend in proportion of 
responders over time. 
Time to improvement in subject’s rating of medication helpfulness will be defined as the number of 
days from the start of treatment to the first time there was an assessment of “fair” to “excellent”. If the 
subject did not have any improvement in their rating of medication helpfulness, time to improvement 
was censored and equaled the number of days from the start of treatment to the last measurement 
during the study. The Kaplan-Meier curves will be compared using the generalized Wilcoxon test for 
survival analysis. 
Secondary Efficacy Endpoints 
The following subject’s ratings will be analyzed and summarized: relief from local pain due to muscle 
spasm, restriction in activities of daily living, restriction of movement, and clinical global impression. 
Time to improvement of subject-rated relief from local pain will be analyzed.  
Subject Ratings 
The subject’s ratings will analyzed separately for the differences between the Placebo and CER 
treatment group using a 2-sample Wilcoxon rank sum test. 
Time to improvement of subject-rated relief from local pain will be defined as the number of days 
from the start of treatment to the first time there was an assessment of “a little relief” to “complete 
relief”. If the subject did not have any improvement in their rating of relief from local pain, time to 
improvement was censored and equaled the number of days from the start of treatment to the last 
measurement recorded for the subject during the study. The Kaplan-Meier curves will be compared 
using the generalized Wilcoxon test for survival analysis. 
Other Efficacy Endpoints 
The physician’s clinical global assessment on Days 3, 7 and 15 of treatment will be analysed in the same 
way as the primary endpoint. 


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Company Confidential Information


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13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
A sample size of at least 77 subjects in each treatment group (total of 154 subjects) is needed to detect 
a difference between Placebo and CER 15 mg in subject’s rating of medication helpfulness 
impression, using a 2-sample Wilcoxon rank sum test with 80% power at a 2-sided significance level 
of 0.05 (Kolassa, J. E. (1995), "A Comparison of Size and Power Calculations for the Wilcoxon 
Statistic for Ordered Categorical Data," Statistics in Medicine, 14, 1577–1581). The assumed 
difference to be detected is based on the observed distribution of the ordinally scored rating scale for 
the respective treatment groups in study 1106. Assuming a 15% dropout rate, 90 subjects in each 
treatment group (total of 180 subjects) will be randomized. 


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14.0 
CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded on 
the (e)CRFs. Source documents are defined as original documents, data, and records. The investigator 
and institution guarantee access to source documents by the sponsor or its designee (CRO) and by the 
IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee (as 
long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, study 
medication, subject medical records, informed consent documentation, documentation of subject 
authorization to use personal health information (if separate from the informed consent forms), and 
review of (e)CRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event of a 
significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as required). 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, increase 
the health risk to the subject, or confound interpretation of primary study assessment. A Protocol 
Deviation Form should be completed by the site and signed by the sponsor or designee for any 
significant deviation from the protocol.  
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an auditing 
visit. The auditor may ask to visit the facilities where laboratory samples are collected, where the 
medication is stored and prepared, and any other facility used during the study. In addition, there is the 
possibility that this study may be inspected by regulatory agencies, including those of foreign 
governments (eg, the FDA, the United Kingdom Medicines and Healthcare products Regulatory 
Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the study site is contacted for 
an inspection by a regulatory body, the sponsor should be notified immediately. The investigator and 
institution guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and titles 
of members who make up the respective IRB or IEC. If any member of the IRB or IEC has direct 
participation in this study, written notification regarding his or her abstinence from voting must also 
be obtained.  
The sponsor or designee will supply relevant documents for submission to the respective IRB or IEC 
for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before commencement 
of the study (ie, before shipment of the sponsor-supplied drug or study specific screening activity). 
The IRB or IEC approval must refer to the study by exact protocol title, number, and version date; 
identify versions of other documents (eg, informed consent form) reviewed; and state the approval 
date. The sponsor will ship drug once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from competent authority 
to begin the trial. Until the site receives drug no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, reports 
and updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must be 
approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all applicable 
laws and regulations. The informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting the 
study. The informed consent form and the subject information sheet (if applicable) further explain the 
nature of the study, its objectives, and potential risks and benefits, as well as the date informed 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 61 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
consent is given. The informed consent form will detail the requirements of the participant and the 
fact that he or she is free to withdraw at any time without giving a reason and without prejudice to his 
or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, subject 
authorization form (if applicable), and subject information sheet (if applicable) must be approved by 
both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information sheet 
(if applicable) must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in the 
study, then the informed consent form and subject authorization form (if applicable) must be signed 
and dated by the subject, or the subject’s legally acceptable representative, at the time of consent and 
prior to the subject entering into the study. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using blue or black 
ballpoint ink. The investigator must also sign and date the informed consent form and subject 
authorization (if applicable) at the time of consent and prior to subject entering into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The investigator 
must document the date the subject signs the informed consent in the subject’s medical record. Copies 
of the signed informed consent form, the signed subject authorization form (if applicable), and subject 
information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the relevant 
subject’s legally acceptable representative in the same manner as the original informed consent. The 
date the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised informed consent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection against 
invasion of privacy. Throughout this study, a subject’s source data will only be linked to the sponsor’s 
clinical study database or documentation via a unique identification number. As permitted by all 
applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth, and 
subject initials may be used to verify the subject and accuracy of the subject’s unique identification 
number. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 62 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific authorization of 
the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain personally 
identifiable information removed (ie, subject name, address, and other identifier fields not collected 
on the subject’s [e]CRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by law 
or regulation. Except as otherwise allowable in the clinical study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for any 
peer-reviewed publication will appropriately reflect contributions to the production and review of the 
document. All publications and presentations must be prepared in accordance with this section and the 
Clinical Study Site Agreement. In the event of any discrepancy between the protocol and the Clinical 
Study Site Agreement, the Clinical Study Site Agreement will prevail. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator.  
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly 
accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and recruiting 
status will be registered and available for public viewing.  
For some registries, Takeda will assist callers in locating trial sites closest to their homes by providing 
the investigator name, address, and phone number to the callers requesting trial information. Once 
subjects receive investigator contact information, they may call the site requesting enrollment into the 
trial. The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial enrollment, 
they should be referred to the sponsor.  


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 63 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.  
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. Refer 
to the Clinical Study Site Agreement regarding the sponsor’s policy on subject compensation and 
treatment for injury. If the investigator has questions regarding this policy, he or she should contact 
the sponsor or sponsor’s designee. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 64 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
16.0 
REFERENCES 
1 Katz WA, Dube J. Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of 
clinical experience. Clin Ther 1988;10:216-28. 
2 Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The effects of cyclobenzaprine on sleep physiology 
and symptoms in patients with fibromyalgia. J Rheumatol 1991;18:452-4. 
3 Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline, cyclobenzaprine, and placebo 
in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum 
1994;37:32-40. 
4 Cramer MP, Saks SR. Translating safety, efficacy and compliance into economic value for 
controlled release dosage forms. Pharmacoeconomics 1994;5:482-504. 
5 Cyclobenzaprine hydrochloride MR Capsules, 15 and 30 mg. Chemistry, Manufacturing and 
Controls Information IND #62,261 Amendment. ECR Pharmaceuticals. To be submitted to the FDA 
June 2002. 
6 Physicians' Desk Reference 2002: Edition 56. Montvale, NJ: Medical Economics Company, Inc.; 
2002:2094-5. 
7 Parfitt K, Ed. Martindale: The Complete Drug Reference. Edition 32. London, UK: Pharmaceutical 
Press; 1999:273-8,1313. 
8 Quimby LG, Gratwick GM, Whitney CD, Block SR. A randomized trial of cyclobenzaprine for the 
treatment of fibromyalgia. J Rheumatol 1989;19(suppl):140-3. 
9 Elliott WJ, Prisant LM. Drug delivery systems for antihypertensive agents. Blood Press Monit 
1997;2:53-60. 
10 Prisant LM, Bottini B, DiPiro JT, Carr AA. Novel drug-delivery systems for hypertension. Am J 
Med 1992;93(suppl.2A):45S-55S. 
11 Col N, Fanale JE, Kronholm P. The role of medication noncompliance and adverse drug reactions 
in hospitalizations of the elderly. Arch Intern Med 1990;150:841-5. 
12 Darnell JC, Murray MD, Martz BL, Weinberger M. Medication use by ambulatory elderly. An 
in-home survey. J Am Geriatrics Soc 1986;34:1-4. 
13 Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin 
Ther 1984;6:592-9. 
14 Harper KJ, Forker AD. Antihypertensive therapy. Current issues and challenges. Postgrad Med 
1992;91:163-6, 171-4, 179-86 passim. 
15 Wright EC. Non-compliance -- or how many aunts has Matilda? Lancet 1993;342:909-13. 
16 Skaer TL, Sclar DA, Robison LM, Won JKH, Markowski DJ. Effect of pharmaceutical 
formulation on health care expenditures for hypertension: a study of verapamil in a Medicaid 
population. Curr Ther Res 1993;53:256-64. 
17 Skaer TL, Sclar DA, Robison LM, Markowski DJ, Won JK. Effect of pharmaceutical formulation 
for diltiazem on health care expenditures for hypertension. Clin Ther 1993;15:905-11. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 65 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
18 Murdoch D, Brogden RN. Sustained release nifedipine formulations. An appraisal of their current 
uses and prospective roles in the treatment of hypertension, ischaemic heart disease and peripheral 
vascular disorders. Drugs 1991;1:737-79. 
19 Kleinbloesem CH, van Brummelen P, Danhof M, Faber H, Urquhart J, Breimer DD. Rate of 
increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects 
in humans. Clin Pharmacol Ther 1987;41:26-30. 
20 McMahon FG, Jain AK, Vargas R, Fillingim J. A double-blind comparison of transdermal 
clonidine and oral captopril in essential hypertension. Clin Ther 1990;12:88-100. 
21 Dimenas ES, Dahlof CG, Heibel B, et al. Subjective symptoms and pharmacokinetics/dynamics of 
metoprolol CR in elderly subjects - a comparison with atenolol. Eur J Clin Pharmacol 1990;38:571-8. 
22 Santandrea S, Montrone F, Sarzi-Puttini P, Boccassini L, Caruso I. A double-blind crossover study 
of two cyclobenzaprine regimens in primary fibromyalgia syndrome. J Int Med Res 1993;21:74-80. 
23 Finkel MJ. Cyclobenzaprine: Summary of Basis of Approval - NDA and ANDA's. NDA 17-821. 
FDA Bureau of Drugs. 26 August 1977. 
24 Greenberg G, Inman WH, Weatherall JA, Adelstein AM, Haskey JC. Maternal drug histories and 
congenital abnormalities. Br Med J 1977;2:853-6. 
25 Winship KA, Cahal DA, Weber JC, Griffin JP. Maternal drug histories and central nervous system 
anomalies. Arch Dis Child 1984;59:1052-60. 
26 Hucker HB, Stauffer SC, Balletto AJ, White SD, Zacchei AG, Arison BH. Physiological 
disposition and metabolism of cyclobenzaprine in the rat, dog, rhesus monkey, and man. Drug Metab 
Dispos 1978;6:659-72. 
27 Hucker HB, Stauffer SC, Albert KS, Lei BW. Plasma levels and bioavailability of cyclobenzaprine 
in human subjects. J Clin Pharmacol 1977;17:719-27. 
28 Basmajian JV. Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar 
region and neck: two double-blind controlled clinical and laboratory studies. Arch Phys Med Rehabil 
1978;59:58-63. 
29 Browning R, Jackson JL, O'Malley PG. Cyclobenzaprine and back pain – A meta-analysis. Arch 
Intern Med. 2001;161:1613-20. 
30 Herman CR, Schiffman EL, Look JO, Rindal DB. The effectiveness of adding pharmacologic 
treatment with clonazepam or cyclobenzaprine to patient education and self-care for the treatment of 
jaw pain upon awakening: A randomized clinical trial. J Orofacial Pain 2002;16:64-79. 
31 Theoharides TC, Harris RS, Weckstein D. Neuroleptic malignant-like syndrome due to 
cyclobenzaprine. J Clin Psychopharmacol 1995;15:79-81. 
32 Bader TF, Newman K. Amitriptyline in human breast milk and the nursing infant's serum. Am J 
Psychiatry 1980;137:855-6. 
33 Brixen-Rasmussen L, Halgrener J, Jorgensen A. Amitriptyline and nortriptyline excretion in 
human breast milk. Psychopharmacol 1982;76:94-5. 


Cyclobenzaprine HCl Extended Release 
 
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Page 66 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
34 Winchell GA, King JD, Chavez-Eng CM, Constanzer ML, Korn SH. Cyclobenzaprine 
pharmacokinetics, including the effects of age, gender, and hepatic insufficiency. J Clin Pharmacol 
2002;42:61-9. 
35 Spiller HA, Winter ML, Mann KV, Borys DJ, Muir S, Krenzelok EP. Five-year multicenter 
retrospective review of cyclobenzaprine toxicity. J Emerg Med 1995;13:781-5. 
36  Kolassa, J. E. (1995), "A Comparison of Size and Power Calculations for the Wilcoxon Statistic 
for Ordered Categorical Data," Statistics in Medicine, 14, 1577–1581 
 


1.0 TITLE P 
Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 67 of 79 
Protocol Amendment 3 
16-Aug-2016 
AGE 
 
Appendix A Schedule of Study Procedures 
 
≤5 Day 
Screeninga 
Day 1 
Randomizationh 
Day 
2 
Day 3 
Day 
4 
Day 
5 
Day 
6 
Day 7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 15 
Study 
Termin
ationb 
Follow 
upc 
 Clinic Visit   
   
  
Visit 1   
 
   
Visit 2   
 
   
   
   
Visit 3   
 
   
   
   
   
   
 
  
Visit 4   
Phone 
contact 
Visit window 
 
 
 
+/- 1 
day 
 
 
 
+/- 1 
day 
 
 
 
 
 
 
 
+1 day 
+/- 1 day 
Informed Consent   
X 
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
Inclusion/Exclusion Criteria   
X 
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
Demographics and 
medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, Concurrent 
medical condition  
X 
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
Vital Signs   
X 
 X   
    
X    
   
   
   
   X 
  
   
   
   
   
   
 
 X   
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Examination   
X 
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 X   
 
Weight, Heightg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Test (if applicable)   
X 
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 X   
 
Clinical Laboratory Testse   
X 
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 X   
 
Concomitant Treatmentsi  
X 
 X   
 
X    
 
   
   
 X   
 
   
   
   
   
   
 
 X   
 
Pre-Treatment/Adverse 
Events   
X   
 X   
 
X     
 
   
   
 X   
 
   
   
   
   
   
 
 X 
X 
Study Drug dispense, return 
and compliance reviewf   
   
 X   
   
 X   
 
 
 
 X   
 
 
 
 
 
 
 
 X   
 
Physician Assessments:  
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
Presence of Muscle Spasm   
   
 X   
 
X    
   
   
   
 X   
 
   
   
   
   
   
 
 X  
 
Presence of Local Pain   
   
 X   
 
X    
   
   
   
 X   
 
   
   
   
   
   
 
 X   
 
Limitation of Range of 
Motion   
   
 X   
 
X    
  
   
   
 X   
 
   
   
   
   
   
 
 X  
 
Limitation of Activities of 
Daily Living   
   
 X   
 
X    
   
   
   
 X   
 
   
   
   
   
   
 
 X  
 
Physician’s Clinical Global 
Assessmentd   
   
   
 
X    
   
   
   
 X   
 
   
   
   
   
   
 
 X   
 
Subject Assessments:   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
Intensity of Local Pain   
   
 X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Subject’s Rating of 
Medication Helpfulnessd   
   
   
 X   
 X   
 X   
 X   
 X   
 X   
 X   
 X   
 X   
 X   
 X   
 X   
X  
 
 


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1.0 TITLE P 
Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 69 of 79 
Protocol Amendment 3 
16-Aug-2016 
AGE 
 
Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRF, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 70 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
 Appendix C Elements of the Subject Informed Consent  
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment. 
10. A description of the possible side effects of the treatment that the subject may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from the 
research. When there is no intended clinical benefit to the subject, the subject should be made 
aware of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject will 
be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, and 
the monitor may inspect the records. By signing a written informed consent form, the subject or 
the subject’s legally acceptable representative is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject. 
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. A statement that the subject or the subject’s legally acceptable representative will be informed in 
a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. 
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated. 


Cyclobenzaprine HCl Extended Release 
 
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CONFIDENTIAL 
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, and 
your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to Takeda’s 
research databases for purposes of developing a better understanding of the safety and 
effectiveness of the study medication(s), studying other therapies for patients, developing a 
better understanding of disease, and improving the efficiency of future clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that the 
restricted use or disclosure of such information may impact the scientific integrity of the 
research; and 
e) that the subject’s identity will remain confidential in the event that study results are 
published. 
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be performed 
throughout the study for all female subjects of childbearing potential. If a subject is found to be 
pregnant during study, study medication will be discontinued and the investigator will offer the 
subject the choice to receive unblinded treatment information. 
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. If the partner or wife of the subject is found to be 
pregnant during the study, the investigator will offer the subject the choice to receive unblinded 
treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 


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CONFIDENTIAL 
Appendix D Investigator Consent to Use of Personal Information  
 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
 Takeda, its affiliates, and licensing partners. 
 Business partners assisting Takeda, its affiliates, and licensing partners. 
 Regulatory agencies and other health authorities. 
 IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and these 
other parties for research purposes including the following: 
 Assessment of the suitability of investigator for the study and/or other clinical studies. 
 Management, monitoring, inspection, and audit of the study. 
 Analysis, review, and verification of the study results. 
 Safety reporting and pharmacovigilance relating to the study. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication. 
 Inspections and investigations by regulatory authorities relating to the study. 
 Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
 Archiving and audit of study records. 
 Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda and 
other parties for the purposes described above. 
 
 


Cyclobenzaprine HCl Extended Release 
 
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CONFIDENTIAL 
Appendix E Instruction for Medical Use – Myorix 
THE MINISTRY OF HEALTHCARE OF THE RUSSIAN FEDERATION 
 
PATIENT INFORMATION LEAFLET  
of medicinal product for medical use 
 
Myorix® 
 
Marketing authorization number:  
Trade name: Myorix® 
International non-proprietary name: Cyclobenzaprine 
Dosage form: sustained-action capsules 
 
Formulation 
One sustained-action capsule contains: 
15 mg dosage: 
Active ingredient: cyclobenzaprine hydrochloride - 15.0 mg  
Excipients: sugar grit1 – 109.7 mg, transparent opadry® YS-1-70062 – 1.2 mg, ethyl cellulose – 5.4 
mg, diethyl phthalate– 0.6 mg; 
Capsule coat: Iron oxide red dye – 0.2379 mg, iron oxide red dye – 0.5947 mg, titanium dioxide – 
0.2942 mg, water – 5.3500 mg, gelatin – 31.5232 mg. 
Identification ink: blue ink TekPrint™ SB-60183 trace quantity 
1sugar grit content: saccharose 68.56 – 100.38 mg, corn starch 9.32 – 41.14 mg; 
2Content of transparent Opadry® YS-1-7006: HPMC 1.091 mg, polyethylene glycol 0.109 mg; 
3Content of blue ink TekPrint™ SB-6018: shellac, dehydrated alcohol, isopropyl alcohol, butyl 
alcohol, propylene glycol, concentrated solution of ammonium hydroxide, blue FD&C dye No. 2 
aluminum lake, indigo carmine. 
30 mg dosage: 
Active ingredient: cyclobenzaprine hydrochloride - 30.0 mg  
Excipients: sugar grit1 – 87.6 mg, transparent opadry® YS-1-70062 – 2.4 mg, ethyl cellulose – 10.7 
mg, diethyl phthalate– 1.2 mg; 
Capsule coat: blue FD&C dye No. 2 – 0.1906 mg, blue FD&C dye No. 1 – 0.0003 mg, red FD&C 
dye No. 40 – 0.0245 mg, yellow FD&C dye No. 6 – 0.0348 mg, titanium dioxide – 0.4399 mg, water 
– 5.4100 mg, gelatin – 31.8999 mg. 
 Identification ink: Opacode® white ink S-1-70854 trace quantity. 
1sugar grit content: saccharose 54.75 – 80.15 mg, corn starch 7.45 – 32.85 mg; 
2Content of transparent Opadry® YS-1-7006: HPMC 2.182 mg, polyethylene glycol 0.218 mg; 
4Content of Opacode® white ink S-1-7085: shellac Glaze-45 % in SD-45 alcohol, titanium dioxide, 
isopropyl alcohol, ammonium hydroxide 28 %, propylene glycol, N-butyl alcohol, simethicon. 
 
Description 


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CONFIDENTIAL 
15 mg dosage capsules.  
Hard gelatin capsules with light orange to orange-brown body with blue imprint “1002-15” and light 
orange to orange-brown cap with blue imprint “EUR”. Capsule content - white to yellow spherical 
granules. 
 
30 mg dosage capsules. 
Hard gelatin capsules with blue to blue-green body with white imprint “1002-30” and red to 
red-orange cap with white imprint “EUR”. Capsule content - white to yellow spherical granules. 
Pharmacotherapeutic group: Central muscle relaxant 
ATC code: M03BX08 
Pharmacological properties 
Pharmacodynamics 
Cyclobenzaprine cures skeletal muscle spasm not affecting muscle function. Animal studies showed 
that cyclobenzaprine does not directly affect neuromuscular transmission or directly skeletal 
muscles. Cyclobenzaprine reduced or eliminated skeletal muscle hypertension on animal models. 
Data of the studies also showed that cyclobenzaprine primarily affects central nervous system at 
cerebral trunk level. Inhibition of neuromuscular transmission at the level of spinal cord also plays 
role in general myorelaxing effect on skeletal muscles. Data available indicate that direct effect of 
cyclobenzaprine is reduction of tonic somatic motor activity by affecting both gamma (γ)- and alpha 
(α)-motor systems. Pharmacological studies on animals demonstrated similar effect of 
cyclobenzaprine and structurally related tricyclic antidepressants, including antagonism in relation 
to reserpine, potentiation of noradrenaline, express peripheral and central anticholinergic effect and 
sedation. Cyclobenzaprine induced slight to moderate increase of heart rate in animal studies.  
 
Pharmacokinetics 
Absorption 
After single administration of cyclobenzaprine in a dose of 15 mg and 30 mg by healthy volunteers 
(n = 15), dose-dependent increase of Cmax, AUC0-168h and AUC0-∞ has been observed. Maximum 
cyclobenzaprine concentration in blood plasma is reached in 7 - 8 hours for both dosages. 
Cyclobenzaprine pharmacokinetics does not depend on food ingestion. Cmax value increases to 35%, 
AUC increases to 20%, however first concentrations of cyclobenzaprine in blood plasma are 
observed in 1.5 hour, with or without food. 
In multiple dose study with administration of 30 mg of cyclobenzaprine once a day within 7 days in 
a group of healthy volunteers (n = 35) with steady state concentration, 2.5 fold increase of 
cyclobenzaprine concentration in blood plasma has been observed. 
Metabolism and excretion 
Cyclobenzaprine to a great degree is metabolized and excreted primarily in the form of glucoronides 
by urinary way. Cytochrome isoenzymes P-450 3A4, 1A2, and to a lesser degree, 2D6, mediate 
N-demethylation - one of oxidation ways of cyclobenzaprine metabolism. Elimination half-time of 
cyclobenzaprine - 32 hours (8- 37 hours range; n = 18); total body clearance - 0.7 L/min after single 
drug dose administration. 
Elderly patients (65 years old and over) 
Despite that fact, that no significant difference in Сmax or Tmax has been observed, AUC of plasma 
cyclobenzaprine increased to 40%, cyclobenzaprine elimination half-time was longer in elderly 
patients at the age of 65 years and more (50 hours) compared to younger patients at the age of 18 -45 
years (32 hours). Pharmacokinetics of cyclobenzaprine after multiple dose administration of drug in 
elderly patients was not evaluated. 


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CONFIDENTIAL 
Patients with liver function abnormality 
In pharmacokinetics study of cyclobenzaprine immediate release in 16 patients with liver 
dysfunction (15 slight, 1 moderate based on Child – Pugh scores), both AUC, and Сmax were 
approximately twice higher compared to values in healthy control group.  Pharmacokinetics of 
cyclobenzaprine in patients with severe liver dysfunction has not been observed. 
 
Indications for use: 
Myorix® is indicated as therapeutic appliance for acute pain control in case of muscle spasm, 
induced by disorders of locomotor system. Drug effect is based on elimination of muscle spasm and 
its symptoms, i.e. pain syndrome and limited excursion. 
Myorix® should be used only during a short period (up to two-three weeks), as long as data on the 
drug efficiency with longer administration are unavailable, and also due to that fact, that muscle 
spasm, related to locomotor system disorders usually has short duration and specific treatment for 
more than three weeks is rarely reasonable. 
It was found that Myorix® is not efficient for treatment of muscle spasms induced by disorders of 
central nervous system, and also with cerebral palsy in children. 
 
Contra indications: 
- hypersensitivity to cyclobenzaprine or other drug components; 
- children under 18 years; 
- coadministration with monoaminooxidase inhibitors (MAO) and administration within 14 days 
after their withdrawal. 
- recent myocardial infarction, fibrillation, AV block or other asequences, congestive heart failure, 
unstable angina; 
- hyperthyroidism. 
 
Administration during pregnancy and breastfeeding 
Pregnancy 
As long as no controlled studies of cyclobenzaprine use in pregnant women have been performed, it 
should not be taken during pregnancy. 
Lactation 
Stop breastfeeding during treatment with cyclobenzaprine, as far as no data of drug permeability to 
breast milk are available. 
 
Posology and administration 
Per os, without chewing, washing down with a small amount of water.  
1 capsule of Myorix® in a dose of 15 mg once a day. Some patients might need dose increase up to 
30 mg/day. In this case, take 1 capsule of Myorix® in a dose of 30 mg once a day, or 2 capsules of 
Myorix® in a dose of 15 mg once a day. 
It is recommended to take the drug at the same time of a day. Treatment course duration - not more 
than 2 - 3 weeks. 
 
Adverse reaction 
Incidence of side effects of the drug is evaluated as follows: 
Very often: ≥1/10, 
Often: >1/100, <1/10; 
Not often: >1/1000, <1/100; 


Cyclobenzaprine HCl Extended Release 
 
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Protocol Amendment 3 
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CONFIDENTIAL 
Seldom: ≥1/10 000, <1/1000, 
Very seldom: <1/10 000. 
 
General disorders: 
Not often: faintness, sickliness, chest pain, edemas; 
Cardiovascular system disorders: 
Not often: tachycardia, fibrillation, vasodilation, rapid heartbeat, arterial hypotension/hypertension, 
myocardial infarction, myocardial conduction defect, stroke; 
Disorders of gastrointestinal tract: 
Very often: dry mouth; 
Often: constipation, nausea, dyspepsia, bad taste; 
Not often: vomiting, anorexia, diarrhea, abdominal pain, gastritis, thirst perception, bloat, 
paraglossa, liver dysfunction; 
Seldom: hepatitis, jaundice, cholestasis, paralytic ileus, discoloration of tongue, stomatitis, 
parotiditis; 
Endocrine system disorders: 
Not often: syndrome of inappropriate antidiuretic hormone; 
Disorders of blood and lymphatic system: 
Not 
often: 
purpura 
(hemorrhagic 
rash), 
myelosuppression, 
leukopenia, 
eosonophilia, 
thrombocytopenia; 
Immune system disorders: 
Not often: hepersensitivity response in the form of anaphylactic edema or angioedema, itching, 
facial edema, urticaria, rash; 
Metabolism and nutritional disorders: 
Not often: high or low blood glucose level, increased or reduced body weight; 
Musculoskeletal system disorders: 
Not often: local muscle weakness, myalgia; 
Nervous system and mental disorders: 
Often: drowsiness, dizziness, increased fatigability, asthenia, blurred vision, headache, nervousness, 
confused consciousness; 
Not often: seizures, coordinatory disturbance, dysarthria, tremor, hypertension, disorientation, 
insomnia, depressive mood, sensation disorders, anxiety, qualm, psychosis, strange dreams, thought 
disorder, hallucinations, high excitation, paraisthesis, diplopia, serotonin syndrome, neuroleptic 
malignant syndrome, high or low libido, gait impairment, delirium, aggressive behavior, paranoia, 
peripheral neuropathy, Bell's palsy, change of EEG, extrapyramidal disorder; 
Respiratory disorders: 
Not often: dyspnea; 
Disorders of skin and subcutaneous tissue: 
Not often: excessive sweating, photosensibilization, alopecia; 
Sensory organs disorders: 
Not often: change or loss of sense of taste, sonitus; 
Disorders of genitourinary system and mammary glands: 
Not often: urinary frequency or delay, disturbed urination, urinary tract dilatation, impotency, 
edema of testicle, gynecomastia, breast augmentation, galactorrhea. 
If any side effects from patient information leaflet deteriorate or any other side effects not indicated 
therein are observed, call the doctor. 
Overdosage 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
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Protocol Amendment 3 
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CONFIDENTIAL 
Overdose symptoms: disturbed consciousness (drowsiness to coma), agitation, nausea, vomiting, 
ataxia, tremor, low or (slightly) high blood pressure, dizziness, convulsive state, sinus tachycardia or 
ventricular tachycardia or bradycardia, change of ECG (QT interval elongation, His bundle block, 
QRS complex dilatation). 
Postmarketing experience of administration showed that most often overdosage with 
cyclobenzaprine was associated with concurrent administration of alcohol and/or other psychotropic 
medication, there are also several reports about fatal cases. 
Based on clinical experience, it is recommended in recipes for cyclobenzaprine to prescribe as low 
volume of the drug as possible, enough for the next visit of patient, in order to reduce risk of 
intended overdose. 
Treatment: symptomatic and supportive therapy. Specific antidotes are not known. Continuous 
monitoring of vital functions is recommended (breathing, blood circulation and heart rhythm). 
Immediate gastric lavage, administration of charcoal to induce drug absorption are recommended in 
case of overdose. It is not recommended to induce vomiting due to risk of vomit aspiration. Forced 
diuresis, dialysis, blood transfusion are inefficient. 
 
 Drug-to-drug interaction 
Due to structural similarity with tricyclic antidepressants, cyclobenzaprine can pose a threat to life 
when interacting with MAO inhibitors. In patients taking cyclobenzaprine concurrently with MAO 
inhibitors hyperthermic episodes and seizures have also been observed. 
The drug can intensify effect of ethanol, barbiturates and other drug products inhibiting CNS; 
increase the risk of seizures in patients taking tramadol. The drug can block antihypertensive effect 
of guanethidine and in the same way acting compounds. 
Cases of serotonin syndrome have been reported during coadministration of cyclobenzaprine with 
other drug products, such as selective serotonin reuptake inhibitors (SSRI), selective serotonin 
noradrenaline reuptake inhibitors (SNRI), tricyclic antidepressants, tramadol, bupropion, 
trimeperidine, verapamil or MAO inhibitors (ref. to Special Precautions Section). 
 
Special precautions 
Considering similar pharmacological effect of cyclobenzaprine with other drug products of tricyclic 
structure, consider probability of withdrawal syndrome with administration of Myorix®, despite 
that fact that similar cases for this drug have not been registered. Sharp treatment cessation after long 
period of administration can cause nausea, headache and sickliness. 
In case of suspected hypersensitivity response (ref. to Side Effect Section) stop administration of 
Myorix®. 
Myorix® should be used only during a short period (up to two-three weeks), as long as data on the 
drug efficiency with longer administration are unavailable, and also due to that fact, that muscle 
spasm, related to locomotor system disorders usually has short duration and specific treatment for 
more than three weeks is rarely reasonable. 
It was found that Myorix® is not efficient for treatment of muscle spasms induced by disorders of 
central nervous system or cerebral palsy in children (ref. to Indications Section). 
Serotonin syndrome 
In case of administration of cyclobenzaprine in combination with other drug products (ref. to 
Drug-to-drug interaction Section) there are reports on potentially life threatening serotonin 
syndrome. Serotonin syndrome symptoms manifest in the form of mental change (e.g., confused 
consciousness, high excitation, hallucinations), autonomic nervous system instability (e.g., 
diaphoresis (diaphoresis), tachycardia, unstable arterial pressure, hyperthermia), disturbed 


Cyclobenzaprine HCl Extended Release 
 
Study No. CYC-RR-001 
Page 78 of 79 
Protocol Amendment 3 
16-Aug-2016 
 
CONFIDENTIAL 
neuromuscular transmission (e.g., tremor, ataxia, hyperreflexia, myoclonus, rigid muscles), 
gastrointestinal disorders (e.g., nausea, vomiting, diarrhea). In case the above reactions take place, 
immediately stop treatment with Myorix® and any associated serotonergic medicinal productand 
start symptomatic treatment. If associated treatment with Myorix® and other serotonergic medicinal 
productis clinically reasonable, it is recommended to provide thorough monitoring, especially 
during the beginning of therapy or dose increase. 
Effects, similar to effects of tricyclic antidepressants. 
Cyclobenzaprine has similar structure with tricyclic antidepressants (amitriptyline, imipramine). 
There are registered reports that tricyclic antidepressants cause heart rhythm disorder, sinus 
tachycardia, increased conduction time based on cardiac conduction system, which may lead to 
myocardial infraction or stroke (ref. to Contraindications Section).  
Some of more serious reactions of CNS, observed in tricyclic antidepressants, were observed also in 
studies of cyclobenzaprine use for other indications and usually in doses far exceeding doses 
recommended for use in case of skeletal muscle spasms. In case of clinically significant symptoms 
of effect on CNS, consider possibility to withdraw treatment with Myorix®. 
Elderly patients 
It is not recommended to use Myorix® in elderly patients due to increase of cyclobenzaprine content 
in plasma to 40 % and increase of elimination half-time to 56 % after administration of the drug by 
elderly patients compared to younger patients.  
Patients with liver function abnormality 
It is not recommended to use Myorix® in patients with slight, moderate or severe liver dysfunction 
due to double increase of cyclobenzaprine content in plasma in patients with slight liver dysfunction 
compared to patients without liver dysfunction due to limited possibility of drug dose change. 
Atropine-like action 
Prescribe Myorix® with care to patients with data on urinary retention, angle-closure glaucoma, 
elevated intraocular pressure in medical history, and in patients taking anticholinergic drugs due to 
atropine-like action of cyclobenzaprine.  
 
Effects on ability to drive and use machines 
Pursuant to adverse reactions profile, it is recommended to abstain from activity, requiring high 
alertness and promptness of psychomotor reaction, e.g., driving vehicles or working with machines 
and mechanisms. 
Presentation  
14 extended release capsules in a blister made of PVC/Al. foil. 1, 2 blisters with Patient Information 
Leaflet in a cardboard pack. 
Storage conditions 
Store at a temperature under 25° C.  
Keep out of reach of children. 
 
Shelf life  
3 years.  
Do not use the drug after expiration date. 
 
Dispensing conditions: 
On prescription. 
 
Manufacturer/MA Holder: 


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter 
Trial to Study the Efficacy and Safety of Cyclobenzaprine HCl Extended Release (CER) 
15 mg in Subjects with acute cervical and/or lower back pain due to Muscle Spasms of 
Local Origin.
NCT Number: NCT02814565
SAP Approve Date: 24-May-2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
Page 1 of 38 
Statistical Analysis Plan 
Sponsor: Takeda Pharmaceutical LLC. 
Sponsor Protocol 
Number: 
CYC-RR-001 
Atlant Clinical 
Protocol Code: 
3502 
Study Title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, 
Multicenter Trial to Study the Efficacy and Safety of Cyclobenzaprine HCl 
Extended Release (CER) 15 mg in Subjects with acute cervical and/or 
lower back pain due to Muscle Spasms of Local Origin. 


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1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 3 of 38 
Table of Contents 
1. 
Abbreviations ............................................................................................................................................ 5 
2. 
Introduction ............................................................................................................................................... 6 
3. 
Protocol Overview .................................................................................................................................... 6 
3.1. 
Study Background ........................................................................................................................... 6 
3.2. 
Study Objectives .............................................................................................................................. 6 
3.2.1. 
Primary Objective ..................................................................................................................... 6 
3.2.2. 
Secondary Objective ............................................................................................................... 7 
3.2.3. 
Additional Objectives ............................................................................................................... 7 
3.3. 
Study Design .................................................................................................................................... 7 
3.4. 
Randomization and Blinding .......................................................................................................... 8 
3.5. 
Sample Size Estimation .................................................................................................................. 8 
3.6. 
Study Population .............................................................................................................................. 8 
3.6.1. 
Inclusion Criteria ...................................................................................................................... 8 
3.6.2. 
Exclusion Criteria ..................................................................................................................... 9 
3.6.3. 
Criteria for Discontinuation or Withdrawal of a Subject ................................................... 11 
3.7. 
Study Assessments ....................................................................................................................... 12 
3.7.1. 
Demographic and baseline data .......................................................................................... 15 
3.7.2. 
Efficacy assessments ............................................................................................................ 15 
3.7.3. 
Safety assessments .............................................................................................................. 18 
3.7.4. 
Compliance ............................................................................................................................. 19 
3.7.5. 
Protocol deviations ................................................................................................................ 19 
4. 
Derived Variables and Definitions ....................................................................................................... 20 
5. 
Statistical Methodology ......................................................................................................................... 20 
5.1. 
General ............................................................................................................................................ 20 
5.2. 
Disposition of subjects .................................................................................................................. 21 
5.3. 
Protocol Deviations ........................................................................................................................ 21 
5.4. 
Analysis Sets .................................................................................................................................. 21 
5.5. 
Demographic and Baseline Data ................................................................................................. 21 
5.6. 
Medical History and Concurrent Medical Conditions ............................................................... 21 
5.7. 
Prior and Concomitant Treatment ............................................................................................... 21 
5.8. 
Efficacy Analysis ............................................................................................................................ 22 
5.8.1. 
Primary Efficacy Endpoints .................................................................................................. 22 


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5.8.2. 
Secondary Efficacy Endpoints ............................................................................................. 23 
5.9. 
Safety Analysis ............................................................................................................................... 23 
5.9.1. 
Adverse events ....................................................................................................................... 23 
5.9.2. 
Safety Laboratory Evaluation ............................................................................................... 24 
5.9.3. 
Vital Signs ............................................................................................................................... 24 
5.9.4. 
ECGs ....................................................................................................................................... 24 
5.9.5. 
Physical Examination ............................................................................................................ 24 
5.9.6. 
Exposure ................................................................................................................................. 24 
5.10. 
Compliance Evaluation ............................................................................................................. 24 
5.11. 
Interim Analysis .......................................................................................................................... 24 
5.12. 
Changes to Planned Analysis .................................................................................................. 24 
6. 
Tables, Figures and Listings ................................................................................................................ 25 
6.1. 
Disposition of subjects .................................................................................................................. 25 
6.2. 
Demographics and baseline data ................................................................................................ 25 
6.3. 
Medical history and concurrent medical conditions .................................................................. 26 
6.4. 
Prior and concomitant treatment ................................................................................................. 27 
6.5. 
Efficacy ............................................................................................................................................ 27 
6.5.1. 
Primary Efficacy Endpoints .................................................................................................. 27 
6.5.2. 
Secondary Efficacy Endpoints ............................................................................................. 29 
6.6. 
Safety ............................................................................................................................................... 31 
6.6.1. 
Adverse events ....................................................................................................................... 31 
6.6.2. 
Safety Laboratory Evaluation ............................................................................................... 33 
6.6.3. 
Vital Signs ............................................................................................................................... 35 
6.6.4. 
ECGs ....................................................................................................................................... 36 
6.6.5. 
Exposure ................................................................................................................................. 36 
6.7. 
Compliance ..................................................................................................................................... 36 
6.8. 
Listings............................................................................................................................................. 36 
7. 
Sign off Page .......................................................................................................................................... 38 
 
 
 


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1. 
Abbreviations 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification system 
CER  
Cyclobenzaprine HCl Extended Release  
DBL 
Data Base Lock 
(e)CRF 
Case Report Form (electronic) 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
GEE 
Generalized Estimating Equations 
hCG 
human Chorionic Gonadotropin 
HCl 
Hydrochloride 
HIV 
Human Immunodeficiency Virus 
HLT 
High Level Term 
ICD-10 
International Classification of Diseases, 10th revision  
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LFT 
Liver Function Tests 
LOCF 
Last Observation Carried Forward 
M 
Mean 
MAO 
Monoamine Oxidase 
Max 
Maximum 
Med 
Median 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
NSAIDs 
Nonsteroidal Anti-Inflammatory Drugs  
pH 
potential of Hydrogen  
PP 
Per-Protocol 
PPS 
Per-Protocol analysis Set 
PT 
Preferred Term  
PTE 
Pretreatment Event 
Q1 
First Quartile 
Q3 
Third Quartile 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software® 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SNRIs 
Serotonin Norepinephrine Reuptake Inhibitors 


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SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSRIs 
Selective Serotonin Reuptake Inhibitors 
TCAs 
Tricyclic Antidepressants 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO DD 
World Health Organization Drug Dictionary 
2. 
Introduction 
According to ICH E9, “a statistical analysis plan is a document that contains a more technical and 
detailed elaboration of the principal features of the analysis described in the protocol, and includes 
detailed procedures for executing the statistical analysis of the primary and secondary variables and 
other data”. 
Additionally SAP describes the derived variables and specifies the statistical outputs – tables, figures 
and listings. 
3. 
Protocol Overview 
3.1. Study Background 
Neck or back pain due to muscle spasms may occur at almost any time during the life cycle.  
Chronic persistent low back and neck pain is seen in 25% to 60% of patients, one-year or longer 
after the initial episode. Spinal pain is associated with significant economic, societal, and health 
impact. Chronic pain syndrome has been defined as a complex condition with physical, 
psychological, emotional, and social components. The prevalence of chronic pain in the adult 
population ranges from 2% to 40%, with a median point prevalence of 15%. [Manchikanti, L; Singh, 
V; Datta, S; Cohen, SP; Hirsch, JA; American Society of Interventional Pain, Physicians (Jul–Aug 
2009). "Comprehensive review of epidemiology, scope, and impact of spinal pain". Pain physician 
12 (4): E35–70. PMID 19668291]. 
Cyclobenzaprine hydrochloride (HCl) is a centrally acting skeletal muscle relaxant closely related to 
the tricyclic antidepressants that acts mainly on the brainstem to decrease tonic somatic motor 
activity. Some activity at spinal cord sites may also contribute to its therapeutic effects. It is used as 
an adjunct treatment for relief of muscle spasm associated with musculoskeletal conditions. 
Cyclobenzaprine may also provide relief in a small percentage of patients with fibromyalgia. 
Following oral administration, its effects begin within one hour and the effects of a single dose last 
as long as 12 to 24 hours. 
3.2. Study Objectives 
3.2.1. Primary Objective 
The primary objective of this study is to assess the effect of CER 15 mg once daily in subjects with 
muscle spasms associated with musculoskeletal conditions. 
Primary Endpoint: 
 The percentage of subjects with subject’s rating of medication helpfulness impression on 
Day 3 of treatment. 


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Company Confidential Information


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Page 8 of 38 
Screening period - ≤5 days prior Randomization (Screening visit) 
Treatment period – 14 days (Visit 1 (Randomization), Visit 2 (Day 3), Visit 3 (Day 7), Final 
Visit/Study Termination (Day 15)) 
Follow up period – 21 days (Follow up phone call) 
Total participation period for a subject will be approximately 35-40 days. 
3.4. Randomization and Blinding 
The randomization list was generated and stored according to Atlant Clinical SOP. The 
randomization is applied via IWRS integrated into EDC system. 
The investigator or the investigator’s designee utilizes the IWRS to randomize the subject into the 
study. The medication identification (ID) number of the investigational drug then is provided by the 
IWRS. The investigational drug is dispensed on the Baseline visit. 
Randomization takes place on Day1 (could be the same day at which Screening visit is performed). 
Study is double-blind. Blinding is applied using IWRS system (IWRS assigns the investigational drug 
bottle number).  
Study data unblinding could be performed after the DBL only. 
The investigator shall not break the IP blinding unless information concerning the investigational drug 
is necessary for the medical treatment of the subject. In the event of a medical emergency, if possible, 
the medical monitor should be contacted before the investigational drug blind is broken to discuss 
the need for unblinding. 
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS. 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The date, 
time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, investigational drug must be stopped immediately and the subject 
must be withdrawn from the study. Such subjects will be excluded from PP analysis set. 
3.5. Sample Size Estimation 
A sample size of at least 77 subjects in each treatment group (total of 154 subjects) is needed to 
detect a difference between Placebo and CER 15 mg in subject’s rating of medication helpfulness 
impression, using a 2-sample Wilcoxon rank sum test with 80% power at a 2-sided significance level 
of 0.05 (Kolassa, J. E. (1995), "A Comparison of Size and Power Calculations for the Wilcoxon 
Statistic for Ordered Categorical Data," Statistics in Medicine, 14, 1577–1581). The assumed 
difference to be detected is based on the observed distribution of the ordinally scored rating scale 
for the respective treatment groups in study 1106. Assuming a 15% dropout rate, 90 subjects in each 
treatment group (total of 180 subjects) will be randomized. 
3.6. Study Population 
Screened subjects could be randomized if met all of the inclusion criteria and none of the exclusion 
criteria. 
3.6.1. Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 


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2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures.  
3. The Subject is experiencing for no more than 14 days cervical and/or lower back pain (as 
assessed by the subject) due to muscle spasms (confirmed by the physician) associated with 
musculoskeletal conditions (defined by codes M54.2 Cervicalgia and/or M54.5 Low back pain 
according to ICD-10). 
4. The subject is male or female and aged 18 to 50 years, inclusive. 
5. Female subjects require to be either 2 years postmenopausal or surgically sterile by bilateral 
tubal ligation, hysterectomy, or bilateral oophorectomy, or, if premenopausal, had to be using an 
approved contraceptive method. 
6. Female subjects of child-bearing potential must have a negative urine human chorionic 
gonadotropin (hCG) test result for pregnancy at study entry. 
7. After signing the informed consent form, the subject agrees not to make changes to dietary, 
exercise, or smoking habits and not to enter a weight loss program during his/her participation in 
the study. 
3.6.2. Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject has muscular pain secondary to acute trauma or fractures (e.g., due to osteoporosis). 
Such conditions could have been ruled out based on medical history, x-ray, or physical 
examination. 
2. The subject suffers from muscle spasms/pain related to polymyalgia rheumatica or ankylosing 
spondylitis (Bekhterev's disease). Such conditions could have been ruled out based on medical 
history, x-ray, or physical examination. 
3. The subject has received any investigational compound within 30 days prior to Screening. 
4. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or 
within 1 month after participating in this study; or intending to donate ova during such time period.  
5. The subject has a history of drug abuse or recent (within the last 12 months) history of excessive 
alcohol consumption defined as >2 drinks/day (>3 oz of 80 proof alcohol or equivalent). 
6. Patients with mild, moderate, severe liver impairment. 
7. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
8. The subject takes any concomitant medication including over-the-counter and herbal products 
for muscle spasms. If a subject is taking such medications, the medications has to be 
discontinued before starting the study. 
9. The subject takes or took within last 14 days medications, such as: 
a. selective serotonin reuptake inhibitors (SSRIs); 
b. serotonin norepinephrine reuptake inhibitors (SNRIs); 
c.  tricyclic antidepressants (TCAs); 
d. MAO inhibitors; 
e. tramadol; 


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f. bupropion;  
g. meperidine;  
h. verapamil; topical anti-inflammatory medications, including patches  
i. 
paracetamol 
j. 
opioid analgesics  
10. The subject takes or took within last 3 days medications, such as: 
a. non-steroid anti-inflammatory drugs (NSAIDs); 
b. Intramuscular vitamin injections containing anaesthetics (such as vitamin Milgamma). 
11. The subject has a history or clinical manifestations of significant medical condition, such as:  
a. hyperthyroidism;  
b. acute recovery phase of myocardial infarction; 
c. arrhythmias, heart block or conduction disturbances; 
d. congestive heart failure; 
e. angle-closure glaucoma; 
f. urinary retention; 
g. increased intraocular pressure. 
12. The subject has abnormal physical findings or a medical condition that might have placed the 
subject at risk or interfered with the subject’s ability to participate in the study. 
13. The subject has any known condition or disorder that might have affected absorption of the study 
drug. 
14. The subject has a history of hypersensitivity or allergies to cyclobenzaprine and/or tricyclic 
antidepressants or any of their components. 
15. The subject has a history of hypersensitivity to any NSAIDs including salicylate sensitivity. 
16. The subject has a history of thrombocytopenia. 
17. The subject has a history of gastro-intestinal bleeding, cerebrovascular bleeding or other 
bleeding disorders. 
18. The subject had active or history of recurrent peptic ulcer/haemorrhage (two or more distinct 
episodes of proven ulceration or bleeding). 
19. The subject has a history of severe renal impairment. 
20. The subject had a major surgery during the 6 months preceding study entry. 
21. The subject has a language barrier or any other problems precluding good communication or 
cooperation. 
22. The subject has any reason to believe that he/she would not be able to complete the evaluations 
needed in this study. 
23. The subject has a known history of positive screen for hepatitis B surface antigen, hepatitis C 
antibody, or human immunodeficiency virus (HIV) antibody. 
24. The subject has a history of malignant disease within 5 years prior to Screening. 


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25. Drug abuse in anamnesis. 
3.6.3. Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the case report form (eCRF) using the following categories.  
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
 
Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section Error! Reference source not found.), if the following 
circumstances occur at any time during study medication treatment: 
 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or 
 
ALT or AST >5 × ULN and persists for more than 2 weeks, or 
 
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or international 
normalized ratio (INR) >1.5, or 
 
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (>5%). 
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented.  
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
(e)CRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE 
or lack of efficacy). 
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
6. Pregnancy. The subject is found to be pregnant.  
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section Error! Reference source not found.. 
7. Lack of efficacy. The necessity to use rescue medication (any analgesics) AND/OR the 
investigator has determined that the subject is not benefiting from investigational treatment and, 
continued participation would pose an unacceptable risk to the subject.  
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF. 
 


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The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described above. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by the 
investigator. In addition, efforts should be made to perform all procedures scheduled for the Early 
Termination Visit. Discontinued or withdrawn subjects will not be replaced. 
3.7. Study Assessments 
The summary of the study procedures are presented on the table 3.1.


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Table 3.1 
Schedule of Study Procedures. 
 
≤5 Day 
Screening
a 
Day 1 
Randomization
h 
Day 
2 
Day 3 
Day 
4 
Day 
5 
Day 
6 
Day 7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 15 
Study 
Termin
ationb 
Follow 
upc 
Clinic Visit   
 
Visit 1   
 
Visit 
2 
 
   
 
Visit 
3 
 
   
   
   
   
   
 
Visit 4 
Phone 
contac
t 
Visit window 
 
 
 
+/- 1 
day 
 
 
 
+/- 1 
day 
 
 
 
 
 
 
 
+1 day 
+/- 1 
day 
Informed Consent   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and 
medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History, 
Concurrent 
medical 
condition  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs   
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Examination   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight, Heightg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy 
Test 
(if 
applicable)   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Laboratory Testse   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant Treatmentsi  
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Pre-Treatment/Adverse 
Events   
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Study 
Drug 
dispense, 
return 
and 
compliance 
reviewf   
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Physician Assessments:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence of Muscle Spasm   
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Presence of Local Pain   
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Limitation of Range of 
Motion   
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Limitation of Activities of 
Daily Living   
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Physician’s Clinical Global 
Assessmentd   
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Subject Assessments:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 15 of 38 
3.7.1. Demographic and baseline data 
The following demographic and baseline data will be collected at the screening visit: 
 
Date of birth, sex, race and smoking status; 
 
Height, Weight; 
 
Prior/Concomitant treatments; 
 
Medical history/Concurrent medical conditions. 
3.7.2. Efficacy assessments 
Physician’s assessments will be performed on every visit during the treatment period. Subject’s 
assessments will be performed every day during the treatment period. 
The measures of effectiveness in this study will include: 
 
 
Subject’s rating of medication helpfulness:  
 
Subjects will be asked to assess it on a daily basis (in the daily diary), using the following 
5-point rating scale: “How would you rate this study medication in improving your 
condition?" 
“0 = poor” 
“1 = fair” 
“2 = good” 
“3 = very good” 
“4 = excellent” 
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 
Physician’s clinical global assessment : 
 
The investigator will be asked to assess their clinical global impression of change 
compared to Baseline, based on physical examination, degree of muscle spasm 
(presence of muscle spasm assessment), reaction to palpation (presence of local pain 
assessment), limitation of range of motion, and evaluation of the patient's reported 
functional assessment (limitation of activities of daily living assessment). The following 5-
point rating scale will be used: 
“1 = worse” 
"2 = no change" 
"3 = slight improvement" 
"4 = moderate improvement" 
“5 = marked improvement” 
Assessment will be made for the Day 3, 7 and 15. 
 
 
The subject-rated relief from local pain: 
Subjects will be asked to assess on a daily basis (in the daily diary) their level of relief 
from local pain due to the muscle spasm (in either the lower back or cervical spine) 
compared to Baseline (Visit 1) using the following 5-point rating scale: 
"1 = no relief” 
“2 = a little relief” 
“3 = some relief” 
“4 = a lot of relief” 
“5 = complete relief”  


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Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 
The subject-rated restriction in activities of daily living: 
Subjects will be asked to assess on a daily basis (in the daily diary) the change in the 
severity of restriction in the activities of daily living compared to Baseline (Visit 1) using 
the following 5-point rating scale: 
“1 = worsening” 
“2 = no change” 
“3 = mild improvement:” 
“4 = moderate improvement” 
”5 = marked improvement”  
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 
The subject-rated restriction of movement: 
Subjects will be asked to assess on a daily basis (in the daily diary), the change in 
restriction of movement due to the muscle spasm compared to Baseline (Visit 1) using the 
following 5-point rating scale: 
“1 = no relief” 
“2 = a little relief” 
“3 = some relief” 
“4 = a lot of relief” 
“5 = complete relief” 
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 
The subject-rated intensity of local pain: 
Subjects will be asked to assess on a daily basis (in the daily diary) their intensity of local 
pain due to the muscle spasm (in either the lower back or cervical spine) using the 
following digital rating scale. It is necessary to mark the intensity of pain by circling a one 
of the 11 points from 0 "No Pain" to 10 "Severe Pain" with an intermediate value of 5 - 
"Moderate Pain". 
Facial pain scale is presented to help the patient to identify the primary area of the intensity 
of the pain experienced: 
 
Assessment of the subject’s answers will be made for the Day 3, 7 and 15. 
 
 
Subject-Rated Clinical Global Impression: 


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1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 18 of 38 
“1 = none” (no pain) 
“2 = mild” (complaint of local discomfort on palpation) 
“3 = moderate” (objective evidence that the area is painful, such as defensive 
movements, reflex dilatation of pupils, etc.) 
“4 = moderately severe” (the area is very painful) 
“5 = severe” (the area is intolerably painful and subject objects to the examination) 
 
 
Limitation of range of motion 
The physician was asked to assess at each visit, the subject’s limitation of range of 
motion using the following 5-point rating scale: 
“1 = none” (no limitation in range of motion) 
“2 = mild” (restriction of the normal motion by 10-15%) 
“3 = moderate” (restriction of the motion by no more than 50%) 
“4 = moderately severe” (restriction of the expected motion by no more than 80%) 
“5 = severe” (the subject has great difficulty in attempting to perform one or more of the 
major motions) 
 
 
Limitation of activities of daily living 
The physician was asked to assess by both direct observation and historical questioning, 
the limitation of activities of daily living using the following 5-point rating scale at each 
visit: 
“1 = none” (no limitation of activities of daily living) 
“2 = mild” (the subject is able to perform his customary tasks, but with discomfort) 
“3 = moderate” (the subject is able to perform partially with discomfort some essential 
tasks and activities) 
“4 = moderately severe” (the subject performs partially with great difficulty some 
essential tasks and activities) 
“5 = severe” (the subject is unable to perform most of the essential tasks or activities) 
3.7.3. Safety assessments 
Adverse events: 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
PTEs are assessed at the Screening visit. 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug. AEs are assessed during the treatment and follow-up 
periods. 
TEAEs are defined as AEs with onset occurring within 30 days (onset date – last date of dose 
+1≤30) after study drug administration. 
Additional explanations for judging PTEs and AEs (TEAEs) are presented in the Study Protocol, 
section 10.1.3. 
Following information about PTEs and AEs (TEAEs) will be collected: 
 
Seriousness (with type of SAE) or not 
 
Severity 
 
Causality 
 
Relationship to Study Procedures 


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 
Start Date 
 
End Date 
 
Frequency 
 
Action Concerning Study Medication 
 
Outcome and date of resolution 
 
Vital Signs: 
 
Sitting blood pressure (resting more than 5 minutes) 
 
Pulse (bpm) 
Vital signs will be collected at every visit during the treatment period. 
 
Physical Examination: 
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) 
extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other (if 
applicable). All subsequent physical examinations should assess clinically significant changes 
from the assessment prior to first dose examination. 
Physical Examination will be collected at the Screening visit and Visit 4. 
 
Clinical Laboratory Tests: 
 
Hematology (Red blood cells (RBC), White blood cells (WBC), Hemoglobin) 
 
Serum Chemistry (Alanine aminotransferase, Albumin, Alkaline phosphatase, Aspartate 
aminotransferase) 
 
Urinalysis (pH, Protein) 
 
Urine (hCG for pregnancy (only for female subjects of childbearing potential)) 
Clinical Laboratory Tests will be collected at the Screening visit and Visit 4. 
 
ECG: 
A standard 12-lead ECG will be recorded at Screening and Study termination. The investigator 
(or a qualified observer at the investigational site) will interpret the ECG using 1 of the following 
categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically 
significant. 
ECG results will be collected at the Screening visit and Visit 4. 
 
3.7.4. Compliance 
Compliance data will be collected on Visits 2, 3 and 4.  
Treatment compliance for entire treatment period will be calculated at Visit 4 using the formula: 
Compliance in % = (# tablets taken during treatment period / # tablets to be taken during treatment 
period)*100. 
3.7.5. Protocol deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria. 


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The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol. 
4. 
Derived Variables and Definitions 
 
Subjects’ AGE will be calculated subtracting Date of the Screening Visit minus Date of 
Birth (integer). 
 
Dates will be converted into ISO8601 format. 
 
Medical history/concurrent medical condition record will be assessed as medical history if 
it stops before the date of the Screening Visit and such record will be assessed as 
concurrent medical condition if it doesn’t. 
 
Prior/concomitant medication record will be assessed as prior medication if it stops before 
the date of the Screening Visit and such record will be assessed as concomitant 
medication if it doesn’t. 
 
Prior/concomitant medication record will be divide into medications and procedures in 
SDTM datasets. 
 
Variables --DY (Study Day) will be derived as (date of interest) minus (TREATMENT VISIT 
1 date) plus 1. In integer days. 
 
Compliance in % = (# tablets taken during treatment period / # tablets to be taken during 
treatment period)*100. 
 
Average scores will be calculated as arithmetic mean. 
5. 
Statistical Methodology 
5.1. General 
All analyses will be performed and presented by treatment group.  
Categorical data will be presented using absolute frequencies and percentages. The percentage 
will not be presented when the absolute frequency is zero. Unless stated otherwise, the 
denominator for percentage calculations will be the total number of subjects in the applicable 
analysis set. 
Continuous data will be summarized using descriptive statistics, and the following parameters will 
be reported: 
 
number of valid observations (n) and missing observations (nmiss); 
 
arithmetic mean (M) and standard deviation (SD); 
 
median (Med); 
 
first (Q1) and third quartiles (Q3); 
 
minimum (Min) and maximum (Max). 
Tests will be two-sided and performed at the 5 % significance level if not otherwise specified. 
When reporting the outcome of significance tests, the p-value will be reported. Raw data will be 
presented to the number of decimal places collected, and derived data will be presented to an 
appropriate number of decimal places. The appropriate number of decimal places will be 
determined by general practice, or mathematical or scientific rationale. Extreme values will be 
presented with a number of decimals equal to the appropriate number for that variable; mean 
values and other descriptive parameters will be presented with one decimal more. Percentages 
will be presented with one decimal and a percentage sign. P-values will be presented with 4 
decimals or as ‘<.0001’. 


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Data will be presented in SDTM and ADaM datasets and listings. Mock tables, figures and listings 
titles are presented in the section 6 of this SAP. Patient data listings will be presented according 
to the ICH Guideline E3 Structure and Contents of Clinical Study Reports. 
All statistical analyses will be performed using SAS® version 9.4 or higher. 
5.2. Disposition of subjects 
The disposition of subjects will be presented in the table for the numbers of screened subjects, 
screening failures (in total and by reason), and randomized subjects. 
 
Screened subject is defined as a subject that has attended the screening visit. 
 
Screening failure is defined as a subject withdrawn before randomization. 
 
Randomized subject is defined as a subject that complies with all inclusion and exclusion 
criteria and got the randomization number in IWRS. 
Based on randomized subjects, the number and percentage of the following subjects subsets will 
be presented: 
 
Subjects did not take any dose of the study medication. 
 
Subjects completed the study. 
 
Subjects prematurely withdrawn from the study in total and by reason. 
 
Subjects in the safety analysis set, the full analysis set and the per-protocol analysis set. 
5.3. Protocol Deviations 
List of all Protocol Deviations/Violations (with decisions to exclude subjects from analysis sets) 
must be finalized before DBL. Protocol Deviations will be presented in a patient data listing. 
5.4. Analysis Sets 
The full analysis set (FAS) will consist of subjects who received at least one dose of investigation 
product. Subjects in the FAS population will be analyzed according to their original treatment 
assignment regardless of the treatment received.  
The safety analysis set will consist of subjects who received at least one dose of investigational 
product. Subjects in the safety population will be analyzed according to their treatment received, 
regardless of treatment assigned; subjects who received ≥ 1 dose of CER 15 mg will be analyzed 
in the CER 15 mg treatment group.  
The per-protocol (PP) analysis set will consist of subjects no major protocol violations, and who 
received at least 1 dose of investigational product. 
5.5. Demographic and Baseline Data 
Age, sex, race, smoking status, height, weight and main diagnosis will be presented descriptively 
for both of the FAS and the PPS. 
5.6. Medical History and Concurrent Medical Conditions 
Medical history and concurrent medical conditions will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0 and presented in the separate tables 
by system organ class (SOC) and preferred term (PT). For each SOC and PT, the number and 
percentage of subjects with a condition in that SOC or PT will be presented descriptively for the 
safety analysis set. 
5.7. Prior and Concomitant Treatment 
Medications will be coded using the World Health Organization Drug Dictionary (WHO DD) 
version Sep 2016. For each therapeutic main group (the second level term in the Anatomical 
Therapeutic Chemical [ATC] classification system) and preferred name, the number and 
percentage of subjects will be presented for the safety analysis set. If the preferred name is not 
available for a medication, the chemical subgroup (ATC level 4) will be displayed instead. 


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Concomitant procedures will be presented in the descriptive table by the original term. For each 
original term, the number and percentage of subjects will be presented descriptively for the safety 
analysis set. 
5.8. Efficacy Analysis 
All efficacy analyses will be based on an FAS subject population. The primary efficacy endpoint 
will also be analyzed using the PP subject population. All statistical tests will be conducted against 
a 2-sided alternative hypothesis at the 0.05 level of significance. 
For all efficacy evaluations, End of Study was defined as Day 15, or if the subject discontinued 
the double-blind treatment phase prior to Day 15, the last available post treatment (final) 
evaluation was used to estimate the remaining missing evaluations (ie, last observation carried 
forward [LOCF]). For reference, the observed values were summarized and analyzed using the 
same methods as the LOCF values. 
If the assumptions underlying planned inferential methods are not adequately met, methods will 
be amended as needed for appropriate analysis. 
5.8.1. Primary Efficacy Endpoints 
For the primary efficacy analysis, the subject's rating of medication helpfulness at Day 3 will be 
analyzed for the difference between the Placebo and the 15mg CER treatment group using a 2-
sample Wilcoxon rank sum test. The primary endpoint is a 5-point ordinal rating scale from 0=Poor 
to 4=Excellent. This study will evaluate differences between Placebo and CER treatment on the 
percentages for each of the 5-grade scale categories. Therefore, the 2-sample Wilcoxon sum 
rank test will compare the shift of ordinal distributions of responses in both treatment groups. Only 
differences between the treatment groups at the significance level of 0.05 will be considered 
statistically significant. Frequency counts and percentages showing the distribution of the 
subject's rating of medication helpfulness at Day 3 will be provided to summarize these 
parameters. 
Supportive analysis: 
A supportive analysis on responders will be done to confirm the results of the primary analysis. A 
responder will be defined as a subject who had a rating of either "very good" or "excellent" for the 
subject's rating of medication helpfulness at Day 3. A continuity-adjusted Chi-square test will be 
used to compare the number of "responders" between the Placebo and the CER treatment group. 
The number and percent of subjects who met the definition of responder at Day 3 will be 
presented. 
The primary analysis and supportive analysis will be repeated for day 7 and day 14. 
Trends in the distribution of ratings: 
Trends in the distribution of ratings by treatment group will be compared across the 3 visits to 
determine if there were any qualitative differences in the pattern of treatment response. 
Differences between treatments in the distribution of ratings at the 3 visits will analyzed using a 
weighted least squares model for marginal homogeneity including a parameter for treatment and 
treatment-by-visit interaction. Trends over time in the proportion of responders among the 
treatment groups will be assess assessed qualitatively by comparing the patterns of change in 
proportion of responders from Day 3 through Day 14. Repeated-measures analysis of proportions 
using Generalized Estimating Equations (GEE) will be used for comparisons among treatments 
of the trend in proportion of responders over time. 
Time to improvement in subject’s rating: 


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1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 25 of 38 
6. Tables, Figures and Listings 
Mock tables and figure titles are listed below. 
6.1. Disposition of subjects 
Table 1. Disposition of subjects 
 
CER 15 mg 
Placebo 
Total 
Screened 
 
 
xxx 
Screening failures  
 
 
xxx 
Randomized 
xx 
xx 
xxx 
Did not take any dose of the study 
medication 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
Prematurely withdrawn 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
Completed 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
 
Analysis sets  
 
 
 
     Safety analysis set  
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     Full analysis set  
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     Per-protocol analysis set  
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
Percentages are based on the number of randomized subjects.  
Table 2. Screening failures 
 
 
 
Total 
Screening failures  
 
 
xxx 
Primary reason 
 
 
 
     <reason> 
 
 
xxx (xx.x%) 
     <reason> 
 
 
xxxx (xx.x%) 
Percentages are based on the number of screening failures.  
Table 3. Reason for premature withdrawal from the study. Randomized subjects 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xxx) 
Prematurely withdrawn 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
Primary reason 
 
 
 
     <reason> 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     <reason> 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
Percentages are based on the number of randomized subjects.  
6.2. 
Demographics and baseline data 
Table 4. Demographics. Full analysis set 
Table 5. Demographics. Per-protocol analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xxx) 
Age (years) 
 
 
xx 
     n/nmiss 
xx/xx 
xx/xx 
xxx/xxx 
     Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
     Median 
xx.x 
xx.x 
xx.x 
     Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
     Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
Sex 
 
 
 
     Female  
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     Male 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 


1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 26 of 38 
 
 
 
 
Race 
 
 
 
     European 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     Other 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
          <race> 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
          <race> 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Smoking status 
 
 
 
     Never smoked 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     Former smoker 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
     Current smoker 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
Height (cm) 
 
 
xx 
     n/nmiss 
xx/xx 
xx/xx 
xxx/xxx 
     Mean (SD) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
xxx.x (xxx.x) 
     Median 
xxx.x 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
xxx, xxx 
 
Weight (kg) 
 
 
xx 
     n/nmiss 
xx/xx 
xx/xx 
xxx/xxx 
     Mean (SD) 
xxx.xx (xxx.xx) 
xxx.xx (xxx.xx) 
xxx.xx (xxx.xx) 
     Median 
xxx.xx 
xxx.xx 
xxx.xx 
     Q1, Q3 
xxx.xx, xxx.xx 
xxx.xx, xxx.xx 
xxx.xx, xxx.xx 
     Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
xxx.x, xxx.x 
n/nmiss – number of subjects with evaluable/missing data, SD – standard deviation, Q1, Q3 – quartiles. 
Percentages are based on the number of subjects in the applicable analysis set. 
Table 6. Main Diagnosis. Full analysis set 
Table 7. Main Diagnosis. Per-protocol analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Cervicalgia 
xx (xx.x%) 
xx (xx.x%) 
Low back pain 
xx (xx.x%) 
xx (xx.x%) 
Cervicalgia and low back pain 
xx (xx.x%) 
xx (xx.x%) 
Other 
xx (xx.x%) 
xx (xx.x%) 
Percentages are based on the number of subjects in the applicable analysis set. 
6.3. Medical history and concurrent medical conditions 
Table 8. Medical history. Safety analysis set 
Table 9. Concurrent medical conditions. Safety analysis set 
System organ class/Preferred term 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
<System organ class> 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
<System organ class> 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
Medical history is coded according to MedDRA 20.0. 
Percentages are based on the number of subjects in the safety analysis set. 


1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 27 of 38 
6.4. Prior and concomitant treatment 
Table 10. Prior treatment. Safety analysis set 
Table 11. Concomitant treatment. Safety analysis set 
Therapeutic main group/Preferred name 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
<Therapeutic main group > 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred name> 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred name> 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
<Therapeutic main group > 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred name> 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred name> 
xx (xx.x%) 
xx (xx.x%) 
Medical history is coded according to WHO DD Sep 2016. 
Percentages are based on the number of subjects in the safety analysis set. 
Table 12. Concomitant procedures. Safety analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
<Procedure> 
xx (xx.x%) 
xx (xx.x%) 
<Procedure> 
xx (xx.x%) 
xx (xx.x%) 
Percentages are based on the number of subjects in the safety analysis set. 
 
6.5. Efficacy 
6.5.1. Primary Efficacy Endpoints 
Table 12. Subject's rating of medication helpfulness. Day 3. Full analysis set 
Table 13. Subject's rating of medication helpfulness. Day 3. Per-protocol analysis set 
Table 14. Subject's rating of medication helpfulness. Day 7. Full analysis set 
Table 15. Subject's rating of medication helpfulness. Day 7. Per-protocol analysis set 
Table 16. Subject's rating of medication helpfulness. Day 14. Full analysis set 
Table 17. Subject's rating of medication helpfulness. Day 14. Per-protocol analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Subject's rating of medication helpfulness 
xx (xx.x%) 
xx (xx.x%) 
     0 = poor 
xx (xx.x%) 
xx (xx.x%) 
     1 = fair 
xx (xx.x%) 
xx (xx.x%) 
     2 = good 
xx (xx.x%) 
xx (xx.x%) 
     3 = very good 
xx (xx.x%) 
xx (xx.x%) 
     4 = excellent 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Subject's rating of medication helpfulness 
xx (xx.x%) 
xx (xx.x%) 
     0-2 = poor, fair or good 
xx (xx.x%) 
xx (xx.x%) 
     3-4 = very good or excellent 
xx (xx.x%) 
xx (xx.x%) 
p-value** 
0.xxxx 
 
Percentages are based on the number of subjects in the applicable analysis set. 


1.0 TITLE P 
CYC-RR-001 
3502_CYC-RR-001_Statistical Analysis Plan_v 1.0_24-May-2017.docx 
 
Page 28 of 38 
* The 2-sample Wilcoxon sum rank test was used to test a null hypothesis of no difference between the 
treatment groups against a two-sided alternative hypothesis at the 0.05 level of significance. 
** The continuity-adjusted Chi-square test will be used to compare the number of "responders" between 
the Placebo and the CER treatment group to test a null hypothesis of no difference between the 
treatment groups against a two-sided alternative hypothesis at the 0.05 level of significance. 
Table 18. Subject's rating of medication helpfulness. Trends in the distribution of ratings. Full 
analysis set 
Table 19. Subject's rating of medication helpfulness. Trends in the distribution of ratings. Per-
protocol analysis set 
Subject's rating of medication helpfulness 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Day 3 
xx (xx.x%) 
xx (xx.x%) 
     0 = poor 
xx (xx.x%) 
xx (xx.x%) 
     1 = fair 
xx (xx.x%) 
xx (xx.x%) 
     2 = good 
xx (xx.x%) 
xx (xx.x%) 
     3 = very good 
xx (xx.x%) 
xx (xx.x%) 
     4 = excellent 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Day 7 
xx (xx.x%) 
xx (xx.x%) 
     0 = poor 
xx (xx.x%) 
xx (xx.x%) 
     1 = fair 
xx (xx.x%) 
xx (xx.x%) 
     2 = good 
xx (xx.x%) 
xx (xx.x%) 
     3 = very good 
xx (xx.x%) 
xx (xx.x%) 
     4 = excellent 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Day 14 
xx (xx.x%) 
xx (xx.x%) 
     0 = poor 
xx (xx.x%) 
xx (xx.x%) 
     1 = fair 
xx (xx.x%) 
xx (xx.x%) 
     2 = good 
xx (xx.x%) 
xx (xx.x%) 
     3 = very good 
xx (xx.x%) 
xx (xx.x%) 
     4 = excellent 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
p-value* 
0.xxxx 
 
Percentages are based on the number of subjects in the applicable analysis set. 
* Differences between treatments in the distribution of ratings at the 3 visits was analyzed using a 
weighted least squares model for marginal homogeneity including a parameter for treatment and 
treatment-by-visit interaction. 
Table 20. Subject's rating of medication helpfulness. Repeated measures analysis. Full analysis 
set 
Table 21. Subject's rating of medication helpfulness. Repeated measures analysis. Per-protocol 
analysis set 
Subject's rating of medication helpfulness 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Day 3 
xx (xx.x%) 
xx (xx.x%) 
     0-2 = poor, fair or good 
xx (xx.x%) 
xx (xx.x%) 
     3-4 = very good or excellent 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Day 7 
xx (xx.x%) 
xx (xx.x%) 
     0-2 = poor, fair or good 
xx (xx.x%) 
xx (xx.x%) 
     3-4 = very good or excellent 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Day 14 
xx (xx.x%) 
xx (xx.x%) 
     0-2 = poor, fair or good 
xx (xx.x%) 
xx (xx.x%) 


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Day 3 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 7 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 14 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
Percentages are based on the number of subjects in the full analysis set. 
* The 2-sample Wilcoxon sum rank test was used to test a null hypothesis of no difference between the 
treatment groups against a two-sided alternative hypothesis at the 0.05 level of significance.. 
Table 29. Physician’s clinical global assessment. Full analysis set 
Physician’s clinical global assessment 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Day 3 
xx (xx.x%) 
xx (xx.x%) 
     1 = worse 
xx (xx.x%) 
xx (xx.x%) 
     2 = no change 
xx (xx.x%) 
xx (xx.x%) 
     3 = slight improvement 
xx (xx.x%) 
xx (xx.x%) 
     4 = moderate improvement 
xx (xx.x%) 
xx (xx.x%) 
     5 = marked improvement 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 7 
xx (xx.x%) 
xx (xx.x%) 
     1 = worse 
xx (xx.x%) 
xx (xx.x%) 
     2 = no change 
xx (xx.x%) 
xx (xx.x%) 
     3 = slight improvement 
xx (xx.x%) 
xx (xx.x%) 
     4 = moderate improvement 
xx (xx.x%) 
xx (xx.x%) 
     5 = marked improvement 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 15 
xx (xx.x%) 
xx (xx.x%) 
     1 = worse 
xx (xx.x%) 
xx (xx.x%) 
     2 = no change 
xx (xx.x%) 
xx (xx.x%) 
     3 = slight improvement 
xx (xx.x%) 
xx (xx.x%) 
     4 = moderate improvement 
xx (xx.x%) 
xx (xx.x%) 
     5 = marked improvement 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
p-value** 
0.xxxx 
 
Percentages are based on the number of subjects in the full analysis set. 
* The 2-sample Wilcoxon sum rank test was used to test a null hypothesis of no difference between the 
treatment groups against a two-sided alternative hypothesis at the 0.05 level of significance. 
** Differences between treatments in the distribution of ratings at the 3 visits was analyzed using a 
weighted least squares model for marginal homogeneity including a parameter for treatment and 
treatment-by-visit interaction. 
Table 30. Presence of muscle spasm. Full analysis set 
Table 31. Presence of local pain. Full analysis set 
Table 32. Limitation of range of motion. Full analysis set 


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Table 33. Limitation of activities of daily living. Full analysis set 
<Parameter> 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Day 1 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 3 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 7 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
 
 
 
Day 15 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
     <response option> 
xx (xx.x%) 
xx (xx.x%) 
p-value* 
0.xxxx 
 
Percentages are based on the number of subjects in the full analysis set. 
* The 2-sample Wilcoxon sum rank test was used to test a null hypothesis of no difference between the 
treatment groups against a two-sided alternative hypothesis at the 0.05 level of significance. 
6.6. Safety 
6.6.1. Adverse events 
Table 34. Overview of adverse events. Safety analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
 
n (%) 
m 
n (%) 
m 
Any pretreatment events 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
Any serious pretreatment events 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
Any treatment-emergent adverse events 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
Any serious treatment-emergent adverse events 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
Any treatment-emergent adverse events leading 
to withdrawal 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
Relationship of treatment-emergent adverse 
events 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     Not related 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     Related 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
Severity of treatment-emergent adverse events 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     Mild 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     Moderate 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     Severe 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
n = number of subjects, m = number of events. 
Percentages are based on the number of subjects in the safety analysis set. 
Table 35. Pretreatment events. Safety analysis set 
Table 36. Serious pretreatment events. Safety analysis set 


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Table 37. Treatment-emergent adverse events. Safety analysis set 
Table 38. Serious treatment-emergent adverse events. Safety analysis set 
Table 39. Treatment-emergent adverse events related to the study drug. Safety analysis set 
Table 40. Treatment-emergent adverse events leading to withdrawal. Safety analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
System organ class/Preferred term 
n (%) 
m 
n (%) 
m 
<System organ class> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
<System organ class> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
Adverse events are coded according to MedDRA 20.0. 
n = number of subjects, m = number of events. 
Percentages are based on the number of subjects in the safety analysis set. 
Table 41. Treatment-emergent adverse events by relationship. Safety analysis set, CER 15 mg 
Table 42. Treatment-emergent adverse events by relationship. Safety analysis set, Placebo 
 
Not Related 
Related 
System organ class/Preferred term 
n (%) 
m 
n (%) 
m 
<System organ class> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
<System organ class> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
Adverse events are coded according to MedDRA 20.0. 
n = number of subjects, m = number of events. 
Percentages are based on the number of subjects in the safety analysis set. 
Table 43. Treatment-emergent adverse events by severity. Safety analysis set, CER 15 mg 
Table 44. Treatment-emergent adverse events by severity. Safety analysis set, Placebo 
 
Mild 
Moderate 
Severe 
System organ 
class/Preferred term 
n (%) 
m 
n (%) 
m 
n (%) 
m 
<System organ class> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
 
 
 
 
 
 
 
<System organ class> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
     <Preferred term> 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
xx (xx.x%) 
xx 
Adverse events are coded according to MedDRA 20.0. 
n = number of subjects, m = number of events. 
Percentages are based on the number of subjects in the safety analysis set. 
Table 45. Treatment-emergent adverse events by relationship and severity. Safety analysis set, 
CER 15 mg 


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Table 46. Treatment-emergent adverse events by relationship and severity. Safety analysis set, 
Placebo 
 
Mild 
Moderate 
Severe 
System organ 
class/Preferred term 
NR 
R 
NR 
R 
NR 
R 
<System organ class> 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
<System organ class> 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     <Preferred term> 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Adverse events are coded according to MedDRA 20.0. 
Number of subjects for: NR – Not Related, R – Related. 
Percentages are based on the number of subjects in the safety analysis set. 
6.6.2. Safety Laboratory Evaluation 
Table 47. Hematology. Red blood cells. Safety analysis set 
Table 48. Hematology. White blood cells. Safety analysis set 
Table 49. Hematology. Hemoglobin. Safety analysis set 
Table 50. Hematology. Red blood cells. Safety analysis set 
Table 51. Serum Chemistry. Alanine aminotransferase. Safety analysis set 
Table 52. Serum Chemistry. Albumin. Safety analysis set 
Table 53. Serum Chemistry. Alkaline phosphatase. Safety analysis set 
Table 54. Serum Chemistry. Aspartate aminotransferase. Safety analysis set 
<Parameter (unit)> 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Baseline 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 
     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.x, xx.x 
xx.x, xx.x 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
     Takeda’s markedly abnormal criteria met, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Final visit (Visit 4) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 
     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.x, xx.x 
xx.x, xx.x 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
     Takeda’s markedly abnormal criteria met, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Change from baseline to final visit 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 


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     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.x, xx.x 
xx.x, xx.x 
Percentages are based on the number of subjects in the safety analysis set. 
The baseline assessment was performed at the screening visit. 
Table 55. Urinalysis. pH. Safety analysis set 
pH 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Baseline 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 
     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.x, xx.x 
xx.x, xx.x 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Final visit (Visit 4) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 
     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.x, xx.x 
xx.x, xx.x 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Change from baseline to final visit 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 
     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.x, xx.x 
xx.x, xx.x 
Percentages are based on the number of subjects in the safety analysis set. 
The baseline assessment was performed at the screening visit. 
Table 56. Urinalysis. Protein. Safety analysis set 
Protein (g/L) 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Baseline 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
x.xxxx (x.xxxx) 
x.xxxx (x.xxxx) 
     Median 
x.xxxx 
x.xxxx 
     Q1, Q3 
x.xxxx, x.xxxx 
x.xxxx, x.xxxx 
     Min, Max 
x.xxx, x.xxx 
x.xxx, x.xxx 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Final visit (Visit 4) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
x.xxxx (x.xxxx) 
x.xxxx (x.xxxx) 
     Median 
x.xxxx 
x.xxxx 
     Q1, Q3 
x.xxxx, x.xxxx 
x.xxxx, x.xxxx 
     Min, Max 
x.xxx, x.xxx 
x.xxx, x.xxx 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Change from baseline to final visit 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
x.xxxx (x.xxxx) 
x.xxxx (x.xxxx) 
     Median 
x.xxxx 
x.xxxx 
     Q1, Q3 
x.xxxx, x.xxxx 
x.xxxx, x.xxxx 
     Min, Max 
x.xxx, x.xxx 
x.xxx, x.xxx 


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Percentages are based on the number of subjects in the safety analysis set. 
The baseline assessment was performed at the screening visit. 
6.6.3. Vital Signs 
Table 57. Systolic blood pressure. Safety analysis set 
Table 58. Diastolic blood pressure. Safety analysis set 
Table 59. Pulse rate. Safety analysis set 
<Parameter (unit)> 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Baseline 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
     Takeda’s markedly abnormal criteria met, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Visit 2 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
     Takeda’s markedly abnormal criteria met, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Change from baseline to visit 2 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
Visit 3 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
     Takeda’s markedly abnormal criteria met, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Change from baseline to visit 3 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
Final visit (Visit 4) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
     Takeda’s markedly abnormal criteria met, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Change from baseline to final visit 
 
 


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     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xxx.x (xx.x) 
xxx.x (xx.x) 
     Median 
xxx.x 
xxx.x 
     Q1, Q3 
xxx.x, xxx.x 
xxx.x, xxx.x 
     Min, Max 
xxx, xxx 
xxx, xxx 
Percentages are based on the number of subjects in the safety analysis set. 
The baseline assessment was performed at the visit 1. 
6.6.4. ECGs 
Table 60. ECG assessment. Safety analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Baseline 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Within normal limits, n (%) 
xx (xx.x%) 
xx (xx.x%) 
     Abnormal but not clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Final visit (Visit 4) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Within normal limits, n (%) 
xx (xx.x%) 
xx (xx.x%) 
     Abnormal but not clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
     Clinically significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
Percentages are based on the number of subjects in the safety analysis set. 
The baseline assessment was performed at the screening visit. 
6.6.5. Exposure 
Table 61. Duration of exposure. Safety analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Duration of exposure (days) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
x.xxxx (x.xxxx) 
x.xxxx (x.xxxx) 
     Median 
x.xxxx 
x.xxxx 
     Q1, Q3 
x.xxxx, x.xxxx 
x.xxxx, x.xxxx 
     Min, Max 
x.xxx, x.xxx 
x.xxx, x.xxx 
6.7. 
Compliance 
Table 62. Treatment compliance. Safety analysis set 
 
CER 15 mg 
(N=xx) 
Placebo 
(N=xx) 
Compliance (%) 
 
 
     n/nmiss 
xx/xx 
xx/xx 
     Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     Median 
xx.xx 
xx.xx 
     Q1, Q3 
xx.xx, xx.xx 
xx.xx, xx.xx 
     Min, Max 
xx.xx, xx.xx 
xx.xx, xx.xx 
Treatment compliance for entire treatment period for each subject is calculated at V4 using the formula: 
Compliance in % = (# tablets taken during treatment period / # tablets to be taken during treatment 
period) * 100%. 
6.8. 
Listings 
Listing 1. Subject-level data 


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Listing 2. Subject disposition 
Listing 3. Screen failure reasons 
Listing 4. Premature withdrawal reasons 
Listing 5. Medical history and concurrent medical conditions 
Listing 6. Concomitant medication 
Listing 7. Concomitant procedures 
Listing 8. Physician’s assessment 
Listing 9. Subject’s assessment 
Listing 10. Adverse events 
Listing 11. Laboratory data 
Listing 12. Vital signs 
Listing 13. ECG 
Listing 14. Physical examination 
 
 


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