Clinical trial NCT02421601
Conditions: Intervertebral Disc Disease Lumbar Disc Disease
Sponsor: Seikagaku Corporation
Start date: 2015-03-01; Completion date: 2018-02-01
Enrollment: 1011 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of SI-6603(Condoliase) in patients with lumbar disc herniation.

Detailed description:

Arms: arm 1: SI-6603: SI-6603 is administrated into the nucleus pulposus of the intervertebral disc
Interventions: intervention 1: Condoliase
Intervention descriptions: intervention 1: 1.25 U, intradiscal injection, one time

Protocol documents:
Prot_SAP_000.pdf: 
 
 
PROTOCOL TITLE  
  
A Multicenter, Open-label Study of SI-6603 in Patients with Lumbar Disc 
Herniation (Phase III)  
 
Sponsor: 
Seikagaku Corporation 
6-1, Marunouchi 1-chome, 
Chiyoda-ku, Tokyo 100-0005, Japan 
 
Clinical Research Organization: 
PAREXEL International 
195 West Street 
Waltham, MA 02451, USA 
Principal Investigator:  
To be assigned  
Sponsor Protocol No.: 
6603/1132 
IND No.: 
100,398 
EudraCT No.: 
2014‐001449‐26 
Study Drug Name: 
SI-6603 
Development Phase: 
Phase III Study 
Date of Protocol: 
24 June 2016 
Version Number 
4.0 
Date of Previous Protocol: 
9 September 2015 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki1 and with other applicable 
regulatory requirements. 
This document contains confidential information of Seikagaku Corporation 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 


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SIGNATURE PAGE 
 
Declaration of Sponsor 
Title: A Multicenter, Open-label study of SI-6603 in Patients with Lumbar Disc 
Herniation (Phase III)  
This study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, 
as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, [2013]1, and the guidelines on Good Clinical 
Practice. 
 
 
 
 
 
_____________________________________ 
_____________________ 
Yosuke Funakoshi 
 
 
 
 
Date 
General Manager, Clinical Development Department  
Research and Development Division  
Seikagaku Corporation 
 
 


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Declaration of the Principal Investigator 
Title: A Multicenter, Open-label study of SI-6603 in Patients with Lumbar Disc 
Herniation (Phase III) 
This study protocol was subjected to critical review and has been approved by the 
Sponsor. The information it contains is consistent with the current risk/benefit evaluation 
of the investigational product as well as with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, as amended in 
[2013]1 and the guidelines on Good Clinical Practice. 
 
Principal Investigator  
 
 
 
 
_____________________________________ 
_____________________ 
Name 
Date 
Title 
Institution 


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Declaration of the National Coordinating Investigator 
Title: A Multicenter, Open-label study of SI-6603 in Patients with Lumbar Disc 
Herniation (Phase III) 
This study protocol was subjected to critical review and has been approved by the 
Sponsor. The information it contains is consistent with the current risk/benefit evaluation 
of the investigational product as well as with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, as amended in 
[2013]1 and the guidelines on Good Clinical Practice. 
 
National Coordinating Investigator 
 
 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 
 


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Declaration of the Investigator 
Title: A Multicenter, Open-label study of SI-6603 in Patients with Lumbar Disc 
Herniation (Phase III) 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, electronic Case Report Form (eCRF) and other 
scientific data. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
No changes will be made to the study protocol without the prior written approval of the 
Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to 
the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
Responsible Investigator of the local study center 
 
 
 
_____________________________________ 
_____________________ 
Signature 
Date 
 
_____________________________________ 
Name (block letters) 
 
_____________________________________ 
Title (block letters) 
 
_____________________________________ 
Institution (block letters) 
 
_____________________________________ 
Phone number 


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PROTOCOL SYNOPSIS 
 
Title 
A Multicenter, Open-label study of SI-6603 in Patients with Lumbar Disc 
Herniation (Phase III). 
Sponsor Study No. 
6603/1132 
Phase 
Phase III Study 
Sponsor 
Seikagaku Corporation 
Principal Investigator 
Not yet assigned  
Study Center(s) 
Approximately 80 centers located in the United States of America (USA) 
and European Union (EU). 
Objective 
The primary study objective is to evaluate the safety of a single-dose 
intervertebral disc injection of SI-6603 (a lyophilized injectable drug 
containing condoliase as the active ingredient) at a dose of 1.25 units (U) in 
patients with lumbar disc herniation, for a 26-week follow-up period.  
Design 
This is a multicenter, open-label study to monitor the safety and efficacy of 
SI-6603. The study duration for each patient will be approximately 
30 weeks: a 4-week Screening period, a 1-day Treatment Administration 
Day, and a 26-week follow-up period. 
Treatment 
Patients will receive a single-dose injection of SI-6603 1.25 U into an 
intervertebral disc. 
Number of Patients 
Approximately 1000 patients are planned to be enrolled into this study. 
Population 
The study population will consist of male and female patients, 30 to 70 
years of age at the time of informed consent, with lumbar disc herniation 
between adjacent lumbar vertebra (L1L2, L2L3, L3L4, L4L5), or 
between the 5th lumbar vertebra and the 1st sacral vertebra (L5S1) 
“protrusion type” or “extrusion type” in the posterior lateral or central 
location as assessed by magnetic resonance imaging (MRI) and clinical 
symptoms corresponding to the level of the impaired nerve root. 
Criteria for Evaluation 
of Safety 
The following safety endpoints will be assessed:  
 
Occurrence of adverse events (AEs)  
 
Stability evaluation of vertebral bodies by X-ray  
- 
Translation of vertebral body  
- 
Vertebral body angle formed by flexion  
 
Changes from baseline in disc height (disc index) assessed by X-ray  
 
Changes of disc degeneration and vertebral body endplates, and 
adjacent bone marrow as assessed by MRI  
- 
Modic classification  
- 
Pfirrmann classification  
 
Clinically significant changes in vital signs  
 
Clinically significant changes in clinical laboratory tests  
 
Serum anti-SI-6603 antibody 
 
Occurrence of post-treatment lumbar surgery other than surgery for 
lumbar disc herniation at the same level of the investigational drug 
administration  


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Criteria for Evaluation 
of Efficacy 
The following secondary efficacy endpoints will be assessed from baseline 
through Week 26:  
 
Worst leg pain during the past 24 hours assessed by Visual Analog 
Scale (VAS). 
 
Worst back pain during the past 24 hours assessed by VAS. 
 
Functional disability measured by the Oswestry Disability Index 
(ODI). 
 
Change of neurological status from baseline determined by 
neurological examinations (Femoral Nerve Stretching [FNS] test [for 
patients with lumbar disc herniation L1L2, L2L3, or L3L4] or 
Straight Leg Raising [SLR] test [for patients with lumbar disc 
herniation L4L5 or L5S1], sensation, muscle strength, and deep 
tendon reflex). 
 
Occurrence of post-treatment surgery for lumbar disc herniation at the 
same level of administration of the investigational drug up to Week 26 
including patients who discontinued from the study.   
Statistical Methods 
All statistical tests will be performed 2-sided with a significance level of 
5%, unless otherwise stated. 
The following populations will be assessed: 
 
Safety: All patients who were treated with the investigational drug 
 
Intent-to-Treat (ITT): All patients who were treated with the 
investigational drug  
The primary objective is the assessment of safety by evaluating the above 
listed safety endpoints. Safety analyses will be performed on the safety 
population. The incidence of AEs and associated 95% confidence interval 
(CI) will be determined and presented. Similar analyses will be conducted 
for other safety endpoints with categorical outcomes. Safety outcomes with 
continuous variables will be summarized descriptively. 
The research hypothesis is that the treatment of 1.25 U of SI-6603 followed 
for 26 weeks after administration of a single dose is a safe treatment. The 
total of 1000 patients are to be enrolled in order to further characterize the 
frequency and outcome of the treatment-related AE. 
Categorical variables will be summarized by the number and percentage of 
patients in each category. Continuous variables will be summarized by 
number of observations, mean, standard deviation, median, inter-quartile 
range, minimum, and maximum. Where data are collected over time, both 
the observed data and change from the Screening period (baseline) will be 
summarized at each time point. 
All electronic Case Report Forms (eCRF) collected and derived data will 
be listed. 
Schedule of Procedures 
The schedule of procedures and assessments is detailed in Table 3 and 
located in Section 7.1. 


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LIST OF STUDY PERSONNEL 
 
Sponsor 
Yosuke Funakoshi 
General Manager, Clinical Development Department 
Research and Development Division 
Seikagaku Corporation 
 
Ryoichi Takagi 
Assistant Manager, Clinical Development Department 
Research and Development Division 
Seikagaku Corporation 
6-1, Marunouchi 1-chome, 
Chiyoda-ku, Tokyo 100-0005, Japan 
Telephone number: +81-(0)-3-5220-8593 
Fax number: +81-(0)-3-5220-8594. 
European Union Legal 
Representatives 
Not assigned yet 
Principal Investigator 
Not assigned yet 
Contract Research 
Organization 
 
PAREXEL International 
195 West Street 
Waltham, MA 02451, USA 
Telephone number: +1-781-487-9900 
Fax number: +1-781-487-0525 
Serious Adverse Event 
Reporting 
PAREXEL North American Medical Services 
One Federal Street 
Billerica, MA 01821, USA 
Serious adverse event (SAE) fax number: +1-781-434-
5957 
SAE hotline: +1-781-434-5010  
Central Laboratory 
Eurofins Global Central Laboratory 
2430 New Holland Pike 
17601 Lancaster 
PA – USA 
Tel: +1 717 556 7350  
 
 
 
 


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Anti-SI-6603-Antibodies  Envigo CRS, Inc. 
Princeton Research Center (PRC) 
Biomarkers, Bioanalysis and Clinical Sciences (BBC) 
100 Mettlers Road 
East Millstone, NJ 08875-2360, USA 
Tel: +1 732 873 2550 
Central X-ray and 
Magnetic Resonance 
Imagining Reader 
BioClinica 
7707 Gateway Boulevard, 3rd Floor 
Newark, CA 94560, USA 
Telephone number: +1-415-817-8900 
Fax number: +1-415-817-8960  
Drug Packaging Vendor 
Catalent Pharma Solutions 
14 Schoolhouse Road 
Somerset, NJ 08873, USA 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................... 6 
LIST OF STUDY PERSONNEL .............................................................................. 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................... 15 
1 
INTRODUCTION........................................................................................ 17 
1.1 
Background .............................................................................................. 17 
1.1.1 
Summary of Clinically Significant Findings Obtained in Non-
Clinical Studies ............................................................................ 18 
1.1.1.1 
Pharmacology ........................................................................ 18 
1.1.1.2 
Safety Pharmacology ............................................................. 18 
1.1.1.3 
Pharmacokinetics and Metabolism ........................................ 18 
1.1.1.4 
Toxicology .............................................................................. 19 
1.1.2 
Summary of Important Findings Obtained in Prior Clinical 
Studies .......................................................................................... 20 
1.1.2.1 
Phase I/II Clinical Study in Patients with Lumbar Disc 
Herniation (Study Number: SKK0197) (Sweden) .................. 20 
1.1.2.2 
Phase I/II Clinical Study in Patients with Lumbar Disc 
Herniation (Study Number: SKK6603J01) (Japan) ............... 21 
1.1.2.3 
Prognostic Study of Patients with Lumbar Disc Herniation 
Administered with SI-6603 in Japanese Phase I/II Clinical 
Study (Japan) ......................................................................... 21 
1.1.2.4 
Prick test of SI-6603-P in Healthy Adult Volunteers 
(Study Number: SKK6603J02) (Japan) ................................. 22 
1.1.2.5 
Phase II/III Clinical Study in Patients with Lumbar Disc 
Herniation (Study Number: 6603/1021) (Japan) ................... 22 
1.1.2.6 
Phase II Clinical Study in Patients with Lumbar Disc 
Herniation (Study Number: 6603/1121) (USA) ..................... 23 
1.1.2.7 
Phase III Clinical Study in Patients with Lumbar Disc 
Herniation (Study Number: 6603/1031) (Japan) ................... 24 
1.1.3 
Additional Information ................................................................ 25 
1.1.4 
Current Study ............................................................................... 25 
1.2 
Rationale .................................................................................................. 26 
1.2.1 
Study Rationale ............................................................................ 26 
1.2.2 
Rationale for Dose and Schedule Selection ................................. 26 
1.3 
Risk-Benefit Assessment ......................................................................... 26 
1.3.1 
Possible Risks .............................................................................. 27 
1.3.1.1 
Treatment-related Adverse Event .......................................... 27 
1.3.1.2 
Allergic Reactions .................................................................. 28 
1.3.1.3 
Back Pain ............................................................................... 29 


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1.3.1.4 
Decrease of Lumbar Disc Height and Change in Bone 
Marrow Adjacent to Vertebral Endplates .............................. 29 
1.3.1.5 
Radiation ................................................................................ 30 
1.3.1.6 
Intradiscal Injection ............................................................... 30 
1.3.2 
Possible Benefits .......................................................................... 35 
1.3.2.1 
Improvement of Leg Pain ....................................................... 35 
1.3.2.2 
Improvement of Back Pain ..................................................... 35 
2 
STUDY OBJECTIVES ................................................................................ 37 
2.1 
Primary Objective ................................................................................... 37 
2.2 
Secondary Objective ............................................................................... 37 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ............................... 38 
3.1 
Overview .................................................................................................. 38 
3.2 
Criteria for Evaluation of the Study ...................................................... 39 
3.2.1 
Safety Endpoints .......................................................................... 39 
3.2.2 
Secondary Efficacy Endpoints ..................................................... 39 
3.3 
Justification of the Study Design ........................................................... 40 
4 
STUDY POPULATION .............................................................................. 41 
4.1 
Inclusion Criteria .................................................................................... 41 
4.2 
Exclusion Criteria ................................................................................... 42 
4.3 
Patient Withdrawal and Replacement .................................................. 44 
4.3.1 
Patient Withdrawal Criteria ......................................................... 44 
4.4 
Planned Sample Size and Number of Study Centers ........................... 45 
4.5 
Patient Identification and Randomization ............................................ 45 
4.5.1 
Patient Identification .................................................................... 45 
4.5.2 
Randomization Scheme ............................................................... 45 
4.5.3 
Allocation/Randomization of Patients to Treatment.................... 45 
5 
STUDY DRUG ............................................................................................. 46 
5.1 
Identity ..................................................................................................... 46 
5.2 
Administration ......................................................................................... 46 
5.3 
Packaging, Labeling and Storage .......................................................... 46 
5.4 
Blinding and Breaking the Blind ........................................................... 46 
5.5 
Drug Accountability ................................................................................ 46 
5.6 
Compliance .............................................................................................. 47 
5.7 
Previous and Concomitant Medications ............................................... 47 
5.7.1 
Permitted Concomitant Medication ............................................. 47 
5.7.2 
Notes Concerning Concomitant Medication Before SI-6603 is 
Administered ................................................................................ 47 


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5.8 
Previous and Concomitant Therapies ................................................... 48 
5.8.1 
Permitted Concomitant Therapies................................................ 48 
5.8.2 
Prohibited Concomitant Therapies .............................................. 48 
6 
VARIABLES AND METHODS OF ASSESSMENT ............................... 49 
6.1 
Safety Variables ....................................................................................... 49 
6.1.1 
Adverse Events ............................................................................ 49 
6.1.1.1 
Collection of Adverse Events ................................................. 49 
6.1.1.2 
Definitions .............................................................................. 49 
6.1.1.3 
Assessment of Adverse Events ................................................ 49 
6.1.1.4 
Recording Adverse Events ..................................................... 51 
6.1.1.5 
Reporting Serious Adverse Events ......................................... 51 
6.1.1.6 
Follow-up of Adverse Events ................................................. 52 
6.1.1.7 
Suspected Unexpected Serious Adverse Reactions ................ 52 
6.1.1.8 
Pregnancy .............................................................................. 53 
6.1.2 
Laboratory Variables ................................................................... 53 
6.1.3 
X-ray Imaging .............................................................................. 54 
6.1.3.1 
Disc Height (Disc Index) ....................................................... 55 
6.1.3.2 
Intervertebral Posterior Angle ............................................... 55 
6.1.3.3 
Vertebral Body Translation ................................................... 55 
6.1.4 
Magnetic Resonance Imaging ...................................................... 55 
6.1.5 
Vital Signs .................................................................................... 55 
6.1.6 
Physical Examinations ................................................................. 56 
6.1.7 
Neurological Examinations and Pain Assessments ..................... 56 
6.2 
Efficacy Variables ................................................................................... 56 
6.3 
Demographics and Baseline Characteristics ........................................ 56 
6.3.1 
Patient Demography..................................................................... 56 
6.3.2 
Disease History ............................................................................ 57 
6.3.3 
Medical History ........................................................................... 57 
6.3.4 
Previous and Concomitant Medications/Therapies ..................... 57 
7 
STUDY CONDUCT ..................................................................................... 58 
7.1 
Schedule of Procedures ........................................................................... 58 
7.2 
Procedures by Visit ................................................................................. 59 
7.2.1 
Screening (Visit 1) ....................................................................... 60 
7.2.2 
Treatment Day 0 (Visit 2) ............................................................ 60 
7.2.3 
Evaluation Period, Week 1 (Visit 3) ............................................ 61 
7.2.4 
Evaluation Period, Week 6 (Visit 4) ............................................ 61 
7.2.5 
Evaluation Period, Week 13 (Visit 5) .......................................... 61 
7.2.6 
Evaluation Period, Week 26 (Visit 6) .......................................... 62 
7.2.7 
Discontinuation Visit ................................................................... 62 


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8 
STATISTICAL METHODS ....................................................................... 63 
8.1 
Study Patients .......................................................................................... 63 
8.1.1 
Disposition of Patients ................................................................. 63 
8.1.2 
Analysis Sets ................................................................................ 63 
8.2 
General Considerations .......................................................................... 63 
8.3 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications ....................................................................... 64 
8.4 
Treatment Compliance ........................................................................... 64 
8.5 
Efficacy Analyses ..................................................................................... 64 
8.6 
Safety Analyses ........................................................................................ 65 
8.6.1 
Adverse Events and Treatment-Related Adverse Events ............ 65 
8.6.2 
Vital Signs .................................................................................... 65 
8.6.3 
Laboratory Tests .......................................................................... 65 
8.6.4 
Serum Anti-SI-6603 Antibody ..................................................... 65 
8.6.5 
Disc Height (Disc Index) ............................................................. 66 
8.6.6 
Intervertebral Posterior Angle ...................................................... 66 
8.6.7 
Vertebral Body Translation.......................................................... 66 
8.6.8 
Change in Bone Marrow Adjacent to Vertebral Endplates (Modic 
Classification) .............................................................................. 66 
8.6.9 
Disc Degeneration (Pfirrmann Classification) ............................. 66 
8.6.10 
Occurrence of Post-Treatment Lumbar Surgery .......................... 67 
8.7 
Interim Analyses ...................................................................................... 67 
8.8 
Determination of Sample Size ................................................................ 67 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .................. 68 
9.1 
Data Quality Assurance .......................................................................... 68 
9.1.1 
Database Management and Quality Control ................................ 68 
9.2 
Case Report Forms and Source Documentation .................................. 68 
9.2.1 
Data collection ............................................................................. 69 


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9.3 
Access to Source Data ............................................................................. 69 
9.4 
Data Processing ....................................................................................... 69 
9.5 
Archiving Study Records ........................................................................ 70 
9.6 
Good Clinical Practice ............................................................................ 70 
9.7 
Informed Consent .................................................................................... 70 
9.8 
Protocol Approval and Amendment ...................................................... 70 
9.9 
Duration of the Study .............................................................................. 71 
9.10 
Premature Termination of the Study .................................................... 71 
9.11 
Confidentiality ......................................................................................... 72 
9.12 
Other Ethical and Regulatory Issues ..................................................... 72 
9.13 
Liability and Insurance ........................................................................... 72 
9.14 
Publication Policy .................................................................................... 72 
10 
REFERENCE LIST ..................................................................................... 73 
11 
APPENDICES .............................................................................................. 75 
11.1 
Injection Procedure and Investigational Drug Management .............. 75 
11.1.1 
Preparation Method for SI-6603 .................................................. 75 
11.1.2 
Precautions in Administering Investigational Drug ..................... 75 
11.1.3 
Intradiscal Administration Procedure for SI-6603 ....................... 76 
11.2 
Package Presentation and Labeling ...................................................... 77 
11.3 
Visual Analog Scale ................................................................................. 78 
11.4 
Oswestry Disability Index, version 2.1a ................................................ 81 
11.5 
Modic Classification ................................................................................ 84 
11.6 
Pfirrmann Classification ........................................................................ 85 
11.7 
Imaging Tests (X-ray and Magnetic Resonance Imaging) .................. 86 
11.7.1 
X-ray Imaging .............................................................................. 86 
11.7.2 
Disc Height (disc index) .............................................................. 86 
11.7.3 
Intervertebral Posterior Angle ...................................................... 86 
11.7.4 
Vertebral Body Translation.......................................................... 86 
11.7.5 
Magnetic Resonance Imaging ...................................................... 87 
11.8 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) .. 88 
 
Tables in Text 
Table 1:  Adverse Events That Occurred in Clinical Studies to Date ......................31 
Table 2:  Laboratory Assessments ............................................................................53 
Table 3:  Schedule of Assessments and Procedures .................................................59 
 
Figures in Text 
Figure 1: Study Design ..............................................................................................38 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence interval 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
DRL 
Drug Reference List 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FNS 
Femoral Nerve Stretching 
HEK 
Human embryonic kidney 
hERG 
human Ether-à-go-go-related gene 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethic Committee 
Ig 
Immunoglobulin  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat (population) 
L1L2 
The disc between the 1st and 2nd lumbar vertebra 
L2L3 
The disc between the 2nd and 3rd lumbar vertebra 
L3L4 
The disc between the 3rd and 4th lumbar vertebra 


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L4L5 
The disc between the 4th and 5th lumbar vertebra 
L5S1 
The disc between the 5th lumbar vertebra and 1st sacral vertebra 
LSM 
Least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
mSv 
Millisievert 
mU 
Milliunit 
NOAEL 
No-observed-adverse-effect level  
ODI 
Oswestry Disability Index 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviations 
SI-6603 
Condoliase, an active ingredient of SI-6603 injectable solution 
SKK 
Seikagaku Corporation 
SLR 
Straight Leg Raising (test) 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
U 
Units 
ULN 
Upper limit of normal 
USA 
United States of America 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Seikagaku Corporation (SKK) is developing SI-6603, a lyophilized injectable drug 
containing condoliase as the active ingredient. In 1991, SKK started investigations into 
the safety and efficacy of SI-6603 as a chemonucleolysis drug for the treatment of 
lumbar disc herniation. The Phase I/II, Phase II/III, Phase III clinical studies in Japan, 
and Phase II clinical study in the United States of America (USA) have been completed, 
and a Phase III clinical study in the USA is currently being conducted. 
Lumbar disc herniation occurs as a result of a protrusion or prolapse of the nucleus 
pulposus of a disc into the spinal canal following partial or complete perforation and 
destruction of the posterior annulus fibrosus. When this occurs, the nerve root is 
compressed by the nucleus pulposus, causing various symptoms including leg pain, back 
pain, and numbness.2 The principal treatment for lumbar disc herniation is conservative, 
resulting in an approximately 90% response.3,4 Conservative treatment includes rest, 
bed-rest, medication (e.g., nonsteroidal anti-inflammatory drugs, steroids, and muscle 
relaxants), corset, traction therapy, thermotherapy, epidural block, nerve root block, and 
physical therapy. Approximately 20% to 50% of the patients are eligible for surgical 
treatment when no improvement is observed following conservative treatment.5 To 
reduce the invasiveness of surgical procedures, new treatment approaches have become 
available, including chemonucleolysis, percutaneous nucleotomy, percutaneous laser disc 
decompression, and microendoscopic discectomy. 
Chemonucleolysis alleviates the symptoms of lumbar disc herniation using the enzyme 
chymopapain (a protease), which is injected into an intervertebral disc to reduce nerve 
root compression through lysis of the nucleus pulposus and reduction of disc pressure.2 
Chemonucleolysis is a valuable treatment for patients who do not respond to other 
conservative treatments, those with severe disorders, and those who are candidates for 
surgery, and is currently positioned as the final step in conservative treatment as 
minimally invasive and effective treatment.6,7  
Although chymopapain has been approved and used in the USA, Europe, Canada, and 
Korea as a drug for chemonucleolysis, the use is limited due to its non-specific protease 
activity.8,9 Although it is rare, serious neurological complications (e.g., paraplegia, 
transverse myelitis, cerebral hemorrhage, subarachnoid hemorrhage, and quadriplegia) 
were reported.8 Therefore, drugs that are highly specific to the nucleus pulposus alone 
and that do not influence nerve tissue surrounding the disc are needed for safe and 
effective chemonucleolysis.10  
Condoliase is a glycosaminoglycan-decomposing enzyme isolated and purified from a 
gram-negative rod, Proteus vulgaris.11 Condoliase has substrate specificity for 
chondroitin sulfate, dermatan sulfate, and hyaluronic acid which are components of 
glycosaminoglycan chains that exists in proteoglycans in nucleus pulposus, but not for 


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keratan sulfate, heparin, or heparan sulfate.12 In addition, unlike chymopapain, 
condoliase lacks protease activity. In lumbar disc herniation, condoliase is thought to 
decompose glycosaminoglycan chains, such as chondroitin sulfate in the proteoglycans 
of the nucleus pulposus and to reduce the high water retention attributable to 
proteoglycans, thereby relieving disc pressure and compression on the spinal nerve root 
caused by lumbar disc herniation. Due to its substrate specificity and lack of protease 
activity when compared with chymopapain, with condoliase chemonucleolysis, the risk 
of adverse effects such as nerve tissue injuries in the area surrounding intervertebral discs 
can be minimized with condoliase chemonucleolysis. 
1.1.1 Summary of Clinically Significant Findings Obtained in Non-Clinical Studies 
1.1.1.1 Pharmacology   
In the primary pharmacology studies of SI-6603, the following effects have been 
investigated: the inhibitory effect on nucleus pulposus swelling and the effect of 
releasing nucleus pulposus components in vitro, the effect of decreasing intradiscal 
pressure, and the disc height reducing effect which is observed as an event accompanied 
with regression of the nucleus pulposus in vivo. The efficacy of SI-6603 for intervertebral 
disc herniation was investigated by the improvement of disc hernia syndrome after 
intradiscal injection of SI-6603 in dogs with disc herniation. 
1.1.1.2 Safety Pharmacology 
In safety pharmacology studies, no effects on the central nervous system or respiratory 
system in rats, or cardiovascular system in dogs were observed after single subcutaneous 
administration of SI-6603 at 0.2, 2 or 20 units (U)/kg. At concentrations up to 
4.36 milliunit (mU)/mL, SI-6603 had no effects on human Ether-à-go-go-related gene 
(hERG) current in a patch-clamp assay using hERG-transfected human embryonic 
kidney (HEK) 293 cells in vitro. 
1.1.1.3 Pharmacokinetics and Metabolism 
When 125I-SI-6603 was injected intradiscally in beagle dogs at a single-dose of 
50 U/disc, the radioactivity concentration was nearly constant for 14 days with a level 
ranging from 0.2 to 0.5 mU equivalent per milliliter (mU eq/mL). Furthermore, the 
plasma SI-6603 concentrations were below the lower limit of quantification at all-time 
points of measurement, and the concentration in major tissues was low, suggesting that 
SI-6603 could be slowly distributed in the systemic circulation after a single intradiscal 
injection. The enzyme activity in the injected intervertebral discs remained up to 14 days 
after the administration, and the radioactivity showed that SI-6603 remained in the 
injected intervertebral disc for a long time while preserving its substantial enzyme 
activity. When the study was repeated in beagle dogs by injecting 125I-SI-6603 
intradiscally at a reduced single-dose of 2 U/disc, the SI-6603 enzyme activity was 


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detected even up to 30 days in the injection site. A similar result was found in 
cynomolgus monkeys when 125I-SI-6603 was injected intradiscally at a single-dose of 
2 U/disc.   
1.1.1.4 Toxicology 
In consideration of the clinical administration route, the potential for tissue injury on or 
surrounding the intervertebral disc following intradiscal administration of SI-6603 was 
evaluated. The potential for systemic toxicity was evaluated in studies using the 
intravenous, subcutaneous and intramuscular routes of administration.  
In the long-term (3-month to 3-years) observation studies following a single-dose 
intradiscal injection of SI-6603, histological changes related to pharmacological effects 
of SI-6603 were observed in cynomolgus monkeys, rabbits and dogs, i.e., degenerative 
changes of the nucleus pulposus and annulus fibrosus. In addition to these common 
changes, in cynomolgus monkeys, other changes were observed from 1 week after 
administration including cellular degeneration and necrosis, and decreased staining in 
both the cartilaginous endplate and epiphysial growth plate. In the vertebral body, 
decrease and necrosis of bone marrow cells and changes associated with new bone 
formation were observed. In addition, cellular regeneration, vascular invasion and 
ossification in the cartilaginous endplate, and focal disappearance of the epiphysial 
growth plate were observed from 4 weeks after administration. At 13 weeks after 
administration, some histological changes showed a clear tendency of recovery, and at 
26 weeks after administration, no necrotic changes were observed in sites ranging from 
the cartilaginous endplate to the vertebral body. The histological features of the 
cartilaginous endplate and epiphysial growth plate at 26 weeks after administration are 
qualitatively similar to those reported in humans, who exhibit aging-related thinning, 
ossification or disappearance of the cartilaginous endplate and epiphysial growth plate. In 
rabbits, no remarkable changes except for osteocyte necrosis in vertebral body adjacent 
to the cartilaginous endplates were observed. In dogs, protrusion of nucleus pulposus 
tissues into the bone marrow cavity of the vertebral body (Schmorl’s nodes-like lesions) 
was observed, associated with degeneration of cartilaginous endplates. 
It is considered that the intervertebral disc structure in the cynomolgus monkey is most 
similar to that in humans among the laboratory animals used. Therefore the cynomolgus 
monkey would be the most relevant species to predict the effects of SI-6603 in humans. 
In cynomolgus monkeys, adverse effects were noted in sites ranging from the 
cartilaginous endplate to a part of the vertebral body from 1 to 13 weeks after 
administration. But these effects were not severe, and some histological changes showed 
a clear tendency of recovery. At 26 weeks after administration, the histological changes 
subsided and the histological features were indicative of recovery, even at a dose just 
below 500 times the recommended clinical dose which was calculated based on the ratio 
of the nucleus pulposus volume. This result suggests that SI-6603 is unlikely to cause 
serious histological changes in the clinical setting.  


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In the short-term (within 7-days) observation studies following a single-dose intradiscal 
injection of SI-6603 in rabbits, which were conducted as local tolerance studies, only 
nucleus pulposus was affected and no changes were seen in the annulus fibrosus, 
cartilaginous endplate, vertebral body, and their surrounding tissues at 0.075 U/disc 
(20 times the recommended clinical dose). At 2 U/disc (534 times the recommended 
clinical dose), pharmacological and its related effects extended to the annulus fibrosus. In 
addition, changes in bone tissues surrounding the intervertebral disc were seen. SI-6603 
was also administered to the spinal subarachnoid space, spinal nerve root or muscle of 
rabbits. The nerve tissues exhibited good tolerance but transient and mild irritation was 
observed in muscle tissues.  
In the single-dose toxicity studies (intravenous, intramuscular, and subcutaneous 
administrations) in mice, rats and dogs, no remarkable findings were observed except for 
sluggishness, whining, ataxia, paralysis and hunching which were transiently observed in 
dogs. Approximate lethal doses were over 2000 U/kg in these species. In the repeated-
dose (1 month) toxicity studies in rats and dogs, no marked abnormalities were found, 
although the appearance of anti-SI-6603 antibodies and subsequent increases in the 
antibody titer were found. No-observed-adverse-effect levels (NOAELs) were considered 
to be 200 U/kg or greater for both species.  
No potential genotoxicity was noted for SI-6603. For the reproductive and 
developmental toxicity studies in rats and rabbits, no abnormalities were seen in early 
embryonic development to implantation, fetal organogenesis, pre- and postnatal 
development, including maternal function in all reproductive and developmental toxicity 
studies. In the dermal irritation studies in guinea pigs, no primary irritative effects on the 
skin were noted after the intradermal administration of SI-6603, although the white 
discoloration around the injection area was observed. The antigenicity studies in guinea 
pigs showed positive results because SI-6603 is a foreign protein derived from the 
bacterium Proteus vulgaris. 
1.1.2 Summary of Important Findings Obtained in Prior Clinical Studies 
1.1.2.1 Phase I/II Clinical Study in Patients with Lumbar Disc Herniation 
(Study Number: SKK0197) (Sweden) 
A Phase I/II study was conducted in patients with lumbar disc herniation of the disc 
between the 4th and 5th lumbar vertebra or between the 5th lumbar and 1st sacral vertebra 
(L4L5 or L5S1), with the intention of administering SI-6603 at doses of 0.25 U/mL 
(0.5 U dose group), 1.25 U/mL (2.5 U dose group) and 5 U/mL (10 U dose group) with a 
maximum volume of 2 mL. A decision was made to discontinue the study for 
non-safety-related reasons and data were compiled for the 0.5 U dose group to the time 
of termination. 
In the 0.5 U dose group (single-dose injections with an upper limit of 0.5 U), 9 adverse 
events (AEs) in 3 patients included back pain (5 events/2 patients), lumbar fatigability 


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(3 events/1 patient), and vomiting (1 event/1 patient). Back pain occurred as a serious 
adverse event (SAE) (1 event/1 patient) and was assessed as being unrelated to SI-6603. 
No AEs involving the cartilage endplates, annulus fibrosus, or adjacent discs were 
recorded. 
1.1.2.2 Phase I/II Clinical Study in Patients with Lumbar Disc Herniation 
(Study Number: SKK6603J01) (Japan) 
This was a single-dose study in patients with lumbar disc herniation (L4L5 or L5S1). 
Eighteen patients who were administered SI-6603 at 0.5 U, 2.5 U, or 10 U reported a 
total of 67 AEs. The AEs occurring at a high frequency and within each dosage group 
included back pain (66.7%) and puncture site reactions (55.6%). The SAEs (seriousness 
criterion: prolonged existing hospitalization) comprised 5 events in 2 patients in the 
0.5 U dose group: back pain in 1 patient and pruritus, exanthem, skin warm and 
dermatitis bullous in another patient. Anti-SI-6603 antibodies (immunoglobulin [Ig] E 
and IgG) were negative in all groups throughout the study. All patients in the 2.5 U and 
10 U dose groups were negative on prick test. In the 10 U dose group, abnormal spinal 
X-rays were detected in 33.3% of cases (2 of 6).  
The 10 U/mL/disc dose was associated with tolerance problems; therefore, the planned 
dose escalation to 40 U was terminated. The safety of SI-6603 at doses up to 2.5 U/mL 
by intervertebral disc administration was established for the treatment of patients with 
lumbar disc herniation. 
Plasma concentrations of SI-6603 determined in each dosage group during 12 weeks 
following administration were all below the lower limit of quantification (100 µU/mL). 
Additionally, the time-course of plasma chondroitin sulfate concentration exhibited a 
slight decrease 2 and 6 hours after administration in the 2.5 U dose group, however, no 
changes were observed at other time points in all dosage groups. Conversely, serum 
keratan sulfate concentrations tended to increase within 24 hours after administration in 
each dosage group and then decreased to roughly baseline values by 12 weeks after 
administration. Analysis of the area under the serum concentration-time curve of keratan 
sulfate in each dosage group revealed a statistically significant dose-response 
relationship. 
1.1.2.3 Prognostic Study of Patients with Lumbar Disc Herniation Administered with 
SI-6603 in Japanese Phase I/II Clinical Study (Japan)  
A retrospective follow-up study was conducted 6 years after the initial study to confirm 
the long-term effects of SI-6603 on the degeneration of nucleus pulposus and vertebral 
stability of intradiscal administration. 
Ten of the total 18 patients who participated in the initial Phase I/II clinical study 
consented to participate in this study. The observation period was 3.2 to 77.8 months 
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No patients had progressive disc height decrease, worsening of clinical symptoms, or 
lumbar surgery after the administration of SI-6603. 
There were no clinically problematic events such as progressive decrease of disc height 
and worsening of clinical symptoms, and the findings were unchanged from the final 
observation time of the initial Phase I/II study (SKK6603J01). In patients who had 
changes in imaging findings, no clinical symptoms accompanied the changes. The results 
of this study supported the long-term safety of the disc and its surrounding tissue after 
administration of SI-6603.  
1.1.2.4 Prick test of SI-6603-P in Healthy Adult Volunteers 
(Study Number: SKK6603J02) (Japan) 
This study in 20 healthy volunteers was to evaluate skin irritation and safety of 
SI-6603-P (lyophilized injectable drug preparation with condoliase as the ingredient). 
The prick test was performed at doses of 5 U/mL, 10 U/mL, 20 U/mL, 40 U/mL, and 
80 U/mL using a prick lancet. None of the patients tested positive and all AEs were 
assessed as unrelated to SI-6603 administration.  
No skin irritation was observed and SI-6603 was confirmed to be safe for clinical 
application. 
1.1.2.5 Phase II/III Clinical Study in Patients with Lumbar Disc Herniation 
(Study Number: 6603/1021) (Japan) 
This was a multicenter, randomized, double-blind, placebo-controlled, comparative study 
that sought to verify the superiority of SI-6603 versus a placebo at 13 weeks after 
single-dose administration of 1.25 U, 2.5 U, or 5 U of SI-6603 or placebo into the 
nucleus pulposus of an intervertebral disc of patients with lumbar disc herniation (L4L5 
or L5S1). An additional objective of this study was to determine a recommended dose 
for SI-6603 by monitoring the stability of the intervertebral disc and surrounding tissue 
for up to 52 weeks after administration.  
The least squares mean (LSM) of the primary endpoint of change from baseline in worst 
leg pain over the past 24 hours at Week 13 was 31.7 mm in the placebo group, 
46.7 mm in the 1.25 U dose group, 41.1 mm in the 2.5 U dose group, and 47.6 mm in 
the 5 U dose group. There were significant differences for all SI-6603 groups compared 
to the placebo group.  
The LSM change from baseline in worst leg pain at the final observation in Week 52 was 
about the same in all SI-6603 groups: 46.1 mm in the placebo group, 60.7 mm in 
the1.25 U dose group, 59.3 mm in the 2.5 U dose group, and 62.6 mm in the 5 U dose 
group. There were significant differences for all SI-6603 groups compared to the placebo 
group. 
SAEs were reported in 5 of the 194 patients treated with SI-6603 or placebo, but no 
causal relationship with SI-6603 or placebo was established for any of these events. 


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Severe AEs occurred in 10 of the 147 patients in the SI-6603 groups. A causal 
relationship with SI-6603 or placebo could not be ruled out for 2 patients in the 2.5 U 
dose group (neutrophil count decreased and lymphadenitis).  
The incidence of treatment-related AEs was found to be dose responsive at 14.9% in the 
placebo group, 46.9% in the 1.25 U dose group, 44.9% in the 2.5 U dose group, and 
61.2% in the 5 U dose group.  
Treatment-related AEs with a high incidence in the SI-6603 groups were nuclear 
magnetic resonance imaging (MRI) abnormal, back pain, and spinal X-ray abnormal. 
Incidences of back pain, nuclear MRI abnormal, and spinal X-ray abnormal were high in 
each of the SI-6603 groups compared to the placebo group, with the latter 
treatment-related AE occurring most frequently in the 5 U dose group. All AEs were 
classified as mild or moderate by the Investigators. There was no observed increase in 
the AE incidence of leg and low back pain accompanying the occurrence of AEs relating 
to stability of the intervertebral disc and surrounding tissues.  
No patients were found to have a definitely elevated serum anti-SI-6603 IgE antibody 
titer. At Week 13, one patient each from the 2.5 U and 5 U dose groups exhibited a 
definitely elevated serum anti-SI-6603 IgG antibody titer, but neither experienced any 
AEs characterized by allergy-like symptoms.  
Plasma SI-6603 concentration was below the limit of quantification in all patients at all 
time points (<100 μU/mL). 
1.1.2.6 Phase II Clinical Study in Patients with Lumbar Disc Herniation (Study 
Number: 6603/1121) (USA) 
This study was an open-label, multicenter, sequential dose-escalation study. The 
objective of this study was to evaluate the safety of SI-6603 in lumbar disc herniation 
patients (L4L5 or L5S1) followed for 52 weeks after administration of SI-6603 into an 
intervertebral disc. Exploratory efficacy endpoints were investigated. Patients received a 
single 1.0 mL injection of SI-6603 (0.5 U, 1.25 U, or 2.0 U) into the nucleus pulposus of 
an intervertebral disc of each patient. A Data Safety Monitoring Board (DSMB) 
evaluated safety and tolerability once the Week 13 data were available for each cohort. 
On the basis of the recommendation of the DSMB, the Sponsor proceeded to the next 
higher dose for the second (1.25 U) and third cohorts (2.0 U).  
A total of 17 patients (94.4%) in the safety population experienced 39 AEs. Two patients 
(11.1%) discontinued the study due to an AE and no patient discontinued due to a 
treatment-related AE. No patient experienced a SAE or died during the study.  
The most frequently observed treatment-related AE with an incidence of ≥3 patients in 
the total safety population was nuclear MRI abnormal (4 patients, 22.2%). The event was 
all mild in intensity and did not require intervention in all patients. The following 
3 treatment-related AEs (each reported for a different patient) were not resolved before 
the end of the study: nuclear MRI abnormal, spinal X-ray abnormal, and dysesthesia. 


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Clinical observations of the patients with these treatment-related AEs were terminated 
after each patient’s condition was determined to be stable.  
Evaluation of translation and angulation of vertebral bodies did not raise safety concerns. 
One patient had a decrease in disc height ≥30%. Overall, 6 patients (33.3%) in the safety 
population had a change to Modic classification Type I or II, which included 1 patient 
(20.0%) in the 0.5 U dose group, 3 patients (50.0%) in the 1.25 U dose group, and 
2 patients (33.3%) in the 2.0 U dose group.  
No patient had an increase in serum anti-SI-6603 IgE antibody titer. At Week 13, one 
patient each from the 0.5 U, 1.25 U and 2.0 U dose groups had an IgG antibody titer that 
was increased by one grade from baseline, but with unclear SI-6603 specificity.  
Efficacy evaluations showed improvement from baseline in leg pain Visual Analog Scale 
(VAS). At Week 13, the mean worst leg pain values that were assessed during the 7 days 
prior to the Week 13 visit were 9.1 mm in the 0.5 U dose group, 38.4 mm in the 1.25 U 
dose group, and 5.1 mm in the 2.0 U dose group. Improvement of the worst leg pain in 
the treatment groups also continued beyond Week 13. At screening (baseline), the values 
were 65.9 mm in the 0.5 U, 70.8mm in the 1.25 U, and 81.7mm in the 2.0 U, at the final 
observation at Week 52 the values were 24.0 mm in the 0.5 U dose group, 39.0 mm in 
the 1.25 U dose group, and 13.2 mm in the 2.0 U dose group. Mean worst back pain 
values at Week 52 that were assessed during the 7 days prior to Week 52 visit were 
lowest in the 2.0 U dose group (11 mm) and highest in the 1.25 U dose group (45 mm).  
The plasma SI-6603 concentration was below the limit of quantification in all patients at 
all time points (<100 μU/mL).  
In conclusion, SI-6603 was well tolerated for up to 52 weeks after administration with no 
major safety concerns. SI-6603 improved leg pain and underlying symptoms of lumbar 
disc herniation. 
1.1.2.7 Phase III Clinical Study in Patients with Lumbar Disc Herniation 
(Study Number: 6603/1031) (Japan)  
This study was a multicenter, randomized, double-blind, placebo-controlled, comparative 
study that sought to verify the superiority of SI-6603 versus a placebo at 13 weeks after 
single-dose administration of 1.25 U of SI-6603 or the placebo into the nucleus pulposus 
of an intervertebral disc of patients with lumbar disc herniation (L4L5 or L5S1). A 
further objective of this study was to monitor the stability of the intervertebral disc and 
surrounding tissue up to 52 weeks after administration. 
The LSM of the primary endpoint of change from baseline in worst leg pain over the past 
24 hours at Week 13 was 34.3 mm in the placebo group and 49.5 mm in the 1.25 U 
group showing significant difference for the 1.25 U group compared to the placebo 
group. 


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The LSM change from baseline in worst leg pain at the final observation in Week 52 was 
42.3 mm in placebo group and 54.2 mm in 1.25 U group; showing significant 
difference for SI-6603 group compared to the placebo group. 
In the safety evaluation, SAEs were seen in 10 of the 163 patients treated with the 
investigational drugs (placebo group: 6 patients and 1.25 U group: 4 patients). In 
10 patients with SAEs, a causal relationship with the investigational drug could not be 
ruled out for 1 patient in the 1.25 U group with back pain. Five patients in the placebo 
group discontinued the study due to an AE but no causal relationship with investigational 
drug was established for any of these events. Severe AEs occurred in 13 of the 
163 patients treated with the investigational drug (placebo group: 7 patients and 1.25 U 
group: 6 patients). A causal relationship with the investigational drug could not be ruled 
out for 1 patient in the 1.25 U group with toxic skin eruption. 
The incidence of treatment-related AEs was 33.3% in the placebo group and 57.3% in the 
1.25 U group, with a significant difference between the 1.25 U group and the placebo 
group. 
In the 1.25 U group, treatment-related AEs with a high incidence were back pain 
(placebo group: 4.9%; 1.25 U group: 24.4%), nuclear MRI abnormal (placebo group: 
12.3%; SI-6603 group: 24.4%), and spinal X-ray abnormal (placebo group: 3.7%; 
SI-6603 group: 23.2%). Treatment-related AEs in the1.25 U group with an incidence that 
is higher by10% or more than placebo were back pain, nuclear MRI abnormal, and spinal 
X-ray abnormal. The severity of all treatment-related AEs with high incidence was mild 
or moderate. Patients in the 1.25 U group with AEs relating to the stability of the 
intervertebral disc (decrease in disc height of ≥30% and intervertebral posterior angle 
of ≥5°) showed a trend towards a high incidence of the treatment-related AE of low back 
pain. 
No patients were found to have an elevated serum anti-SI-6603 IgE antibody titer. One 
patient each from the placebo group and the 1.25 U group exhibited an elevated serum 
anti-SI-6603 IgG antibody titer but neither experienced any AEs characterized by 
allergy-like symptoms. 
1.1.3 Additional Information 
Further details can be found in the current Investigator's Brochure (IB), which contains 
comprehensive information on SI-660313. 
1.1.4 Current Study 
The current study is a Phase III, multicenter, open-label, study of SI-6603 in patients 
with lumbar disc herniation. Patients will receive a single intradiscal dose of SI-6603 
1.25 U injection. Safety and efficacy will be followed for 26 weeks after investigational 
drug administration. See Section 3.1 for details concerning the design of the current 
study and Section 3.3 for study design justification of this study. 


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1.2 
Rationale 
1.2.1 Study Rationale 
Lumbar disc herniation is treated primarily with conservative non-operative therapy. 
However, in patients who fail to respond to this therapy, surgery is one of the only 
remaining options. The target population of this study is patients with signs and 
symptoms of lumbar disc herniation who failed conservative therapy and who have not 
received surgery at the target level or who qualify for surgery but wish to avoid it. 
Patients who require immediate surgical intervention such as those with significant 
neurologic deficit will be excluded. 
The results of the Japanese Phase II/III clinical study (Study Number: 6603/1021) 
suggest that SI-6603 intradiscal injection is safe and effective in improving the signs and 
symptoms of lumbar disc herniation. In addition, the Japanese Phase III clinical study 
(Study Number: 6603/1031) verified that SI-6603 intradiscal injection is safe and 
effective in improving the signs and symptoms of lumbar disc herniation. Therefore, 
conducting a further clinical study intended to assess safety and efficacy of intradiscal 
SI-6603 at a dose of 1.25 U was proposed. 
1.2.2 Rationale for Dose and Schedule Selection 
The intradiscal route was selected as the route of SI-6603 administration for this study. 
SI-6603 acts by decreasing intradiscal pressure and ameliorating pressure on the spinal 
nerve root by decomposing glycosaminoglycan chains (e.g., chondroitin sulfate) of 
proteoglycan present in the nucleus pulposus of an intervertebral disc. This reduced the 
water retention by the proteoglycan.  
The dose selected for this study was 1.25 U administered as a single injection into the 
intervertebral disc, based on the result of the Japanese Phase II/III clinical study (Study 
Number: 6603/1021) and the Japanese Phase III clinical study (Study 
Number: 6603/1031), where the 1.25 U dose was shown to be safe and effective.  
A retrospective follow-up prognostic study of patients with lumbar disc herniation was 
conducted 6 years after the Japanese Phase I/II clinical study (Study Number: 
SKK6603J01). There were no occurrences of lumbar surgery or worsening of the clinical 
symptoms (see Section 1.1.2.3). 
Single-dose administration was selected for SI-6603 rather than repeat dose 
administration due to the risk of allergic reaction with multiple injections that is unlikely, 
but possible, to occur due to the heterologous protein preparation of Proteus vulgaris.  
1.3 
Risk-Benefit Assessment 
Lumbar disc herniation is treated primarily with conservative nonoperative therapy. 
However, in patients who fail to respond to this therapy, surgery is one of the only 
remaining options. This indicates an unmet medical need for a less invasive and safe 


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therapy that is effective in treating lumbar disc herniation in patients who fail to improve 
with nonoperative therapy. 
The more common possible risks of injecting SI-6603 are back pain, nuclear MRI 
abnormal (Modic change), and spinal X-ray abnormal (decrease of disc height) Table 1. 
In past studies, the severity of back pain was mostly mild to moderate and symptoms 
recovered or resolved either without intervention or after appropriate treatment in most of 
the patients. Modic change and decrease of disc height were assessed as mild in severity 
in past studies and none of the affected patients exhibited any clinical symptoms posing 
safety concerns. Decrease of disc height in SI-6603 treated patients was assessed mild in 
severity in past studies and the degree of disc height decrease was considered comparable 
to or less than the lumbar discectomy. 
In Japanese Phase II/III and Phase III studies, administration of SI-6603 1.25 U/mL 
demonstrated clinically significant improvement of leg pain and favorable improvement 
of back pain in lumbar disc herniation patients with contained-type hernia (unruptured 
posterior longitudinal ligament) who failed to improve after undergoing conservative 
treatment for a period of more than 6 weeks.  
Taken together, it is considered that the risks of SI-6603 are manageable and the 
potential benefits outweigh those risks. During the study, X-ray and MRI assessments 
will be conducted to investigate the possibility of abnormalities. If any abnormalities 
occur, patients will be able to obtain immediate proper treatment. Detailed assessment of 
anticipated possible risks and benefits are stated below. 
1.3.1 Possible Risks 
1.3.1.1 Treatment-related Adverse Event 
Information on major AEs and treatment-related AEs that were observed in SI-6603 
clinical studies in patients with lumbar disc herniation are summarized below. The 
follow-up periods in the previous clinical studies were up to one year after the 
administration of a single-dose of SI-6603 into the intervertebral disc (Table 1). 
1. The SAEs for which a causal relationship with SI-6603 could not be ruled out 
included: 4 events (pruritus, exanthema, skin warmth, and bullous dermatitis) in 
1 patient in the 0.5 U dose group in the Japanese Phase I/II clinical study. All events 
were moderate in severity. However, they were processed as SAEs because of 
prolongation of an existing hospitalization.  
1 event (back pain) in 1 patient in the 1.25 U dose group in the Japanese Phase III 
clinical study. Although the event was moderate in severity, it was processed as SAE 
because inpatient hospitalization was required for nucleotomy. 
2. The high incidence AEs for which a causal relationship with SI-6603 could not be 
ruled out:  


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back pain, nuclear MRI abnormal (change in bone marrow adjacent to vertebral 
endplates; Modic change), and spinal X-ray abnormal (30% decrease of disc height). 
3. Severe AEs for which a causal relationship with SI-6603 could not be ruled out: 
2 events (lymphadenitis and neutrophil count decreased) in 2 patients in the 2.5 U 
dose group in the Japanese Phase II/III study, 1 event (back pain) in 1 patient in the 
2.0 U dose group in the USA Phase II study, and 1 event (toxic skin eruption) in 
1 patient in the 1.25 U dose group in the Japanese Phase III study. 
4. Abnormal laboratory values considered to be AEs for which a causal relationship 
with SI-6603 could not be ruled out:  
neutrophil count decreased, C-reactive protein increased, blood triglycerides 
increased, white blood cell count decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, blood bilirubin increased, 
Lasegue’s test positive, eosinophil count increased and platelet count decreased. Of 
these AEs, only neutrophil count decrease (1 patient in the 2.5 U dose group in the 
Japanese Phase II/III study) was determined to be severe. 
5. In the non-clinical data of the SI-6603 long-term (3 months to 3 years) observation 
studies following a single-dose intradiscal administration, bulging of nucleus 
pulposus tissues into the bone marrow cavity of the vertebral body (Schmorl’s 
nodes-like lesions) associated with degeneration of cartilaginous endplates was 
observed in dogs. However, similar findings were not observed in clinical studies in 
Sweden, Japan, and the USA, or in non-clinical studies using rabbits and cynomolgus 
monkeys. 
A listing of the AEs that occurred in clinical studies to date in SI-6603 treatment groups 
(269 patients in total; 0.5 U, 1.25 U, 2.0 U, 2.5 U, 5 U, and 10 U dose groups) and 
placebo (128 patients) are shown in Table 1. 
1.3.1.2 Allergic Reactions 
As SI-6603 is a foreign protein, it has the potential to cause anaphylaxis or severe 
allergic reactions. Anaphylaxis or severe allergic reactions were not observed in the 
Phase I/II, Phase II/III, and Phase III studies in Japan, and the Phase II study in the USA.  
In the Phase I/II study in Japan, 2 of the 18 patients exhibited AEs in the form of 
allergy-like symptoms for which a causal relationship with SI-6603 could not be ruled 
out. One of these patients developed a moderate case of pruritus, skin warm, exanthema, 
and dermatitis bullous, and the other patient developed a mild exanthema.  
In the Phase II/III and Phase III studies in Japan, 6 of the 229 patients exhibited AEs in 
the form of allergy-like symptoms for which a causal relationship with SI-6603 could not 
be ruled out. One of these patients developed a severe toxic skin eruption.  
All of these AEs in the form of allergy-like symptoms appeared 1 to 7 days after 
administration, but resolved after standard dermatological treatment.  


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No patients were found to have increased serum anti-SI-6603 IgE antibody titers. 
1.3.1.3 Back Pain 
Treatment-related AEs of back pain were the highest reported incidence in past studies 
(64/269 patients). Severity was mostly mild to moderate with 2 severe events from the 
Phase III study in Japan and Phase II study in the USA, respectively. 
Occurrence of back pain is likely to be influenced by the primary disease. However, back 
pain that occurred soon after administration of SI-6603 may be attributable to nucleus 
pulposus degradation. Thus, it is assumed that nucleus pulposus degradation by SI-6603 
administration will accompany the spine’s architecture and create dynamic changes that 
lead to the occurrence of temporary back pain. It is also assumed that a 1 mL 
intervertebral injection of SI-6603 may lead to an occurrence of back pain, which is 
caused by a temporary increase on intervertebral disc inner pressure. 
1.3.1.4 Decrease of Lumbar Disc Height and Change in Bone Marrow Adjacent to 
Vertebral Endplates 
In past studies with SI-6603 administration, treatment-related AEs of nuclear MRI 
abnormal (change in bone marrow adjacent to vertebral endplates; Modic change) were 
reported in 22.3% (60/269 patients) and spinal X-ray abnormal were reported in 14.1% 
(38/269 patients). Among 38 patients reporting spinal X-ray abnormal, AEs included 
intervertebral posterior angle dilation (7 events) and 30 % decrease of disc height 
(34 events). However, none of the affected patients exhibited any clinical symptoms 
posing safety concerns. Furthermore, there was no leg pain or back pain accompanying 
the occurrence of instability of the intervertebral disc and surrounding tissues. The 
clinical significance of Modic changes remains unclear and past SI-6603 studies did not 
reveal any increase of leg pain or back pain in conjunction with Modic changes. 
Spinal imaging changes following lumbar discectomy were reported by McGirt, et al. as 
18%, 21%, and 26% decreases of disc height at 3 months, 6 months, and 2 years post 
surgery, respectively.14 In a follow-up study until 2 years after lumbar discectomy 
patients, Ohtori, et al. reported Modic changes in 7 (15.6%) of the 45 patients, with 1 of 
the 22 patients exhibiting a change from Modic Type 0 to Type 1, 3 of the 22 patients 
changing from Modic Type 0 to Type 2, and 3 of the 23 patients changing from Modic 
Type 1 to Type 2.15 In a Phase II/III study in Japan, percent decrease in disc heights was 
highest in the 5 U dose group at 17.4% at Week 13, 18.9% at Week 26, and 21.8% at 
Week 52. The reductions in disc height in the SI-6603 groups were equal to or milder 
than those of the above-mentioned lumbar discectomy patients. The incidence of 
treatment-related Modic changes was slightly higher in the SI-6603 groups than in the 
lumbar discectomy patients at 22.3%. 
There is a possibility that changes in the bone marrow adjacent to vertebral endplates and 
decreases of lumbar disc height may occur as the result of SI-6603 administration in the 


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same degree as seen in lumbar discectomy. In addition, there is a possibility of vertebral 
body instability (intervertebral posterior angle and vertebral body translation).  
1.3.1.5 Radiation 
The effective radiation dose from each radiograph is: 
 
During Screening or Follow-up visits 
- 
Lateral lumbar spine: 0.290 millisievert (mSv) 
- 
Anteroposterior lumbar spine: 0.690 mSv 
 
During the injection procedure: 1.1 mSv (varies depending on the procedure of 
each site or Investigator) 
In this study, the total radiation dose for each Screening or Follow-up visit will be 
1.56 mSv and the total for 5 visits of the study will be 7.8 mSv. In addition, during the 
injection, the radiation dose will be 1.1 mSv, which may vary depending on the 
procedure of each site or Investigator.  
1.3.1.6 Intradiscal Injection 
Due to the procedure itself, temporary discomfort, injection-site pain, bleeding, vascular 
damage, bruising vagal reaction, nerve damage, disc damage and/or infection at the 
injection site may occur. 
 
 


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Table 1: 
 
Adverse Events That Occurred in Clinical Studies to Date 
Adverse event 
SOC/PT 
 
SI-6603 Group (N=269) 
 
 
Placebo Group (N=128) 
 
 
AE 
Subjects (%) 
Drug related AE 
Subjects (%) 
AE 
Subjects (%) 
Drug related 
AE 
Subjects (%) 
Infections and infestations 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngitis 
 
41  (15.2) 
 
 
 
 
14  (10.9) 
 
 
 
 
Influenza 
 
5  
(1.9) 
 
 
 
 
2  
(1.6) 
 
 
 
 
Pharyngitis 
 
3  
(1.1) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Gingivitis 
 
3  
(1.1) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Tonsillitis 
 
2  
(0.7) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Mastitis 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Otitis media 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Periodontitis 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Hordeolum 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Bronchitis 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Rhinitis 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Urinary tract infection 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Oral herpes 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Gastroenteritis 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Infected dermal cyst 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
 
 
 
 
 
 
 
 
Uterine leiomyoma 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
Blood and lymphatic system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphadenitis 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
Immune system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergy to arthropod sting 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Metabolism and nutrition disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperlipidaemia 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
Dyslipidaemia 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Hyperkalaemia 
 
 
 
 
 
 
 
1  
(0.8) 
 
1  
(0.8) 
Psychiatric disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Insomnia 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
Panic disorder 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Anxiety disorder 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
Nervous system disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoaesthesia 
 
8  
(3.0) 
 
1  
(0.4) 
 
7  
(5.5) 
 
1  
(0.8) 
 
Headache 
 
6  
(2.2) 
 
3  
(1.1) 
 
5  
(3.9) 
 
 
 
 
Dizziness 
 
3  
(1.1) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Sensory disturbance 
 
2  
(0.7) 
 
1  
(0.4) 
 
1  
(0.8) 
 
 
 
 
Dysaesthesia 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Lumbar radiculopathy 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Cervicobrachial syndrome 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Migraine 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Convulsion 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Hyporeflexia 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Presyncope 
 
 
 
 
 
 
 
2  
(1.6) 
 
 
 
 
Radial nerve palsy 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 


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Adverse event 
SOC/PT 
 
SI-6603 Group (N=269) 
 
 
Placebo Group (N=128) 
 
 
AE 
Subjects (%) 
Drug related AE 
Subjects (%) 
AE 
Subjects (%) 
Drug related 
AE 
Subjects (%) 
 
Sciatica 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Somnolence 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Tremor 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Piriformis syndrome 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Vagus nerve disorder 
 
 
 
 
 
 
 
1  
(0.8) 
 
1  
(0.8) 
Eye disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conjunctivitis allergic 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Dry eye 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
Ear and labyrinth disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vertigo positional 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arrhythmia 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
Vascular disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flushing 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Orthostatic hypotension 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Hypertension 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
Respiratory, thoracic and mediastinal disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Asthma 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
Upper respiratory tract inflammation 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Pneumothorax spontaneous 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Hyperventilation 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Allergic cough 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Gastrointestinal disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhoea 
 
3  
(1.1) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Nausea 
 
3  
(1.1) 
 
 
 
 
2  
(1.6) 
 
 
 
 
Anal fissure 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
Haemorrhoids 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
1  
(0.4) 
 
1  
(0.4) 
 
2  
(1.6) 
 
1  
(0.8) 
 
Gastritis atrophic 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Gastritis erosive 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Dental caries 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Varices oesophageal 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Gastrooesophageal reflux disease 
 
1  
(0.4) 
 
 
 
 
2  
(1.6) 
 
 
 
 
Duodenal ulcer 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Abdominal discomfort 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Constipation 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Gastric polyps 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Gastric ulcer 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Gastritis 
 
 
 
 
 
 
 
2  
(1.6) 
 
 
 
 
Lower gastrointestinal haemorrhage 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Hepatobiliary disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatic function abnormal 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
Alcoholic liver disease 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Hepatic steatosis 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 


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Adverse event 
SOC/PT 
 
SI-6603 Group (N=269) 
 
 
Placebo Group (N=128) 
 
 
AE 
Subjects (%) 
Drug related AE 
Subjects (%) 
AE 
Subjects (%) 
Drug related 
AE 
Subjects (%) 
Skin and subcutaneous tissue disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dermatitis contact 
 
7  
(2.6) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Rash 
 
6  
(2.2) 
 
4  
(1.5) 
 
1  
(0.8) 
 
 
 
 
Pruritus 
 
2  
(0.7) 
 
2  
(0.7) 
 
 
 
 
 
 
 
Urticaria 
 
2  
(0.7) 
 
2  
(0.7) 
 
 
 
 
 
 
 
Toxic skin eruption 
 
2  
(0.7) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Blister 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Drug eruption 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Skin warm 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Erythema 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Eczema 
 
1  
(0.4) 
 
 
 
 
2  
(1.6) 
 
 
 
 
Alopecia 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
Musculoskeletal and connective tissue disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Back pain 
 
95  (35.3) 
 
64  (23.8) 
 
42  (32.8) 
 
6  
(4.7) 
 
Pain in extremity 
 
46  (17.1) 
 
11  
(4.1) 
 
35  (27.3) 
 
3  
(2.3) 
 
Myalgia 
 
7  
(2.6) 
 
 
 
 
 
 
 
 
 
 
Arthralgia 
 
3  
(1.1) 
 
 
 
 
 
 
 
 
 
 
Osteoarthritis 
 
3  
(1.1) 
 
 
 
 
 
 
 
 
 
 
Musculoskeletal pain 
 
2  
(0.7) 
 
1  
(0.4) 
 
2  
(1.6) 
 
1  
(0.8) 
 
Intervertebral disc protrusion 
 
2  
(0.7) 
 
 
 
 
8  
(6.3) 
 
 
 
 
Periarthritis 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Arthritis 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Tendonitis 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Myofascial pain syndrome 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Muscular weakness 
 
1  
(0.4) 
 
 
 
 
2  
(1.6) 
 
1  
(0.8) 
 
Neck pain 
 
1  
(0.4) 
 
1  
(0.4) 
 
2  
(1.6) 
 
 
 
 
Muscle fatigue 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Limb discomfort 
 
1  
(0.4) 
 
1  
(0.4) 
 
1  
(0.8) 
 
 
 
 
Muscle spasms 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Muscle tightness 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Renal and urinary disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematuria 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Reproductive system and breast disorders 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cervical polyp 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Prostatitis 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
General disorders and administration site 
conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection site pain 
 
33  (12.3) 
 
 
 
 
10  
(7.8) 
 
 
 
 
Pyrexia 
 
5  
(1.9) 
 
4  
(1.5) 
 
7  
(5.5) 
 
4  
(3.1) 
 
Chills 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Injection site discomfort 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Feeling hot 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Vessel puncture site pain 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
Investigations 
 
 
 
 
 
 
 
 
 
 
 
 


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Adverse event 
SOC/PT 
 
SI-6603 Group (N=269) 
 
 
Placebo Group (N=128) 
 
 
AE 
Subjects (%) 
Drug related AE 
Subjects (%) 
AE 
Subjects (%) 
Drug related 
AE 
Subjects (%) 
 
Nuclear magnetic resonance imaging 
abnormal 
 
69  (25.7) 
 
60  (22.3) 
 
16  (12.5) 
 
10  
(7.8) 
 
Spinal X-ray abnormal 
 
52  (19.3) 
 
38  (14.1) 
 
10  
(7.8) 
 
3  
(2.3) 
 
Blood triglycerides increased 
 
11  
(4.1) 
 
2  
(0.7) 
 
5  
(3.9) 
 
 
 
 
Neutrophil count decreased 
 
10  
(3.7) 
 
6  
(2.2) 
 
8  
(6.3) 
 
7  
(5.5) 
 
Gamma-glutamyltransferase increased 
 
10  
(3.7) 
 
 
 
 
1  
(0.8) 
 
 
 
 
C-reactive protein increased 
 
9  
(3.3) 
 
3  
(1.1) 
 
2  
(1.6) 
 
1  
(0.8) 
 
Alanine aminotransferase increased 
 
8  
(3.0) 
 
1  
(0.4) 
 
 
 
 
 
 
 
White blood cell count decreased 
 
5  
(1.9) 
 
2  
(0.7) 
 
3  
(2.3) 
 
3  
(2.3) 
 
Aspartate aminotransferase increased 
 
4  
(1.5) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Blood uric acid increased 
 
4  
(1.5) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Blood bilirubin increased 
 
3  
(1.1) 
 
1  
(0.4) 
 
1  
(0.8) 
 
1  
(0.8) 
 
Protein total increased 
 
2  
(0.7) 
 
 
 
 
 
 
 
 
 
 
White blood cell count increased 
 
2  
(0.7) 
 
 
 
 
1  
(0.8) 
 
1  
(0.8) 
 
Lasegue's test positive 
 
2  
(0.7) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Blood glucose increased 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Eosinophil count increased 
 
1  
(0.4) 
 
1  
(0.4) 
 
1  
(0.8) 
 
1  
(0.8) 
 
Body temperature increased 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Platelet count decreased 
 
1  
(0.4) 
 
1  
(0.4) 
 
 
 
 
 
 
 
Weight increased 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Band neutrophil count increased 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Blood pressure increased 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Blood pressure systolic increased 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Liver function test abnormal 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Lymphocyte count increased 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Blood creatinine increased 
 
 
 
 
 
 
 
1  
(0.8) 
 
1  
(0.8) 
 
Blood pressure diastolic increased 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Glucose urine present 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Neutrophil count increased 
 
 
 
 
 
 
 
1  
(0.8) 
 
1  
(0.8) 
Injury, poisoning and procedural complications 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ligament sprain 
 
2  
(0.7) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Foot fracture 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Contusion 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Bone contusion 
 
1  
(0.4) 
 
 
 
 
 
 
 
 
 
 
Muscle strain 
 
1  
(0.4) 
 
 
 
 
1  
(0.8) 
 
 
 
 
Animal bite 
 
 
 
 
 
 
 
2  
(1.6) 
 
 
 
 
Wound 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Arthropod sting 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
Spinal compression fracture 
 
 
 
 
 
 
 
1  
(0.8) 
 
 
 
 
AE: Adverse event, SOC: System organ class, PT: Preferred term, N: number of patient   


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1.3.2 Possible Benefits 
Non-clinical data suggests SI-6603 appears to decrease pressure in the intervertebral disc 
by reducing the high water-holding capacity of proteoglycan, thereby reducing excessive 
pressure on the nerve root due to lumbar disc herniation. Clinical data suggests single 
administration of 1.0 mL of the 1.25 U/mL, 2.5 U/mL, and 5.0 U/mL formulations 
injected into the intervertebral disc relieved leg pain; the major complaint of patients 
with lumbar disc herniation. 
Data suggesting efficacy of 1.25 U/mL SI-6603 administration from the Japanese 
Phase II/III and Phase III studies is summarized below.  
1.3.2.1 Improvement of Leg Pain 
In the Japanese Phase III study, statistically significant differences were observed in the 
LSM change from baseline in worst leg pain at Week 13 in the 1.25 U dose group 
compared to the placebo group, at 34.3 mm in the placebo group and 49.5 mm in the 
1.25 U dose group. This finding demonstrates superiority of SI-6603 over placebo. The 
mean worst leg pain at baseline was 74.6 mm in the placebo group and 72.4 mm in the 
1.25 U dose group. At Week 13, the mean worst leg pain that is assessed during 7 days 
prior to Week 13 visit was 39.2 mm in the placebo group and 22.9 mm in the 1.25 U dose 
group. The decrease in mean worst leg pain in the treatment groups continued beyond 
Week 13, and at the final observation at Week 52, the values were 30.9 mm in the 
placebo group and 18.5 mm in the 1.25 U dose group.  
In the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials 
(IMMPACT recommendation), Dworkin et al. advocated that an improvement of ≥30% 
is “moderately important” while an improvement of ≥50% is “substantial 
improvement”.16 The ratio of patients in the Japanese Phase III study in the 1.25 U dose 
group who exhibited a ≥50% improvement in worst leg pain was higher than placebo at 
all time points. At Week 13, the ratio was 50.6% in the placebo group and 72.8% in the 
1.25 U dose group. At Week 52, it was 63.0% in the placebo group and 79.3% in the 
1.25 U dose group. 
A common surgical procedure for the treatment of lumbar disc herniation is a lumbar 
discectomy whereby the hernia is extracted after making an incision in the back either 
under direct vision or using a microscope or endoscope. Leg pain scores typically shift 
by an average of 20 mm following lumbar discectomy.14 The ratio of patients in the 
Japanese Phase III study in the 1.25 U dose group whose worst leg pain improved to 
20 mm was higher than placebo at all time points. At Week 13, the ratio was 40.7% in 
the placebo group and 67.1% in the 1.25 U dose group. At Week 52, it was 55.6% in the 
placebo group and 72.0% in the 1.25 U dose group.  
These results in worst leg pain evaluation indicate that SI-6603 treatment has clinically 
significant effects to improve leg pain. 
1.3.2.2 Improvement of Back Pain 
In the Japanese Phase III study, the LSM change from baseline in worst back pain at 
Week 13 was 21.4 mm in the placebo group and 28.5 mm in the 1.25 U dose group. 
No statistically significant differences were observed in the 1.25 U dose group compared 


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to the placebo group. The mean worst back pain at baseline was 52.4 mm in the placebo 
group and 50.2 mm in the 1.25 U dose group. The mean worst back pain at Week 13 was 
30.2 mm in the placebo group and 22.2 mm in the 1.25 U dose group. Statistically 
significant differences were observed in the LSM change from baseline in worst back 
pain at Week 52 in the 1.25 U dose group compared to the placebo group, at 24.5 mm 
in placebo group and 34.0 mm in the 1.25 U dose group. 
A study by McGirt, et al. assessing the VAS scores of 108 lumbar discectomy patients 
showed that back pain improved from 4.6 cm before surgery to 2.1 cm at 6 weeks post 
surgery. The back pain continued to be the same up to 24 months post surgery.14 In the 
Japanese Phase III study, mean worst back pain at baseline in the treatment groups was 
52.4 mm in the placebo group and 50.2 mm in the 1.25 U dose group. At Week 13, it was 
30.2 mm in the placebo group and 22.2 mm in the 1.25 U dose group. At Week 52, back 
pain had decreased to 26.9 mm in the placebo group and 16.8 mm in the 1.25 U dose 
group. These results indicate that improvement in back pain is considered to be clinically 
beneficial. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary study objective is to evaluate the safety of a single-dose intervertebral disc 
injection of SI-6603 at a dose of 1.25 U in patients with lumbar disc herniation, for a 
26-week follow-up period. 
2.2 
Secondary Objective 
The secondary study objective is to evaluate the efficacy of a single-dose intervertebral 
disc injection of SI-6603 at a dose of 1.25 U in patients with lumbar disc herniation, for a 
26-week follow-up period. 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a multicenter, open-label study where a single intradiscal injection of SI-6603 
1.25 U will be administered to all patients. The study will be conducted at approximately 
60 sites in the USA and European Union (EU). 
The study duration for each patient will be approximately 30 weeks: a 4-week Screening 
period, a 1-day Treatment Administration Day, and a 26-week follow-up period (see 
Figure 1).  
The study population will consist of 1000 male and female patients, 30 to 70 years of age 
at the time of informed consent, with lumbar disc herniation between adjacent lumbar 
vertebra (L1L2, L2L3, L3L4, L4L5), or between the 5th lumbar vertebra and the 1st 
sacral vertebra (L5S1) “protrusion type” or “extrusion type” in the posterior lateral or 
central location as assessed by MRI and clinical symptoms corresponding to the level of 
the impaired nerve root. Following the 4-week Screening period, on Day 0 all patients 
will receive a single intradiscal injection of SI-6603 1.25 U. The patients will then have a 
26-week follow-up period for evaluation of safety and secondary efficacy endpoints (for 
schedule of assessments, see Table 3). 
Safety will be assessed throughout the study. All AEs will be followed until they are 
resolved or stabilized; however, if AEs are ongoing at the time of the last study visit, 
only treatment-related AEs will be followed beyond 26 weeks after investigational drug 
administration.  
The end of the study is last patient, last visit. 
 
Screening 
Treatment 
Evaluation Period/Follow-up 
Eligible 
patients 
(n=1000) 
SI-6603 1.25 U intradiscal 
 
 
 
 
 
Appendix 11.1 
 
 
 
 
X 
Before 
administratio
n 
After 
administration 
X 
X 
X 
X 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Days 28 
to 1 
Day 0 
Week 1 
(±3 days) 
Week 6 
(±14 days) 
Week 13 
(±14 days) 
Week 26 
(±14 days) 
Section 7.2.1 
Section 7.2.2 
Section 7.2.
3 
Section 7.2.
4 
Section 7.2.5 
Section 7.2.6 
 
Figure 1: Study Design  


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3.2 
Criteria for Evaluation of the Study 
3.2.1 Safety Endpoints 
The following safety endpoints will be assessed: 
 
Occurrences of AEs  
 
Stability evaluation of vertebral bodies by X-ray at the times specified in the 
schedule of events 
- 
Translation of vertebral body 
- 
Vertebral body angle formed by flexion 
 
Changes from baseline in disc height (disc index) assessed by X-ray at the times 
specified in the schedule of events 
 
Changes of disc degeneration, vertebral body endplates, and adjacent bone 
marrow assessed by MRI at the times specified in the schedule of events 
- 
Modic classification 
- 
Pfirrmann classification 
 
Clinically significant change in vital signs at the times specified in the schedule 
of events 
 
Clinically significant change in clinical laboratory tests at the times specified in 
the schedule of events 
 
Serum anti-SI-6603 antibody at the times specified in the schedule of events 
 
Occurrence of post-treatment lumbar surgery other than surgery for lumbar disc 
herniation at the same level of the investigational drug administration 
3.2.2 Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed at the times specified in the 
schedule of events and overall time-course, and changes from baseline will be analyzed:  
 
Worst leg pain during the past 24 hours assessed by VAS.  
 
Worst back pain during the past 24 hours assessed by VAS.  
 
Functional disability measured by the Oswestry Disability Index (ODI).  
 
Change of neurological status from baseline determined by neurological 
examinations:  
- 
Femoral Nerve Stretching (FNS) test for patients with lumbar disc 
herniation L1L2, L2L3, or L3L4 or  
- 
Straight Leg Raising (SLR) test [for patients with lumbar disc herniation 
L4L5 or L5S1, and 
- 
Sensation, muscle strength, and deep tendon reflex.  
 
Occurrence of post-treatment surgery for lumbar disc herniation at the same level 
of administration of the investigational drug up to Week 26 including patients 
who discontinued from the study.  


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3.3 
Justification of the Study Design 
This study is planned to investigate the safety and efficacy of SI-6603 as a single 
intradiscal injection for the treatment of lumbar disc herniation. 
An open-label single treatment group design has been chosen to assess the safety of the 
treatment in a large number of patients. 
The patients in the current study are people who have lumbar disc herniation and who 
have seen no improvement from adequate conservative treatment prior to screening. 
There will be no limitations on concomitant medications used to treat lumbar disc 
herniation, in order to enable data collection from a population that more realistically 
represents the target population. 
The study has been designed to ensure the safety of the patients. The dosing scheme has 
been chosen on the basis of data currently available. Efficacy will be assessed as 
secondary endpoints using validated tools (VAS, ODI) and neurological examinations. 
A 26-week follow-up period is considered adequate to assess safety effects of a 
single-dose treatment. 


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4 
STUDY POPULATION 
The study population will consist of patients with lumbar disc herniation (L1L2, 
L2L3, L3L4, L4L5, or L5S1) “protrusion type” or “extrusion type” in the posterior 
lateral or central location as assessed by MRI and clinical symptoms corresponding to the 
level of the impaired nerve root. Patients must be able to provide written consent and 
meet all the inclusion criteria and none of the exclusion criteria. 
The Investigator is responsible to ensure the patient fulfills all the inclusion criteria, does 
not meet the exclusion criteria, and provides written consent to participate in the study on 
a voluntary basis. 
4.1 
Inclusion Criteria 
Patients will be allowed to participate in this study only if they meet all of the following 
criteria: 
1. Patients who have given their written informed consent to participate in a clinical 
study based on voluntary agreement after a thorough explanation of the patient's 
participation is provided to them. Patients must have adequate reading and writing 
abilities such that they can comprehend and answer the questions on the 
patient-completed assessments and Informed Consent Form (ICF). 
2. Patients with lumbar disc herniation (L1L2, L2L3, L3L4, L4L5, or L5S1) 
“protrusion type*” or “extrusion type**” in the posterior lateral or central location as 
assessed by MRI and clinical symptoms corresponding to the level of the impaired 
nerve root; if the sixth lumbar vertebra (L6) is present, patients with impaired L5 or 
S1 nerve root and corresponding clinical symptoms 
* ”Protrusion type” is herniation where the nucleus pulposus has disrupted the 
posterior lateral or central location of annulus fibrosus partially which leads to 
compression of the nerve root.  
**“Extrusion type” is herniation where the nucleus pulposus has disrupted the 
posterior lateral or central location of annulus fibrosus completely which leads to 
compression of the nerve root. 
3. Patients with positive FNS ≤70° (L1L2, L2L3, or L3L4) or SLR ≤70° (L4L5 or 
L5S1) on the symptomatic side 
4. Patients with sciatica or anterior thigh pain/femoral neuropathy in either leg prior to 
the time of informed consent 
5. Patients with no improvement from adequate conservative treatment* prior to the 
time of informed consent 
*Adequate conservative treatment includes pharmacotherapy (e.g., nonsteroidal 
anti-inflammatory drugs, opiate preparations, or nonopioid analgesics). Physical 
therapy and/or spinal injection, epidural injection, or nerve block may also be 
included. 
6. Patients with the worst leg pain (by VAS ≥30 mm) during the past 24 hours at the 
time of informed consent. 


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7. Male or female patients 30 to 70 years of age at the time of informed consent 
8. Female patients are not pregnant and do not plan to become pregnant during the 
study. Females of childbearing potential must provide a negative serum pregnancy 
test during the Screening period, must be using reliable contraception, and must 
continue to use reliable contraception until end of study (reliable methods of 
contraception are defined in exclusion criterion #6 below). Non-childbearing 
potential is defined as postmenopausal for at least 2 years or surgical sterilization or 
hysterectomy at least 3 months before study start. 
4.2 
Exclusion Criteria 
Patients will not be allowed to participate in this study if they meet any of the following 
criteria: 
1. Patients who have 2 or more symptomatic lumbar disc herniations as assessed by 
MRI 
Two or more level symptomatic lumbar disc herniations are defined as a patient 
having clinical symptoms and MRI findings consistent with radiculopathy in more 
than one nerve root distribution as assessed by the Investigator. 
2. Patients with a contraindication to receiving an MRI 
3. Patients in whom a rupture into the posterior longitudinal ligament as assessed by 
MRI shows sequestration (free fragment) type lumbar disc herniation. 
Transligamentous extrusion type of disc herniation is allowed.  
4. Patients who previously received SI-6603 administration at any time 
5. Patients who are pregnant, breast-feeding or women of childbearing potential with 
positive pregnancy tests. Female patients with posthysterectomy and/or bilateral tubal 
ligation or postmenopausal* do not need to take the pregnancy tests. 
* Postmenopausal is defined as either 12 months of spontaneous amenorrhea, or 6 
months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml, or 6 weeks 
postsurgical bilateral oophorectomy with or without hysterectomy. 
6. Sexually active female patients of childbearing potential who are not willing to use 
adequate contraceptive measures to avoid pregnancy until end of the study. Sexually 
active male patients who are not willing to use adequate contraceptive measures until 
end of the study. 
Adequate methods of birth control include the following: 
 
Hormonal contraception (female patients) or use of at least one acceptable 
double-barrier method 
Acceptable double-barrier methods include the following: 
- 
diaphragm plus a spermicidal agent 
- 
condoms (male or female) plus a spermicidal agent 
 
Vasectomy, intrauterine device, and/or exclusive sexual partner for whom one of 
the above acceptable methods applies 


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7. Patients who have undergone lumbar operation, lumbar percutaneous nucleotomy or 
lumbar intradiscal therapies (e.g., chemonucleolysis or intradiscal electrothermal 
treatment) under any of the following conditions: 
 
At the affected level of lumbar disc herniation 
 
Within the last 2 years at any lumbar spine level other than affected level 
 
With symptoms not completely improved by the above procedure at any lumbar 
spine level other than affected level 
8. Patients with the following medical conditions or diseases:  
 
Vertebral body angle formed by flexion ≥5° 
 
Neurological disorders including cauda equina syndrome that is severe or that 
demonstrates rapid progression. Patient with clinically symptomatic neurological 
deficit (e.g., motor paresis, sphincter dysfunction), warranting an alternative 
option of care that would be more appropriate for their presentation, will be also 
excluded. 
 
Spondylosis deformans, spondylolisthesis (translation of vertebral body ≥3 mm), 
spinal deformity, spinal canal stenosis (except for complication of lumbar disc 
herniation), spinal tumor, ankylosing spondylitis, diskitis, or clinically 
significant disorders of the lumbar spine other than disc herniation. 
 
Osteophyte at lumbar spine (Nathan's classification ≥3rd degree) 
 
Cancer: patients who have cancer or a past history of any cancer within 5 years 
prior to the time of informed consent, with the exception of basal cell or 
squamous cell carcinoma of the skin curatively treated or localized gynecologic 
cancer treated by total hysterectomy. 
 
Human immunodeficiency virus (HIV) infection or a clinically significant 
infection 
 
A clinically significant disorder such as cerebrovascular disease, pulmonary 
infarction, ischemic heart disease, cardiac dysrhythmia, myocardial infarction, or 
congestive heart failure 
 
Chronic diseases such as osteoporosis, rheumatoid arthritis, uncontrolled 
diabetes mellitus, uncontrolled pulmonary disease (asthma), or uncontrolled 
hypertension 
 
Patients who have evidence of major psychiatric disease, mental disorder, drug 
dependency, alcohol dependency, or substance use disorders. 
 
Patients who have a tendency to bleed or with bleeding disorders such as (but not 
limited to) hemophilia, hypoplastic anemia, cirrhosis of the liver, leukemia and 
vitamin K deficiency. Patients using medication for purpose of anticoagulation, 
including heparin and warfarin which cannot be reversed preoperatively will also 
be excluded. 
9. Patients with medical conditions and/or diseases that the Investigator believes could 
affect the study results or the safe conduct of the study. 
10. Patients who meet any of the following criteria: 


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 
Hepatic function: AST or ALT: ≥2.5 x upper limit of normal (ULN) 
 
Total-bilirubin: ≥1.5 x ULN 
 
Renal function: Serum creatinine: ≥1.5 x ULN 
11. Patients who are receiving compensation according to the Workers' Compensation 
Act or are involved in personal injury litigation due to a lumbar-related injury. 
12. Patients who participated in another clinical study within 4 months prior to the time 
of informed consent, or who are expected to participate in another study during the 
period of this study. 
4.3 
Patient Withdrawal and Replacement 
Patients may withdraw from the entire study, including follow up, at any time without 
penalty and for any reason without prejudice to his or her future medical care. 
In all cases, the reason(s) for withdrawal, including the primary reason, must be recorded 
on the electronic Case Report Form (eCRF). If a patient is prematurely withdrawn from 
the study for any reason, the Investigator must make every effort to perform the 
evaluations described for the appropriate discontinuation visit.  
If a patient withdraws consent and still agrees to undergo a final examination, this will be 
documented in the eCRF.  
A patient may also be withdrawn from study by the Investigator, Sponsor, Regulatory 
Authorities, or Institutional Review Boards (IRBs). 
Patients will also be withdrawn if the entire study is terminated prematurely as described 
in Section 9.10. 
Withdrawn patients will not be replaced. 
4.3.1 Patient Withdrawal Criteria 
The Investigator will withdraw a patient from the clinical study if any of the following 
situations occur: 
1. When the patient withdraws his or her consent 
2. When the occurrence of an AE, such as noted below, leads the Investigator to judge it 
necessary for the patient to have surgical intervention or to withdraw the patient from 
the clinical study: 
 
Significant neurologic deficit, e.g., progressive weakness or sudden loss of 
muscle strength in L1L2, L2L3, L3L4, L4L5 or L5S1 innervated muscles, 
bowel or bladder dysfunction, or other signs and symptoms of cauda 
equine/conus medullaris involvement, or 
 
Abnormal X-ray or MRI findings coupled with correlating clinical symptoms 
posing safety concerns 
3. When a poor response to the investigational drug leads the Investigator to judge it 
necessary to perform a surgical intervention for back pain/leg pain or to withdraw the 
patient from the clinical study 


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4. If the Investigator judges it inappropriate to include a patient in the efficacy/safety 
assessment 
5. If a patient becomes pregnant 
6. Others: 
 
No investigational drug could be administered. 
 
The continuation of the study makes the risk to a patient’s health unacceptable. 
 
The Sponsor prematurely terminates the study. 
 
The Investigator judges it necessary to withdraw a patient from the study. 
4.4 
Planned Sample Size and Number of Study Centers 
It is planned to recruit 1000 patients at approximately 80 sites in the USA and EU for this 
study. See Section 8.8 for a discussion of sample size. 
4.5 
Patient Identification and Randomization 
4.5.1 Patient Identification 
At the screening visit, a unique 6-digit patient number will be assigned consecutively for 
each patient after he or she signs the ICF. Unique patient numbers will begin with the 
clinical site number, e.g., 001 followed by a 3 digit number starting with 001. The unique 
patient numbers will be assigned sequentially. For example, for clinical site number 002, 
the unique patient numbers will be as follows: 002-001, 002-002, 002-003. The patient 
will keep this unique patient number for the duration of the study. 
Patients who drop out of the study before randomization will retain their unique patient 
number (i.e., the patient number will not be reassigned). If a patient is rescreened after 
being designated as a screen failure, the patient will receive a new unique patient number 
upon rescreening. 
4.5.2 Randomization Scheme 
No randomization will be performed. All patients will be assigned into active treatment 
with SI-6603. 
4.5.3 Allocation/Randomization of Patients to Treatment 
Not applicable. 


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5 
STUDY DRUG 
For details and handling of the investigational drug (SI-6603), refer to the IB and 
Appendix 11.1, Injection Procedure, and Investigational Drug Management Procedure. 
5.1 
Identity 
SI-6603 will be administered as a lyophilized injection which, when reconstituted with 
1.2 mL of saline, provides 1.0 mL containing the ingredients given below. 
Ingredient 
Active ingredient 
Condoliase 
Inactive ingredients 
Monosodium phosphate dihydrate (United States Pharmacopoeia 
[USP]) 
Sodium dihydrogen phosphate dehydrate (European 
Pharmacopoeia[EP]) 
Disodium hydrogen phosphate, dodecahydrate (USP) 
Disodium phosphate dodecahydrate (EP) 
Sucrose (National Formulary [NF], EP) 
Polyethylene glycol 3350 (NF) 
Macrogol 3350 (EP) 
SI-6603 for injection (1.25 U [1.5 U/vial]) will be manufactured for reconstitution with 
the 1.2 mL of saline for delivery of 1.25 U in 1.0 mL. 
5.2 
Administration 
An SI-6603 for injection vial will be reconstituted with 1.2 mL of saline to prepare a 
1.25 U/mL solution of SI-6603. A volume of 1.0 mL will be administered into the 
intervertebral disc in a single-dose (see Appendix 11.1). 
5.3 
Packaging, Labeling and Storage 
SI-6603 will be packaged by the vendor according to all local legal requirements. 
SI-6603 will be labeled in accordance with applicable regulatory requirements (see 
Appendix 11.2, Package Presentation and Labeling). 
All SI-6603 supplies must be stored in the original boxes in accordance with the 
manufacturer’s instructions (2 to 8°C and shielded from light). SI-6603 must be stored in 
a securely locked area, accessible to authorized personnel only. 
5.4 
Blinding and Breaking the Blind 
The study is not blinded. 
5.5 
Drug Accountability 
The Investigator is responsible for maintaining accurate SI-6603 accountability records 
throughout the study. Each dispensing of SI-6603 must be documented in the patient 
source record and eCRF. The Investigator is responsible for returning all unused or 
partially used SI-6603 to the Sponsor and must verify that no remaining supplies are in 
the Investigator’s possession. 


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5.6 
Compliance 
Compliance with the injection procedure is to be monitored and recorded by site staff. 
Study treatment consists of the investigational drug administered on Day 0 (a single 
intradiscal injection of SI 6603). 
5.7 
Previous and Concomitant Medications 
Any medication the patient takes other than the investigational drug, including herbal and 
other nontraditional remedies, is considered a concomitant medication. All concomitant 
medications must be recorded in the patient source record and eCRF for each 
concomitant medication as follows: generic name (for combination drug only, trade name 
must be recorded), route of administration, start date, stop date, dosage, and indication. 
Any changes in the dosage or regimen of a concomitant medication must be recorded in 
the patient source record and eCRF. 
Previous and concomitant medication data will be captured beginning at the time of 
informed consent. At screening, patients will be asked what medications they have taken 
during the last 6 weeks. At each subsequent study visit, patients will be asked what 
concomitant medications they are currently taking or have taken since the last visit. 
5.7.1 Permitted Concomitant Medication 
Concomitant medications used in the treatment of lumbar disc herniation and 
complications associated with disc herniation are allowed. There is no restriction on 
concomitant medications used in treatment of diseases or disorders other than lumbar 
disc herniation. 
5.7.2 Notes Concerning Concomitant Medication Before SI-6603 is Administered 
SI-6603 is a foreign protein preparation of Proteus vulgaris and may have the potential to 
cause an allergic reaction. The concomitant use of drugs that are contraindicated during 
the use of epinephrine may interfere with the effect of the epinephrine, which is used for 
treatment in the early stage of anaphylactic reaction. Therefore, other alternatives should 
be considered for treatment of anaphylactic reaction for patients using the following 
classes of drugs: 
 
Contraindicated drug of epinephrine (e.g., antipsychotic drug or α-blocker) 
 
β-blocker 
 
Intradiscal injection procedure itself has risk of bleeding and/or infection at the injection 
site. Patients continuously being treated with anticoagulants and/or immunosuppressants 
should be taken to in account for an extra caution before receiving intradiscal injection, 
according to following instructions:  
 
During the assessment of patient eligibility in screening visit and before 
performing the intradiscal injection, review patient medical records to assure 
there are no concomitant use of anticoagulants and/or immunosuppressants. 
 
If concomitant use of anticoagulants and/or immunosuppressants are recognized, 
investigators should assess whether such patients are eligible to go through 
intradiscal injection procedure. 


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5.8 
Previous and Concomitant Therapies 
Any therapy the patient uses in the treatment of lumbar disc herniation is considered a 
concomitant therapy. All concomitant therapies must be recorded in the patient source 
record and eCRF. The following information must be recorded in the patient source 
record and eCRF for each concomitant therapy: therapy name, frequency, start date, stop 
date. Any changes in the frequency and administration method of a concomitant 
medication must be recorded in the patient source record and eCRF. 
Previous and concomitant therapy data will be captured beginning at the time of 
informed consent. At screening, patients will be asked what therapies they have used 
during the last 6 weeks. At each subsequent study visit, patients will be asked what 
concomitant therapies they are currently taking or have taken since the last visit. 
5.8.1 Permitted Concomitant Therapies 
The conservative therapies used in the treatment of lumbar disc herniation prior to the 
time of informed consent are allowed. There is no restriction on therapies used in 
treatment of diseases or disorders other than lumbar disc herniation. 
5.8.2 Prohibited Concomitant Therapies 
Lumbar operation, lumbar percutaneous nucleotomy, or lumbar intradiscal therapies 
(e.g., chemonucleolysis, intradiscal electrothermal treatment) for treatment of back pain 
and leg pain are prohibited from the time of informed consent up to the final observation 
(Week 26 after investigational drug administration). A patient who requires lumbar 
operation, lumbar percutaneous nucleotomy, or lumbar intradiscal therapies 
(e.g., chemonucleolysis or intradiscal electrothermal treatment) in the clinical study 
period must be discontinued from the clinical study. 
In addition, discography for diagnostic purpose is also prohibited from the time of 
informed consent through Week 13 after investigational drug administration.  


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6 
VARIABLES AND METHODS OF ASSESSMENT 
6.1 
Safety Variables 
6.1.1 Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
terminology (Section 9.4).   
6.1.1.1 Collection of Adverse Events 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) 
derived by spontaneous, unsolicited reports of patients, by observation and by routine 
open questionings e.g., "How have you felt since I last saw you?" 
6.1.1.2 Definitions 
An AE is any untoward medical occurrence that occurs in a patient or clinical 
investigation subject administered a pharmaceutical product, and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the product. 
For this study, the following imaging findings will be recorded as AEs: 
 
Disc height (disc index): decrease in disc height ≥30% compared to baseline 
value 
 
Vertebral posterior angle: vertebral body angle formed by flexion of ≥5° 
 
Vertebral body translation: vertebral body translation of ≥3 mm 
 
Change in vertebral body endplates and adjacent bone marrow: Type 1, Type 2, 
or Type 3 change (Modic Classification) 
Note: The above events are limited to the targeted level of the procedure and the adjacent 
vertebral bodies. 
All AEs, including intercurrent illnesses, occurring during the study will be documented 
in the eCRF. Concomitant illnesses, which existed before entry into the study, will not be 
considered AEs unless they worsen during the treatment period.  All AEs, regardless of 
the source of identification (e.g., physical examination, laboratory assessment, or 
reported by patient), must be documented. 
Pre-existing conditions will be recorded in the eCRF on the Medical History or 
appropriate page.   
A treatment-emergent adverse event will be defined as an AE that begins or that worsens 
in severity after the study drug has been administered. 
6.1.1.3 Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the following categories. 
6.1.1.3.1 Seriousness 
A SAE is defined as any untoward medical occurrence that at any dose: 


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 
Results in death 
 
Is life-threatening 
This means that the patient is at risk of death at the time of the event; it does not 
mean that the event hypothetically might have caused death if it were more 
severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event(s) that may not be immediately life-threatening or 
result in death or hospitalization but that may jeopardize the patient or require 
intervention to prevent one of the above outcomes. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether a case is 
serious and whether expedited reporting is appropriate. 
6.1.1.3.2 Intensity 
The intensity of each AE must be assessed by the Investigator using one of the following 
categories, and recorded in the eCRF: 
 
Mild: No particular interference with the patient’s activities of daily living 
(ADL) or, despite slight interference, no particular intervention indicated; 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 (see 
Appendix 11.8) 
 
Moderate: Interference with the patient’s ADL and minimal intervention 
indicated; CTCAE Grade 2 
 
Severe: Disabling and almost complete interference with the patient’s ADL or 
systemic intervention indicated; CTCAE Grade 3/4 
6.1.1.3.3 Causality 
The Investigator will assess the causality / relationship between the study drug and the 
AE and record that assessment in the eCRF. Causality will be shown as related or not 
related. 
The most likely cause of an SAE (e.g., disease under treatment, concomitant disease, 
concomitant medication, other) will be indicated on the eCRF with details of the 
concomitant disease or medication or other cause. 
The causal relationship of the AE to the study drug will be described in terms of: 
 
Not related: There is no temporal correlation or attributability to the 
investigational medicinal product, but to any other factor, such as the underlying 
disease, a complication, a concomitant drug, a predisposition, or concomitant 
intervention, by which the AE can be explicitly explained. 


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 
Related: There is a reasonable possibility that the relevant event can be judged to 
be at least due to the investigational drug or a causal relationship cannot be ruled 
out. 
6.1.1.4 Recording Adverse Events 
The AE recording into the eCRF will extend from the signing of the ICF until completion 
of final visit. All AEs will be followed until they are resolved or stabilized; however, if 
AEs are ongoing at the time of the last study visit, only treatment-related AEs will be 
followed beyond 26 weeks after investigational drug administration.  
All AEs, regardless of the relationship to study drug, will be recorded in the eCRF 
system.  
All AE reports should contain a brief description of the event, date and time of onset, 
date and time of resolution, intensity, treatment required, relationship to study drug, 
action taken with the study drug, outcome, and whether the event is classified as serious. 
6.1.1.5 Reporting Serious Adverse Events 
All SAEs that occur during the period of observation, and all SAEs occurring up to 
26 weeks after receiving the dose of study drug, whether considered to be associated with 
the study drug or not, must be reported within 24 hours by fax, email or telephone to the 
PAREXEL Safety Contact using the numbers, and specific mailbox in the List of Study 
Personnel. 
Any SAE occurring after the end of the study should be reported to the 
Sponsor/PAREXEL by the Investigator if the Investigator considers there is a causal 
relationship with the study drug. 
The minimum information required for an initial report is: 
 
Name of person sending the report (i.e., name, address of Investigator) 
 
Patient identification (screening/randomization number, initials, NOT patient 
name) 
 
Protocol number 
 
Description of SAE 
 
Causality assessment, if possible. 
However, as far as possible all points on the SAE form should be covered in the initial 
report, or the completed SAE form itself must be faxed to the PAREXEL Safety Contact. 
In addition, the event must be documented in the eCRF. 
In case the PAREXEL Safety Contact cannot be contacted (e.g., out of normal working 
hours or at weekends), SAE reports will be received by PAREXEL. The required 
information should be faxed, emailed or a message should be left on the voicemail 
service (for phone/fax/email, see the contacts in the List of Study Personnel). 
After receipt of the initial report, the safety center will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the 
event. PAREXEL will be responsible for all information processing and reporting 
according to local legal requirements. Where necessary, Investigators will inform 
Regulatory Authorities in their own countries. 


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PAREXEL International 
 
SAE Fax (24-hour service): 
USA and EU region (Billerica): +1 781 434 5957 
 
Medical hotline: 
USA and EU region (Billerica): +1 781 434 5010 
 
Email: 
USA and EU region: NorthAmerica_Medical@parexel.com 
 
Medical Monitor:  
USA region: Karla Kanis (+1 781 434 5010) 
EU region: Christine Mellerowicz (+49 30 30685 5171) 
 
Details for the reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
can be found in Section 6.1.1.7. 
6.1.1.6 Follow-up of Adverse Events 
During the study, all AEs experienced by a patient, irrespective of the suspected 
causality, will be monitored until the AE has resolved, any abnormal laboratory values 
have returned to baseline or stabilized at a level acceptable to the Investigator and 
Medical Monitor, until there is a satisfactory explanation for the changes observed, until 
the patient is lost to follow-up, or until the patient has died. If the AEs are ongoing at the 
time of the last study visit, only treatment-related AEs will be followed beyond 26 weeks 
after investigational drug administration until the AE has resolved, any abnormal 
laboratory values have returned to baseline or stabilized at a level acceptable to the 
Investigator and Medical Monitor, or until there is a satisfactory explanation for the 
changes observed. Follow-up of the AEs beyond the entire study duration will be 
evaluated on case-by-case basis by the Medical Monitor and the Sponsor.  
6.1.1.7 Suspected Unexpected Serious Adverse Reactions  
Any AE that is serious, associated with the use of the study drug, and unexpected 
(SUSAR) has additional reporting requirements, will be reported to regulatory authorities 
and Independent Ethic Committees (IECs) according to the local requirements. 
The Sponsor will notify the Investigators in a timely fashion of relevant information 
about SUSARs that could adversely affect the safety of patients. Follow-up information 
may be submitted if necessary.  
The Sponsor will also provide annual safety updates to the Regulatory Authorities and 
IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 


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6.1.1.8 Pregnancy  
The Sponsor has a responsibility to monitor the outcome of pregnancies where there has 
been maternal exposure to the study drug.  
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication. 
Elective abortions without complications should not be handled as AEs, unless they were 
therapeutic abortions (see below). Hospitalization for normal delivery of a healthy 
newborn should not be considered a SAE. 
All pregnancies must be reported by the Investigator to PAREXEL on the initial 
pregnancy report form within 30 days after becoming aware of the pregnancy. The 
Investigator must follow up and document the course and the outcome of all pregnancies 
even if the patient was discontinued from the study or if the study has finished. 
All outcomes of pregnancy must be reported by the Investigator to PAREXEL/Sponsor 
on the pregnancy outcome report form within 30 days after he or she has gained 
knowledge of the normal delivery or elective abortion. 
Any SAE that occurs during pregnancy (including SAEs occurring after last 
administration of study drug) must be recorded on the SAE report form (e.g., maternal 
serious complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, or birth defect) and reported within 24 hours in 
accordance with the procedure for reporting SAEs. 
If a female partner of a male study patient who has been exposed to the investigational 
drug becomes pregnant before the end of Week 26, the pregnancy and outcome of 
pregnancy should be reported. 
6.1.2 Laboratory Variables 
Laboratory assessments will be performed by a central laboratory, as identified in the 
List of Study Personnel. The Investigator or site staff will collect blood samples 
according to the “Investigator Laboratory Manual for SI-6603” separately specified.  
The following laboratory variables will be determined in accordance with schedule of 
assessments Table 3. 
 
Table 2: 
 
Laboratory Assessments 
Hematology: 
hemoglobin 
hematocrit 
platelets 
red blood cell count 
white blood cell 
count with 
differential 
 
 
Clinical 
chemistry: 
creatinine 
C-reactive protein 
Liver 
enzymes: 
alkaline phosphatase 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 


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total protein 
direct bilirubin 
total bilirubin 
total cholesterol 
triglycerides 
urea nitrogen 
uric acid 
lactic dehydrogenase 
-glutamyl transpeptidase 
albumin 
Electrolytes: 
calcium 
chloride 
magnesium 
potassium 
sodium 
Serological 
marker: 
Human immunodeficiency virus 
(HIV) test will be performed at 
Screening 
Pregnancy 
test: 
In women with childbearing potential a serum pregnancy test will be 
performed at Screening. A urine pregnancy test will be performed at 
Visit 1 
Approximately 15 to 20 mL (3 to 4 teaspoons) of blood will be collected each time at 
Screening, Evaluation period visits or upon discontinuation. In addition, before 
administration of the investigational drug, at Week 13, at Week 26, or upon 
discontinuation, approximately 3 mL (½ teaspoon) will be collected for the serum anti-
SI-6603 antibody. All blood samples collected for the serum anti-SI-6603 antibody will 
be appropriately stored and will be destroyed upon completion of the measurements of 
serum anti-SI-6603 antibody. If necessary, the blood samples collected for the serum 
anti-SI-6603 antibody will be used for assay development and will be destroyed upon 
completion of the assay development. All other blood samples collected will be 
destroyed at the end of the study or completion of all laboratory assessments. 
For serum anti-SI-6603 antibody, titer of SI-6603 specific antibody will be measured, 
and isotype of immunogloblin (IgG, IgM or IgE) will be identified on blood samples 
which contain SI-6603 specific antibody. 
 
6.1.3 X-ray Imaging 
Disc height, intervertebral posterior angle, and translation of vertebral body will be 
assessed by X-ray in accordance with the schedule of assessments Table 3.  
The following will be reported as AEs:  
 
a decrease in disc height ≥30% compared to baseline  
 
vertebral body angle formed by flexion of ≥5° 
 
vertebral body translation of ≥3 mm  
Events are limited to the targeted level of the investigational drug administration and the 
adjacent vertebral bodies (see Appendix 11.7). 
Anteroposterior and lateral-intermediate, flexion, and extension spinal x-rays will be 
obtained according to the “Procedure Manual for Radiographic Examinations of the 
Lumbar Spine”. The X-ray images obtained will be sent to the central imaging reader 
(BioClinica) for assessment. 


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6.1.3.1 Disc Height (Disc Index) 
The central imaging reader will measure the disc index for the intervertebral disc treated 
with the investigational drug using  
a) the posterior height of the superior vertebral body adjacent to the target segment,  
b) the anterior disc space, and  
c) the posterior disc space.  
A decrease in disc height ≥30% compared to baseline value will be recorded as an AE 
(see Appendix 11.7 for additional details regarding imaging tests). 
6.1.3.2 Intervertebral Posterior Angle 
The central imaging reader will measure the intervertebral posterior angle of the 
intervertebral disc treated with the investigational drug. When the measured value is 
≤-5°, the relevant result will be entered as “posterior intervertebral angulation” in the 
eCRF. A vertebral body angle formed by flexion of ≥5° will be recorded as an AE 
(see Appendix 11.7 for details regarding imaging tests). 
6.1.3.3 Vertebral Body Translation 
The central imaging reader will determine the difference in vertebral body translation at 
the extension and flexion positions of the intervertebral disc treated with the 
investigational drug. When the post-treatment vertebral body translation is ≥3 mm, the 
relevant result will be entered as “vertebral body translation” in the eCRF. A vertebral 
body translation of ≥3 mm will be recorded as an AE (see Appendix 11.7 for details 
regarding imaging tests). 
6.1.4 Magnetic Resonance Imaging 
Changes of disc degeneration, vertebral body endplates, and adjacent bone marrow will 
be assessed by MRI in accordance with the schedule of assessments Table 3.  
The criteria are as follows: Modic Type 1, Type 2, or Type 3 change in vertebral body 
endplates and adjacent bone marrow (see Appendix 11.5) and Grade I (mild), Grade II 
(moderate), or Grade III (severe) in disc degeneration using Pfirrmann classification 
(see Appendix 11.6). When the post-treatment Modic Type 1, Type 2, or Type 3 change 
in vertebral body endplates and adjacent bone marrow occur, the relevant result will be 
entered as “Modic Type 1”, “Modic Type 2” or “Modic Type 3” in the eCRF. Modic 
Type 1, Type 2, or Type 3 change in vertebral body endplates and adjacent bone marrow 
will be reported as an AE. 
The MRI will be obtained according to the “Procedure Manual for MRI Examination”. 
All MRIs obtained will be sent to the central imaging reader (BioClinica) for assessment. 
6.1.5 Vital Signs 
The following vital signs will be assessed in accordance the schedule of assessments 
Table 3: 
 
Blood pressure (systolic and diastolic; mmHg) after being supine for 5 minutes 
 
Heart rate (beats per minute) 
 
Body temperature (°F/C) 


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 
Respiration rate (breaths per minute) 
6.1.6 Physical Examinations 
Physical examinations will be performed in accordance with the schedule of assessments 
Table 3. The physical examination should include evaluation of the skin, head, neck, 
throat, ears, eyes, nose, heart, lungs, abdomen, extremities, and musculoskeletal systems. 
6.1.7 Neurological Examinations and Pain Assessments 
Neurological examinations and pain assessments will be performed in accordance with 
the schedule of assessments Table 3. 
Neurological testing will include an FNS or SLR test, sensation, muscle strength, and 
deep tendon reflex. Any neurological finding that worsens after the administration of the 
investigational drug and that is considered to be clinically significant in the Investigator’s 
judgment meets AE reporting criteria.  
Cases where leg pain or back pain increase over the Screening period (baseline value) 
and, in the Investigator’s judgment, is clinically aggravated, meet AE reporting criteria. 
Cases considered clinically exacerbated, in the Investigator’s judgment, based on 
post treatment improvement followed by the reappearance of pain of equal severity than 
before improvement meet AE reporting criteria. 
6.2 
Efficacy Variables 
The following efficacy variables will be used for assessment of the secondary endpoints 
in this study (for secondary efficacy endpoints, refer to Section 3.2.2, for times of 
assessment, refer to Table 3). 
 
VAS (see Appendix 11.3) for assessment of worst leg pain and worst back pain 
 
ODI (see Appendix 11.4) for assessment of functional disability  
 
FNS or SLR test, sensation, muscle strength, and deep tendon reflex for 
assessment of neurological status   
 
Record of occurrence of post-treatment surgery for lumbar disc herniation at the 
same level of administration of the investigational drug up to Week 26 including 
patients who discontinued from the study. 
6.3 
Demographics and Baseline Characteristics 
6.3.1 Patient Demography 
For patient demography the following will be documented: 
 
Year of birth 
 
Age 
 
Gender 
 
Race 
 
Smoking history 
 
Occupation (Heavy labor/Light labor) 


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6.3.2 Disease History 
For disease history the following will be documented: 
 
Lumbar disc herniation (L1L2, L2L3, L3L4, L4L5, or L5S1) “protrusion 
type” or “extrusion type” in the posterior lateral or central location as assessed 
by MRI 
 
A positive FNS ≤70° (L1L2, L2L3, or L3L4) or SLR ≤70° (L4L5 or 
L5S1) on the symptomatic side 
 
No improvement from adequate conservative treatment prior to the time of 
informed consent 
 
Sciatica or anterior thigh pain/femoral neuropathy in either leg prior to the time 
of informed consent 
 
A worse leg pain by VAS ≥30 mm during the past 24 hours at the time of 
informed consent 
6.3.3 Medical History 
For documentation of the medical history, any previous and concomitant diseases within 
the last 26 weeks and any significant medical history occurring before the time of 
informed consent will be documented. 
The medical history will be obtained by interviewing the patient or by inspecting his/her 
medical records. 
For coding of medical history, see Section 9.4. 
6.3.4 Previous and Concomitant Medications/Therapies 
Previous and concomitant medication/therapy will be documented as described in 
Section 5.7 and Section 5.8. For coding of previous and concomitant 
medications/therapies, see Section 9.4. 
 


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7 
STUDY CONDUCT 
7.1 
Schedule of Procedures 
Each patient will be asked to complete 6 study visits including a screening evaluation: 
 
Screening visit 
 
Treatment Day 0  
 
Evaluation period/Follow-up visits at Week 1, Week 6, Week 13, and Week 26 
 
Patients terminating the study early will be asked to complete a discontinuation 
visit.   


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Table 3: 
 
Schedule of Assessments and Procedures 
Observation Period 
 
 
 
 
 
 
 
 
Observation /  
Examination Items 
Before 
4 Weeks 
(Day 28 to Day 0) 
Treatment 
Administration 
Day 0 
Week 1 
Week 6 
Week 13 
Week 26 
Upon Discontinuation 
 
Outpatienta 
Screening 
Period 
Before 
Administration
After 
Evaluation Period/ 
Follow-up 
 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 6 
 
Permissible lag time for 
observation/examination  
 
 
 
±3D 
±14D 
±14D 
±14D 
+14D 
Verify conformance with entry criteria Obtain 
informed consent 
X 
 
 
 
 
 
 
 
Patient characteristics 
X 
 
 
 
 
 
 
 
Serum/urine pregnancy testb 
X 
X 
 
 
 
 
 
 
Patient enrollment  
 
X 
 
 
 
 
 
 
Administration of the investigational drug 
 
  ▼ 
 
 
 
 
 
Pain assessment by patients (VAS） 
X 
X 
 
X 
X 
X 
X 
X 
ODI 
 
X 
 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
 
 
Neurological examination 
X 
 
 
X 
X 
X 
X 
X 
Imaging (X-ray, MRI)c  
X 
 
 
 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
Laboratory tests 
X 
 
 
X 
X 
X 
 
X 
Serum anti-SI-6603 antibody d 
 
X 
 
 
 
X 
X 
X 
Concomitant drug/therapy 
 
 
 
 
 
 
 
X 
AE/SAE 
 
 
 
 
 
 
 
X 
Record occurrence of lumbar surgerye 
 
 
 
 
 
 
 
X 
=Administration of the investigational drug; D=day; X=Essential examination 
AE=Adverse event; MRI=Magnetic Resonance Imaging; ODI=Oswestry Disability Index; SAE=Serious 
adverse event; VAS=Visual Analog Scale 
7.2 
Procedures by Visit 
Visits should occur within the time indicated for each scheduled visit. All times should 
                                                          
a Hospitalization on the day at administration is allowed if it is required by the site. 
b Serum pregnancy test will be performed at Screening, and urine pregnancy test will be performed at 
Visit 2 before administration of the investigational drug. 
c If repeat imaging is needed, the permissible lag time will be extended by a maximum of an additional 
14 days. 
d Examined when considered necessary in unscheduled visit 
e Patients who discontinued the study will be followed until the Week 26 visit. 


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be recorded using the 24-hour clock (e.g., 23:20, not 11:20 pm). 
7.2.1 Screening (Visit 1) 
 
Obtain written informed consent 
 
Record demographic and medical history 
 
Record the use of concomitant drug/therapy 
 
Document occurrence of lumbar surgery  
 
Verify conformance with entry criteria 
 
Perform vital signs assessments (temperature, blood pressure, heart and 
respiration rate) 
 
Perform physical examination  
 
Perform neurological examination 
 
Complete pain assessment (VAS) 
 
Perform imaging tests (X-ray and MRI) 
 
Obtain study entry laboratory specimens (blood for HIV; pregnancy [for women 
of childbearing potential]; and hematology, hepatic, and chemistry panels) 
7.2.2 Treatment Day 0 (Visit 2) 
The following will be performed on the day of study drug administration (Day 0) before 
study drug administration: 
 
Enroll the patient if not done the day before 
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs since previous visit 
 
Document occurrence of lumbar surgery 
 
Perform vital sign assessments (temperature, blood pressure, heart and 
respiration rate) 
 
Perform physical examination  
 
Complete pain assessment (VAS) and ODI  
 
Obtain blood specimen for serum anti-SI-6603 antibody 
 
Perform urine pregnancy test 
 
Administration of SI-6603  
The following will be done after study drug administration: 
Require patients to rest for at least 4 hours. During this resting period the patient’s vital 
signs and general health status will be monitored. After patient monitoring, the 
Investigator will judge if the patient is ready for discharge based on observation and 
verification that there are no findings that negatively influence discharging the patient.  
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs  


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 
Perform vital sign assessments (temperature, blood pressure, heart and 
respiration rate) 
7.2.3 Evaluation Period, Week 1 (Visit 3) 
 
Complete pain assessment (VAS) and ODI 
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs since previous visit 
 
Document occurrence of lumbar surgery 
 
Perform vital sign assessments (temperature, blood pressure, heart and 
respiration rate) 
 
Perform neurological examination  
 
Obtain laboratory specimens (blood for hematology, hepatic, and chemistry 
panels) 
7.2.4 Evaluation Period, Week 6 (Visit 4) 
 
Complete pain assessment (VAS) and ODI 
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs since previous visit 
 
Document occurrence of lumbar surgery 
 
Perform vital sign assessments (temperature, blood pressure, heart and 
respiration rate) 
 
Perform neurological examination  
 
Perform imaging tests (X-ray and MRI) 
 
Obtain laboratory specimens (blood for hematology, hepatic, and chemistry 
panels) 
7.2.5 Evaluation Period, Week 13 (Visit 5) 
 
Complete pain assessment (VAS) and ODI 
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs since previous visit 
 
Document occurrence of lumbar surgery 
 
Perform vital sign assessments (temperature, blood pressure, heart and 
respiration rate) 
 
Perform neurological examination  
 
Perform imaging tests (X-ray and MRI) 
 
Obtain laboratory specimens (blood for hematology, hepatic, and chemistry 
panels) 


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 
Obtain blood specimen for serum anti-SI-6603 antibody 
7.2.6 Evaluation Period, Week 26 (Visit 6) 
 
Complete pain assessment (VAS) and ODI 
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs since previous visit 
 
Document occurrence of lumbar surgery 
 
Perform neurological examination 
 
Perform imaging tests (X-ray and MRI) 
 
Obtain blood specimen for serum anti-SI-6603 antibody 
7.2.7 Discontinuation Visit  
 
Complete pain assessment (VAS) and ODI 
 
Record concomitant drug and therapy information, including drugs or therapy 
used to treat an AE  
 
Record AEs and SAEs since previous visit 
 
Document occurrence of lumbar surgery 
 
Perform vital sign assessments (temperature, blood pressure, heart and 
respiration rate) 
 
Perform neurological examination  
 
Perform imaging tests (X-ray and MRI) 
 
Obtain laboratory specimens (blood for hematology, hepatic, and chemistry 
panels) 
 
Obtain blood specimen for serum anti-SI-6603 antibody 
Patients who discontinue early from the study should, if possible, have a Discontinuation 
Visit. This visit should take place as soon as possible after it was learned that the patient 
will not be able to complete the study (see also Section 4.3).  


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8 
STATISTICAL METHODS 
The statistical considerations summarized in this section outline the plan for data analysis 
of this study.  
Before database lock, a Statistical Analysis Plan (SAP) will be finalized, providing 
detailed methods for the analyses outlined below. The analyses specified in the SAP will 
be performed and the Clinical Study Report (CSR) will be prepared upon database lock. 
Any changes from the planned analyses will be described and justified in the final CSR. 
8.1 
Study Patients 
8.1.1 Disposition of Patients 
Patient disposition and reasons for discontinuation will be summarized for all enrolled 
patients. 
8.1.2 Analysis Sets 
The following populations will be assessed: 
 
Safety: 
 All patients who were treated with an investigational drug. 
 
Intent-to-Treat (ITT): All patients who were treated with an investigational drug. 
If considered necessary, further populations may be defined in the SAP. 
8.2 
General Considerations 
Categorical variables will be summarized in a contingency table by the number and 
percentage of patients in each category. Continuous variables will be summarized by the 
number of observations, mean, standard deviation (SD), median, inter-quartile range, 
minimum, and maximum. Where data are collected over time, both the observed data and 
change from the Screening period (baseline) will be summarized at each time point. All 
eCRFs collected and derived data will be listed. 
Methods for imputation of missing data and criteria for inclusion of patients in efficacy 
analyses will be specified.  
All statistical tests will be performed 2-sided with a significance level of 5%, unless 
otherwise stated. 
Analysis and Data Conventions: 
Definition of baseline 
For vital signs, laboratory tests, imaging procedures, neurological examinations, and 
ODI, the last valid assessment made before administration of investigational drug will be 
used as the baseline for all analyses of that parameter. 
For the efficacy parameters of pain assessment measured by VAS, the baseline value of 
the worst leg pain and back pain over the past 24 hours (VAS) will be the VAS obtained 
on the day of enrollment (Day 1/Day 0). 
Visit windows 


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All data collected during study follow-up will be displayed and analyzed according to the 
actual visit date in the eCRF. Assessments taken outside of protocol allowable windows 
will be displayed according to the eCRF assessment recorded by the Investigator. 
Unscheduled assessments 
Unscheduled assessments (laboratory data or vital signs associated with non-protocol 
clinical visits or obtained in investigating or managing AEs) will be included in listings, 
but not presented in the summary tables. If more than one laboratory value is available 
for a given visit, the last assessment will be used at the Screening visit, and the first valid 
observation will be used at all other post-baseline visits in summary tables and all 
observations will be presented in listings. It is noted that invalid laboratory data may not 
be used (from hemolyzed samples, mishandled samples, quantity not sufficient, or other 
conditions that would render values invalid). 
Missing data conventions 
In general, data will not be imputed for safety analyses.  
8.3 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic data and other baseline characteristics will be summarized by descriptive 
statistics with number of patients, mean, SD, median, inter-quartile range, minimum, and 
maximum. Categorical variables (e.g., sex and race) will be tabulated using frequency 
and percentage for each category of interest. Medical history and concomitant medication 
data will be provided in separate listings. 
8.4 
Treatment Compliance 
Treatment compliance on administration volume (1.0 mL or any other amount) of 
investigational drug will be measured. 
8.5 
Efficacy Analyses 
Efficacy analyses will be performed for the ITT population. 
The following efficacy endpoints will be analyzed using the appropriate parametric or 
nonparametric statistical method: 
 
Worst leg pain during the past 24 hours assessed by VAS from baseline through 
Week 26 
 
Worst back pain during the past 24 hours assessed by VAS from baseline 
through Week 26 
 
Functional disability measured by the ODI from baseline through Week 26 
 
Change of neurological status from baseline determined by neurological 
examinations FNS or SLR test, sensation, muscle strength, and deep tendon 
reflex) from baseline through Week 26 
 
Occurrence of post-treatment surgery for lumbar disc herniation at the same level 
of administration of the investigational drug up to Week 26 


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The descriptive statistics of the worst leg pain, back pain, ODI, and their change from 
baseline will be calculated and presented for each time point. A longitudinal plot will be 
used to display the mean change from baseline and the associated 95% confidence 
intervals (CIs) at each time point.   
For analysis of change of neurological status from baseline, the number (%) of patients 
with negative FNS or SLR test results, negative neurological tests for hypoesthesia, 
muscle weakness, or diminished deep tendon reflex results will be presented for each 
time point. Furthermore, the percentage of patients with a negative neurological test will 
be calculated and presented for each time point. The time-course changes will also be 
presented graphically with bar chart by time points. 
In the analysis of occurrence of post-treatment surgery for lumber disc herniation at the 
same level of administered disc, the number (%) of patients having such surgery will be 
calculated and presented.   
8.6 
Safety Analyses 
Evaluation of the safety of SI-6603 will be based on the occurrence of AEs, vital signs, 
laboratory, imaging, and other clinical assessments. The safety analyses will use the 
safety population. 
8.6.1 Adverse Events and Treatment-Related Adverse Events 
The incidence of AEs and associated 95% CIs will be determined and presented. A 
similar analysis will be conducted for each level of severity. After the terms of AEs 
observed are coded with corresponding MedDRA terms, data on the incidence of AEs 
will be compiled for each system organ class (SOC) or preferred term (PT). Furthermore, 
data on the incidence of AEs, as classified by SOC or PT, will be compiled for each level 
of severity. Of the AEs observed, those whose causal relationship to the investigational 
drug is classified as “related” will be defined as treatment-related AEs and evaluated in 
the same manner as AEs. 
Concerning SAEs, their incidence and associated 95% CIs will be determined and 
presented. In addition, data on the incidence of SAEs, as classified by SOC or PT, will be 
compiled. The same analyses will be repeated for SAEs classified as “related”. 
8.6.2 Vital Signs 
For body temperature, blood pressure, heart rate and respiration rate, descriptive statistics 
will be calculated at each time point. 
8.6.3 Laboratory Tests 
For laboratory data, descriptive statistics will be calculated for each time point.  
8.6.4 Serum Anti-SI-6603 Antibody 
The proportion and 95% CI of patient with serum anti-SI-6603 antibody positive will be 
calculated for each group at each time point. Furthermore, the proportion of each isotype 
of immunoglobulin (IgG, IgM and IgE) will be calculated. The proportion and 95% CI of 
patient with immunogenicity status will be calculated for each group at each time point.  


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8.6.5 Disc Height (Disc Index) 
For the change from baseline and percent change from baseline of intervertebral disc 
height, descriptive statistics will be calculated at each time point to make a time-course 
change plot. The percentage of the patients who showed an intervertebral disc height 
change of ≤30% and associated 95% CIs will be calculated and presented. 
Association between decreased intervertebral disc height and leg pain (VAS) or back 
pain (VAS) will be assessed. 
8.6.6 Intervertebral Posterior Angle 
For the intervertebral posterior angle, descriptive statistics will be calculated for time 
point to draw a time-course change plot. The percentage of the patients who showed a 
posterior intervertebral angulation angle of ≥5° and associated 95% CIs will be 
calculated and presented.  
Association between posterior intervertebral angulation and leg pain (VAS) or back pain 
(VAS) will be assessed. 
8.6.7 Vertebral Body Translation 
For the vertebral body translation, descriptive statistics will be calculated at each time 
point to make a time-course change plot. The percentage of the patients who showed a 
vertebral body translation of ≥3 mm and associated 95% CIs will be calculated and 
presented. 
Association between vertebral body translation and leg pain (VAS) or back pain (VAS) 
will be assessed. 
8.6.8 Change in Bone Marrow Adjacent to Vertebral Endplates (Modic 
Classification) 
Modic classifications will be displayed in a tabular form using frequencies by 
observation day. Shift tables will also be constructed to display Modic classifications. 
These tables will illustrate the change in a patient’s classification between baseline and 
follow up visits.  
For Modic classifications, proportions of patients with Modic’s Type 0, Type 1, Type 2, 
and Type 3 will be calculated. In addition, proportions of patients (for each of Type 1, 
Type 2, and Type 3) whose Modic’s types changed from “No” to “Yes” and associated 
95% CI will also be calculated and presented.  
A cross-tabulation of patients with any Modic’s types changing from “No” to “Yes” and 
patients with AEs associated with leg pain and back pain will be displayed. In addition, 
changes from baseline of leg pain (VAS) and back pain (VAS) across time will be 
displayed separately for those 2 different Modic groups. 
8.6.9 Disc Degeneration (Pfirrmann Classification) 
Pfirrmann classifications will be tabulated to display the proportion of patients per 
observation day. Shift tables will also be constructed to display Pfirrmann classifications. 
These tables will illustrate the change in a patient’s classification between baseline and 
follow-up visits.  


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For Pfirrmann classifications, proportions of patients with Pfirrmann’s Grade 0, Grade I, 
Grade II, and Grade III will be calculated.  
The percentage of patients whose Pfirrmann’s grade increased with respect to the grade 
at baseline and associated 95% CIs will be calculated, analyzed and presented. 
A cross-tabulation of patients whose Pfirrmann’s grade increased with respect to the 
grade at baseline and patients with AEs associated with leg pain and back pain will be 
displayed. In addition, changes from baseline of leg pain (VAS) and back pain (VAS) 
across time will be displayed separately for those 2 different Pfirrmann groups. 
8.6.10 Occurrence of Post-Treatment Lumbar Surgery 
As to occurrence of post-treatment lumbar surgery, the percentage of the patients having 
such surgery will be calculated and presented. In addition, the percentage of the patients 
with post-treatment lumbar surgery at the site of treatment injection and the percentage 
of the patients with post-treatment lumbar surgery at other sites will be calculated and 
reported. 
8.7 
Interim Analyses 
No interim analysis is planned. 
8.8 
Determination of Sample Size 
The total number of 1000 patients will be enrolled. In order to further characterize the 
frequency and outcome of the rather infrequent treatment-related AE, the current study 
will have approximately 1000 patients treated with SI-6603. This sample size will allow 
for estimating a cumulative incidence rate of 0.3% (n=3 patients with events) with a 95% 
CI of (0.06%, 0.87%), or an incidence rate of 1.5% (n=15 patients with events) with a 
95% CI of (0.84%, 2.46%). This calculation assumes that distribution of 
treatment-related AE is binomially distributed. The 95% CI is calculated using the 
Clopper-Pearson method in SAS 9.2.   


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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The Sponsor (or Sponsor’s designated agent) will conduct a site visit to verify the 
qualifications of each Investigator, inspect the site facilities, and inform the Investigator 
of responsibilities and the procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded in the eCRF for this study must be consistent with 
the patients’ source documentation (i.e., medical records). 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study site 
using eCRFs. Data from external sources (such as laboratory data) will be imported into 
the database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. 
The reason for change, the name of the person who performed the change, together with 
the time and date will be logged to provide an audit trail.  
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the eCRF page. The appropriate staff at the study site will answer queries sent to 
the Investigator. The name of the staff member responding to the query, and time and 
date stamp, will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the monitor will freeze the eCRF page. 
The specific procedures to be used for data entry and query resolution using the eCRF 
will be provided to study sites in a training manual. In addition, site personnel will 
receive training in the eCRF. 
9.2 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the eCRFs promptly. All source 
documents from which eCRF entries are derived should be placed in the patient’s 
medical records. Measurements for which source documents are usually available 
include laboratory assessments, MRIs, and X rays.  
The original eCRF entries for each patient may be checked against source documents at 
the study site by the PAREXEL site monitor.  
After review by the site monitor, completed eCRF entries will be uploaded and 
forwarded to PAREXEL. Instances of missing or uninterpretable data will be discussed 
with the Investigator for resolution.  
The specific procedures to be used for data entry and query resolution using the eCRF 
will be provided to study sites in a training manual.  In addition, site personnel will 
receive training in the eCRF. 


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9.2.1 Data collection  
The Investigators (and appropriately authorized staff) will be given access to an eCRF 
system which is 21 CFR Part 11 compliant. This system is specifically designed for the 
collection of the clinical data in electronic format. Access and right to the eCRF system 
will be carefully controlled and configured according to each individual’s role 
throughout the study. In general, only the Investigator and authorized staff will be able to 
enter data and make corrections in the eCRFs. 
The eCRF should be completed for each patient included in the study and should reflect 
the latest observations on the patients participating in the study. Therefore, the eCRFs are 
to be completed as soon as possible during or immediately after the patient’s visit or 
assessment. The Investigator must verify that all data entries in the eCRF are accurate 
and correct. If some assessments cannot be done, or if certain information is unavailable, 
not applicable or unknown, the Investigator should indicate this in the eCRF.  
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and 
the site will be informed about new issues to be resolved on-line. All discrepancies will 
be solved on-line directly by the Investigator or by authorized staff. Off-line edit checks 
will be done to examine relationships over time and across panels to facilitate quality 
data. 
After completion, the Investigator will be required to electronically sign off the clinical 
data. 
Data about all study drug dispensed to the patient and any dosage changes will be tracked 
on the eCRF.  
9.3 
Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare 
eCRF entries and individual patient’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with 
source documents, will be required to monitor the progress of the study. Moreover, 
Regulatory Authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical 
Quality Assurance Group may wish to carry out such source data checks and/or on-site 
audit inspections. Direct access to source data will be required for these inspections and 
audits; they will be carried out giving due consideration to data protection and medical 
confidentiality. The Investigator assures PAREXEL and the Sponsor of the necessary 
support at all times. 
9.4 
Data Processing 
All data will be entered by site personnel into eCRF as detailed in Section 9.2.1.  
The data review and data handling document, to be developed during the initiation phase 
of the study, will include specifications for consistency and plausibility checks on data 
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for unresolved queries will be sent to the study monitors for resolution with the 
Investigator. The database will be updated on the basis of signed corrections.  
Previous and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Reference List (DRL), which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history, previous and 
concomitant diseases as well as AE will be coded using the MedDRA terminology. 
The versions of the coding dictionaries will be provided in the CSR. 
9.5 
Archiving Study Records 
According to International Conference on Harmonization (ICH) guidelines, essential 
documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. However, these 
documents should be retained for a longer period if required by the applicable legal 
requirements. 
9.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the Good Clinical Practice guidelines of the ICH, 
and of the Declaration of Helsinki (2013).1 The study also will be carried out in keeping 
with local legal requirements.  
9.7 
Informed Consent 
Before each patient is admitted to the study, informed consent will be obtained from the 
patient according to the regulatory and legal requirements of the participating country. 
This consent form must be dated and retained by the Investigator as part of the study 
records. The Investigator will not undertake any investigation specifically required only 
for the clinical study until valid consent has been obtained. The terms of the consent and 
when it was obtained must also be documented in the eCRF. 
If a protocol amendment is required, the ICF may need to be revised to reflect the 
changes to the protocol. If the consent form is revised, it must be reviewed and approved 
by the appropriate IEC/IRB, and signed by all patients subsequently enrolled in the study 
as well as those currently enrolled in the study. 
9.8 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/IRB/Competent Authorities, in accordance with local legal 
requirements. The Sponsor must ensure that all ethical and legal requirements have been 
met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive 
IRB/IEC/Competent Authority approval prior to implementation (if appropriate). 


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Following approval, the protocol amendment(s) will be submitted to the Investigational 
New Drug (IND) under which the study is being conducted.  
Administrative changes (not affecting the patient benefit/risk ratio) may be made without 
the need for a formal amendment. All amendments will be distributed to all protocol 
recipients, with appropriate instructions. 
9.9 
Duration of the Study 
For an individual patient, the maximum duration of the study will be up to 30 weeks 
(including up to 4 weeks for screening, 1 day treatment and up to 26 weeks follow-up).  
The study will close when the last patient has completed the Visit Week 26 or the 
Discontinuation Visit. 
9.10 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to patients if the study continues, the study may be 
terminated after appropriate consultation between the relevant parties. The study may 
also be terminated early at the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination of the study include, but are not limited to: 
 
The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study (e.g., AE other than those listed in Table 1) 
 
The occurrence of an AE, as noted below: 
a. Significant neurologic deficit; for example, progressive weakness or sudden 
loss of muscle strength, bowel or bladder dysfunction, or other signs and 
symptoms of cauda equine / conus medullaris involvement, or 
b. Abnormal X-ray findings of instability, defined as vertebral body angle 
formed by flexion of ≥5° or vertebral body translation of ≥3 mm 
c. Abnormal X-ray or MRI findings which patients exhibit correlating clinical 
symptoms posing safety concerns, leading the Investigator to judge it 
necessary for the patient to have surgical intervention 
At time of occurrence of these treatment-related AEs, the Sponsor will notify the 
DSMB and provide the necessary information. DSMB chairperson will 
determine to make one of two decisions - (1) Continue the study as planned or 
(2) Request an ad hoc meeting. The Sponsor will judge discontinuation of the 
study based on the recommendation of the DSMB. The details of the DSMB 
procedure will be provided in the DSMB charter. 
 
Failure to enroll patients at an acceptable rate 
 
A decision on the part of the Sponsor to suspend or discontinue development of 
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9.11 Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior 
written approval from the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be identified 
on the eCRF and other documents submitted to PAREXEL by their patient number, 
initials and/or birth date, not by name. Documents not to be submitted to PAREXEL that 
identify the patient (e.g., the signed informed consent) must be maintained in confidence 
by the Investigator.  
9.12 Other Ethical and Regulatory Issues  
If a significant safety issue is identified, either from an individual case report or review 
of aggregate data, then the Sponsor will issue prompt notification to all parties – 
Regulatory Authorities, Investigators, and IRB/IECs. 
A significant safety issue is one that has a significant impact on the course of the clinical 
study or program (including the potential for suspension of the development program or 
amendments to protocols) or warrants immediate update of informed consent. 
9.13 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance cover in accordance 
with all local legal requirements. The civil liability of the Investigator, the persons 
instructed by him or her and the hospital, practice, or institute in which they are 
employed and the liability of the Sponsor with respect to financial loss due to personal 
injury and other damage that may arise as a result of the carrying out of this study are 
governed by the applicable law. 
The Sponsor will arrange for patients participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products being tested 
or by medical steps taken in the course of the study.  
9.14 Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the study 
for the purposes of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, Regulatory Authorities will be 
notified of the Investigator's name, address, qualifications and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance.   


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10 REFERENCE LIST 
1 
World Medical Association Declaration of Helsinki. Recommendations guiding 
physicians in biomedical research involving human subjects. Adopted by the 18th 
WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th 
WMA General Assembly, Tokyo, Japan, October 1975, the 35th WMA General 
Assembly, Venice, Italy, October 1983, the 41st WMA General Assembly, Hong 
Kong, September 1989, the 48th WMA General Assembly, Somerset West, 
Republic of South Africa, October 1996, the 52nd WMA General Assembly, 
Edinburgh, Scotland, October 2000, the Note of Clarification on Paragraph 29 
added by the WMA General Assembly, Washington 2002, the Note of Clarification 
on Paragraph 30 added by the 55th WMA General Assembly, Tokyo 2004, the 59th 
WMA General Assembly, Seoul, South Korea, October 2008, and the 64th WMA 
General Assembly, Fortaleza, Brazil, October 2013. JAMA 2013;310(20):2191-
2194. 
2  
The Japanese Society of Spinal Surgery. Glossary of spinal surgery. Tokyo: 
Nanko-do; 1995. 
3  
Kawabata M. Lumbar disc herniation. Clinical Orthopaedic Surgery 1989;24:825-
831. 
4  
Itoh T, Yuasa N, Takano Y. The period of conservative treatment for lumbar disc 
herniation. Clinical Orthopaedic Surgery 2001;36:487-490. 
5  
The Japanese Orthopaedic Association. The Guideline of treatment for Lumbar 
Disc Herniation. 2nd ed. Tokyo: Nanko-do; 2011. 
6  
Iwata H, Kato F. Chondroitinase ABC chemonucleolysis. Igaku-no-Ayumi 
1988;144(10):807. 
7  
Takahashi K, Kitara H. Enzyme injection therapy into the intervertebral disc. 
Current Therapy 1991;9(12):81-87. 
8  
Agre K, Wilson RR, Brim M, McDermott DJ. Chymodiactin post-marketing 
surveillance, demographic and adverse experience data in 29075 patients. Spine 
1984;9(5):479-485. 
9  
Macnab I, McCulloch JA, Transfeldt EE. Macnab's Backache. 3rd ed. New York, 
NY: Lippincott Williams & Wilkin; 1997. 
10  
Yamagishi M, Nemoto O, Shimmai M. Experimental and clinical medicine of 
chemonucleolysis. Orthopedic Surgery 1991;42(7):1117-1123. 
11  
Yamagata T, Saito H, Habuchi O, Suzuki S. Purification and properties of bacterial 
chondroitinase and chondrosulfatase. J Biol Chem 1968;243(7):1523-1535. 
12  
Hamai A, Hashimoto N, Mochizuki H, et al. Two distinct chondroitin sulfate ABC 
lyases. An endoeliminase yielding tetrasaccharides and an exoeliminase 
preferentially acting on oligosaccharides. J Biol Chem. 1997; 272(14),9123-9130. 
13  
SI-6603 Investigator’s Brochure, US.13.00.000 ed. December 25, 2013.  
14  
McGirt MJ, Eustacchio S, Varga P, et al. A prospective cohort study of close 
interval computed tomography and magnetic resonance imaging after primary 
 
 
 


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lumbar discectomy: factors associated with recurrent disc herniation and disc 
height loss. Spine 2009;34(19):2044-2051. 
15  
Ohtori S, Yamashita M, Yamauchi K, et al. Low back pain after lumbar discectomy 
in patients showing endplate modic type 1 change. Spine 2010;35(13):E596-600. 
16  
Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of 
treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. 
J Pain. 2008;9(2):105-121. 


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11 APPENDICES 
11.1 Injection Procedure and Investigational Drug Management  
11.1.1 Preparation Method for SI-6603 
The SI-6603 will be prepared in an aseptic manner according to the following procedure: 
1. Take one box of SI-6603 and saline out of the secure, temperature-controlled storage 
and allow it to stand at room temperature for about 20 minutes. The drugs must be 
kept in their original boxes during this time. 
2. Using a disposable injection syringe, accurately aspirate 1.2 mL of saline from the 
saline vial in Step 1. Do not use glass syringes. 
3. Slowly inject the 1.2 mL of saline aspirated in Step 2, into the SI-6603 vial from 
Step 1. If the SI-6603 vial does not have negative pressure, the vial should not be 
used. 
4. Slowly reconstitute the SI-6603 in Step 3, avoiding bubbling and vigorous shaking. 
5. After reconstitution, check the vial to ensure that the solution is a colorless, clear 
liquid free from suspended or other foreign materials. If turbidity or foreign materials 
are observed, the solution will not be used. 
6. Record the drug preparation time in the medical records. 
7. No other ingredient/substance should be added to the reconstituted SI-6603 from 
Step 5. 
8. Following reconstitution, the SI-6603 will be kept at room temperature and must be 
administered within 2 hours. 
9. Attach a needle to a syringe and aspirate 1.1 mL from the vial containing 
reconstituted SI-6603. Do not use glass syringes. 
10. Any residual SI-6603 will not be used in any other patient. 
11.1.2 Precautions in Administering Investigational Drug 
1. The investigational drug must be administered in a study site location that has 
appropriate fluoroscopic equipment and must be administered within 2 hours of 
reconstitution. 
2. Full/general anesthesia is prohibited during investigational drug administration. 
3. Circulatory status should be closely monitored during investigational drug 
administration. 
4. Preparations should be in place to provide appropriate emergency care to the patient. 
Preparations for the possible occurrence of an allergic reaction or anaphylaxis should 
include: 
 
Establishing a peripheral intravenous line. 


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 
Having medications for treatment of anaphylaxis (e.g., epinephrine, dopamine, 
antihistamine, adrenal cortex hormone) and intubation equipment 
(e.g., endotracheal tubes, handheld resuscitator), readily available in the case of 
signs and symptoms of anaphylaxis or any other cardio-respiratory emergency. 
For cautions on medications before investigational drug administration, please 
also see Section 5.7.2 “Notes Concerning Concomitant Medication Before SI-
6603 is Administered”. 
5. Giving close attention to the patient’s general physical condition (e.g., respiratory 
status or any patient complaint) during and following investigational drug 
administration. 
6. If anaphylaxis symptoms (e.g., breathing difficulties, hives, angioedema, or itching) 
appear during investigational drug administration, administration of the 
investigational drug must be discontinued immediately. 
11.1.3 Intradiscal Administration Procedure for SI-6603 
The intradiscal administration procedure for SI-6603 will be performed as follows: 
1. Have the patient lie down on a fluoroscopy bench in lateral or prone position. 
2. Under fluoroscopic guidance, position the patient so the intervertebral disc space is 
parallel to the X-ray. 
3. Under fluoroscopic guidance, locate the insertion point while observing the target 
area. 
4. Widely sterilize the operative field centering on the entry point and extending to the 
lateral region. 
5. Insert the spinal needle in the median plane of the patient, carefully advancing the 
needle into the dorsal transverse temporal fibrous ring of the intervertebral disc. Do 
not make any median transdural punctures. 
6. Under fluoroscopic guidance, insert the spinal needle tip into the center of the 
intervertebral disc, feeling the spinal needle as it penetrates into the nucleus pulposus 
through the annulus fibrosus. 
7. After the puncture of the intervertebral disc, take a lateral X-ray image of the 
involved disc, then move the C-arm of the X-ray machine to accurately take a frontal 
view of the involved disc checking to ensure the needle tip is correctly positioned in 
the center of the intervertebral disc. The images will confirm correct needle 
placement and will be kept in the medical record. Send the copy of the images to 
BioClinica for confirmation of injection level. 
8. Attach the syringe containing the previously drawn amount (1.1 mL) of reconstituted 
drug as outlined in Section 11.1.1.  
9. Remove the inner needle and administer whole amount (1.1 mL) of the freshly 
reconstituted SI-6603 solution to deliver 1.0 mL to intervertebral disc. Inject the 
solution slowly and stop immediately if any resistance is felt. 


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10. Record the date, hour, and amount of SI-6603 administered in the eCRF. Any volume 
other than 1 mL will be recorded in the eCRF.  
11. After the administration of SI-6603, antibiotics may be used for the prevention of 
infection at the site of injection. 
11.2 Package Presentation and Labeling 
This information will be provided later by the vendor. 
 
 


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11.3 Visual Analog Scale 
 
VAS Measurement Method 
 
The instructions for visual analog scale (VAS) measurements that will be recorded in the 
electronic case report form (eCRF) are explained in this manual. The purpose of this 
manual is to minimize the variation of the VAS values among measurers. 
 
The patients will evaluate their pain by themselves on VAS Scale Form at each scheduled 
visit at the site. 
 
Tools for measurement: Metallic straight measure is provided by Sponsor. 
 
Method of VAS measurement: 
1. Principal Investigators, sub Investigators or study coordinator set the 0 mm point at 
the left edge of the left portion of the horizontal line on the VAS as the origination 
and measure the VAS from this point to the right. 
2. Measure the distance from the point of origination at 0 mm to the point at the 
intersection of the written vertical VAS line by use of the specified mm scale on the 
horizontal line. 
3. Set the VAS measurement value from 0 mm at the origination to 100 mm at the 
termination, read in 1 mm increments, and round off a VAS measurement value of 
less than 1 mm. If the VAS measurement value is under 0 mm, record 0 mm. If the 
VAS measurement value is over 100 mm, record 100 mm. 
4. Record the VAS measurement value in the patient diary and the eCRF. 
 
Notes at the time of pain evaluation: 
1. Definition of leg pain and back pain 
Leg pain: Pain of the leg and the buttocks               Back pain: Pain near the waist 
(belt) 
 
 
 
 
 
 
 
 
 
 


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Investigator confirms patient's site of pain at the time of screening, and instructs a patient 
to evaluate the pain as leg pain and/or back pain. In addition, Investigator instructs a 
patient to evaluate pain only and not include numbness. 
 
2. Definition of "the worst pain experienced in the past" 
The worst pain experienced by the lumbar disc herniation is considered as "the worst 
pain experienced in the past (100 mm)" and VAS of leg pain and back pain should be 
evaluated based on it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measure the distance in mm from the origination at 0 mm to the point of the intersection 
of the vertical written line with the left edge point of written lines, if “X” is written in 
VAS. 
 
 
 
 
 
2
3
4
0
1
Example 1: The VAS measurement value in this example below is 22 mm 
because the left edge point of intersection of the vertical written line 
lies to the left of the point of 23 mm. 
2
3
4
0
1
Example 2: The measurement value in this example below is 21 mm because the 
left edge point of the intersection of the vertical written line lies to 
the right of the point of 21 mm. 


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If ○ or ● is used to mark or indicate the VAS measurement on the horizontal, measure the 
distance from the origination at 0 mm to marks in the same way as measuring the vertical 
VAS written line. 
 
 
2
3
4
0
1
Example 3: The measurement value in this example below is 21 mm because 
the left edge point of the intersection of the vertical written lines lies to the left 
of the point of 22 mm. 


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11.4 Oswestry Disability Index, version 2.1a  
 
This questionnaire is designed to give us information as to how your back (or leg) trouble 
affects your ability to manage in everyday life. 
 
Please answer every section. Mark one box only in each section that most closely 
describes you today. 
 
Section 1—Pain intensity 
(0)  
I have no pain at the moment. 
(1)  
The pain is very mild at the moment. 
(2)  
The pain is moderate at the moment. 
(3)  
The pain is fairly severe at the moment. 
(4)  
The pain is very severe at the moment. 
(5)  
The pain is the worst imaginable at the moment. 
 
Section 2—Personal care (washing, dressing, etc.) 
(0)  
I can look after myself normally without causing extra pain. 
(1)  
I can look after myself normally but it is very painful. 
(2)  
It is painful to look after myself and I am slow and careful. 
(3)  
I need some help but manage most of my personal care. 
(4)  
I need help every day in most aspects of self care. 
(5)  
I do not get dressed, wash with difficulty and stay in bed. 
 
Section 3—Lifting 
(0)  
I can lift heavy weights without extra pain. 
(1)  
I can lift heavy weights but it gives extra pain. 
(2)  
Pain prevents me from lifting heavy weights off the floor but I can manage 
if they are conveniently positioned, e.g. on a table. 
(3)  
Pain prevents me from lifting heavy weights but I can manage light to 
medium weights if they are conveniently positioned. 
(4)  
I can lift only very light weights. 
(5)  
I cannot lift or carry anything at all. 
 


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Section 4—Walking 
(0)  
Pain does not prevent me walking any distance. 
(1)  
Pain prevents me walking more than one mile. 
(2)  
Pain prevents me walking more than a quarter of a mile. 
(3)  
Pain prevents me walking more than 100 yards. 
(4)  
I can only walk using a stick or crutches. 
(5)  
I am in bed most of the time and have to crawl to the toilet. 
 
Section 5—Sitting 
(0)  
I can sit in any chair as long as I like. 
(1)  
I can sit in my favorite chair as long as I like. 
(2)  
Pain prevents me from sitting for more than 1 hour. 
(3)  
Pain prevents me from sitting for more than half an hour. 
(4)  
Pain prevents me from sitting for more than 10 minutes. 
(5)  
Pain prevents me from sitting at all. 
 
Section 6—Standing 
(0)  
I can stand as long as I want without extra pain. 
(1)  
I can stand as long as I want but it gives me extra pain. 
(2)  
Pain prevents me from standing for more than 1 hour. 
(3)  
Pain prevents me from standing for more than half an hour. 
(4)  
Pain prevents me from standing for more than 10 minutes. 
(5)  
Pain prevents me from standing at all. 
 
Section 7—Sleeping 
(0)  
My sleep is never disturbed by pain. 
(1)  
My sleep is occasionally disturbed by pain. 
(2)  
Because of pain I have less than 6 hours sleep. 
(3)  
Because of pain I have less than 4 hours sleep. 
(4)  
Because of pain I have less than 2 hours sleep. 
(5)  
Pain prevents me from sleeping at all. 
 


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Section 8—Sex life (if applicable) 
(0)  
My sex life is normal and causes no extra pain. 
(1)  
My sex life is normal but causes some extra pain. 
(2)  
My sex life is nearly normal but is very painful. 
(3)  
My sex life is severely restricted by pain. 
(4)  
My sex life is nearly absent because of pain. 
(5)  
Pain prevents any sex life at all. 
 
Section 9—Social life 
(0)  
My social life is normal and causes me no extra pain. 
(1)  
My social life is normal but increases the degree of pain. 
(2)  
Pain has no significant effect on my social life apart from limiting my more 
energetic interests, e.g. sport, etc. 
(3)  
Pain has restricted my social life and I do not go out as often. 
(4)  
Pain has restricted social life to my home. 
(5)  
I have no social life because of pain. 
 
Section 10—Travelling 
(0)  
I can travel anywhere without pain. 
(1)  
I can travel anywhere but it gives extra pain. 
(2)  
Pain is bad but I manage journeys over two hours. 
(3)  
Pain restricts me to journeys of less than one hour. 
(4)  
Pain restricts me to short necessary journeys under 30 minutes. 
(5)  
Pain prevents me from travelling except to receive treatment. 
 
 
Reference: Fairbank JCT, Couper J, Davies JB, O’Brien JP. The Oswestry Low Back 
Pain Disability Questionnaire. Physiotherapy. 1980;66:271-273 
 
 
 


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11.5 Modic Classification 
 
Modic Classification of Abnormalities in Bone Marrow Adjacent to Vertebral Endplates 
(Sagittal MRI) 
Modic Change 
MRI Signal Intensity 
0 
Normal signal 
Type 1 
Decreased signal intensity on T1-weighted images and increased signal 
intensity on T2-weighted images (inflammatory phase) 
Type 2 
Increased signal intensity on T1-weighted images and isointense or 
slightly increased signal intensity on T2-weighted images (fatty phase) 
Type 3 
Hypointense signal on T1- and T2-weighted images with marked sclerosis 
adjacent to the endplates 
 
 
 


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11.6 Pfirrmann Classification 
 
Pfirrmann’s Classification of Disc Degeneration   
(T2-weighted sagittal MRI) 
Pfirrmann Grade 
Nucleus Pulposus and 
Fibrous Ring 
Differentiation 
Signal Intensity (T2-weighted image) of 
Nucleus Pulposus 
Grade 0 (normal) 
Present 
Hyperintense with horizontal dark bands 
Grade I (mild) 
Blurred 
Slightly decreased with minor irregularities 
Grade II (moderate) 
Absent 
Moderately decreased with hypointense 
zones 
Grade III (severe) 
Absent 
Hypointense with or without horizontal 
hyperintense band (black disc) 
 
 
 


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11.7 Imaging Tests (X-ray and Magnetic Resonance Imaging) 
11.7.1 X-ray Imaging 
In X-ray imaging, an anteroposterior and lateral-intermediate, flexion, and extension 
spinal will be obtained according to the “Procedure Manual for Radiographic 
Examinations of the Lumbar Spine”.  
11.7.2 Disc Height (disc index) 
The central reader will measure the disc index for the intervertebral disc treated with the 
investigational drug using (A) the posterior height of the superior vertebral body adjacent 
to the target segment, (B) the anterior disc space and (C) the posterior disc space.  
 
 
Calculation of the disc height 
11.7.3 Intervertebral Posterior Angle 
The central reader will measure the intervertebral posterior angle of the intervertebral 
disc treated with the investigational drug.  
 
Method of measuring the intervertebral posterior angle 
11.7.4 Vertebral Body Translation 
The central reader will determine the difference in vertebral body translation at the 
extension and flexion positions of the intervertebral disc treated with the investigational 
drug.  
Neutral 
*) The anatomical index (A) may be observed at another 
site according to the condition of the vertebral body. 
However, the index will be obtained at the same site 
(anterior or posterior) of the same vertebral body 
throughout this study. 
Disc Index =  
2A  
B + C
後方開大角度
屈曲位
後方開大角度
屈曲位
Posterior angle 
Flexion 
A*
C
A*
B
C


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Method of measuring vertebral body translation as an adverse event 
11.7.5 Magnetic Resonance Imaging 
An MRI image will be created by the T1-weighted fast spin echo technique, T2-weighted 
fast spin echo technique, and T2-weighted fast spin echo technique with fat suppression 
in the sagittal plane, and by the T1-weighted fast spin echo technique and T2-weighted 
fast spin echo technique in the axial plane according to the “Procedure Manual for MRI 
Examination”. 
 
 
屈曲位
）
A
伸展位
）
B
すべり= ｜A – B｜
※対象の椎間板に隣接する
上位の椎体が下位の椎体よ
り後方になった場合、負の
値となる。
屈曲位
）
A
屈曲位
）
A
）
A
伸展位
）
B
伸展位
）
B
すべり= ｜A – B｜
※対象の椎間板に隣接する
上位の椎体が下位の椎体よ
り後方になった場合、負の
値となる。
Translation =
When, of the vertebral bodies 
adjacent to the target 
intervertebral disc, the upper is 
behind the lower, the measured 
value becomes negative. 
 
Flexion position 
 Extension position 


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11.8 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
 
Grades 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this general guideline: 
 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
Grade 3 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
A semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available. 
Publish Date: May 28, 2009